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ESC GUIDELINES

European Heart Journal (2019) 00, 171


doi:10.1093/eurheartj/ehz425

2019 ESC Guidelines for the diagnosis and

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management of chronic coronary syndromes
The Task Force for the diagnosis and management of chronic
coronary syndromes of the European Society of Cardiology (ESC)

Authors/Task Force Members: Juhani Knuuti* (Finland) (Chairperson),


William Wijns* (Ireland) (Chairperson), Antti Saraste (Finland), Davide Capodanno
(Italy), Emanuele Barbato (Italy), Christian Funck-Brentano (France),
Eva Prescott (Denmark), Robert F. Storey (United Kingdom), Christi Deaton
(United Kingdom), Thomas Cuisset (France), Stefan Agewall (Norway),
Kenneth Dickstein (Norway), Thor Edvardsen (Norway), Javier Escaned (Spain),
Bernard J. Gersh (United States of America), Pavel Svitil (Czech Republic),
Martine Gilard (France), David Hasdai (Israel), Robert Hatala (Slovak Republic),
Felix Mahfoud (Germany), Josep Masip (Spain), Claudio Muneretto (Italy),
Marco Valgimigli (Switzerland), Stephan Achenbach (Germany), Jeroen J. Bax
(Netherlands)

Document Reviewers: Franz-Josef Neumann (Germany) (CPG Review Coordinator), Udo Sechtem
(Germany) (CPG Review Coordinator), Adrian Paul Banning (United Kingdom), Nikolaos Bonaros
(Austria), Héctor Bueno (Spain), Raffaele Bugiardini (Italy), Alaide Chieffo (Italy), Filippo Crea (Italy),

* Corresponding authors: Juhani Knuuti, Department of Clinical Physiology, Nuclear Medicine and PET and Turku PET Centre, Turku University Hospital, Kiinamyllynkatu 4-8, FI-
20520 Turku, Finland. Tel: þ358 500 592 998, Email: juhani.knuuti@tyks.fi. William Wijns, The Lambe Institute for Translational Medicine and Curam, National University of
Ireland, Galway, University Road, Galway, H91 TK33, Ireland. Tel: þ353 91 524411, Email: william.wyns@nuigalway.ie.
Author/Task Force Member Affiliations: listed in the Appendix.
ESC Committee for Practice Guidelines (CPG) and National Cardiac Societies document reviewers: listed in the Appendix.
ESC entities having participated in the development of this document:
Associations: Acute Cardiovascular Care Association (ACCA), Association of Cardiovascular Nursing & Allied Professions (ACNAP), European Association of Cardiovascular
Imaging (EACVI), European Association of Preventive Cardiology (EAPC), European Association of Percutaneous Cardiovascular Interventions (EAPCI), European Heart Rhythm
Association (EHRA), Heart Failure Association (HFA).
Councils: Council for Cardiology Practice.
Working Groups: Atherosclerosis and Vascular Biology, Cardiovascular Pharmacotherapy, Cardiovascular Surgery, Coronary Pathophysiology and Microcirculation,
Thrombosis.
The content of these ESC Guidelines has been published for personal and educational use only. No commercial use is authorized. No part of the ESC Guidelines may be trans-
lated or reproduced in any form without written permission from the ESC. Permission can be obtained upon submission of a written request to Oxford University Press, the
publisher of the European Heart Journal and the party authorized to handle such permissions on behalf of the ESC (journals.permissions@oxfordjournals.org).
Disclaimer. The ESC Guidelines represent the views of the ESC and were produced after careful consideration of the scientific and medical knowledge, and the evidence available
at the time of their publication. The ESC is not responsible in the event of any contradiction, discrepancy, and/or ambiguity between the ESC Guidelines and any other official recom-
mendations or guidelines issued by the relevant public health authorities, in particular in relation to good use of healthcare or therapeutic strategies. Health professionals are encour-
aged to take the ESC Guidelines fully into account when exercising their clinical judgment, as well as in the determination and the implementation of preventive, diagnostic, or
therapeutic medical strategies; however, the ESC Guidelines do not override, in any way whatsoever, the individual responsibility of health professionals to make appropriate and
accurate decisions in consideration of each patient’s health condition and in consultation with that patient and, where appropriate and/or necessary, the patient’s caregiver. Nor do
the ESC Guidelines exempt health professionals from taking into full and careful consideration the relevant official updated recommendations or guidelines issued by the competent
public health authorities, in order to manage each patient’s case in light of the scientifically accepted data pursuant to their respective ethical and professional obligations. It is also the
health professional’s responsibility to verify the applicable rules and regulations relating to drugs and medical devices at the time of prescription.
C The European Society of Cardiology 2019. All rights reserved. For permissions please email: journals.permissions@oup.com.
V
2 ESC Guidelines

Martin Czerny (Germany), Victoria Delgado (Netherlands), Paul Dendale (Belgium),


Frank Arnold Flachskampf (Sweden), Helmut Gohlke (Germany), Erik Lerkevang Grove (Denmark),
Stefan James (Sweden), Demosthenes Katritsis (Greece), Ulf Landmesser (Germany), Maddalena Lettino
(Italy), Christian M. Matter (Switzerland), Hendrik Nathoe (Netherlands), Alexander Niessner (Austria),
Carlo Patrono (Italy), Anna Sonia Petronio (Italy), Steffen E. Pettersen (United Kingdom), Raffaele Piccolo
(Italy), Massimo Francesco Piepoli (Italy), Bogdan A. Popescu (Romania), Lorenz Ra €ber (Switzerland),
Dimitrios J. Richter (Greece), Marco Roffi (Switzerland), Franz X. Roithinger (Austria), Evgeny Shlyakhto

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(Russian Federation), Dirk Sibbing (Germany), Sigmund Silber (Germany), Iain A. Simpson
(United Kingdom), Miguel Sousa-Uva (Portugal), Panos Vardas (Greece), Adam Witkowski (Poland),
Jose Luis Zamorano (Spain)

The disclosure forms of all experts involved in the development of these Guidelines are available on the
ESC website www.escardio.org/guidelines

For the Supplementary Data which include background information and detailed discussion of the data
that have provided the basis for the Guidelines see https://academic.oup.com/eurheartj/article-lookup/doi/
10.1093/eurheartj/ehz425#supplementary-data

...................................................................................................................................................................................................
Keywords Guidelines • chronic coronary syndromes • angina pectoris • myocardial ischaemia • coronary artery
disease • diagnostic testing • imaging • risk assessment • lifestyle modifications • anti-ischaemic drugs •
antithrombotic therapy • lipid-lowering drugs • myocardial revascularization • microvascular angina •
vasospastic angina • screening

..
Table of contents .. 3.1.6.1 Definition of levels of risk . . . . . . . . . . . . . . . . . . . . . . . . . . . 22
.. 3.2 Lifestyle management . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23
1. Preamble . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
.. 3.2.1 General management of patients with coronary artery
..
2. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7 .. disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23
2.1 What is new in the 2019 Guidelines? . . . . . . . . . . . . . . . . . . . . . . . . . . 8
.. 3.2.2 Lifestyle modification and control of risk factors . . . . . . . . . . 23
..
3. Patients with angina and/or dyspnoea, and suspected .. 3.2.2.1 Smoking . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23
coronary artery disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10
.. 3.2.2.2 Diet and alcohol . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24
..
3.1 Basic assessment, diagnosis, and risk assessment . . . . . . . . . . . . . . 10 .. 3.2.2.3 Weight management . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24
..
3.1.1 Step 1: symptoms and signs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11 .. 3.2.2.4 Physical activity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24
3.1.1.1 Stable vs. unstable angina . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12 .. 3.2.2.5 Cardiac rehabilitation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24
..
3.1.1.2 Distinction between symptoms caused by .. 3.2.2.6 Psychosocial factors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24
epicardial vs. microvascular/vasospastic disease . . . . . . . . . . . . . 13 .. 3.2.2.7 Environmental factors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25
..
3.1.2 Step 2: comorbidities and other causes of symptoms . . . . . . 13 .. 3.2.2.8 Sexual activity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25
3.1.3 Step 3: basic testing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13 .. 3.2.2.9 Adherence and sustainability . . . . . . . . . . . . . . . . . . . . . . . . 25
..
3.1.3.1 Biochemical tests . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13 .. 3.2.2.10 Influenza vaccination . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25
3.1.3.2 Resting electrocardiogram and ambulatory .. 3.3 Pharmacological management . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26
..
monitoring . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14 .. 3.3.1 Anti-ischaemic drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26
3.1.3.3 Echocardiography and magnetic resonance .. 3.3.1.1 General strategy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26
..
imaging at rest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14 .. 3.3.1.2 Available drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26
3.1.3.4 Chest X-ray . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15 ... 3.3.1.3 Patients with low blood pressure . . . . . . . . . . . . . . . . . . . . 29
3.1.4 Step 4: assess pre-test probability and clinical likelihood .. 3.3.1.4 Patients with low heart rate . . . . . . . . . . . . . . . . . . . . . . . . . 29
..
of coronary artery disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15 .. 3.3.2 Event prevention . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 30
3.1.5 Step 5: select appropriate testing . . . . . . . . . . . . . . . . . . . . . . . . . 16
.. 3.3.2.1 Antiplatelet drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 30
..
3.1.5.1 Functional non-invasive tests . . . . . . . . . . . . . . . . . . . . . . . . 16 .. 3.3.2.2 Anticoagulant drugs in sinus rhythm . . . . . . . . . . . . . . . . . 30
3.1.5.2 Anatomical non-invasive evaluation . . . . . . . . . . . . . . . . . 17
.. 3.3.2.3 Anticoagulant drugs in atrial fibrillation . . . . . . . . . . . . . . . 31
..
3.1.5.3 Role of the exercise electrocardiogram . . . . . . . . . . . . . . 17 .. 3.3.2.4 Proton pump inhibitors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 31
3.1.5.4 Selection of diagnostic tests . . . . . . . . . . . . . . . . . . . . . . . . . 18
.. 3.3.2.5 Cardiac surgery and antithrombotic therapy . . . . . . . . . 31
..
3.1.5.5 The impact of clinical likelihood on the selection .. 3.3.2.6 Non-cardiac surgery and antithrombotic therapy . . . . 32
of a diagnostic test . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18
.. 3.3.3 Statins and other lipid-lowering drugs . . . . . . . . . . . . . . . . . . . . 34
..
3.1.5.6 Invasive testing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19 .. 3.3.4 Renin-angiotensin-aldosterone system blockers . . . . . . . . . . 34
..
3.1.6 Step 6: assess event risk . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21 .. 3.3.5 Hormone replacement therapy . . . . . . . . . . . . . . . . . . . . . . . . . . 35
ESC Guidelines 3

3.4 Revascularization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 35
.. Basic biochemistry testing in the initial diagnostic management
..
4. Patients with new onset of heart failure or reduced left .. of patients with suspected coronary artery disease . . . . . . . . . . . . . . . . . . 13
..
ventricular function . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 36 .. Resting electrocardiogram in the initial diagnostic management
5. Patients with a long-standing diagnosis of chronic coronary .. of patients with suspected coronary artery disease . . . . . . . . . . . . . . . . . . 14
..
syndromes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 38 .. Ambulatory electrocardiogram monitoring in the initial
5.1 Patients with stabilized symptoms <1 year after an acute .. diagnostic management of patients with suspected coronary
..
coronary syndrome or patients with recent revascularization . . . . . 38 .. artery disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14

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5.2 Patients >1 year after initial diagnosis or revascularization . . . . . 38 .. Resting echocardiography and cardiac magnetic resonance in
..
6. Angina without obstructive disease in the epicardial .. the initial diagnostic management of patients with suspected
coronary arteries . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 40 .. coronary artery disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15
..
6.1 Microvascular angina . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 41 .. Chest X-ray in the initial diagnostic management of patients
6.1.1 Risk stratification . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 41 .. with suspected coronary artery disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15
..
6.1.2 Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 41 .. Use of diagnostic imaging tests in the initial diagnostic
6.1.3 Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 41 .. management of symptomatic patients with suspected coronary
..
6.2 Vasospastic angina . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 42 .. artery disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20
6.2.1 Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 42
.. Performing exercise electrocardiogram in the initial diagnostic
..
6.2.2 Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 42 .. management of patients with suspected coronary artery disease . . . . . 20
7. Screening for coronary artery disease in asymptomatic subjects . . . 43
.. Recommendations for risk assessment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22
..
8. Chronic coronary syndromes in specific circumstances . . . . . . . . . . . 44 .. Recommendations on lifestyle management . . . . . . . . . . . . . . . . . . . . . . . . 25
8.1 Cardiovascular comorbidities . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 44
.. Recommendations on anti-ischaemic drugs in patients with
..
8.1.1 Hypertension . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 44 .. chronic coronary syndromes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29
8.1.2 Valvular heart disease (including planned transcatheter
.. Recommendations for event prevention I . . . . . . . . . . . . . . . . . . . . . . . . . . . 32
..
aortic valve implantation) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 44 .. Recommendations for event prevention II . . . . . . . . . . . . . . . . . . . . . . . . . . 35
..
8.1.3 After heart transplantation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 44 .. General recommendations for the management of patients with
8.2 Non-cardiovascular comorbidities . . . . . . . . . . . . . . . . . . . . . . . . . . . 45 .. cnronic coronary syndromes and symptomatic heart failure
..
8.2.1 Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 45 .. due to ischaemic cardiomyopathy and left ventricular systolic
8.2.2 Diabetes mellitus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 45 .. dysfunction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 37
..
8.2.3 Chronic kidney disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 46 .. Recommendations for patients with a long-standing diagnosis
8.2.4 Elderly . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 46 .. of chronic coronary syndromes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 40
..
8.3 Sex . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 46 .. Investigations in patients with suspected coronary microvascular
8.4 Patients with refractory angina . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 47 .. angina . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 42
..
9. Key messages . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 48 .. Recommendations for investigations in patients with suspected vasospas-
10. Gaps in the evidence . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 49 .. tic angina . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 42
..
10.1 Diagnosis and assessment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 49 .. Recommendations for screening for coronary artery disease in
10.2 Assessment of risk . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 49 .. asymptomatic subjects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 43
..
10.3 Lifestyle management . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 49 .. Recommendations for hypertension treatment in chronic
10.4 Pharmacological management . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 49 .. coronary syndromes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 44
..
10.5 Revascularization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 49 .. Recommendations for valvular disease in chronic coronary
10.6 Heart failure and left ventricular dysfunction . . . . . . . . . . . . . . . . . 49
.. syndromes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 44
..
10.7 Patients with long-standing diagnosis of chronic .. Recommendations for active cancer in chronic coronary
coronary syndromes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 49
.. syndromes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 45
..
10.8 Angina without obstructive coronary artery disease . . . . . . . . . 49 .. Recommendations for diabetes mellitus in chronic coronary
10.9 Screening in asymptomatic subjects . . . . . . . . . . . . . . . . . . . . . . . . . 49
.. syndromes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 45
..
10.10 Comorbidities . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 50 .. Recommendations for chronic kidney disease in chronic
10.11 Patients with refractory angina . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 50
.. coronary syndromes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 46
..
11. ’What to do’ and ’what not to do’ messages from the .. Recommendations for elderly patients with chronic
..
Guidelines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 50 .. coronary syndromes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 46
12. Supplementary data . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 54 .. Recommendation for sex issues and chronic coronary
..
13. Appendix . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 54 .. syndromes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 47
14. References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 55 .. Recommendations for treatment options for refractory angina . . . . . . 48
..
.. Recommendations: ’what to do’ and ’what not to do’ . . . . . . . . . . . . . . . . 50
..
..
..
Recommendations ..
..
List of tables
..
2019 New major recommendations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8
.. Table 1 Classes of recommendations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6
..
Changes in major recommendations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10 . Table 2 Levels of evidence . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6
4 ESC Guidelines

Table 3 Traditional clinical classification of suspected anginal


..
.. ACS Acute coronary syndrome(s)
symptoms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12 .. ACTION A Coronary disease Trial Investigating Outcome
Table 4 Grading of effort angina severity according to the
..
.. with Nifedipine gastrointestinal therapeutic system
Canadian Cardiovascular Society . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12 .. AF Atrial fibrillation
..
Table 5 Pre-test probabilities of obstructive coronary artery .. ARB Angiotensin receptor blocker
disease in 15 815 symptomatic patients according to age, sex, .. AUGUSTUS An Open-label, 2  2 Factorial, Randomized
..
and the nature of symptoms in a pooled analysis of contemporary .. Controlled, Clinical Trial to Evaluate the Safety of

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data . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16 .. Apixaban vs. Vitamin K Antagonist and Aspirin vs.
..
Table 6 Definitions of high event risk for different test modalities .. Aspirin Placebo in Patients With Atrial Fibrillation
in patients with established chronic coronary syndromes . . . . . . . . . . . . 21 .. and Acute Coronary Syndrome or Percutaneous
..
Table 7 Lifestyle recommendations for patients with chronic .. Coronary Intervention
coronary syndromes. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23 ..
.. BARI-2D Bypass Angioplasty Revascularization Investigation
Table 8 Healthy diet characteristics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24 .. 2 Diabetes
Table 9 Treatment options for dual antithrombotic therapy in ..
.. BEAUTIFUL If Inhibitor Ivabradine in Patients with Coronary
combination with aspirin 75-100 mg daily in alphabetical order in .. Artery Disease and Left Ventricular Dysfunction
patients who have a high or moderate risk of ischaemic events, ..
.. b.i.d. Bis in die (twice a day)
and do not have a high bleeding risk. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 34 .. BMI Body mass index
Table 10 Blood pressure thresholds for definition of hypertension ..
.. BP Blood pressure
with different types of blood pressure measurement . . . . . . . . . . . . . . . . 44 .. b.p.m. Beats per minute
Table 11 Potential treatment options for refractory angina and
..
.. CABG Coronary artery bypass grafting
summary of trial data . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 47 .. CAD Coronary artery disease
..
.. CAPRIE Clopidogrel vs. Aspirin in Patients at Risk of
.. Ischaemic Events
..
List of figures .. CASS Coronary Artery Surgery Study
.. CCB Calcium channel blocker
Figure 1 Schematic illustration of the natural history of chronic ..
.. CCS Chronic coronary syndrome(s)
coronary syndromes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7 .. CFR Coronary flow reserve
Figure 2 Approach for the initial diagnostic management of patients ..
.. CHA2DS2- Cardiac failure, Hypertension, Age >_75
with angina and suspected coronary artery disease . . . . . . . . . . . . . . . . . . 11 .. VASc [Doubled], Diabetes, Stroke [Doubled] 
Figure 3 Determinants of clinical likelihood of obstructive coronary ..
.. Vascular disease, Age 6574 and Sex category
artery disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17 .. [Female]
Figure 4 Main diagnostic pathways in symptomatic patients
..
.. CHD Coronary heart disease
with suspected obstructive coronary artery disease . . . . . . . . . . . . . . . . . 18 .. CI Confidence interval
Figure 5 Ranges of clinical likelihood of coronary artery disease
..
.. CKD Chronic kidney disease
in which the test can rule-in or rule-out obstructive coronary ..
artery disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19
.. CMR Cardiac magnetic resonance
.. COMPASS Cardiovascular Outcomes for People Using
Figure 6 Comparison of risk assessments in asymptomatic ..
apparently healthy subjects (primary prevention) and patients with
.. Anticoagulation Strategies
.. COURAGE Clinical Outcomes Utilizing Revascularization and
established chronic coronary syndromes (secondary prevention) . . . . 21 ..
Figure 7 The five As of smoking cessation . . . . . . . . . . . . . . . . . . . . . . . . . . . 24
.. Aggressive Drug Evaluation
.. CPG Committee for Practice Guidelines
Figure 8 Suggested stepwise strategy for long-term ..
.. CRT Cardiac resynchronization therapy
anti-ischaemic drug therapy in patients with chronic coronary .. CT Computed tomography
syndromes and specific baseline characteristics . . . . . . . . . . . . . . . . . . . . . 28 ..
.. CTA Computed tomography angiography
Figure 9 Decision tree for patients undergoing invasive coronary .. CVD Cardiovascular disease
angiography . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 36 ..
.. DAPT Dual antiplatelet therapy
Figure 10 Proposed algorithm according to patient types .. DES Drug-eluting stent(s)
commonly observed at chronic coronary syndrome outpatient ..
.. DHP Dihydropyridine
clinics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 39 .. ECG Electrocardiogram
..
.. eGFR Estimated glomerular filtration rate
.. ESC European Society of Cardiology
Abbreviations and acronyms ..
.. FAME 2 Fractional Flow Reserve versus Angiography for
.. Multivessel Evaluation 2
ABI Ankle-brachial index ..
ACE Angiotensin-converting enzyme
.. FFR Fractional flow reserve
.
ESC Guidelines 5

..
FFRCT Computed tomography-based fractional flow .. SIGNIFY Study Assessing the MorbidityMortality Benefits
reserve .. of the If Inhibitor Ivabradine in Patients with
..
GEMINI- A Study to Compare the Safety of Rivaroxaban .. Coronary Artery Disease
ACS Versus Acetylsalicylic Acid in Addition to Either
.. SPECT Single-photon emission computed tomography
..
Clopidogrel or Ticagrelor Therapy in Participants .. VKA Vitamin K antagonist
With Acute Coronary Syndrome
..
..
GFR Glomerular filtration rate ..

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GLS Global longitudinal strain
.. 1 Preamble
..
GOSPEL Global secondary prevention strategies to limit ..
event recurrence after myocardial infarction
.. Guidelines summarize and evaluate available evidence with the aim of
.. assisting health professionals in proposing the best management
HbA1c Glycated haemoglobin ..
.. strategies for an individual patient with a given condition. Guidelines
HF Heart failure ..
.. and their recommendations should facilitate decision making of
ICA Invasive coronary angiography
.. health professionals in their daily practice. However, the final deci-
IMR Index of microcirculatory resistance ..
.. sions concerning an individual patient must be made by the responsi-
IMT Intima-media thickness
.. ble health professional(s) in consultation with the patient and
IONA Impact Of Nicorandil in Angina ..
iwFR Instantaneous wave-free ratio (instant flow .. caregiver as appropriate.
.. A great number of guidelines have been issued in recent years by
reserve) ..
LAD Left anterior descending .. the European Society of Cardiology (ESC), as well as by other soci-
.. eties and organizations. Because of their impact on clinical practice,
LBBB Left bundle branch block ..
LDL-C Low-density lipoprotein cholesterol .. quality criteria for the development of guidelines have been estab-
.. lished in order to make all decisions transparent to the user. The rec-
LM Left main (coronary artery) ..
LV Left ventricular .. ommendations for formulating and issuing ESC Guidelines can be
.. found on the ESC website (http://www.escardio.org/Guidelines-&-
LVEF Left ventricular ejection fraction ..
MI Myocardial infarction .. Education/Clinical-Practice-Guidelines/Guidelines-development/
.. Writing-ESC-Guidelines). The ESC Guidelines represent the offi-
MRA Mineralocorticoid receptor antagonist ..
NOAC Non-vitamin K antagonist oral anticoagulant
.. cial position of the ESC on a given topic and are regularly updated.
.. The ESC carries out a number of registries which are essential to
NT-proBNP N-terminal pro-B-type natriuretic peptide ..
OAC Oral anticoagulant
.. assess, diagnostic/therapeutic processes, use of resources and adher-
.. ence to Guidelines. These registries aim at providing a better under-
o.d. Omni die (once a day) ..
ORBITA Objective Randomised Blinded Investigation with
.. standing of medical practice in Europe and around the world, based
.. on data collected during routine clinical practice.
optimal medical Therapy of Angioplasty in stable ..
angina
.. The guidelines are developed together with derivative educational
.. material addressing the cultural and professional needs for cardiolo-
PAD Peripheral artery disease ..
.. gists and allied professionals. Collecting high-quality observational
PCI Percutaneous coronary intervention .. data, at appropriate time interval following the release of ESC
PCSK9 Proprotein convertase subtilisin-kexin type 9 ..
.. Guidelines, will help evaluate the level of implementation of the
PEGASUS- Prevention of Cardiovascular Events in Patients ..
.. Guidelines, checking in priority the key end points defined with the
TIMI 54 with Prior Heart Attack Using Ticagrelor
.. ESC Guidelines and Education Committees and Task Force members
Compared to Placebo on a Background of ..
AspirinThrombolysis in Myocardial Infarction 54 .. in charge.
.. The Members of this Task Force were selected by the ESC,
PET Positron emission tomography ..
PROMISE Prospective Multicenter Imaging Study for .. including representation from its relevant ESC sub-specialty
.. groups, in order to represent professionals involved with the
Evaluation of Chest Pain ..
PTP Pre-test probability .. medical care of patients with this pathology. Selected experts in
.. the field undertook a comprehensive review of the published evi-
RAS Renin-angiotensin system ..
RCT Randomized clinical trial .. dence for management of a given condition according to ESC
.. Committee for Practice Guidelines (CPG) policy. A critical evalua-
REACH Reduction of Atherothrombosis for Continued ..
Health
.. tion of diagnostic and therapeutic procedures was performed,
.. including assessment of the riskbenefit ratio. The level of evidence
RIVER-PCI Ranolazine for Incomplete Vessel Revascularization ..
Post-Percutaneous Coronary Intervention
.. and the strength of the recommendation of particular manage-
.. ment options were weighed and graded according to predefined
SCORE Systematic COronary Risk Evaluation ..
SCOT- Scottish Computed Tomography of the HEART
.. scales, as outlined in Tables 1 and 2.
.. The experts of the writing and reviewing panels provided declara-
HEART ..
. tion of interest forms for all relationships that might be perceived as
6 ESC Guidelines

Table 1 Classes of recommendations

Wording to use

Class I Evidence and/or general agreement Is recommended or is indicated


Classes of recommendations

that a given treatment or procedure is

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Class II

Class IIa Weight of evidence/opinion is in Should be considered

Class IIb May be considered


established by evidence/opinion.

Class III Evidence or general agreement that the Is not recommended

©ESC 2019
given treatment or procedure is not
useful/effective, and in some cases
may be harmful.

Table 2 Levels of evidence

Level of Data derived from multiple randomized clinical trials


evidence A or meta-analyses.

Level of Data derived from a single randomized clinical trial


evidence B or large non-randomized studies.

Level of Consensus of opinion of the experts and/or small studies,


©ESC 2019

evidence C retrospective studies, registries.

..
real or potential sources of conflicts of interest. These forms were .. endorsement process of these Guidelines. The ESC Guidelines
compiled into one file and can be found on the ESC website (http:// .. undergo extensive review by the CPG and external experts. After
..
www.escardio.org/guidelines). Any changes in declarations of interest .. appropriate revisions the Guidelines are approved by all the
that arise during the writing period were notified to the ESC and .. experts involved in the Task Force. The finalized document is
..
updated. The Task Force received its entire financial support from .. approved by the CPG for publication in the European Heart
the ESC without any involvement from the healthcare industry. .. Journal. The Guidelines were developed after careful considera-
..
The ESC CPG supervises and coordinates the preparation of .. tion of the scientific and medical knowledge and the evidence
new Guidelines. The Committee is also responsible for the .. available at the time of their dating.
ESC Guidelines 7

The task of developing ESC Guidelines also includes the crea-


.. consideration of each patient’s health condition and in consultation
..
tion of educational tools and implementation programmes for the .. with that patient or the patient’s caregiver where appropriate and/or
recommendations including condensed pocket guideline versions,
.. necessary. It is also the health professional’s responsibility to verify
..
summary slides, booklets with essential messages, summary cards .. the rules and regulations applicable in each country to drugs and devi-
..
for non-specialists and an electronic version for digital applications ces at the time of prescription.
...
(smartphones, etc.). These versions are abridged and thus, for ..
more detailed information, the user should always access to the ..
..

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full text version of the Guidelines, which is freely available via the .. 2 Introduction
ESC website and hosted on the EHJ website. The National ..
..
Societies of the ESC are encouraged to endorse, translate and .. Coronary artery disease (CAD) is a pathological process character-
implement all ESC Guidelines. Implementation programmes are .. ized by atherosclerotic plaque accumulation in the epicardial arteries,
..
needed because it has been shown that the outcome of disease .. whether obstructive or non-obstructive. This process can be modi-
may be favourably influenced by the thorough application of clini- .. fied by lifestyle adjustments, pharmacological therapies, and invasive
..
cal recommendations. .. interventions designed to achieve disease stabilization or regression.
Health professionals are encouraged to take the ESC Guidelines .. The disease can have long, stable periods but can also become unsta-
..
fully into account when exercising their clinical judgment, as well as in .. ble at any time, typically due to an acute atherothrombotic event
the determination and the implementation of preventive, diagnostic .. caused by plaque rupture or erosion. However, the disease is
..
or therapeutic medical strategies. However, the ESC Guidelines do .. chronic, most often progressive, and hence serious, even in clinically
not override in any way whatsoever the individual responsibility of
.. apparently silent periods. The dynamic nature of the CAD process
..
health professionals to make appropriate and accurate decisions in . results in various clinical presentations, which can be conveniently

Subclinical Recent diagnosis or Long-standing diagnosis


phase revascularization
(≤12 months)

Higher risk with


12 month
insufficiently controlled
Cardiac risk (death, MI)

post ACS
risk factors, suboptimal
lifestyle modifications
and/or medical therapy,
ACS
Revascularization large area at risk of
myocardial ischaemia

12 month
post ACS

ACS Lower risk with


12 month optimally controlled risk
post ACS factors, lifestyle changes,
adequate therapy for
ACS
secondary prevention
Revascularization (e.g. aspirin, statins, ACE
inhibitors) and
appropriate
revascularization

Revascularization
©ESC 2019

Time

Figure 1 Schematic illustration of the natural history of chronic coronary syndromes. ACE = angiotensin-converting enzyme; ACS = acute coronary
syndromes; CCS = chronic coronary syndromes; MI = myocardial infarction.
8 ESC Guidelines

..
categorized as either acute coronary syndromes (ACS) or chronic .. (MI)], and the risk may change over time. Development of an ACS may
coronary syndromes (CCS). The Guidelines presented here refer to .. acutely destabilize each of these clinical scenarios. The risk may increase
..
the management of patients with CCS. The natural history of CCS is .. as a consequence of insufficiently controlled cardiovascular risk factors,
illustrated in Figure 1. .. suboptimal lifestyle modifications and/or medical therapy, or unsuccess-
..
The most frequently encountered clinical scenarios in patients .. ful revascularization. Alternatively, the risk may decrease as a conse-
with suspected or established CCS are: (i) patients with suspected .. quence of appropriate secondary prevention and successful
..
CAD and ‘stable’ anginal symptoms, and/or dyspnoea (see section 3); .. revascularization. Hence, CCS are defined by the different evolutionary

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(ii) patients with new onset of heart failure (HF) or left ventricular .. phases of CAD, excluding situations in which an acute coronary artery
..
(LV) dysfunction and suspected CAD (see section 4); (iii) asympto- .. thrombosis dominates the clinical presentation (i.e. ACS).
matic and symptomatic patients with stabilized symptoms <1 year .. In the present Guidelines, each section deals with the main clinical
..
after an ACS, or patients with recent revascularization (see section .. scenarios of CCS. This structure aims to simplify the use of the
5.1); (iv) asymptomatic and symptomatic patients >1 year after initial
.. Guidelines in clinical practice. Additional information, tables, figures,
..
diagnosis or revascularization (see section 5.2); (v) patients with .. and references are available in the Supplementary Data on the ESC
angina and suspected vasospastic or microvascular disease (see sec-
.. website (www.escardio.org) as well as in The ESC Textbook of
..
tion 6); and (vi) asymptomatic subjects in whom CAD is detected at .. Cardiovascular Medicine.
screening (see section 7).
..
..
All of these scenarios are classified as a CCS but involve different risks ..
for future cardiovascular events [e.g. death or myocardial infarction
.. 2.1 What is new in the 2019 Guidelines?
..

New/revised concepts in 2019

The Guidelines have been revised to focus on CCS instead of stable CAD.
This change emphasizes the fact that the clinical presentations of CAD can be categorized as either ACS or CCS. CAD is a dynamic process of atheroscler-
otic plaque accumulation and functional alterations of coronary circulation that can be modified by lifestyle, pharmacological therapies, and revascularization,
which result in disease stabilization or regression.
In the current Guidelines on CCS, six clinical scenarios most frequently encountered in patients are identified: (i) patients with suspected CAD and ‘stable’ anginal
symptoms, and/or dyspnoea; (ii) patients with new onset of HF or LV dysfunction and suspected CAD; (iii) asymptomatic and symptomatic patients with stabilized
symptoms <1 year after an ACS or patients with recent revascularization; (iv) asymptomatic and symptomatic patients >1 year after initial diagnosis or revasculariza-
tion; (v) patients with angina and suspected vasospastic or microvascular disease; (vi) asymptomatic subjects in whom CAD is detected at screening.
The PTP of CAD based on age, gender and nature of symptoms have undergone major revisions. In addition, we introduced a new phrase ’Clinical likelihood of CAD’
that utilizes also various risk factors of CAD as PTP modifiers. The application of various diagnostic tests in different patient groups to rule-in or rule-out CAD have been
updated.
The Guidelines emphasize the crucial role of healthy lifestyle behaviours and other preventive actions in decreasing the risk of subsequent cardiovascular
events and mortality.

ACS = acute coronary syndromes; CAD = coronary artery disease; CCS = chronic coronary syndromes; HF = heart failure; LV = left ventricular; PTP = pre-test probability.

New major recommendations in 2019

Basic testing, diagnostics, and risk assessment


Non-invasive functional imaging for myocardial ischaemia or coronary CTA is recommended as the initial test for diagnosing CAD in
I
symptomatic patients in whom obstructive CAD cannot be excluded by clinical assessment alone.
It is recommended that selection of the initial non-invasive diagnostic test be based on the clinical likelihood of CAD and other patient
I
characteristics that influence test performance, local expertise, and the availability of tests.
Functional imaging for myocardial ischaemia is recommended if coronary CTA has shown CAD of uncertain functional significance or is
I
not diagnostic.
Invasive angiography is recommended as an alternative test to diagnose CAD in patients with a high clinical likelihood and severe symptoms
refractory to medical therapy, or typical angina at a low level of exercise and clinical evaluation that indicates high event risk. Invasive func- I
tional assessment must be available and used to evaluate stenoses before revascularization, unless very high grade (>90% diameter stenosis).
Invasive coronary angiography with the availability of invasive functional evaluation should be considered for confirmation of the diagnosis
IIa
of CAD in patients with an uncertain diagnosis on non-invasive testing.
Coronary CTA should be considered as an alternative to invasive angiography if another non-invasive test is equivocal or non-diagnostic. IIa
Coronary CTA is not recommended when extensive coronary calcification, irregular heart rate, significant obesity, inability to cooperate
III
with breath-hold commands, or any other conditions make good image quality unlikely.
Continued
ESC Guidelines 9

Antithrombotic therapy in patients with CCS and sinus rhythm


Addition of a second antithrombotic drug to aspirin for long-term secondary prevention should be considered in patients with a high
IIa
risk of ischaemic events and without high bleeding risk (see options in section 3.3.2).
Addition of a second antithrombotic drug to aspirin for long-term secondary prevention may be considered in patients with at least a
IIb
moderately increased risk of ischaemic events and without high bleeding risk (see options in section 3.3.2).
Antithrombotic therapy in patients with CCS and AF

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When oral anticoagulation is initiated in a patient with AF who is eligible for a NOAC, a NOAC is recommended in preference to a
I
VKA.
Long-term OAC therapy (a NOAC or VKA with time in therapeutic range >70%) is recommended in patients with AF and a CHA2DS2-
I
VASc score >_2 in males and >_3 in females.
Long-term OAC therapy (a NOAC or VKA with time in therapeutic range >70%) should be considered in patients with AF and a
IIa
CHA2DS2-VASc score of 1 in males and 2 in females.
Antithrombotic therapy in post-PCI patients with AF or another indication for OAC
In patients who are eligible for a NOAC, it is recommended that a NOAC (apixaban 5 mg b.i.d., dabigatran 150 mg b.i.d., edoxaban 60
I
mg o.d., or rivaroxaban 20 mg o.d.) is used in preference to a VKA in combination with antiplatelet therapy.
When rivaroxaban is used and concerns about high bleeding risk prevail over concerns about stent thrombosis or ischaemic stroke, rivar-
oxaban 15 mg o.d. should be considered in preference to rivaroxaban 20 mg o.d. for the duration of concomitant single or dual antiplate- IIa
let therapy.
When dabigatran is used and concerns about high bleeding risk prevail over concerns about stent thrombosis or ischaemic stroke, dabi-
gatran 110 mg b.i.d. should be considered in preference to dabigatran 150 mg b.i.d. for the duration of concomitant single or dual antipla- IIa
telet therapy
After uncomplicated PCI, early cessation (<_1 week) of aspirin, and continuation of dual therapy with OAC and clopidogrel, should be
considered if the risk of stent thrombosis is low or if concerns about bleeding risk prevail over concerns about risk of stent thrombosis, IIa
irrespective of the type of stent used.
Triple therapy with aspirin, clopidogrel, and an OAC for >_1 month should be considered when the risk of stent thrombosis outweighs
the bleeding risk, with the total duration (<_6 months) decided upon according to the assessment of these risks and clearly specified at IIa
hospital discharge.
In patients with an indication for a VKA in combination with aspirin and/or clopidogrel, the dose intensity of the VKA should be carefully
IIa
regulated with a target international normalized ratio in the range of 2.0 - 2.5 and with time in therapeutic range >70%.
Dual therapy with an OAC and either ticagrelor or prasugrel may be considered as an alternative to triple therapy with an OAC, aspirin,
IIb
and clopidogrel in patients with a moderate or high risk of stent thrombosis, irrespective of the type of stent used.
Other pharmacological therapy
Concomitant use of a proton pump inhibitor is recommended in patients receiving aspirin monotherapy, DAPT, or OAC monotherapy
I
who are at high risk of gastrointestinal bleeding.
Lipid-lowering drugs: if goals are not achieved with the maximum tolerated dose of statin, combination with ezetimibe is recommended. I
Lipid-lowering drugs: for patients at very high risk who do not achieve their goals on a maximum tolerated dose of statin and ezetimibe,
I
combination with a PCSK9 inhibitor is recommended.
ACE inhibitors should be considered in CCS patients at very high risk of cardiovascular adverse events. IIa
The sodium-glucose co-transporter 2 inhibitors empagliflozin, canagliflozin, or dapagliflozin are recommended in patients with diabetes
I
mellitus and CVD.
A glucagon-like peptide-1 receptor agonist (liraglutide or semaglutide) is recommended in patients with diabetes mellitus and CVD. I
Screening for CAD in asymptomatic subjects
Carotid ultrasound IMT for cardiovascular risk assessment is not recommended. III
Recommendations for treatment options for refractory angina
A reducer device for coronary sinus constriction may be considered to ameliorate symptoms of debilitating angina refractory to optimal
IIb
medical and revascularization strategies.
a
Class of recommendation.
ACE = angiotensin-converting enzyme; ACS = acute coronary syndromes; AF = atrial fibrillation; b.i.d. = bis in die (twice a day); CAD = coronary artery disease; CCS = chronic
coronary syndromes; CHA2DS2-VASc = Cardiac failure, Hypertension, Age >_75 [Doubled], Diabetes, Stroke [Doubled]  Vascular disease, Age 6574 and Sex category
[Female]; CTA = computed tomography angiography; CVD = cardiovascular disease; HF = heart failure; IMT = intima-media thickness; LV = left ventricular; NOAC = non-vita-
min K antagonist oral anticoagulant; OAC = oral anticoagulant; o.d. = omni die (once a day); PCI = percutaneous coronary intervention; PCSK9 = proprotein convertase subtili-
sin-kexin type 9; VKA = vitamin K antagonist.
10 ESC Guidelines

Changes in major recommendations

2013 Classa 2019 Classa


Exercise ECG is recommendedas the initial test to estab- Exercise ECG is recommended for the assessment of exercise tol-
lish a diagnosis of stable CAD in patients withsymptoms erance, symptoms, arrhythmias, BP response, and event risk in I
of angina and intermediate PTP of CAD (1565%), free selected patients.
I

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of anti-ischaemic drugs, unless they cannot exercise or Exercise ECG may be considered as an alternative test to rule-in
display ECG changes that make the ECG non-evaluable. or rule-out CAD when other non-invasive or invasive imaging IIb
methods are not available.
Exercise ECG should be considered in patients on treat- Exercise ECG may be considered in patients on treatment to evalu-
IIa IIb
ment to evaluate control of symptoms and ischaemia. ate control of symptoms and ischaemia.
For second-line treatment it is recommended that long- Long-acting nitrates should be considered as a second-line treat-
acting nitrates, ivabradine, nicorandil, or ranolazine are ment option when initial therapy with a beta-blocker and/or a non-
IIa IIa
added according to heart rate, BP, and tolerance. DHP-CCB is contraindicated, poorly tolerated, or inadequate in
controlling angina symptoms.
For second-line treatment, trimetazidine may be Nicorandil, ranolazine, ivabradine, or trimetazidine should be con-
considered, sidered as a second-line treatment to reduce angina frequency and
improve exercise tolerance in subjects who cannot tolerate, have IIa
contraindications to, or whose symptoms are not adequately con-
IIb trolled by beta-blockers, CCBs, and long-acting nitrates.
In selected patients, the combination of a beta-blocker or a CCB
with second-line drugs (ranolazine, nicorandil, ivabradine, and tri-
IIb
metazidine) may be considered for first-line treatment according
to heart rate, BP, and tolerance.
In patients with suspected coronary microvascular angina: Guidewire-based CFR and/or microcirculatory resistance measure-
intracoronary acetylcholine and adenosine with Doppler ments should be considered in patients with persistent symptoms,
IIa
measurements may be considered during coronary arte- but coronary arteries that are either angiographically normal or
riography, if the arteriogram is visually normal, to assess have moderate stenoses with preserved iwFR/FFR.
IIb
endothelium-dependent and non-endothelium-dependent Intracoronary acetylcholine with ECG monitoring may be consid-
CFR, and detect microvascular/epicardial vasospasm. ered during angiography, if coronary arteries are either angiograph-
IIb
ically normal or have moderate stenoses with preserved iwFR/FFR,
to assess microvascular vasospasm.
In patients with suspected coronary microvascular angina: Transthoracic Doppler of the LAD, CMR, and PET may be consid-
transthoracic Doppler echocardiography of the LAD, ered for non-invasive assessment of CFR.
with measurement of diastolic coronary blood flow fol- IIb IIb
lowing intravenous adenosine and at rest, may be consid-
ered for non-invasive measurement of CFR.
a
Class of recommendation.
BP = blood pressure; CAD = coronary artery disease; CCB = calcium channel blocker; CFR = coronary flow reserve; CMR = cardiac magnetic resonance; DHP-CCB = dihy-
dropyridine calcium channel blockers; ECG = electrocardiogram; FFR = fractional flow reserve; iwFR = instantaneous wave-free ratio (instant flow reserve); LAD = left anterior
descending; PET = positron emission tomography; PTP = pre-test probability.

..
3 Patients with angina and/or .. ACS (step 1). In patients without unstable angina or other ACS,
.. the next step is to evaluate the patient’s general condition and
dyspnoea, and suspected coronary .. quality of life (step 2). Comorbidities that could potentially influ-
..
artery disease ..
..
ence therapeutic decisions are assessed and other potential
.. causes of the symptoms are considered. Step 3 includes basic test-
3.1 Basic assessment, diagnosis, and risk .. ing and assessment of LV function. Thereafter, the clinical likeli-
..
assessment .. hood of obstructive CAD is estimated (step 4) and, on this basis,
The general approach for the initial diagnostic management of .. diagnostic testing is offered to selected patients to establish the
.. diagnosis of CAD (step 5). Once a diagnosis of obstructive CAD
patients with angina and suspected obstructive CAD is presented ..
in Figure 2. The diagnostic management approach includes six .. has been confirmed, the patient’s event risk will be determined
..
steps. The first step is to assess the symptoms and signs, to .. (step 6) as it has a major impact on the subsequent therapeutic
identify patients with possible unstable angina or other forms of .. decisions.
..
ESC Guidelines 11

STEP 1 Assess symptoms and perform clinical investigations Unstable angina? Follow ACS guidelines

Revascularization
STEP 2 Consider comorbidities and quality of life Medical therapya
futile

Resting ECG, biochemistry, chest X-ray in selected

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STEP 3 LVEF <50% See section 4
patients, echocardiography at restb

Cause of chest pain Treat as appropriate or


STEP 4 Assess pre-test probability and clinical likelihood of CADc other than CAD? investigate other causes

Offer diagnostic testing


testing mandated

Coronary CTAf
No diagnostic

Invasive
Choice of the test based on clinical
angiography
likelihood, patient characteristics
STEP 5 (with iwFR/FFR)e
and preference, availability, Testing for ischaemia
as well as local expertised (imaging testing preferred)

Very low Clinical likelihood of obstructive CAD Very high

©ESC 2019
STEP 6 Choose appropriate therapy based on symptoms and event riskg

Figure 2 Approach for the initial diagnostic management of patients with angina and suspected coronary artery disease. ACS = acute coronary
syndrome; BP = blood pressure; CAD = coronary artery disease; CTA = computed tomography angiography; ECG = electrocardiogram; FFR = frac-
tional flow reserve; iwFR = instantaneous wave-free ratio; LVEF = left ventricular ejection fraction. aIf the diagnosis of CAD is uncertain, establishing
a diagnosis using non-invasive functional imaging for myocardial ischaemia before treatment may be reasonable. bMay be omitted in very young and
healthy patients with a high suspicion of an extracardiac cause of chest pain, and in multimorbid patients in whom the echocardiography result has
no consequence for further patient management. cConsider exercise ECG to assess symptoms, arrhythmias, exercise tolerance, BP response, and
event risk in selected patients. dAbility to exercise, individual test-related risks, and likelihood of obtaining diagnostic test result. eHigh clinical likeli-
hood and symptoms inadequately responding to medical treatment, high event risk based on clinical evaluation (such as ST-segment depression,
combined with symptoms at a low workload or systolic dysfunction indicating CAD), or uncertain diagnosis on non-invasive testing. fFunctional
imaging for myocardial ischaemia if coronary CTA has shown CAD of uncertain grade or is non-diagnostic. gConsider also angina without obstruc-
tive disease in the epicardial coronary arteries (see section 6).

..
After these steps, appropriate therapies are to be initiated, .. exacerbating or relieving factors. The discomfort caused by myo-
which include lifestyle management (see section 3.2), medical .. cardial ischaemia is usually located in the chest, near the sternum,
..
therapy (see section 3.3), and revascularization when indicated .. but may be felt anywhere from the epigastrium to the lower jaw
(see section 3.4). .. or teeth, between the shoulder blades, or in either arm to the
..
.. wrist and fingers. The discomfort is often described as pressure,
.. tightness, or heaviness; sometimes strangling, constricting, or
3.1.1. Step 1: Symptoms and signs
... burning. It may be useful to ask the patient directly about the pres-
A careful history is the cornerstone of the diagnosis of angina. It ..
is possible to achieve a high degree of certainty on a diagnosis .. ence of ‘discomfort’ as many do not feel ‘pain’ or ‘pressure’ in their
.. chest. Shortness of breath may accompany angina, and chest dis-
based on history alone, although physical examination and objec- ..
tive tests are most often necessary to confirm the diagnosis, .. comfort may also be accompanied by less-specific symptoms such
.. as fatigue or faintness, nausea, burning, restlessness, or a sense of
exclude alternative diagnoses, and assess the severity of underly- ..
ing disease. The history should include any manifestation of cardi- .. impending doom. Shortness of breath may be the sole symptom of
.. CAD and it may be difficult to differentiate this from shortness of
ovascular disease (CVD) and risk factors (i.e. family history of ..
CVD, dyslipidaemia, diabetes, hypertension, smoking, and other .. breath caused by other conditions.
.. The duration of the discomfort is brief—<_10 min in the majority
lifestyle factors). ..
The characteristics of discomfort related to myocardial ischae-
.. of cases, and more commonly just a few minutes or less—and
..
mia (angina pectoris) may be divided into four categories: location, .. chest pain lasting for seconds is unlikely to be due to CAD. An
character, duration, and relationship to exertion, and other
.. important characteristic is the relationship to exercise. Symptoms
12 ESC Guidelines

classically appear or become more severe with increased levels of


.. mended that practitioners obtain the body mass index (BMI) and
..
exertion—such as walking up an incline or against a breeze, or in .. search for evidence of non-coronary vascular disease, which may be
cold weather—and rapidly disappear within a few minutes when
.. asymptomatic [includes palpation of peripheral pulses, and ausculta-
..
these causal factors abate. Exacerbations of symptoms after a .. tion of carotid and femoral arteries, as well as assessment of the
heavy meal or after waking up in the morning are classic features
.. ankle-brachial index (ABI)], and other signs of comorbid conditions
..
of angina. Angina may paradoxically be reduced with further exer- .. such as thyroid disease, renal disease, or diabetes. This should
cise (walk-through angina) or on second exertion (warm-up
.. be used in the context of other clinical information, such as the pres-
..

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angina).1 Sublingual nitrates rapidly relieve angina. Symptoms are .. ence of cough or stinging pain, making CAD more unlikely. One
..
unrelated to respiration or position. The angina threshold, and .. should also try to reproduce the symptoms by palpation10 and test
hence symptoms, may vary considerably from day to day and even .. the effect of sublingual nitroglycerin in order to classify the symptoms
..
during the same day. .. (Table 3).
Definitions of typical and atypical angina are summarized in ..
..
Table 3. The classification, although subjective, is practical and of .. 3.1.1.1 Stable vs. unstable angina
proven value in determining the likelihood of obstructive CAD.2,3 .. Unstable angina may present in one of three ways: (i) as rest
..
Studies published since 2015 have reported that the majority of .. angina, i.e. pain of characteristic nature and location occurring at
patients suspected of having CAD present with atypical or non- .. rest and for prolonged periods (>20 min); (ii) new-onset angina,
..
anginal chest pain,46 with as few as 10 - 15% presenting with typi- .. i.e. recent (2 months) onset of moderate-to-severe angina
cal angina.3,7,8 The Canadian Cardiovascular Society classification .. (Canadian Cardiovascular Society grade II or III); or (iii) crescendo
..
is still widely used as a grading system for angina,9 to quantify the .. angina, i.e. previous angina, which progressively increases in
threshold at which symptoms occur in relation to physical activ- .. severity and intensity, and at a lower threshold, over a short
..
ities (Table 4). .. period of time. Management of angina fulfilling these criteria is
Physical examination of a patient with suspected CAD is important .. dealt with in the ESC Guidelines for the management of ACS.11,12
..
to assess the presence of anaemia, hypertension, valvular heart dis- .. New-onset angina is generally regarded as unstable angina; how-
ease, hypertrophic cardiomyopathy, or arrhythmias. It is also recom-
.. ever, if angina occurs for the first time with heavy exertion and
..
.. subsides at rest, the suspected condition falls under the definition
.. of CCS rather than unstable angina. In patients with unstable
..
.. angina identified as being at low risk, it is recommended that the
Table 3 Traditional clinical classification of suspected .. diagnostic and prognostic algorithms presented in these
anginal symptoms
..
.. Guidelines be applied once the period of instability has subsided.11
.. Low-risk patients with unstable angina are characterized by no
Typical angina Meets the following three characteristics: ..
(i) Constricting discomfort in the front of the chest or .. recurrence of angina, no signs of HF, no abnormalities in the initial
..
in the neck, jaw, shoulder, or arm; .. or subsequent electrocardiogram (ECG), and no rise in troponin
(ii) Precipitated by physical exertion; .. levels.11 In this setting, a non-invasive diagnostic strategy is recom-
..
(iii) Relieved by rest or nitrates within 5 min. .. mended before deciding on an invasive strategy. Based on the defi-
.. nition above, stable and unstable angina may overlap, and many
Atypical angina Meets two of these characteristics. ..
Non-anginal Meets only one or none of these characteristics. .. CCS patients pass through a period of experiencing unstable
.. angina.
chest pain ..

Table 4 Grading of effort angina severity according to the Canadian Cardiovascular Society
Grade Description of angina severity
I Angina only with strenuous exertion Presence of angina during strenuous, rapid, or prolonged ordinary
activity (walking or climbing the stairs).
II Angina with moderate exertion Slight limitation of ordinary activities when they are performed
rapidly, after meals, in cold, in wind, under emotional stress, or
during the first few hours after waking up, but also walking uphill,
climbing more than one flight of ordinary stairs at a normal pace,
and in normal conditions.
III Angina with mild exertion Having difficulties walking one or two blocks, or climbing one
flight of stairs, at normal pace and conditions.
IV Angina at rest No exertion needed to trigger angina.
ESC Guidelines 13

3.1.1.2 Distinction between symptoms caused by epicardial vs. microvas- .. conditions, and to determine prognosis. Haemoglobin as part of a
..
cular/vasospastic disease .. full blood count and—where there is a clinical suspicion of a thy-
A distinction between symptoms caused by an epicardial stenosis and
.. roid disorder—thyroid hormone levels provide information
..
symptoms caused by microvascular or vasospastic disease cannot be .. related to possible causes of ischaemia. Fasting plasma glucose and
made with reasonable certainty. Reliance on ischaemia testing or
.. glycated haemoglobin (HbA1c) should be measured in every
..
depiction of the coronary anatomy is often unavoidable to exclude .. patient with suspected CAD. If both are inconclusive, an additional
obstructive CAD, which can be absent in symptomatic patients.13,14
.. oral glucose tolerance test is recommended.16 Knowledge of glu-
..

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A diagnostic workup for microvascular or vasospastic disease is dis- .. cose metabolism is important because of the well-recognized asso-
cussed in section 6 of these Guidelines.
..
.. ciation between diabetes and adverse cardiovascular outcome.
.. Patients with diabetes should be managed according to specific
..
.. Guidelines.15,16 A lipid profile, including total cholesterol, high-
3.1.2 Step 2: Comorbidities and other causes of .. density lipoprotein cholesterol, low-density lipoprotein cholesterol
symptoms ..
Before any testing is considered, one must assess the patient’s general
.. (LDL-C), and triglycerides, should also be evaluated in any patient
.. with suspected CAD to establish the patient’s risk profile and
health, comorbidities, and quality of life. If revascularization is unlikely ..
.. ascertain the need for treatment.15,17 To characterize severe dysli-
to be an acceptable option, further testing may be reduced to a clini- ..
.. pidaemia or follow-up on high triglyceridaemia, fasting values are
cally indicated minimum and appropriate therapy should be insti-
.. recommended.17
tuted, which may include a trial of antianginal medication even if a .. Peripheral artery disease (PAD) and renal dysfunction increase the
diagnosis of CAD has not been fully demonstrated. Non-invasive ..
.. likelihood of CAD, and have a negative impact on prognosis.1820
functional imaging for ischaemia may be an option if there is need to .. Hence, baseline renal function should be evaluated with estimation of
verify the diagnosis (Figure 2). ..
.. the glomerular filtration rate (GFR). It may also be reasonable to
If the pain is clearly non-anginal, other diagnostic testing may be .. measure the uric acid level, as hyperuricaemia is a frequent comorbid
indicated to identify gastrointestinal, pulmonary, or musculoskeletal ..
.. condition and may also affect renal function.
causes of chest pain. Nevertheless, these patients should also .. If there is a clinical suspicion of CAD instability, biochemical
receive Guideline-based risk-factor modification based on commonly ..
.. markers of myocardial injury—such as troponin T or troponin I—
applied risk charts such as SCORE (Systematic COronary Risk .. should be measured, preferably using high-sensitivity assays, and
Evaluation) (www.heartscore.org).15 ..
.. management should follow the Guidelines for ACS without persis-
.. tent ST-segment elevation.11 If high-sensitivity assays are employed,
..
3.1.3 Step 3: Basic testing .. low levels of troponin can be detected in many patients with stable
..
Basic (first-line) testing in patients with suspected CAD includes stand- .. angina. Increased troponin levels are associated with adverse out-
ard laboratory biochemical testing, a resting ECG, possible ambulatory .. come2125 and small studies have indicated a possible incremental
..
ECG monitoring, resting echocardiography, and, in selected patients, a .. value in diagnosing CAD,26,27 but larger trials are needed to verify
chest X-ray. Such testing can be done on an outpatient basis. .. the utility of systematic assessment in patients suspected of CAD.
..
.. While multiple biomarkers may be useful for prognostication
3.1.3.1 Biochemical tests
.. (see section 5), they do not yet have a role in diagnosing obstructive
..
Laboratory investigations are used to identify possible causes of .. CAD.
ischaemia, to establish cardiovascular risk factors and associated
..

Basic biochemistry testing in the initial diagnostic management of patients with suspected coronary artery disease

Recommendations Classa Levelb

If evaluation suggests clinical instability or ACS, repeated measurements of troponin, preferably using high-sensitivity or
I A
ultrasensitive assays, are recommended to rule-out myocardial injury associated with ACS.28,29
The following blood tests are recommended in all patients:
• Full blood count (including haemoglobin);30 I B
• Creatinine measurement and estimation of renal function;31,32 I A
• A lipid profile (including LDL-C).33,34 I A
It is recommended that screening for type 2 diabetes mellitus in patients with suspected and established CCS is imple-
mented with HbA1c and fasting plasma glucose measurements, and that an oral glucose tolerance test is added if HbA1c I B
and fasting plasma glucose results are inconclusive.16,35
Assessment of thyroid function is recommended in case of clinical suspicion of thyroid disorders. I C

ACS = acute coronary syndromes; CAD = coronary artery disease; CCS = chronic coronary syndromes; HbA1c = glycated haemoglobin; LDL-C = low-density lipoprotein
cholesterol.
a
Class of recommendation.
b
Level of evidence.
14 ESC Guidelines

3.1.3.2 Resting electrocardiogram and ambulatory monitoring


Ambulatory electrocardiogram monitoring in the initial
The paradigm of diagnosing myocardial ischaemia has, for almost a
diagnostic management of patients with suspected coro-
century, been based on the detection of repolarization abnormalities, nary artery disease
mainly in the form of ST-segment depressions. Thus, the resting 12
lead ECG remains an indispensable component of the initial evalua- Recommendations Classa Levelb
tion of a patient with chest pain without an obviously non-cardiac
Ambulatory ECG monitoring is recommended
cause. Two scenarios of clinical evaluation are encountered: (i) a

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in patients with chest pain and I C
patient without symptoms of chest pain or discomfort, and (ii) a
suspected arrhythmias.
patient with ongoing anginal symptoms.
Ambulatory ECG recording, preferably moni-
The former situation is far more prevalent and a normal resting
toring with 12 lead ECG, should be consid-
ECG is frequently recorded. However, even in the absence of repola- IIa C
ered in patients with suspected vasospastic
rization abnormalities, an ECG can demonstrate indirect signs of
angina.
CAD, such as signs of previous MI (pathological Q waves) or conduc-
tion abnormalities [mainly left bundle branch block (LBBB) and Ambulatory ECG monitoring should not be
impairment of atrioventricular conduction]. Atrial fibrillation (AF) is a used as a routine examination in patients with III C
frequent finding in patients with chest pain (usually atypical). ST- suspected CCS.
segment depression during supraventricular tachyarrhythmias is not CAD = coronary artery disease; CCS = chronic coronary syndromes; ECG =
predictive of obstructive CAD.3639 electrocardiogram.
a
Class of recommendation.
The ECG can be crucial for diagnosing myocardial ischaemia if b
Level of evidence.
dynamic ST-segment changes are recorded during ongoing angina.
The diagnosis of Prinzmetal and vasospastic angina is based on the
detection of typical transient ST-segment elevation or depression ..
.. 3.1.3.3 Echocardiography and magnetic resonance imaging at rest
during an angina attack (usually at rest). .. An echocardiographic study will provide important information about
Long-term ambulatory ECG monitoring and recording should not ..
.. cardiac function and anatomy. LV ejection fraction (LVEF) is often nor-
be used to replace exercise testing; however, 12 lead ECG monitor- .. mal in patients with CCS.44 A decreased LV function and/or regional
ing can be considered in selected patients to detect anginal episodes ..
.. wall motion abnormalities may increase the suspicion of ischaemic
unrelated to physical exercise. Ambulatory ECG monitoring may .. myocardial damage,45 and a pattern of LV dysfunction following the
reveal evidence of silent myocardial ischaemia in patients with ..
.. theoretical distribution territory of the coronary arteries is typical in
CCS, but rarely adds relevant diagnostic or prognostic information .. patients who have already had an MI.46,47 The detection of regional
that cannot be derived from stress testing.40 ECG changes suggesting
..
.. wall motion abnormalities can challenging by visual assessment, and
ischaemia on ambulatory ECG monitoring are very frequent in .. detection of early systolic lengthening, decreased systolic shortening,
women, but do not correlate with findings during stress testing.41
..
.. or post-systolic shortening by strain imaging techniques might be help-
Most importantly, therapeutic strategies targeting silent ischaemia .. ful in patients with apparently normal LV function but with clinical sus-
detected by ambulatory monitoring have not demonstrated clear
..
.. picion of CCS.4850 Decreased diastolic LV function has been
survival benefits.42,43 .. reported to be an early sign of ischaemic myocardial dysfunction and
..
.. could also be indicative of microvascular dysfunction.51,52
.. Echocardiography is an important clinical tool for the exclusion of
Resting electrocardiogram in the initial diagnostic man- ..
agement of patients with suspected coronary artery .. alternative causes of chest pain and also aids in diagnosing concurrent
disease .. cardiac diseases, such as valvular heart diseases, HF, and most cardio-
..
.. myopathies,53 but it is important to remember that these diseases
Recommendations Classa Levelb .. often coexist with obstructive CAD. The use of an echocardio-
..
A resting 12 lead ECG is recommended in all .. graphic contrast agent can be useful in patients with poor acoustic
..
patients with chest pain without an obvious I C .. windows.54
non-cardiac cause. .. Cardiac magnetic resonance (CMR) may be considered in
..
A resting 12 lead ECG is recommended in all .. patients with suspected CAD when the echocardiogram (having
patients during or immediately after
.. used contrast) is inconclusive.55 CMR will provide useful informa-
I C ..
an episode of angina suspected to be indicative .. tion on cardiac anatomy and systolic cardiac function, similar to
of clinical instability of CAD.
.. that from an echocardiogram, in patients with no contraindications
..
ST-segment alterations recorded during .. for CMR. CMR can assess global and regional function,56 and the
.. use of late gadolinium enhancement CMR can reveal a typical pat-
supraventricular tachyarrhythmias should not III C ..
be used as evidence of CAD. .. tern of scarred myocardium in patients who have already experi-
.. enced an MI.57
CAD = coronary artery disease; CCS = chronic coronary syndromes; ECG =
..
.. Assessment of LV function is important in all patients for risk strati-
electrocardiogram. .. fication (see Supplementary Data section 3.2) and should therefore be
a
Class of recommendation. ..
b
Level of evidence. .. performed in all symptomatic patients with suspected CAD.
ESC Guidelines 15

..
Management of patients with either angina or HF symptoms, with .. population studied and, thus, the likelihood that a given patient will
reduced LVEF <40% or a mid-range reduced LVEF of 40-49%, is .. actually have CAD. Diagnostic testing is most useful when the likeli-
..
described in section 4 of the Guidelines. .. hood is intermediate. When likelihood is high, a large number of
.. patients need to be studied to identify the few patients that do not
..
Resting echocardiography and cardiac magnetic reso- .. have disease, and a negative test result can seldom rule out the pres-
nance in the initial diagnostic management of patients
.. ence of obstructive CAD (i.e. the negative predictive value is low).
..
with suspected coronary artery disease .. When the likelihood is low, a negative test can rule out the disease,

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.. but the lower the likelihood, the higher the likelihood of a false-
Classa Levelb
..
Recommendations .. positive test (i.e. a positive test in the absence of obstructive CAD).
.. In patients at the extreme ends of the probability range, it is therefore
A resting transthoracic echocardiogram is rec- ..
ommended in all patients for:
.. reasonable to refrain from diagnostic testing, and assume that the
.. patient does or does not have obstructive CAD based on clinical
(1) Exclusion of alternative causes of angina; ..
(2) Identification of regional wall motion
.. evaluation alone.
I B .. The likelihood of obstructive CAD is influenced by the prevalence
abnormalities suggestive of CAD; ..
(3) Measurement of LVEF for risk stratifica-
.. of the disease in the population studied, as well as by clinical features
.. of an individual patient. A simple predictive model can be used to esti-
tion; and ..
(4) Evaluation of diastolic function.44,45,52,58
.. mate the pre-test probability (PTP) of obstructive CAD based on
.. age, sex, and the nature of symptoms.59 In the previous version of
Ultrasound of the carotid arteries should be ..
.. these Guidelines,60 estimation of the PTP was based on data gathered
considered, and be performed by adequately .. by Genders et al.,61 which updated previous data from Diamond and
trained clinicians, to detect plaque in patients IIa C ..
.. Forrester.59 Notably, the prevalence of disease for a given constella-
with suspected CCS without known athero- ..
.. tion of age, sex, and nature of symptoms was lower than in
sclerotic disease.
.. the Diamond and Forrester data. Since the previous version of the
CMR may be considered in patients with an ..
inconclusive echocardiographic test.
IIb C .. Guidelines was published, several studies have indicated that
.. the prevalence of obstructive disease among patients with suspected
..
CAD = coronary artery disease; CCS = chronic coronary syndromes; CMR = .. CAD is lower than in the previous update.7,8,62,63
cardiac magnetic resonance imaging; LVEF = left ventricular ejection fraction. .. A pooled analysis64 of three contemporary study cohorts, includ-
a
Class of recommendation. ..
b
Level of evidence. .. ing patients evaluated for suspected CAD,7,8,62 has indicated that the
.. PTP based on age, sex, and symptoms is approximately one-third of
..
.. that predicted by the model used in the previous version of the
3.1.3.4 Chest X-ray .. Guidelines.57,62 Overestimation of PTP is an important contributory
Chest X-ray is frequently used in the assessment of patients with
..
.. factor to a low diagnostic yield of non-invasive and invasive testing.
chest pain. However, in CCS, it does not provide specific information .. The new set of PTPs presented in Table 5 may substantially reduce
for diagnosis or event risk stratification. The test may occasionally be
..
.. the need for non-invasive and invasive tests in patients with suspected
helpful in assessing patients with suspected HF. Chest X-ray may also .. stable CAD. The table now also includes patients presenting with
be useful in patients with pulmonary problems, which often accom-
..
.. dyspnoea as their main symptom. However, it should be noted that
pany CAD, or to rule-out another cause of chest pain in atypical .. the PTPs presented in Table 5 (as well as the PTP table in the previous
..
presentations. .. version of the Guidelines) are based mainly on patients from coun-
.. tries with low CVD risk, and may vary between regions and
..
.. countries.
Chest X-ray in the initial diagnostic management of .. Application of the new PTPs (Table 5) has important conse-
patients with suspected coronary artery disease ..
.. quences for the referral of patients for diagnostic testing. If diag-
Classa Levelb
.. nostic testing was deferred in patients with a new PTP <15%, this
Recommendation ..
.. would result in a large increase in the proportion of patients for
Chest X-ray is recommended for patients ..
.. whom diagnostic testing was not recommended, because more
with atypical presentation, signs and symptoms I C .. patients are classified as having a PTP <15%. In data derived from
of HF, or suspicion of pulmonary disease. ..
.. the PROMISE (Prospective Multicenter Imaging Study for
HF = heart failure. .. Evaluation of Chest Pain) trial, 50% of patients previously classified
a
Class of recommendation. ..
b
Level of evidence.
.. as having an intermediate likelihood of obstructive CAD were
.. reclassified to a PTP <15% according to the new PTP.62 In data
..
.. derived from the pooled analysis64 (Table 5), 57% of all patients
3.1.4 Step 4: Assessment of pre-test probability and clini- .. were classified to a PTP <15%.
..
cal likelihood of coronary artery disease .. Studies have shown that outcomes in patients classified with
The performance of the available methods in diagnosing obstructive .. the new PTP <15% is good (annual risk of cardiovascular death
..
CAD (i.e. the likelihood that the patient has disease if the test is .. or MI is <1%).7,62 Hence, it is safe to defer routine testing in
abnormal, and the likelihood that the patient does not have disease if .. patients with PTP <15%, thus reducing unnecessary procedures
..
the test is normal) depends on the prevalence of disease in the . and costs.
16 ESC Guidelines

Table 5 Pre-test probabilities of obstructive coronary artery disease in 15 815 symptomatic patients according to age,
sex, and the nature of symptoms in a pooled analysis64 of contemporary data7,8,62

Typical Atypical Non-anginal Dyspnoeaa


Age Men Women Men Women Men Women Men Women

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30–39 3% 5% 4% 3% 1% 1% 0% 3%
40–49 22% 10% 10% 6% 3% 2% 12% 3%
50–59 32% 13% 17% 6% 11% 3% 20% 9%

©ESC 2019
60–69 44% 16% 26% 11% 22% 6% 27% 14%
70+ 52% 27% 34% 19% 24% 10% 32% 12%

CAD = coronary artery disease; PTP = pre-test probability.


a
In addition to the classic Diamond and Forrester classes,59 patients with dyspnoea only or dyspnoea as the primary symptom are included. The regions shaded dark green
denote the groups in which non-invasive testing is most beneficial (PTP >15%). The regions shaded light green denote the groups with PTPs of CAD between 515%, in which
testing for diagnosis may be considered after assessing the overall clinical likelihood based on the modifiers of PTPs presented in Figure 3.

Recent studies have also demonstrated that, when tested, the


.. optimal use of these factors in improving PTP assessment has not yet
..
true observed prevalence of obstructive CAD has been <5% in .. been established, they should be considered in addition to the PTP
patients who had a PTP <15% according to the 2013 version of
.. based on sex, age, and the nature of symptoms to determine the
..
these Guidelines.7,63 Therefore, this Task Force recognizes that .. overall clinical likelihood of obstructive CAD, as summarized in
the performance of diagnostic testing in patients with a new PTP
.. Figure 3. This is particularly important in refining the likelihood of
..
of 5 - 15% more closely reflects current clinical practice and may .. CAD patients with a PTP of 515% based on age, sex, and the nature
..
be considered, particularly if symptoms are limiting and require .. of symptoms.
clarification.7,63 Patient preference, local resources and the avail- ..
..
ability of tests, clinical judgement, and appropriate patient informa- .. 3.1.5 Step 5: Selecting appropriate testing
tion remain important when making a decision to proceed with .. In patients in whom revascularization is futile due to comorbidities
..
non-invasive diagnostic testing for an individual patient when the .. and overall quality of life, the diagnosis of CAD can be made clini-
PTP is 5 - 15%, and the higher likelihood of a false-positive test .. cally and only medical therapy is required. If the diagnosis of CAD
..
must be considered. Patients with a PTP <_5% can be assumed to .. is uncertain, establishing a diagnosis using non-invasive functional
have such a low probability of disease that diagnostic testing .. imaging for myocardial ischaemia before treatment is reasonable
..
should be performed only for compelling reasons. Implementation .. (Figure 2).
of the new PTPs also indicates that patients should not be rou- .. In a patient with a high clinical likelihood of CAD, symptoms unre-
..
tinely referred directly to invasive assessment unless clinical or .. sponsive to medical therapy or typical angina at a low level of exer-
other data indicate a high likelihood of obstructive CAD. .. cise, and an initial clinical evaluation (including echocardiogram and,
..
Clinical models that incorporate information on risk factors for .. in selected patients, exercise ECG) that indicates a high event risk,
CVD, resting ECG changes, or coronary calcification have improved
..
.. proceeding directly to invasive coronary angiography (ICA) without
the identification of patients with obstructive CAD compared with .. further diagnostic testing is a reasonable option. Under such circum-
age, sex, and symptoms alone.3,7,60,6568 Therefore, the presence of
..
.. stances, the indication for revascularization should be based on
risk factors for CVD (such as family history of CVD, dyslipidaemia, .. appropriate invasive confirmation of the haemodynamic significance
..
diabetes, hypertension, smoking, and other lifestyle factors) that .. of a stenosis.71,72
increase the probability of obstructive CAD can be used as modifiers .. In other patients in whom CAD cannot be excluded by
of the PTP estimate. If available, Q-wave, ST-segment, or T-wave
..
.. clinical assessment alone, non-invasive diagnostic tests are recom-
changes on the ECG, LV dysfunction suggestive of ischaemia, and .. mended to establish the diagnosis and assess the event risk.
..
findings on exercise ECG, as well as information on coronary calcium .. The current Guidelines recommend the use of either non-
obtained by computed tomography (CT), can be used to improve .. invasive functional imaging of ischaemia or anatomical imaging using
..
estimations of the PTP of obstructive CAD.3,69 In particular, the .. coronary CT angiography (CTA) as the initial test for diagnosing CAD.
absence of coronary calcium (Agatston score = 0) is associated with ..
..
a low prevalence of obstructive CAD (<5%), and low risk of death or .. 3.1.5.1 Functional non-invasive tests
non-fatal MI (<1% annual risk).69,70 However, it should be noted that .. Functional non-invasive tests for the diagnosis of obstructive CAD
..
coronary calcium imaging does not exclude coronary stenosis caused .. are designed to detect myocardial ischaemia through ECG
by a non-calcified atherosclerotic lesion,70 and the presence of coro- .. changes, wall motion abnormalities by stress CMR or stress echo-
..
nary calcium is a weak predictor of obstructive CAD.69 Although the . cardiography, or perfusion changes by single-photon emission CT
ESC Guidelines 17

PTP based on sex, age and nature of symptoms (Table 5)

Decreases likelihood Increases likelihood


• Normal exercise ECGa • Risk factors for CVD
• No coronary calcium by CT (dyslipidaemia, diabetes,
(Agatston score = 0)a hypertension, smoking,

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family history of CVD)
• Resting ECG changes
(Q-wave or ST-segment/
T-wave changes)
• LV dysfunction suggestive
of CAD
• Abnormal exercise ECGa
• Coronary calcium by CTa

©ESC 2019
Clinical likelihood of CAD

Figure 3 Determinants of the clinical likelihood of obstructive coronary artery disease. CAD = coronary artery disease; CT = computed tomography,
CVD = cardiovascular disease, ECG = electrocardiogram, LV = left ventricular; PTP = pre-test probability. aWhen available.

..
(SPECT), positron emission tomography (PET), myocardial con- .. predominantly of exercise ECG.6 Other randomized, prospective clin-
trast echocardiography, or contrast CMR. Ischaemia can be pro- .. ical trials have demonstrated that diagnostic testing with coronary
..
voked by exercise or pharmacological stressors, either by .. CTA is associated with clinical outcomes similar to those for func-
increased myocardial work and oxygen demand, or by heteroge- .. tional imaging in patients with suspected CAD.4,6,76 In patients with
..
neity in myocardial perfusion by vasodilatation. Non-invasive func- .. extensive CAD, coronary CTA complemented by CT-based FFR was
tional tests are associated with high accuracy for the detection of .. non-inferior to ICA and FFR for decision-making, and the identification
..
flow-limiting coronary stenosis compared with invasive functional .. of targets for revascularization.77
testing [fractional flow reserve (FFR)].73 However, lower-grade
..
..
coronary atherosclerosis not linked with ischaemia remains unde- .. 3.1.5.3 Role of the exercise electrocardiogram
tected by functional testing and, in the presence of a negative func-
.. Exercise ECG has inferior diagnostic performance compared with
..
tional test, patients should receive risk-factor modification based .. diagnostic imaging tests, and has limited power to rule-in or rule-out
on commonly applied risk charts and recommendations.
.. obstructive CAD.73 Since the publication of the previous version of
..
.. these Guidelines, randomized clinical trials (RCTs) have compared
3.1.5.2 Anatomical non-invasive evaluation
.. the effects of diagnostic strategies based on exercise ECG or an imag-
..
Anatomical non-invasive evaluation, by visualizing the coronary artery .. ing diagnostic test6,78,79 on clinical outcomes. These studies have
..
lumen and wall using an intravenous contrast agent, can be performed .. shown that the addition of coronary CTA5,6,78,80 or functional
with coronary CTA, which provides high accuracy for the detection .. imaging79 clarifies the diagnosis, enables the targeting of preventive
..
of obstructive coronary stenoses defined by ICA,73 because both tests .. therapies and interventions, and potentially reduces the risk of MI
are based on anatomy. However, stenoses estimated to be 5090% .. compared with an exercise ECG. Some, although not all, registry
..
by visual inspection are not necessarily functionally significant, i.e. they .. studies have also shown similar benefits regarding the use of an imag-
do not always induce myocardial ischaemia.73,74 Therefore, either ... ing diagnostic test in patients treated in everyday clinical practice.81,82
non-invasive or invasive functional testing is recommended for further .. Therefore, these Guidelines recommend the use of an imaging diag-
..
evaluation of angiographic stenosis detected by coronary CTA or .. nostic test instead of exercise ECG as the initial test for to diagnose
invasive angiography, unless a very high-grade (>90% diameter steno- .. obstructive CAD.
..
sis) stenosis is detected via invasive angiography. The presence or .. An exercise ECG alone may be considered as an alternative to
absence of non-obstructive coronary atherosclerosis on coronary .. diagnose obstructive CAD if imaging tests are not available, keeping
..
CTA provides prognostic information, and can be used to guide pre- .. in mind the risk of false-negative and false-positive test results.73,83
ventive therapy.75 The SCOT-HEART (Scottish Computed .. An exercise ECG is of no diagnostic value in patients with ECG
..
Tomography of the HEART) trial demonstrated a significantly lower .. abnormalities that prevent interpretation of the ST-segment changes
rate of the combined endpoint of cardiovascular death or non-fatal MI
.. during stress (i.e. LBBB, paced rhythm, Wolff-Parkinson-White syn-
..
(2.3 vs. 3.9% during 5 year follow-up) in patients in whom coronary .. drome, >_0.1 mV ST-segment depression on resting ECG, or who are
CTA was performed in addition to routine testing, which consisted
.. being treated with digitalis). An exercise ECG provides
..
18 ESC Guidelines

complementary clinically useful information beyond ECG changes .. Coronary CTA is the preferred test in patients with a lower range
..
and valuable prognostic information. Therefore, application of an .. of clinical likelihood of CAD, no previous diagnosis of CAD, and
exercise ECG may be considered in selected patients to complement
.. characteristics associated with a high likelihood of good image quality.
..
clinical evaluation for the assessment of symptoms, ST-segment .. It detects subclinical coronary atherosclerosis, but can also accu-
changes, exercise tolerance, arrhythmias, blood pressure (BP)
.. rately rule out both anatomically and functionally significant CAD
..
response, and event risk. .. (Figure 5). It has higher accuracy values when low clinical likelihood
.. populations are subjected to examination.85 Trials evaluating out-
..

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3.1.5.4 Selection of diagnostic tests .. comes after coronary CTA to date have mostly included patients
Either a functional or anatomical test can be used to establish a diag-
.. with a low clinical likelihood.4,5
..
nosis of obstructive CAD. A summary of the main diagnostic path- .. The non-invasive functional tests for ischaemia typically have bet-
..
ways is displayed in Figure 4. For revascularization decisions, .. ter rule-in power. In outcome trials, functional imaging tests have
information on both anatomy and ischaemia is needed. .. been associated with fewer referrals for downstream ICA compared
..
.. with a strategy relying on anatomical imaging.55,76,86 Before revascula-
3.1.5.5 The impact of clinical likelihood on the selection of a diagnostic test .. rization decisions can be made, functional evaluation of ischaemia
..
Each non-invasive diagnostic test has a particular range of clinical like- .. (either non-invasive or invasive) is required in most patients.
lihood of obstructive CAD where the usefulness of its application is .. Therefore, functional non-invasive testing may be preferred in
..
maximal. The likelihood ratios of the tests constitute useful parame- .. patients at the higher end of the range of clinical likelihood if revascu-
ters of their abilities to correctly classify patients, and can be used to .. larization is likely or the patient has previously diagnosed CAD.
..
facilitate the selection of the most useful test in any given patient.73,84 .. Patients in whom CAD is suspected, but who have a very low clini-
Given a clinical likelihood of obstructive CAD and the likelihood ratio .. cal likelihood (<_5%) of CAD, should have other cardiac causes of
..
of a particular test, one can assess the post-test probability of .. chest pain excluded and their cardiovascular risk factors adjusted,
obstructive CAD after performing such a test. Using this approach, .. based on a risk-score assessment. In patients with repeated, unpro-
..
one can estimate the optimal ranges of clinical likelihood for each .. voked attacks of anginal symptoms mainly at rest, vasospastic angina
test, where they can reclassify patients from intermediate to either .. should be considered, diagnosed, and treated appropriately
..
low or high post-test probability of CAD (Figure 5).73 .. (see section 6).

Preferentially considered if:


Non-invasive  High clinical likelihood
testing for  Revascularization likely
ischaemia  Local expertise and availability

 Viability assessment also required


Preferentially considered if:
 Low clinical likelihood
 Patient characteristics suggest
high image quality Coronary Drug
 Local expertise and availability CTA therapyb
 Information on atherosclerosis

desired Ongoing
 No history of CAD symptomsa
Preferentially considered if:
 High clinical likelihood and severe
Invasive symptoms refractory to medical therapy
coronary  Typical angina at low level of exercise and

angiography clinical evaluation including exercise ECG


indicates high-risk of events
 LV dysfunction suggestive of CAD

Stenosis >90%
or with established
Functional correlation to ischaemia
Drug
therapyb assessment
©ESC 2019

Revascularization

Figure 4 Main diagnostic pathways in symptomatic patients with suspected obstructive coronary artery disease. Depending on clinical conditions and
the healthcare environment, patient workup can start with either of three options: non-invasive testing, coronary computed tomography angiography, or
invasive coronary angiography. Through each pathway, both functional and anatomical information is gathered to inform an appropriate diagnostic and
therapeutic strategy. Risk-factor modification should be considered in all patients. CAD = coronary artery disease; CTA = computed tomography angiog-
raphy; ECG = electrocardiogram; LV = left ventricular. aConsider microvascular angina. bAntianginal medications and/or risk-factor modification.
ESC Guidelines 19

A Test Clinical Likelihood of ICA-significant CAD B Test Clinical Likelihood of FFR-significant CAD
Results 0% 50% 100% Results 0% 50% 100%

Stress ECG ICA

Coronary CTA Coronary CTA

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PET PET

Stress Stress
CMR CMR

Stress SPECT
Echocardiography

15% 85%
SPECT
Clinical Likelihood range where test

©ESC 2019
15% 85% can rule-in CAD (Post-test probability will rise above 85%)

Clinical Likelihood range where test


can rule-out CAD (Post-test probability will rise below 15%)

Figure 5 Ranges of clinical likelihood of coronary artery disease in which a given test can rule-in (red) or rule-out (green) obstructive coronary
artery disease. (A) Reference standard is anatomical assessment using invasive coronary angiography. (B) Reference standard is functional assess-
ment using fractional flow reserve. Note in (B) that the data with stress echocardiography and single-photon emission computed tomography are
more limited than with the other techniques.73 The crosshairs mark the mean values and their 95% confidence intervals. Figure adapted from
Knuuti et al.73 CAD = coronary artery disease; CMR = cardiac magnetic resonance; CTA = computed tomography angiography; ECG = electrocar-
diogram; FFR = fractional flow reserve; ICA = invasive coronary angiography; PET = positron emission tomography; SPECT = single-photon emis-
sion computed tomography.
..
In addition to diagnostic accuracy and clinical likelihood, the selec- .. However, ICA may be indicated if non-invasive assessment suggests
tion of a non-invasive test depends on other patient characteristics, .. high event risk for determination of options for revascularization.88
..
local expertise, and the availability of tests. Some diagnostic tests may .. In a patient with a high clinical likelihood of CAD, and symptoms
perform better in some patients than others. For example, irregular .. unresponsive to medical therapy or with typical angina at a low level
..
heart rate and the presence of extensive coronary calcification are .. of exercise, and initial clinical evaluation indicates a high event risk,
associated with increased likelihood of non-diagnostic image quality .. early ICA without previous non-invasive risk stratification may be
..
of coronary CTA, and it is not recommended in such patients.85 .. reasonable to identify lesions potentially amenable to revasculariza-
Stress echocardiography or SPECT perfusion imaging can be com- .. tion (Figure 4). Invasive functional assessment should complement
..
bined with dynamic exercise testing, and may be preferred if addi- .. ICA, especially in patients with coronary stenoses of 50 - 90% or mul-
tional information available from the exercise test, such as exercise
.. tivessel disease, given the frequent mismatch between the angio-
..
tolerance or heart rate response to exercise, is considered impor- .. graphic and haemodynamic severities of coronary stenoses.8991
tant. Exercise ECG cannot be used for diagnostic purposes in the
.. Systematic integration of ICA with FFR has been shown to result in
..
presence of ECG abnormalities that prevent the evaluation of ischae- .. changes to the management strategies of 30 - 50% of patients under-
mia. Risks related to different diagnostic tests need to be weighed
.. going elective ICA.92,93 Methods used to perform ICA have improved
..
against the benefits to the individual.87 For example, exposure to ion- .. substantially, resulting in a reduction of complication rates with rapid
izing radiation associated with coronary CTA and nuclear perfusion
.. ambulation. This is especially true for ICA performed via the radial
..
imaging needs to be taken into account, especially in young individu- .. artery.94 The composite rate of major complications associated with
..
als.87 Similarly, contraindications to pharmacological stressors and .. routine femoral diagnostic catheterization—mainly bleeding requir-
contrast agents (iodine-based contrast agents and gadolinium-based .. ing blood transfusions—is still 0.52%.95 The composite rate of
..
chelates) need to be taken into account. When testing is used appro- .. death, MI, or stroke is of the order of 0.10.2%.96 ICA should not be
priately, the clinical benefit from accurate diagnosis and therapy .. performed in patients with angina who refuse invasive procedures,
..
exceeds the projected risks of testing itself.87 .. prefer to avoid revascularization, who are not candidates for percuta-
.. neous coronary intervention (PCI) or coronary artery bypass grafting
..
3.1.5.6 Invasive testing .. (CABG), or in whom revascularization is not expected to improve
For diagnostic purposes, ICA is only necessary in patients with sus- .. functional status or quality of life. Intracoronary techniques for the
..
pected CAD in cases of inconclusive non-invasive testing or, exception- .. diagnostic assessment of coronary anatomy are briefly mentioned in
ally, in patients from particular professions, due to regulatory issues.88 .. the Supplementary Data of this document.
20 ESC Guidelines

Use of diagnostic imaging tests in the initial diagnostic management of symptomatic patients with suspected coronary
artery disease

Recommendations Classa Levelb

Non-invasive functional imaging for myocardial ischaemiac or coronary CTA is recommended as the initial test to diagnose
I B
CAD in symptomatic patients in whom obstructive CAD cannot be excluded by clinical assessment alone.4,5,55,73,7880

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It is recommended that selection of the initial non-invasive diagnostic test is done based on the clinical likelihood of CAD
I C
and other patient characteristics that influence test performance,d local expertise, and the availability of tests.
Functional imaging for myocardial ischaemia is recommended if coronary CTA has shown CAD of uncertain functional sig-
I B
nificance or is not diagnostic.4,55,73
Invasive coronary angiography is recommended as an alternative test to diagnose CAD in patients with a high clinical likeli-
hood, severe symptoms refractory to medical therapy or typical angina at a low level of exercise, and clinical evaluation
I B
that indicates high event risk. Invasive functional assessment must be available and used to evaluate stenoses before revas-
cularization, unless very high grade (>90% diameter stenosis).71,72,74
Invasive coronary angiography with the availability of invasive functional evaluation should be considered for confirmation
IIa B
of the diagnosis of CAD in patients with an uncertain diagnosis on non-invasive testing.71,72
Coronary CTA should be considered as an alternative to invasive angiography if another non-invasive test is equivocal or
IIa C
non-diagnostic.
Coronary CTA is not recommended when extensive coronary calcification, irregular heart rate, significant obesity, inabil-
III C
ity to cooperate with breath-hold commands, or any other conditions make obtaining good image quality unlikely.
Coronary calcium detection by CT is not recommended to identify individuals with obstructive CAD. III C

CAD = coronary artery disease; CT = computed tomography; CTA = computed tomography angiography.
a
Class of recommendation.
b
Level of evidence
c
Stress echocardiography, stress cardiac magnetic resonance, single-photon emission CT, or positron emission tomography.
d
Characteristics determining ability to exercise, likelihood of good image quality, expected radiation exposure, and risks or contraindications.

Use of exercise electrocardiogram in the initial diagnostic management of patients with suspected coronary artery
disease

Recommendations Classa Levelb

Exercise ECG is recommended for the assessment of exercise tolerance, symptoms, arrhythmias, BP response, and event
I C
risk in selected patients.c
Exercise ECG may be considered as an alternative test to rule-in and rule-out CAD when non-invasive imaging is not
IIb B
available.73,83
Exercise ECG may be considered in patients on treatment to evaluate control of symptoms and ischaemia. IIb C
Exercise ECG is not recommended for diagnostic purposes in patients with >_0.1 mV ST-segment depression on resting
III C
ECG or who are being treated with digitalis.

BP = blood pressure; CAD = coronary artery disease; ECG = electrocardiogram.


a
Class of recommendation.
b
Level of evidence.
c
When this information will have an impact on diagnostic strategy or management.
ESC Guidelines 21

..
3.1.6 Step 6: Assessment of event risk .. stratification using clinical evaluation, the assessment of LV function by
Assessment of event risk is recommended in every patient being eval- .. resting echocardiography, and, in the majority of cases, non-invasive
..
uated for suspected CAD or with a newly diagnosed CAD, as it has .. assessment of ischaemia or coronary anatomy. Although the diagnos-
major impacts on therapy decisions. The process of risk stratification .. tic value of an exercise ECG is limited,73 the occurrence of ST-
..
serves to identify patients at high event risk who will benefit from .. segment depression at a low workload combined with exertional
revascularization beyond the amelioration of symptoms. Event risk .. symptoms (angina or dyspnoea), low exercise capacity, complex ven-
..
stratification is usually based on the assessments used to make a diag- .. tricular ectopy, or arrhythmias and abnormal BP response are

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nosis of CAD. All patients should undergo cardiovascular event risk .. markers of a high risk of cardiac mortality.97100 Patients with typical

Table 6 Definitions of high event risk for different test modalities in patients with established chronic coronary syndro-
mesa 102104

Exercise ECG Cardiovascular mortality >3% per year according to Duke Treadmill Score
SPECT or PET perfusion imaging Area of ischaemia >_10% of the left ventricle myocardium
Stress echocardiography >_3 of 16 segments with stress-induced hypokinesia or akinesia
CMR >_2 of 16 segments with stress perfusion defects or >_3 dobutamine-induced dysfunctional segments
Coronary CTA or ICA Three-vessel disease with proximal stenoses, LM disease, or proximal anterior descending disease
Invasive functional testing FFR <_0.8, iwFR <_0.89
CTA = computed tomography angiography; CMR = cardiac magnetic resonance; ECG = electrocardiogram; FFR = fractional flow reserve; ICA = invasive coronary angiography;
iwFR = instantaneous wave-free ration (instant flow reserve); LM = left main; PET = positron emission tomography; SPECT; single-photon emission computed tomography.
a
For detailed explanations, refer to the Supplementary Data.

Asymptomatic apparently healthy subjects Symptomatic patients with established CCS


10 year risk of cardiovascular mortality Annual risk of cardiac mortality
40 4

SECONDARY PREVENTION
PRIMARY PREVENTION

35 3,5 3% and over High-risk

30 3

Very high-risk 25 2,5

20 2 1%–2.9% Moderate risk


15% and over

15 1,5
10%–14%
10 1
High-risk 5%–9%
5 0,5 0%–0.9% Low-risk
©ESC 2019

3%–4%
Low-to-moderate risk 2%
1%
<1% 0 0

Figure 6 Comparison of risk assessments in asymptomatic apparently healthy subjects (primary prevention) and patients with established chronic coro-
nary syndromes (secondary prevention). Note that in asymptomatic subjects (left panel), SCORE estimates 10 year cardiovascular mortality, while in
symptomatic patients (right panel), annual cardiac mortality is estimated. CCS = chronic coronary syndromes; SCORE = Systematic COronary Risk
Evaluation.
22 ESC Guidelines

..
angina and LV systolic dysfunction in a pattern that indicates CAD are .. The definitions of high event risk based on findings of diagnostic tests in
also at high risk of cardiac mortality.101 ICA for risk stratification will .. symptomatic patients or in patients with established CCS are shown in
..
only be required in a selected subgroup of patients and additional FFR .. Table 6.
may be required for event risk stratification as appropriate (Figure 4). .. Notably, the level of risk is different from the risk assessment based
..
Risk assessment in patients with HF and LV dysfunction, asymptomatic .. on SCORE in asymptomatic individuals without diabetes who are
patients with known CAD, and patients with recurrent symptoms .. apparently healthy (see section 7). SCORE defines 10 year cardiovas-
..
after previous coronary intervention is discussed in sections 4 and 5. .. cular mortality in asymptomatic subjects. Differences in these risk-

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.. assessment tools and the scales are illustrated in Figure 6. The findings
..
3.1.6.1 Definition of levels of risk .. of different test modalities that correspond to high event risk are pre-
In patients with established CCS, the risk of annual cardiac mortality is
.. sented in Table 6 and are discussed in more detail in the
..
used to describe the event risk. As in the previous version of the .. Supplementary Data (sections 1.1 and 1.2).102104 For all non-invasive
Guidelines,60 high event risk is defined as a cardiac mortality rate >3%
.. tests presented in Table 6, a normal test result is associated with a low
..
per year and low event risk as a cardiac mortality rate <1% per year. .. event risk.105
..

Recommendations on risk assessment

Recommendations Classa Levelb

Risk stratification is recommended based on clinical assessment and the result of the diagnostic test initially employed to
I B
diagnose CAD.6,75,102,103
Resting echocardiography is recommended to quantify LV function in all patients with suspected CAD. I C
Risk stratification, preferably using stress imaging or coronary CTA (if permitted by local expertise and availability), or
alternatively exercise stress ECG (if significant exercise can be performed and the ECG is amenable to the identification I B
of ischaemic changes), is recommended in patients with suspected or newly diagnosed CAD.6,75,102,106
In symptomatic patients with a high-risk clinical profile, ICA complemented by invasive physiological guidance (FFR) is rec-
ommended for cardiovascular risk stratification, particularly if the symptoms are responding inadequately to medical treat- I A
ment and revascularization is considered for improvement of prognosis.104,107
In patients with mild or no symptoms, ICA complemented by invasive physiological guidance (FFR/iwFR) is recommended
for patients on medical treatment, in whom non-invasive risk stratification indicates a high event risk and revascularization I A
is considered for improvement of prognosis.104,107
ICA complemented by invasive physiological guidance (FFR) should be considered for risk-stratification purposes in
IIa B
patients with inconclusive or conflicting results from non-invasive testing.74
If coronary CTA is available for event risk stratification, additional stress imaging should be performed before the referral
IIa B
of a patient with few/no symptoms for ICA.108,109
Echocardiographic assessment of global longitudinal strain provides incremental information to LVEF and may be consid-
IIb B
ered when LVEF is >35%.110114
Intravascular ultrasound may be considered for the risk stratification of patients with intermediate LM stenosis.115,116 IIb B
ICA is not recommended solely for risk stratification. III C

CAD = coronary artery disease; CTA = computed tomography angiography; ECG = electrocardiogram; FFR = fractional flow reserve; ICA = invasive coronary angiography;
iwFR = instantaneous wave-free ratio; LM = left main; LV = left ventricular; LVEF = LV ejection fraction.
a
Class of recommendation.
b
Level of evidence.
ESC Guidelines 23

..
3.2 Lifestyle management .. Netherlands were found to be as effective as general practitioners in
.. decreasing cardiovascular risk in another randomized study.123
3.2.1 General management of patients with coronary ..
artery disease ..
.. 3.2.2.1 Smoking
General management of CCS aims to reduce symptoms and ..
improve prognosis through appropriate medications and inter- .. Smoking cessation improves the prognosis in patients with CCS,
.. including a 36% risk reduction in mortality for those who quit.124
ventions, and to control risk factors including lifestyle behaviours. ..
Optimal medical therapy in the COURAGE (Clinical Outcomes .. Measures to promote smoking cessation include brief advice, coun-

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.. selling and behavioural interventions, and pharmacological therapy
Utilizing Revascularization and Aggressive Drug Evaluation) trial ..
included the promotion of medication adherence, behavioural .. including nicotine replacement. Patients should also avoid passive
.. smoking.
counselling, and support for the managing lifestyle risk factors ..
delivered by nurse case managers.117 Achievement of optimal
.. Brief advice, relative to no treatment, doubles the likelihood of
.. smoking cessation in the short-term, but more intensive advice and
management may be best accomplished through a multidiscipli- ..
nary team approach that can provide tailored and flexible support
.. support (behavioural interventions, telephone support, or self-help
..
measures) is more effective than brief advice, especially if continued
to patients. ...
Patient-reported outcome measures can provide relevant and .. over 1 month.125,126 All forms of nicotine-replacement therapy,
systematic information about patients’ symptoms, functioning, and
.. bupropion, and varenicline are more effective in increasing smoking
..
concerns. Patient-reported outcome measures are increasingly .. cessation than control, and combining behavioural and pharmacologi-
.. cal approaches is effective and highly recommended.125 A network
being implemented sequentially in healthcare, and have been ..
shown to improve clinical care and patient experiences, communi- .. meta-analysis of 63 clinical trials (including eight trials in CVD
.. patients) found no increase in major adverse cardiovascular events
cation between providers and patients (including sensitive sub- ..
jects), save time in consultations, and improve provider .. linked to nicotine-replacement therapy, bupropion, or varenicline.127
.. Nicotine-replacement therapy was associated with minor events
satisfaction.118 ..
.. such as arrhythmias and angina, and bupropion appeared to have a
.. protective effect against major adverse cardiovascular events.127 The
..
3.2.2 Lifestyle modification and control of risk factors
.. use of e-cigarettes is considered to be a reduced-harm alternative to
.. conventional cigarettes, but they are not harm-free. Newer devices
Implementing healthy lifestyle behaviours decreases the risk of subse- ..
.. can deliver higher nicotine contents, and e-cigarettes emit other con-
quent cardiovascular events and mortality, and is additional to appro- .. stituents such as carbonyls and fine and ultrafine particulates.128
priate secondary prevention therapy. Lifestyle recommendations and ..
.. Although previous systematic reviews have found very limited and
interventions are described in more detail in the 2016 ESC .. inconsistent evidence that e-cigarettes (primarily first-generation
Guidelines on CVD prevention in clinical practice.15 Lifestyle factors ..
.. devices) are useful in improve smoking cessation compared with pla-
are important and the implementation of healthy behaviours (includ- .. cebo or nicotine-replacement therapy, a recent large clinical trial
ing smoking cessation, recommended physical activity, a healthy diet, ..
.. found e-cigarettes to be more effective than nicotine-replacement
and maintaining a healthy weight; see Table 7) significantly decreases .. therapy in smoking cessation.129133 In this randomised trial of 886
the risk of future cardiovascular events and death, even when con- ..
.. smokers, those assigned to e-cigarettes had a sustained 1 year absti-
trolling for evidence-based secondary prevention therapy and inter- ..
.. nence rate of 18% compared with 9.9% for nicotine-replacement
ventions.119122 Benefits are evident as early as 6 months after an .. therapy [relative risk, 1.83; 95% confidence interval (CI) 1.30 to 2.58;
index event.119 ..
.. P < 0.001].133
Primary care providers have an important role to play in preven- .. In clinical encounters with smokers, clinicians should follow the
tion. The primary care arm of the EUROACTION cluster random- ..
ized trial demonstrated that a nurse-co-ordinated programme in
.. ‘Five As’: ask about smoking, advise to quit, assess readiness to quit,
.. assist with smoking cessation (pharmacological support and referral
primary care was more effective in helping patients achieve lifestyle ..
and risk-factor goals than usual care.123 Practice nurses in the
.. for behavioural counselling), and arrange follow-up (Figure 7).

Table 7 Lifestyle recommendations for patients with chronic coronary syndromes


Lifestyle factor
Smoking cessation Use pharmacological and behavioural strategies to help patients quit smoking. Avoid passive smoking.
Healthy diet Diet high in vegetables, fruit, and wholegrains. Limit saturated fat to <10% of total intake. Limit alcohol to <100 g/week or 15 g/day.
Physical activity 30 - 60 min moderate physical activity most days, but even irregular activity is beneficial.
Healthy weight Obtain and maintain a healthy weight (<25 kg/m2), or reduce weight through recommended energy intake and increased
physical activity.
Other Take medications as prescribed. Sexual activity is low risk for stable patients not symptomatic at low-to-moderate activity levels.
24 ESC Guidelines

Table 8 Healthy diet characteristics134,137,141,142


Arrange Ask about Characteristics
follow-up smoking
Increase consumption of fruits and vegetables (>_200 g each per day).
3545 g of fibre per day, preferably from wholegrains.
Moderate consumption of nuts (30 g per day, unsalted).

5As 12 servings of fish per week (one to be oily fish).

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Limited lean meat, low-fat dairy products, and liquid vegetable oils.
Assist with
Advise to Saturated fats to account for <10% of total energy intake; replace with
smoking
quit
cessation polyunsaturated fats.
As little intake of trans unsaturated fats as possible, preferably no intake
from processed food, and <1% of total energy intake.
Assess
<_56 g of salt per day.

©ESC 2019
readiness
to quit If alcohol is consumed, limiting intake to <_100 g/week or <15 g/day is
recommended.
Avoid energy-dense foods such as sugar-sweetened soft drinks.

Figure 7 The five As of smoking cessation.


..
.. 3.2.2.4 Physical activity
.. Exercise has been referred to as a ‘polypill’ due to its numerous bene-
3.2.2.2 Diet and alcohol ..
Unhealthy diets are a leading contributor to CAD and its progres- .. ficial effects on cardiovascular risk factors and cardiovascular system
.. physiology.146,147 Exercise improves angina through enhanced oxy-
sion, and changes to healthy eating patterns in patients with CCS ..
have resulted in a reduction in mortality and cardiovascular .. gen delivery to the myocardium, and increasing exercise capacity is
.. an independent predictor of increased survival among men and
events134 (recommended diet characteristics are detailed in ..
Table 8). .. women with CCS, even among those with a regimen consistent with
.. evidence-based management.122,147,148
A Mediterranean dietary pattern high in fruit, vegetables, ..
legumes, fibre, polyunsaturated fats, nuts, and fish, avoiding or lim- .. Every 1 mL/kg/min increase in exercise peak oxygen consumption
.. was associated with a 1417% reduction of risk for cardiovascular
iting refined carbohydrates, red meat, dairy, and saturated fat, is ..
advocated.135138 Although light-to-moderate alcohol intake .. and all-cause death in women and men.122
.. Physical activity recommendations for patients with CCS are
(12 drinks per day) does not increase risk of MI, levels >100 g ..
per week were associated with higher all-cause and other CVD .. 3060 min of moderate-intensity aerobic activity >_5 days per
..
mortality in a large individual-data meta-analysis.139 The Global .. week.147 Even irregular leisure-time physical activity decreases mortal-
Burden of Disease 19902016 analysis concluded that zero alco-
.. ity risk among previously sedentary patients,149 and increasing activity
..
hol intake was the level at which risk for death and disability was .. is associated with lower cardiovascular mortality.150 Previously seden-
minimized.140
.. tary patients will need support to work up to 3060 min most days,
..
.. reassurance that exercise is beneficial, and education regarding what
3.2.2.3 Weight management .. to do if angina occurs while being active. Resistance exercises maintain
..
In a population-based study, lifetime risk of incident CVD, and car- .. muscle mass, strength, and function and, with aerobic activity, have
diovascular morbidity and mortality, were higher in those who .. benefits regarding insulin sensitivity and control of lipids and BP.
..
were overweight or obese compared with those with a normal ..
BMI (20 - 25 kg/m2). Obesity was associated with a shorter overall .. 3.2.2.5 Cardiac rehabilitation
..
lifespan, and overweight was associated with developing CVD at .. Exercise-based cardiac rehabilitation has consistently demonstrated
an earlier age.143 Waist circumference is a marker of central obe- .. its effectiveness in reducing cardiovascular mortality and hospitaliza-
..
sity and is strongly associated with developing CVD and diabetes. .. tions compared with no exercise controls in patients with CAD, and
Waist circumference <_94 cm for men (<90 cm for South Asian
.. this benefit persists into the modern era.151153 Most patients partici-
..
and Asian men) and <_80 cm for women is recommended. .. pating in cardiac rehabilitation are referred following an acute MI or
In subjects with CAD, intentional weight loss is associated with a
.. after revascularization, with 0 - 24% of patients found to be referred
..
significantly lower risk of adverse clinical outcomes.144 Although .. for CCS in 12 European countries.154 Importantly, the benefits of car-
there has been much argument regarding the relative benefits of low-
.. diac rehabilitation occur across diagnostic categories.151153
..
fat vs. low-carbohydrate diets, Gardner et al.145 found similar weight ..
loss and benefits in patients randomized to either healthy low-fat or
.. 3.2.2.6 Psychosocial factors
..
low-carbohydrate diets. This finding held, regardless of patients’ gen- .. Patients with heart disease have a two-fold increased risk of mood
..
otype patterns and baseline insulin secretion. Healthy diets with .. and anxiety disorders compared with people without heart dis-
energy intake limited to the amount needed to obtain and maintain a .. ease.155,156 Psychosocial stress, depression, and anxiety are associ-
..
healthy weight (BMI <25 kg/m2), and increasing physical activity, are .. ated with worse outcomes, and make it difficult for patients to make
recommended for weight management. .. positive changes to their lifestyles or adhere to a therapeutic regimen.
ESC Guidelines 25

The ESC Prevention Guidelines recommend assessment for psycho-


.. non-adherence and higher rates of hospitalizations.170 Drug prescrip-
..
social risk factors.15 Clinical trials have shown that psychological (e.g. .. tions should prioritize medications that have proved their benefit
..
counselling and/or cognitive behavioural therapy) and pharmacologi- .. with the highest level of evidence and those for whom the amplitude
cal interventions have a beneficial effect on depression, anxiety, and .. of benefit is largest. Simplifying medication regimens may help, and
..
stress, with some evidence of a reduction in cardiac mortality and .. there is some evidence of benefits of cognitive educational strategies,
events compared with placebo.157159 .. electronically monitored feedback, and support by nurse case manag-
..
.. ers. Medication reviews by primary care providers may be helpful in

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3.2.2.7 Environmental factors .. patients with multiple comorbidities to minimize the risk of adverse
..
Air pollutants are estimated to be one of the 10 leading risk factors for .. interactions and to simplify medication regimens.117,171173
global mortality. Exposure to air pollution increases risk of MI, as well .. Promoting behaviour change and medication adherence should be
..
as hospitalization and death from heart failure, stroke, and arrhyth- .. part of each clinical encounter in primary care and specialist follow-up,
mia.160 Patients with CCS should avoid heavily traffic-congested areas. .. emphasising its importance, referring for support when needed, and con-
..
Air purifiers with high-efficiency particulate air (‘HEPA’) filters reduce .. gratulating patients for their achievements. Long-term support (intensive
indoor pollution, and wearing N95 respirator face masks in heavily pol- .. in the first 6 months, then every 6 months for 3 years) in the GOSPEL
..
luted areas has been shown to be protective.160 Environmental noise .. (Global secondary prevention strategies to limit event recurrence after
also increases the risk of CVD.161 Policies and regulations that reduce
.. myocardial infarction) trial resulted in significant improvements in risk
..
air pollution and environmental noise should be supported, and .. factors, and decreases in several clinical mortality and morbidity end-
patients should be advised about these risks.
.. points.121 The Multicenter Lifestyle Demonstration Project showed that
..
.. CCS patients could make intensive lifestyle changes and improve their
3.2.2.8 Sexual activity
.. risk factors and fitness, with changes sustained at 12 months.174
..
Patients with CCS often worry about the cardiovascular risk associ- ..
ated with sexual activity and/or experience sexual dysfunction.162
.. 3.2.2.10 Influenza vaccination
..
The risk of triggering sudden death or an acute MI is very low, espe- .. An annual influenza vaccination can improve prevention of acute MI
..
cially when sexual activity is with a stable partner in a familiar environ- .. in patients with CCS,175,176 change HF prognosis,177 and decrease
ment without stress, or excessive intake of food or alcohol .. cardiovascular mortality in adults aged >_65 years.178180 Therefore,
..
beforehand.163,164 Although sexual activity transiently increases the .. annual influenza vaccination is recommended for patients with CAD,
risk of MI, it is the cause of <1% of acute MIs and <11.7% of sudden .. especially in the elderly.
..
deaths occur during sexual activity.164 The energy expenditure during .
sexual activity is generally low-to-moderate (3 - 5 metabolic equiva- Recommendations on lifestyle management
lents) and climbing two flights of stairs is often used as an equivalent
activity in terms of energy expended.163,164 Regular physical activity Recommendations Classa Levelb
decreases the risk of adverse events during sexual activity.165 Sexual
Improvement of lifestyle factors in addition
dysfunction in patients with CCS includes decreased libido and sexual
to appropriate pharmacological management is I A
activity, and a high prevalence of erectile dysfunction. Sexual dysfunc-
recommended.119122,124,148153
tion may be caused by underlying vascular conditions, psychosocial
Cognitive behavioural interventions are rec-
factors, specific medications, number of medications, and changes in
ommended to help individuals achieve a I A
relationships.166 Thiazide diuretics and beta-blockers (except nebivo-
healthy lifestyle.181183
lol) may negatively influence erectile function, but studies published
since 2011 have not found a consistent relationship between most Exercise-based cardiac rehabilitation is recom-
contemporary cardiovascular medications and erectile dysfunc- mended as an effective means for patients
I A
tion.162,164,165 Phosphodiesterase-5 inhibitors to treat erectile dys- with CCS to achieve a healthy lifestyle and
151153
function are generally safe in CCS patients, but should not be used in manage risk factors.
those taking nitrates.164 Healthcare providers should ask patients Involvement of multidisciplinary healthcare pro-
about sexual activity, and offer advice and counselling. fessionals (e.g. cardiologists, GPs, nurses, dieti-
I A
cians, physiotherapists, psychologists, and
3.2.2.9 Adherence and sustainability pharmacists) is recommended.121,123,181,184
Adherence to lifestyle modifications and to medications is a chal- Psychological interventions are recommended
lenge. A systematic review of epidemiological studies indicated that a to improve symptoms of depression in I B
substantial proportion of patients do not adhere to cardiovascular patients with CCS.126,157
medications, and that 9% of cardiovascular events in Europe were Annual influenza vaccination is recommended
attributable to poor adherence.167 In older men with ischaemic heart for patients with CCS, especially in the I B
disease, greater adherence to medication guidelines appears to be elderly.175,176,178,179,185187
positively associated with better clinical outcomes, independent of
CCS = chronic coronary syndrome; GPs = general practitioners.
other conditions.168 Polypharmacy plays a negative role in adherence a
Class of recommendation.
to treatment,169 and complexity of drug regimen is associated with b
Level of evidence.
26 ESC Guidelines

..
3.3 Pharmacological management .. events in most patients with CCS. Supplementary Table 3 in the
The aims of pharmacological management of CCS patients are to
.. Supplementary Data summarizes the principal major side effects,
..
reduce angina symptoms and exercise-induced ischaemia, and to pre- .. contraindications, drugdrug interactions, and precautions relating
.. to anti-ischaemic drugs. Supplementary Table 2 summarizes the main
vent cardiovascular events. ..
Immediate relief of anginal symptoms, or the prevention of symp- .. mechanisms of action of anti-ischaemic drugs.
..
toms under circumstances likely to elicit angina, is usually obtained ..
with rapidly acting formulations of nitroglycerin. Anti-ischaemic .. 3.3.1.2.1 Nitrates.

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.. Short-acting nitrates for acute effort angina
drugs—but also lifestyle changes, regular exercise training, patient ..
education, and revascularization—all play a role in minimizing or .. Sublingual and spray nitroglycerin formulations provide immediate
.. relief of effort angina. Spray nitroglycerin acts more rapidly than sub-
eradicating symptoms over the long-term (long-term prevention). ..
Prevention of cardiovascular events targets MI and death associ- .. lingual nitroglycerin.199 At the onset of angina symptoms, the patient
.. should rest in a sitting position (standing promotes syncope, and lying
ated with CAD, and focuses primarily on reducing the incidence of ..
acute thrombotic events and the development of ventricular dysfunc- .. down enhances venous return and preload) and take nitroglycerin
.. (0.30.6 mg tablet sublingually and not swallowed, or 0.4 mg spray
tion. Strategies include pharmacological and lifestyle interventions, as ..
detailed in the 2016 European Guidelines on CVD prevention in clini- .. to the tongue and not swallowed or inhaled) every 5 min until the
.. pain disappears, or a maximum of 1.2 mg has been taken within 15
cal practice.15 ..
.. min. During this time frame, if angina persists, immediate medical
.. attention is needed. Nitroglycerin can be administered for prophy-
..
3.3.1 Anti-ischaemic drugs .. laxis before physical activities known to provoke angina. Isosorbide
.. dinitrate (5 mg sublingually) has a slightly slower onset of action than
3.3.1.1 General strategy ..
Optimal treatment can be defined as the treatment that satisfactorily .. nitroglycerin due to hepatic conversion to mononitrate. The effect of
..
controls symptoms and prevents cardiac events associated with CCS, .. isosorbide dinitrate may last <_1 h if the drug is taken sublingually or
with maximal patient adherence and minimal adverse events.188191 .. persist for several hours if the drug is taken by oral ingestion.
..
However, there is no universal definition of an optimal treatment in .. Long-acting nitrates for angina prophylaxis
patients with CCS, and drug therapies must be adapted to each .. Long-acting nitrate formulations (e.g. nitroglycerin, isosorbide dini-
..
patient’s characteristics and preferences.192 Initial drug therapy usually .. trate, and isosorbide mononitrate) should be considered as second-
consists of one or two antianginal drugs, as necessary, plus drugs for .. line therapy for angina relief when initial therapy with a beta-blocker or
..
secondary prevention of CVD.193 The initial choice of antianginal .. non-dihydropyridine (non-DHP) CCB is contraindicated, poorly toler-
drug(s) depends on the expected tolerance related to the individual .. ated, or insufficient to control symptoms. In fact, there is a paucity of
..
patient’s profile and comorbidities, potential drug interactions with co- .. data comparing nitrates with beta-blockers or CCB from which to
administered therapies, the patient’s preferences after being informed .. draw firm conclusions about their relative efficacies.200 When taken
..
of potential adverse effects, and drug availability. Whether combination .. over a prolonged period, long-acting nitrates provoke tolerance with
therapy with two antianginal drugs [e.g. a beta-blocker and a calcium
.. loss of efficacy, which requires prescription of a nitrate-free or nitrate-
..
channel blocker (CCB)] is superior to monotherapy with any class of .. low interval of 1014 h.201 Nitroglycerin can be administered orally
antianginal drug in reducing clinical events remains unclear.194197
.. or transdermally through slow-release patch systems. Bioavailability of
..
Beta-adrenergic blockers or CCBs are recommended as the first .. isosorbide dinitrate depends on the interindividual variability in hepatic
choice, although no RCT to date has compared this strategy to an
.. conversion and is generally lower than the bioavailability of isosorbide
..
alternative strategy using initial prescription of other anti-ischaemic .. mononitrate (its active metabolite), which is 100% bioavailable.
drugs, or the combination of a beta-blocker and a CCB.191,195 The
.. Titration of dose is essential with all formulations to obtain the maximal
..
results of a network meta-analysis of 46 studies and 71 treatment com- .. control of symptoms at a tolerable dose. Discontinuation should be
.. tapered and not abrupt to avoid a rebound increase in angina.202 The
parisons supported the initial combination of a beta-blocker and a ..
CCB.198 The same meta-analysis suggested that several second-line .. most common side effects are hypotension, headache, and flushing.
..
add-on anti-ischaemic drugs (long-acting nitrates, ranolazine, trimetazi- .. Contraindications include hypertrophic obstructive cardiomyopathy,
dine, and, to a lesser extent, ivabradine) may prove beneficial in combi- .. severe aortic valvular stenosis, and co-administration of phosphodies-
..
nation with a beta-blocker or a CCB as first-line therapy, while no data .. terase inhibitors (e.g. sildenafil, tadalafil, or vardenafil) or riociguat.
were available for nicorandil. However, it should be noted that the ..
..
study pooled RCTs using endpoints of nitrate use, angina frequency, .. 3.3.1.2.2 Beta-blockers. The dose of beta-blockers should be adjusted
time to angina or to ST-segment depression, and total exercise time, .. to limit the heart rate to 5560 b.p.m. (beats per minute) at
..
and no study or meta-analysis has yet assessed with sufficient power .. rest.203,204 Discontinuation should be tapered and not abrupt. Beta-
the influence of combining a beta-blocker or a CCB with a second-line .. blockers can be combined with DHP CCBs to reduce DHP-induced
..
anti-ischaemic drug on morbidity or mortality events.198 Regardless of .. tachycardia, but with uncertain incremental clinical value.205208
the initial strategy, response to initial antianginal therapy should be .. Caution is warranted when a beta-blocker is combined with verapa-
..
reassessed after 24 weeks of treatment initiation. .. mil or diltiazem due to the potential for developing worsening of HF,
.. excessive bradycardia, and/or atrioventricular block. Combination of
..
3.3.1.2 Available drugs .. a beta-blocker with a nitrate attenuates the reflex tachycardia of
Anti-ischaemic drugs have proved benefits regarding symptoms asso-
.. the latter. The principal side effects of beta-blockers are fatigue,
..
ciated with myocardial ischaemia but do not prevent cardiovascular . depression, bradycardia, heart block, bronchospasm, peripheral
ESC Guidelines 27

..
vasoconstriction, postural hypotension, impotence, and masking of .. blockade.232 In the large placebo-controlled ACTION (A Coronary
hypoglycaemia symptoms. .. disease Trial Investigating Outcome with Nifedipine gastrointestinal
..
In certain patients with recent MI and those with chronic HF with .. therapeutic system) trial, addition of long-acting nifedipine [60 mg
reduced ejection fraction, beta-blockers have been associated with a .. o.d. (once a day)] to conventional treatment of angina had no effect
..
significant reduction in mortality and/or cardiovascular events,209215 .. on major cardiovascular event-free survival. Long-acting nifedipine
but the protective benefit in patients with CAD without prior MI or .. proved to be safe, and reduced the need for coronary angiography
..
HF is less well established and lacks placebo-controlled trials.216 A .. and cardiovascular interventions.232 Relative contraindications to

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retrospective analysis of 21 860 matched patients from the REACH .. nifedipine are few (severe aortic stenosis, hypertrophic obstructive
..
(REduction of Atherothrombosis for Continued Health) Registry .. cardiomyopathy, or HF), and careful combination with beta-blockade
showed no reduction in cardiovascular mortality with beta-blockers .. is usually feasible and desirable. Vasodilatory side effects include
..
in patients with either CAD with risk factors only, known prior MI, or .. headache and ankle oedema.
known CAD without MI.217 In a retrospective national registry of .. Amlodipine. The very long half-life of amlodipine and its good toler-
..
755 215 patients aged >_65 years with a history of CAD without prior .. ability make it an effective once-a-day antianginal and antihyperten-
MI or HF with reduced ejection fraction undergoing elective PCI, .. sive agent, setting it apart from drugs that are taken either twice or
..
beta-blocker use at discharge was not associated with any reduction .. three times daily. Side effects are few, mainly ankle oedema. In
in cardiovascular morbidity or mortality at 30 day and 3 year follow-
.. patients with CCS and normal BP (75% receiving a beta-blocker),
..
up.218 However, in patients with or without previous MI undergoing .. amlodipine 10 mg/day reduced coronary revascularizations and hos-
CABG, beta-blockers were associated with lower risk of long-term
.. pitalizations for angina in a 24 month trial.233 Exercise-induced ischae-
..
mortality and adverse cardiovascular events.219 Other observational .. mia is more effectively reduced by amlodipine, 5 mg titrated to
studies and meta-analyses have questioned the benefit of long-term
.. 10 mg/day, than by the beta-blocker atenolol, 50 mg/day, and their
..
(>1 year) beta-blocker therapy in patients with a previous .. combination is even better.234 However, the CCBbeta-blocker
..
MI.216,220224 This is still a matter for debate,225 and uncertainties .. combination is often underused, even in some studies reporting ‘opti-
remain on the comparative role of beta-blockers and angiotensin- .. mally treated’ stable effort angina.
..
converting enzyme (ACE) inhibitors. ..
.. 3.3.1.2.4 Ivabradine. Ivabradine has been reported to be non-inferior
..
3.3.1.2.3 Calcium channel blockers. While CCBs improve symptoms .. to atenolol or amlodipine in the treatment of angina and ischaemia in
and myocardial ischaemia, they have not been shown to reduce .. patients with CCS.235,236 Adding ivabradine 7.5 mg b.i.d. [bis in die
..
major morbidity endpoints or mortality in patients with .. (twice a day)] to atenolol therapy gave better control of heart rate
CCS.192,226228 .. and anginal symptoms.237 In 10 917 patients with limiting previous
..
.. angina enrolled in the morbiditymortality evaluation of the
NON-DIHYDROPYRIDINE AGENTS (HEART RATE-LOWERING CALCIUM CHANNEL
.. BEAUTIFUL (If Inhibitor Ivabradine in Patients With Coronary Artery
..
BLOCKERS) .. Disease and Left Ventricular Dysfunction) trial, ivabradine did not
Verapamil. Verapamil has a large range of approved indications, .. reduce the composite primary endpoint of cardiovascular death, hos-
..
including all varieties of angina (effort, vasospastic, and unstable), .. pitalization with MI, or HF.238 Also, in the SIGNIFY (Study Assessing
supraventricular tachycardias, and hypertension. Indirect evidence
.. the MorbidityMortality Benefits of the If Inhibitor Ivabradine in
..
suggests good safety but with risks of heart block, bradycardia, and .. Patients with Coronary Artery Disease) study, consisting of 19 102
HF. Compared with metoprolol, the antianginal activity was simi-
.. patients with CAD without clinical HF and a heart rate >_70 b.p.m.,
..
lar.229 Compared with atenonol in hypertension with CAD, verapa- .. there was no significant difference between the ivabradine group and
mil is associated with fewer cases of diabetes, fewer anginal
.. the placebo group in the incidence of the primary composite end-
..
attacks,230 and less psychological depression.231 Beta-blockade com- .. point of death from cardiovascular causes or non-fatal MI.239
bined with verapamil is not advised (due to risk of heart block).
.. Ivabradine was associated with an increase in the incidence of the pri-
..
Diltiazem. Diltiazem, with its low-side effect profile, has advantages .. mary endpoint among 12 049 patients with activity-limiting angina but
..
compared with verapamil in the treatment of effort angina. Like vera- .. not among those without activity-limiting angina (P=0.02 for interac-
pamil, it acts by peripheral vasodilation, relief of exercise-induced .. tion). In 2014, the European Medicines Agency issued recommenda-
..
coronary constriction, a modest negative inotropic effect, and sinus .. tions to reduce the risk of bradycardia and placed ivabradine under
node inhibition. There have been no outcome studies comparing dil- .. additional monitoring.240 In aggregate, these results support the use
..
tiazem and verapamil. .. of ivabradine as a second-line drug in patients with CCS.
In some selected patients, non-DHP agents may be combined with ..
..
beta-blockers for the treatment of angina. However, on such occa- .. 3.3.1.2.5 Nicorandil. Nicorandil is a nitrate derivative of nicotinamide,
sions they must be used under close monitoring of patients’ tolerance .. with antianginal effects similar to those of nitrates or beta-block-
..
regarding excessive bradycardia or signs of HF. Use of non-DHP .. ers.241244 Side effects include nausea, vomiting, and potentially
CCBs in patients with LV dysfunction is not advised. .. severe oral, intestinal, and mucosal ulcerations.245
..
.. In the placebo-controlled IONA (Impact Of Nicorandil in Angina)
DIHYDROPYRIDINE AGENTS .. trial (n = 5126), nicorandil significantly reduced the composite of cor-
..
Long-acting nifedipine. This agent is a powerful arterial vasodilator with .. onary heart disease (CHD) death, non-fatal MI, or unplanned hospital
few serious side effects. Long-acting nifedipine has been especially .. admission for suspected anginal symptoms in patients with CCS, but
..
well tested in hypertensive anginal patients when added to beta- . there was no effect on death from ischaemic heart disease or non-
28 ESC Guidelines

fatal MI.246 These results support the use of nicorandil as a second-


.. hospitalization without revascularization in 2651 patients with a his-
..
line drug in patients with CCS. .. tory of chronic angina and incomplete revascularization after PCI,
..
.. including those with and without PCI for a CAD indication, nor did it
3.3.1.2.6 Ranolazine. Ranolazine is a selective inhibitor of the late .. reduce angina symptoms at 1 year.250,251
..
inward sodium current. Side effects include dizziness, nausea, and .. These results support the use of ranolazine as a second-line drug
constipation. In addition, ranolazine increases QTc, and should there- .. in CCS patients with refractory angina despite commonly used anti-
..
fore be used carefully in patients with QT prolongation or on QT- .. anginal agents such as beta-blockers, CCBs, and/or long-acting

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prolonging drugs. .. nitrates. Conversely, there is a lack of evidence to support the use of
..
In a placebo-controlled trial of 6560 patients with non-ST-segment .. ranolazine in patients with CCS following PCI with incomplete
elevation ACS, the addition of ranolazine to standard treatment did .. revascularization.
..
not prove effective in reducing the primary efficacy endpoint of cardi- ..
ovascular death, MI, or recurrent ischaemia.247 However, in the rela- .. 3.3.1.2.7 Trimetazidine. Trimetazidine appears to have a haemodynami-
..
tively large subgroup of patients with chronic angina (n = 3565), .. cally neutral side effect profile.252 Trimetazidine (35 mg b.i.d.) added to
significant reductions in recurrent ischaemia, worsening angina, and .. beta-blockade (atenolol) improved effort-induced myocardial ischae-
..
intensification of antianginal therapy were observed.248 In another .. mia, as reviewed by the European Medicines Agency in June
placebo-controlled trial of patients with diabetes and CAD receiving
.. 2012.253,254 It remains contraindicated in Parkinson’s disease and
..
one or two antianginal drugs, ranolazine reduced angina and sublin- .. motion disorders, such as tremor (shaking), muscle rigidity, walking dis-
gual nitroglycerin use with good tolerability.249 In the RIVER-PCI
.. orders, and restless leg syndrome. A 2014 meta-analysis of 13, mostly
..
(Ranolazine for Incomplete Vessel Revascularization Post- .. Chinese, studies consisting of 1628 patients showed that treatment
Percutaneous Coronary Intervention) trial, ranolazine did not reduce
.. with trimetazidine on top of other antianginal drugs was associated
..
the composite of ischaemia-driven revascularization or .. with a smaller weekly mean number of angina attacks, lower weekly
.

©ESC 2019

Figure 8 Suggested stepwise strategy for long-term anti-ischaemic drug therapy in patients with chronic coronary syndromes and specific baseline char-
acteristics. The proposed stepwise approach must be adapted to each patient’s characteristics and preferences. BB = beta-blocker; bpm = beats per
minute; CCB = [any class of] calcium channel blocker; DHP-CCB = dihydropyridine calcium channel blocker; HF = heart failure; LAN = long-acting nitrate;
LV = left ventricular; NDHP-CCB = non-dihydropyridine calcium channel blocker.
a
Combination of a BB with a DHP-CCB should be considered as first step; combination of a BB or a CCB with a second-line drug may be considered as a
first step; bThe combination of BB and non-DHP-CCB should initially use low doses of each drug under close monitoring of tolerance, particularly heart
rate and blood pressure; cLow dose of ivabradine (2.5 mg) should first be tested, and should not be combined with non-DHP-CCB; dAddition of ivabradine
may only be considered if heart rate is >80 bpm and tolerance is good at step 2.
ESC Guidelines 29

..
nitroglycerin use, longer time to 1 mm ST-segment depression, .. characteristics and preferences, and does not necessarily follow the
higher total work, and longer exercise duration at peak exercise than .. steps indicated in the figure.
..
treatment with the other antianginal drugs for stable angina pecto- ..
ris.255 These results support the use of trimetazidine as a second-line .. 3.3.1.3 Patients with low blood pressure
..
drug in patients with CCS whose symptoms are not adequately con- .. In patients with low BP, it is recommended to start antianginal drugs at
trolled by, or who are intolerant to, other medicines for angina
.. very low doses, with preferential use of drugs with no or limited effects
..
pectoris. .. on BP. A low-dose beta-blocker or low-dose non-DHP-CCB can be

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.. tested first under close monitoring of tolerance. Ivabradine (in patients
..
3.3.1.2.8 Allopurinol. In 2010, a randomized crossover study of 65 .. with sinus rhythm), ranolazine, or trimetazidine can also be used.
patients with CAD showed that allopurinol 600 mg/day increased
..
..
times to ST-segment depression and to angina.256 An observational .. 3.3.1.4 Patients with low heart rate
study of 29 298 episodes of incident allopurinol use found an associa-
.. Increased heart rate correlates linearly with cardiovascular
..
tion of allopurinol use with a reduction in the risk of incident MI in .. events, and the benefit of heart-rate reduction as a treatment
..
the elderly, particularly when used for >2 years.257 However, the .. goal in subgroups of CCS patients has been demonstrated using
role of allopurinol in reducing clinical events in CVD remains .. various drugs.203,259261 However, in patients with baseline bra-
..
unclear.258 .. dycardia (e.g. heart rate <60 b.p.m.) heart rate-lowering drugs
A stepwise strategy for anti-ischaemic drug therapy in CCS is pro- .. (beta-blockers, ivabradine, and heart-rate lowering CCBs) should
..
posed, depending on some baseline patient characteristics (Figure 8). .. be avoided or used with caution, and—if needed—started at very
Incomplete responses or poor tolerance at each step justify moving .. low doses. Antianginal drugs without heart rate-lowering effects
..
to the next step. The strategy must be adapted to each patient’s .. should preferably be given.
.

Recommendations on anti-ischaemic drugs in patients with chronic coronary syndromes

Recommendations Classa Levelb

General considerations
Medical treatment of symptomatic patients requires one or more drug(s) for angina/ischaemia relief in association with
I C
drug(s) for event prevention.
It is recommended that patients are educated about the disease, risk factors, and treatment strategy. I C
Timely review of the patient’s response to medical therapies (e.g. 24 weeks after drug initiation) is recommended.262 I C
c
Angina/ischaemia relief
Short-acting nitrates are recommended for immediate relief of effort angina.195,263 I B
First-line treatment is indicated with beta-blockers and/or CCBs to control heart rate and symptoms.205,264 I A
If angina symptoms are not successfully controlled on a beta-blocker or a CCB, the combination of a beta-blocker with a
IIa C
DHP-CCB should be considered.
Initial first-line treatment with the combination of a beta-blocker and a DHP-CCB should be considered.194,198,264 IIa B
Long-acting nitrates should be considered as a second-line treatment option when initial therapy with a beta-blocker and/or a
IIa B
non-DHP-CCB is contraindicated, poorly tolerated, or inadequate to control angina symptoms.200,201
When long-acting nitrates are prescribed, a nitrate-free or low-nitrate interval should be considered to reduce tolerance.201 IIa B
241244,246 248,265 235237 252,255
Nicorandil, ranolazine, ivabradine, or trimetazidine should be considered as a second-line treat-
ment to reduce angina frequency and improve exercise tolerance in subjects who cannot tolerate, have contraindications to, IIa B
or whose symptoms are not adequately controlled by beta-blockers, CCBs, and long-acting nitrates.
In subjects with baseline low heart rate and low BP, ranolazine or trimetazidine may be considered as a first-line drug to
IIb C
reduce angina frequency and improve exercise tolerance.
In selected patients, the combination of a beta-blocker or a CCB with second-line drugs (ranolazine, nicorandil, ivabradine,
IIb B
and trimetazidine) may be considered for first-line treatment according to heart rate, BP, and tolerance.198
Nitrates are not recommended in patients with hypertrophic obstructive cardiomyopathy266 or co-administration of phos-
III B
phodiesterase inhibitors.267

BP = blood pressure; CCB = calcium channel blocker; CCS = chronic coronary syndromes; DHP-CCB = dihydropyridine calcium channel blocker.
a
Class of recommendation.
b
Level of evidence.
c
No demonstration of benefit on prognosis.
30 ESC Guidelines

..
3.3.2 Event prevention .. monotherapy in patients with previous PCI.281 Ticagrelor, with a 180
3.3.2.1 Antiplatelet drugs .. mg loading dose followed by 90 mg b.i.d., achieved greater reduction
..
Platelet activation and aggregation is the driver for symptomatic cor- .. of ischaemic events compared with clopidogrel in aspirin-treated
onary thrombosis, forming the basis for the use of antiplatelet drugs .. ACS patients, regardless of revascularization strategy, at the expense
..
in patients with CCS in view of a favourable balance between the pre- .. of more non-fatal bleeding.282,283 Ticagrelor at doses of 90 or 60 mg
vention of ischaemic events and increased risk of bleeding. Dual anti- .. b.i.d. reduced the 3 year combined incidence of MI, stroke, or cardio-
..
platelet therapy (DAPT) with aspirin and an oral P2Y12 inhibitor is .. vascular death compared with placebo in stable aspirin-treated

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the mainstay of antithrombotic therapy after MI and/or PCI. .. patients with a history of MI 13 years previously.284 Both ticagrelor
..
.. doses increased non-fatal but not fatal bleeding. The equivalent effica-
3.3.2.1.1 Low-dose aspirin. Aspirin acts via irreversible inhibition of pla- .. cies and similar safeties of the two ticagrelor doses were explained
..
telet cyclooxygenase-1 and thus thromboxane production, which is .. by similar levels of platelet inhibition.285 Ticagrelor may cause dysp-
normally complete with chronic dosing >_75 mg/day. The gastrointes- .. noea, which is often transient and most often mild and tolerable, but
..
tinal side effects of aspirin increase at higher doses, and current evi- .. occasionally necessitates switching to a thienopyridine.286,287
dence supports a daily dose of 75100 mg for the prevention of .. Ticagrelor is metabolized via CYP3A, and consequently should not be
..
ischaemic events in CAD patients with or without a history of .. used with strong CYP3A inhibitors or inducers.
MI.268270 As cyclooxygenase-1 inhibition by aspirin is consistent and
.. The optimal timing of initiation of P2Y12 inhibition before coronary
..
predictable in adherent patients, no platelet function testing is .. angiography and possible PCI in patients with CCS is uncertain, but
required to monitor individual response.271 Although other non-
.. increasing use of a radial artery approach and clinical experience has
..
selective non-steroidal anti-inflammatory drugs, such as ibuprofen, .. allowed consideration of clopidogrel pre-treatment in patients who
reversibly inhibit cyclooxygenase-1, their adverse effects on cardio-
.. have a high chance of requiring PCI.284 Limited pharmacodynamic
..
vascular risk indicate that they cannot be recommended as an alter- .. studies support the unlicensed use of prasugrel or ticagrelor in stable
native treatment in patients with aspirin intolerance.272
..
.. patients undergoing elective PCI who have a high risk of stent throm-
.. bosis, but the safety/efficacy balance of this approach, compared with
..
3.3.2.1.2 Oral P2Y12 inhibitors. P2Y12 inhibitors block the platelet P2Y12 .. clopidogrel, has not been established.288
receptor, which plays a key role in platelet activation and the amplifi- ..
..
cation of arterial thrombus formation. Clopidogrel and prasugrel are .. 3.3.2.1.3 Duration of dual antiplatelet therapy. After PCI for stable
thienopyridine prodrugs that irreversibly block P2Y12 via active .. angina, 6 months of DAPT achieves the optimum balance of efficacy
..
metabolites. Ticagrelor is a reversibly-binding P2Y12 inhibitor that .. and safety in most patients.284 Premature discontinuation of a P2Y12
does not require metabolic activation. .. inhibitor is associated with an increased risk of stent thrombosis and
..
The CAPRIE (Clopidogrel vs. Aspirin in Patients at Risk of .. is discouraged.284 However, a shorter duration of DAPT may be con-
Ischaemic Events) trial showed an overall slight benefit of clopidogrel .. sidered in those at high risk of life-threatening bleeding in view of the
..
compared with aspirin, with a similar safety profile, in preventing car- .. very low risk of stent thrombosis after 13 months.284 On the basis
diovascular events in patients with previous MI, previous stroke, or .. of phase III trials, 12 months is the recommended default duration of
..
PAD.273 Subgroup analysis suggested greater benefit of clopidogrel in .. DAPT after ACS, but shorter duration may again be considered in
patients with PAD. Despite its lesser antiplatelet efficacy, clopidogrel .. those at high bleeding risk.11,284 A DAPT study of patients undergoing
..
demonstrated equivalent efficacy to ticagrelor in patients with .. PCI showed that extended therapy beyond 12 months with clopidog-
PAD.274 Clopidogrel is limited by variable pharmacodynamic effects
.. rel or prasugrel reduced ischaemic events and stent thrombosis, but
..
related to variable efficiency of conversion to its active metabolite, .. without mortality benefit and at the expense of increased bleeding.289
partly associated with loss-of-function variants in the CYP2C19 gene,
.. A greater benefit of extended clopidogrel or prasugrel was seen in
..
leading to a lack of efficacy in some patients.271 Drugs that inhibit .. patients who were treated for MI.290
CYP2C19, such as omeprazole, may reduce the response to
.. The PEGASUS-TIMI 54 (Prevention of Cardiovascular Events in
..
clopidogrel.275 .. Patients with Prior Heart Attack Using Ticagrelor Compared to
Prasugrel has more rapid, more predictable, and, on average,
..
.. Placebo on a Background of AspirinThrombolysis In Myocardial
greater antiplatelet effect compared with clopidogrel, and is not sus- .. Infarction 54) trial demonstrated that long-term therapy with ticagre-
..
ceptible to drug interactions or the effect of CYP2C19 loss-of- .. lor 60 or 90 mg b.i.d., commenced in stable patients >_1 year after MI,
function variants. Prasugrel has greater efficacy than clopidogrel in .. reduced ischaemic events at the expense of more non-fatal bleed-
..
aspirin-treated patients with ACS undergoing PCI, but not in medically- .. ing.284 The 60 mg dose appeared better tolerated and is approved in
managed patients with ACS.276,277 Prasugrel has been associated with .. many countries for this indication. Subgroup analysis demonstrated
..
more non-fatal and fatal bleeding events than clopidogrel in ACS .. greater absolute reductions in ischaemic events with long-term tica-
patients undergoing PCI, leading to apparent harm in those with a his- .. grelor (60 mg b.i.d.) in higher-risk post-MI patients with diabetes,
..
tory of ischaemic stroke, and a lack of apparent benefit in those aged .. PAD, or multivessel CAD.291293
>75 years or with body weight <60 kg.276 ..
..
Ticagrelor has the most predictable and consistently high level of .. 3.3.2.2 Anticoagulant drugs in sinus rhythm
P2Y12 inhibition during maintenance therapy in adherent patients,219 .. Anticoagulant drugs inhibit the action and/or formation of thrombin,
..
and also has more rapid onset, as well as more rapid and predictable .. which plays a pivotal role in both coagulation and platelet activation.
offset of action compared with clopidogrel.278280 Ticagrelor as .. Consequently, anticoagulants have been shown to reduce the risk of
..
monotherapy appears to have similar efficacy and safety to aspirin . arterial thrombotic events. The superior efficacy and safety of DAPT,
ESC Guidelines 31

..
compared with aspirin and anticoagulation, in preventing stent .. particular NOAC regimen.300 Radial artery access is preferred along
thrombosis led to the latter strategy being abandoned in favour of .. with intraprocedural unfractionated heparin either at a standard dose
..
DAPT following PCI.284 Combination of antiplatelet therapy and .. (70100 U/kg) or, in those with uninterrupted VKA, at a lower dose
standard anticoagulant doses of warfarin or apixaban for secondary .. of 3050 U/kg.300 Pre-treatment with aspirin 75100 mg daily is rec-
..
prevention after ACS was associated with an unfavourable balance of .. ommended, and clopidogrel (300600 mg loading dose if not on
efficacy and bleeding.294,295 However, recently reported studies have .. long-term maintenance therapy) is recommended in preference to
..
renewed interest in combining lower anticoagulant doses with anti- .. prasugrel or ticagrelor.300 VKA-treated patients receiving aspirin and

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platelet therapy. .. clopidogrel post-PCI should have a target international normalized
..
.. ratio in the range of 2.02.5, aiming for high time in therapeutic range
3.3.2.2.1 Low-dose rivaroxaban. Rivaroxaban is a factor Xa inhibitor
.. (>70%).300 Subsequent to post-PCI trials of different antithrombotic
..
that has been studied at a low dose of 2.5 mg b.i.d. in several popula- .. regimens considered in previous Guidelines,88,284 the AUGUSTUS
tions of patients in sinus rhythm, this dose being one-quarter of the .. trial (An Open-label, 2  2 Factorial, Randomized Controlled,
..
standard dose used for anticoagulation in patients with AF. .. Clinical Trial to Evaluate the Safety of Apixaban vs. Vitamin K
Rivaroxaban 2.5 mg b.i.d., compared with placebo, reduced the com-
.. Antagonist and Aspirin vs. Aspirin Placebo in Patients With Atrial
..
posite of MI, stroke, or cardiovascular death in stabilized patients .. Fibrillation and Acute Coronary Syndrome or Percutaneous
treated predominantly with aspirin and clopidogrel following ACS, at
.. Coronary Intervention) showed, firstly, that apixaban 5 mg b.i.d. (i.e.
..
the expense of increased bleeding but with evidence of a reduction in .. the licensed dose for thromboprophylaxis in AF) was associated with
cardiovascular death.296 Subsequently, in the COMPASS
.. significantly less major or clinically relevant non-major bleeding than
..
(Cardiovascular Outcomes for People Using Anticoagulation .. VKA; and, secondly, that aspirin, compared with placebo, was associ-
Strategies) trial, the same regimen in combination with aspirin was
.. ated with significantly more bleeding, with the safest combination
..
compared with aspirin alone, as well as rivaroxaban 5 mg b.i.d. alone, .. being apixaban and placebo in addition to P2Y12 inhibitor (predomi-
..
in patients with CCS or PAD, and showed reduced ischaemic events .. nantly clopidogrel).301 However, there were numerically, but not
at the expense of increased risk of predominantly non-fatal bleed- .. statistically significantly, more stent thrombosis events with placebo
..
ing.297 Of note, the pre-specified significance thresholds for cardio- .. than with aspirin, and the trial was not powered to assess differences
vascular mortality and all-cause mortality were not met. Greater .. in these events between groups.301 Consequently, when concerns
..
absolute risk reductions were seen in higher-risk patients with diabe- .. about thrombotic risk prevail over concerns about bleeding risk, >_1
tes, PAD, or moderate chronic kidney disease (CKD), as well as cur- .. month of triple therapy [oral anticoagulant (OAC), aspirin, and clopi-
..
rent smokers. In GEMINI-ACS (A Study to Compare the Safety of .. dogrel] is recommended to cover the period when the risk of stent
Rivaroxaban Versus Acetylsalicylic Acid in Addition to Either .. thrombosis is presumed to exceed the risk of bleeding.300,301 There
..
Clopidogrel or Ticagrelor Therapy in Participants With Acute .. is currently limited evidence to support the use of OACs with tica-
Coronary Syndrome), rivaroxaban 2.5 mg b.i.d. was compared with .. grelor or prasugrel as dual therapy after PCI as an alternative to triple
..
aspirin in patients treated with a P2Y12 inhibitor who were stable fol- .. therapy.300,301
lowing PCI. The results suggested similar safety of rivaroxaban to ..
..
aspirin in this setting, but larger studies are required to substantiate .. 3.3.2.3.2 Long-term combination therapy in patients with atrial fibrillation
this finding.298 In addition, the safety of performing PCI without
.. or another indication for anticoagulation. OAC monotherapy is gener-
..
aspirin pre-treatment is unknown. .. ally recommended 612 months after PCI in patients with AF, as
.. there is a lack of specific data supporting long-term treatment with an
..
3.3.2.3 Anticoagulant drugs in atrial fibrillation .. OAC and a single antiplatelet agent; however, in highly selected cases
Anticoagulant therapy is recommended in patients with AF and CCS
.. with high ischaemic risk, dual therapy with an OAC and aspirin or clo-
..
for reduction of ischaemic stroke and other ischaemic events. .. pidogrel may be considered.300
Anticoagulants in AF patients have demonstrated superiority over
..
..
aspirin monotherapy or clopidogrel-based DAPT for stroke preven- .. 3.3.2.4 Proton pump inhibitors
..
tion, and are therefore recommended for this indication.299 When .. Proton pump inhibitors reduce the risk of gastrointestinal bleeding in
oral anticoagulation is initiated in a patient with AF who is eligible for .. patients treated with antiplatelet drugs and may be a useful adjunctive
.. treatment for improving safety.275 Long-term proton pump inhibitor
a non-vitamin K antagonist oral anticoagulant (NOAC; apixaban, ..
dabigatran, edoxaban, or rivaroxaban), a NOAC is recommended in .. use is associated with hypomagnesaemia, but the role of monitoring
..
preference to a vitamin K antagonist (VKA).299 .. serum magnesium levels is uncertain. Proton pump inhibitors that
.. inhibit CYP2C19, particularly omeprazole and esomeprazole, may
..
3.3.2.3.1 Combination anticoagulant and antiplatelet therapy following per- .. reduce the pharmacodynamic response to clopidogrel. Although this
cutaneous coronary intervention for patients with atrial fibrillation or .. has not been shown to affect the risk of ischaemic events or stent
another indication for oral anticoagulation. No studies to date have spe-
..
.. thrombosis, co-administration of omeprazole or esomeprazole with
cifically focused on CCS patients with AF undergoing PCI and clinical .. clopidogrel is generally not recommended.
..
decisions must be based on clinical trials that have included a large ..
proportion of patients with ACS. For peri-procedural management, .. 3.3.2.5 Cardiac surgery and antithrombotic therapy
..
it is recommended that interruption of VKA is avoided, if feasible, .. Aspirin should normally be continued in patients with CCS under-
whereas it is recommended that NOAC therapy is stopped for .. going elective cardiac surgery, and other antithrombotic drugs
..
1248 h before elective PCI, depending on renal function and the . stopped at intervals according to their duration of action and
32 ESC Guidelines

..
indication (prasugrel stopped >_7 days before; clopidogrel >_5 days .. completed. Usually, this will mean delaying surgery until 6 months
before; ticagrelor >_3 days before; and rivaroxaban, apixaban, edoxa- .. after PCI, but surgery between 36 months may be considered by
..
ban, and dabigatran 12 days before depending on dose and renal .. a multidisciplinary team, including an interventional cardiologist, if
function). Reloading of aspirin after CABG surgery may improve graft .. clinically indicated. In most types of surgery, aspirin should be con-
..
patency.302 The role of DAPT or dual therapy with aspirin and rivar- .. tinued as the benefit outweighs the bleeding risk, but this may not
oxaban after CABG surgery is uncertain as large prospective studies .. be appropriate for procedures associated with extremely high
..
are lacking. However, RCT results have suggested higher graft .. bleeding risk (intracranial procedures, transurethral prostatectomy,

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patency rates with DAPT compared with aspirin .. intraocular procedures, etc.).284 The COMPASS study included
..
monotherapy.284,303,304 .. CCS patients with a history of peripheral revascularization proce-
.. dures, and demonstrated benefits of aspirin and rivaroxaban 2.5 mg
..
3.3.2.6 Non-cardiac surgery and antithrombotic therapy .. b.i.d. compared with aspirin alone, including reductions in major
Non-cardiac surgery is associated with an increased risk of MI.
.. adverse limb events and mortality, suggesting the need to risk-
..
Following PCI, whenever possible, it is recommended to postpone .. stratify patients after non-cardiac vascular surgery for atheroscler-
elective surgery until the recommended course of DAPT has been
.. otic disease.305,306
.

Recommendations for event prevention I

Recommendations Classa Levelb

Antithrombotic therapy in patients with CCS and in sinus rhythm


Aspirin 75100 mg daily is recommended in patients with a previous MI or revascularization.270 I A
273
Clopidogrel 75 mg daily is recommended as an alternative to aspirin in patients with aspirin intolerance. I B
Clopidogrel 75 mg daily may be considered in preference to aspirin in symptomatic or asymptomatic patients, with either
IIb B
PAD or a history of ischaemic stroke or transient ischaemic attack.273
Aspirin 75100 mg daily may be considered in patients without a history of MI or revascularization, but with definitive evi-
IIb C
dence of CAD on imaging.
Adding a second antithrombotic drug to aspirin for long-term secondary prevention should be considered in patients with
IIa A
a high risk of ischaemic eventsc and without high bleeding riskd (see Table 9 for options).289,296,297,307
Adding a second antithrombotic drug to aspirin for long-term secondary prevention may be considered in patients with at
least a moderately increased risk of ischaemic eventse and without high bleeding riskd (see Table 9 for IIb A
options).289,296,297,307
Antithrombotic therapy post-PCI in patients with CCS and in sinus rhythm
Aspirin 75100 mg daily is recommended following stenting.284 I A
Clopidogrel 75 mg daily following appropriate loading (e.g. 600 mg or >5 days of maintenance therapy) is recommended,
in addition to aspirin, for 6 months following coronary stenting, irrespective of stent type, unless a shorter duration (13 I A
months) is indicated due to risk or the occurrence of life-threatening bleeding.284
Clopidogrel 75 mg daily following appropriate loading (e.g. 600 mg or >5 days of maintenance therapy) should be consid-
IIa A
ered for 3 months in patients with a higher risk of life-threatening bleeding.284
Clopidogrel 75 mg daily following appropriate loading (e.g. 600 mg or >5 days of maintenance therapy) may be considered
IIb C
for 1 month in patients with very high risk of life-threatening bleeding.284
Prasugrel or ticagrelor may be considered, at least as initial therapy, in specific high-risk situations of elective stenting (e.g.
suboptimal stent deployment or other procedural characteristics associated with high risk of stent thrombosis, complex IIb C
left main stem, or multivessel stenting) or if DAPT cannot be used because of aspirin intolerance.
Antithrombotic therapy in patients with CCS and AF
When oral anticoagulation is initiated in a patient with AF who is eligible for a NOAC,f a NOAC is recommended in pref-
I A
erence to a VKA.299301,308311
Long-term OAC therapy (NOAC or VKA with time in therapeutic range >70%) is recommended in patients with AF and
I A
a CHA2DS2-VASc scoreg >_2 in males and >_3 in females.299
Continued
ESC Guidelines 33

Long-term OAC therapy (NOAC or VKA with time in therapeutic range >70%) should be considered in patients with AF
IIa B
and a CHA2DS2-VASc scoreg of 1 in males and 2 in females.299
Aspirin 75100 mg daily (or clopidogrel 75 mg daily) may be considered in addition to long-term OAC therapy in patients
IIb B
with AF, history of MI, and at high risk of recurrent ischaemic eventsc who do not have a high bleeding risk.d 295,297,299
Antithrombotic therapy in post-PCI patients with AF or another indication for an OAC
It is recommended that peri-procedural aspirin and clopidogrel are administered to patients undergoing coronary stent
I C

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implantation.
In patients who are eligible for a NOAC, it is recommended that a NOAC (apixaban 5 mg b.i.d., dabigatran 150 mg b.i.d.,
edoxaban 60 mg o.d., or rivaroxaban 20 mg o.d.)f is used in preference to a VKA in combination with antiplatelet I A
therapy.300,301,308,310,311
When rivaroxaban is used and concerns about high bleeding riskd prevail over concerns about stent thrombosish or
ischaemic stroke,g rivaroxaban 15 mg o.d. should be considered in preference to rivaroxaban 20 mg o.d. for the duration IIa B
of concomitant single or dual antiplatelet therapy.300,301,308,310
When dabigatran is used and concerns about high bleeding riskd prevail over concerns about stent thrombosish or ischae-
mic stroke,g dabigatran 110 mg b.i.d. should be considered in preference to dabigatran 150 mg b.i.d. for the duration of IIa B
concomitant single or dual antiplatelet therapy.300,301,308
After uncomplicated PCI, early cessation (<_1 week) of aspirin and continuation of dual therapy with an OAC and clopi-
dogrel should be considered if the risk of stent thrombosish is low, or if concerns about bleeding risk prevail over con- IIa B
cerns about the risk of stent thrombosis,h irrespective of the type of stent used.301,308310
Triple therapy with aspirin, clopidogrel, and an OAC for >_1 month should be considered when the risk of stent throm-
bosish outweighs the bleeding risk, with the total duration (<_6 months) decided according to assessment of these risks IIa C
and clearly specified at hospital discharge.
In patients with an indication for a VKA in combination with aspirin and/or clopidogrel, the dose intensity of the VKA
should be carefully regulated with a target international normalized ratio in the range of 2.02.5 and with time in thera- IIa B
300,301,308310
peutic range >70%.
Dual therapy with an OAC and either ticagrelor or prasugrel may be considered as an alternative to triple therapy with
an OAC, aspirin, and clopidogrel in patients with a moderate or high risk of stent thrombosis,h irrespective of the type of IIb C
stent used.
The use of ticagrelor or prasugrel is not recommended as part of triple antithrombotic therapy with aspirin and an OAC. III C
Use of proton pump inhibitors
Concomitant use of a proton pump inhibitor is recommended in patients receiving aspirin monotherapy, DAPT, or OAC
I A
monotherapy who are at high risk of gastrointestinal bleeding.284

AF = atrial fibrillation; b.i.d. = bis in die (twice a day); CAD = coronary artery disease; CCS = chronic coronary syndromes; CHA2DS2-VASc = Cardiac failure, Hypertension,
Age >_75 [Doubled], Diabetes, Stroke [Doubled]  Vascular disease, Age 6574 and Sex category [Female]; CKD = chronic kidney disease; DAPT = dual antiplatelet therapy;
eGFR = estimated glomerular filtration rate; HF = heart failure; MI = myocardial infarction; NOAC = non-vitamin K antagonist oral anticoagulant; OAC = oral anticoagulant;
o.d. = omni die (once a day); PAD = peripheral artery disease; PCI = percutaneous coronary intervention; VKA = vitamin K antagonist.
a
Class of recommendation.
b
Level of evidence.
c
Diffuse multivessel CAD with at least one of the following: diabetes mellitus requiring medication, recurrent MI, PAD, or CKD with eGFR 1559 mL/min/1.73 m2.
d
Prior history of intracerebral haemorrhage or ischaemic stroke, history of other intracranial pathology, recent gastrointestinal bleeding or anaemia due to possible gastrointes-
tinal blood loss, other gastrointestinal pathology associated with increased bleeding risk, liver failure, bleeding diathesis or coagulopathy, extreme old age or frailty, or renal fail-
ure requiring dialysis or with eGFR <15 mL/min/1.73 m2.
e
At least one of the following: multivessel/diffuse CAD, diabetes mellitus requiring medication, recurrent MI, PAD, HF, or CKD with eGFR 1559 mL/min/1.73 m2.
f
See summary of product characteristics for reduced doses or contraindications for each NOAC in patients with CKD, body weight <60 kg, age >7580 years, and/or drug
interactions.
g
Congestive HF, hypertension, age >_75 years (2 points), diabetes, prior stroke/transient ischaemic attack/embolus (2 points), vascular disease (CAD on imaging or angiogra-
phy,312 prior MI, PAD, or aortic plaque), age 6574 years, and female sex.
h
Risk of stent thrombosis encompasses (i) the risk of thrombosis occurring and (ii) the risk of death should stent thrombosis occur, both of which relate to anatomical, proce-
dural, and clinical characteristics. Risk factors for CCS patients include stenting of left main stem, proximal LAD, or last remaining patent artery; suboptimal stent deployment;
stent length >60 mm; diabetes mellitus; CKD; bifurcation with two stents implanted; treatment of chronic total occlusion; and previous stent thrombosis on adequate antith-
rombotic therapy.
34 ESC Guidelines

Table 9 Treatment options for dual antithrombotic therapy in combination with aspirin 75 2 100 mg daily in patients
who have a higha or moderateb risk of ischaemic events, and do not have a high bleeding riskc
Drug option Dose Indication Additional cautions References
289,290
Clopidogrel 75 mg o.d. Post-MI in patients who have tolerated DAPT for 1 year
289,290,313
Prasugrel 10 mg o.d or 5 mg o.d.; if body Post-PCI for MI in patients who have tolerated Age >75 years
weight <60 kg or age >75 years DAPT for 1 year

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297
Rivaroxaban 2.5 mg b.i.d. Post-MI >1 year or multivessel CAD Creatinine clearance
15 - 29 mL/min
291293,307,314
Ticagrelor 60 mg b.i.d. Post-MI in patients who have tolerated DAPT for 1 year
Treatment options are presented in alphabetical order.
b.i.d. = bis in die (twice a day); CAD = coronary artery disease; CKD = chronic kidney disease; DAPT = dual antiplatelet therapy; eGFR = estimated glomerular filtration rate;
HF = heart failure; MI = myocardial infarction; o.d. = omni die (once a day); PAD = peripheral artery disease; PCI = percutaneous coronary intervention.
a
High risk of ischaemic events is defined as diffuse multivessel CAD with at least one of the following: diabetes mellitus requiring medication, recurrent MI, PAD, or CKD with
eGFR 15 - 59 mL/min/1.73 m2.
b
Moderately increased risk of ischaemic events is defined as at least one of the following: multivessel/diffuse CAD, diabetes mellitus requiring medication, recurrent MI, PAD,
HF, or CKD with eGFR 15 - 59 mL/min/1.73 m2.
c
High bleeding risk is defined as history of intracerebral haemorrhage or ischaemic stroke, history of other intracranial pathology, recent gastrointestinal bleeding or anaemia
due to possible gastrointestinal blood loss, other gastrointestinal pathology associated with increased bleeding risk, liver failure, bleeding diathesis or coagulopathy, extreme old
age or frailty, or renal failure requiring dialysis or with eGFR <15 mL/min/1.73 m2.

3.3.3 Statins and other lipid-lowering drugs .. 3.3.4 Reninangiotensinaldosterone system blockers
..
Dyslipidaemia should be managed according to lipid guidelines with .. ACE inhibitors can reduce mortality, MI, stroke, and HF among patients
pharmacological and lifestyle intervention.315 Patients with estab-
.. with LV dysfunction,328330 previous vascular disease,331333 and high-
..
lished CAD are regarded as being at very high risk for cardiovascular .. risk diabetes.334 It is recommended that ACE inhibitors [or angiotensin
events and statin treatment must be considered, irrespective of LDL-
.. receptor blockers (ARBs) in cases of intolerance] be considered for the
..
C levels. The goal of treatment is to lower LDL-C by at least 50% .. treatment of patients with CCS with coexisting hypertension, LVEF
from baseline and to <1.4 mmol/L (<55 mg/dL) although a lower tar-
.. <_40%, diabetes, or CKD, unless contraindicated (e.g. severe renal
..
get LDL-C of <1.0 mmol/L (<40 mg/dL) may be considered in .. impairment, hyperkalaemia, etc.). However, not all trials have demon-
patients who have experience a second vascular event within 2 years,
.. strated that ACE inhibitors reduce all-cause death, cardiovascular death,
..
not necessarily of the same type as the first event, whilst taking maxi- .. non-fatal MI, stroke, or HF in patients with atherosclerosis and without
..
mally tolerated statin-based therapy. When this level cannot be .. impaired LV function.331,332,335 A meta-analysis, including 24 trials and
achieved, the addition of ezetimibe has been demonstrated to .. 61 961 patients, documented that, in CCS patients without HF,
..
decrease cholesterol and cardiovascular events in post-ACS patients, .. renin-angiotensin system (RAS) inhibitors reduced cardiovascular
and in those with diabetes,316 with no further effect on mortality.317 .. events and death only when compared with placebo, but not when
..
In addition to exercise, diet, and weight control, which should be rec- .. compared with active controls.336 Hence, ACE inhibitor therapy in
ommended to all patients, dietary supplements including phytosterols .. CCS patients without HF or high cardiovascular risk is not generally rec-
..
may lower LDL-C to a lesser extent, but have not been shown to .. ommended, unless required to meet BP targets.
improve clinical outcomes.318 These are also used in patients with .. Neprilysin is an endogenous enzyme that degrades vasoactive pepti-
..
intolerance to statins who constitute a group at higher risk for cardio- .. des such as bradykinin and natriuretic peptides. Pharmacological inhibi-
vascular events.319 Trials published since 2015 have demonstrated .. tion of neprilysin raises the levels of these peptides, enhancing diuresis,
..
that proprotein convertase subtilisin-kexin type 9 (PCSK9) inhibitors .. natriuresis, myocardial relaxation, and antiremodelling, and reducing
(evolocumab320 and alirocumab321323) are very effective at reducing .. renin and aldosterone secretion. The first in class is LCZ696, which
..
cholesterol, lowering LDL-C in a stable fashion to <_1.3 mmol/L (50 .. combines valsartan and sacubitril (neprilysin inhibitor) in a single pill. In
mg/dL). In outcomes trials, these agents have demonstrated a reduc- .. patients with HF (LVEF <_35%) who remain symptomatic despite opti-
..
tion of cardiovascular and mainly ischaemic events, with little or no .. mal treatment with an ACE inhibitor, a beta-blocker, and a mineralo-
impact on mortality.324 Very low levels of cholesterol are well toler-
.. corticoid receptor antagonist (MRA), sacubitril/valsartan is
..
ated and associated with fewer events,325 but the high cost of PCSK9 .. recommended as a replacement for an ACE inhibitor to further reduce
inhibitors, unaffordable for many health systems,326 and their
.. the risk of HF hospitalization and death in ambulatory patients.337
..
unknown long-term safety have limited their use to date. Low- .. Aldosterone blockade with spironolactone or eplerenone is rec-
density lipoprotein apheresis and new therapies such as mipomersen
.. ommended for use in post-MI patients who are already receiving
..
and lomitapide need further research. .. therapeutic doses of an ACE inhibitor and a beta-blocker, have an
For patients undergoing PCI, high-dose atorvastatin has been
.. LVEF <_35%, and have either diabetes or HF.338,339 Caution should be
..
shown to reduce the frequency of peri-procedural events in both .. exercised when MRAs are used in patients with impaired renal func-
..
statin-naı̈ve patients and patients receiving chronic statin .. tion [estimated GFR (eGFR) <45 mL/min/1.73 m2] and in those with
therapy.327 .. serum potassium levels >_5.0 mmol/L.340
..
.
ESC Guidelines 35

Recommendations for event prevention II

Lipid-lowering drugs Classa Levelb

Statins are recommended in all patients with CCS.c 341,342 I A


c
If a patient’s goal is not achieved with the maximum tolerated dose of statin, combination with ezetimibe is
I B
recommended.317,320

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For patients at very high risk who do not achieve their goalc on a maximum tolerated dose of statin and ezetimibe,
I A
combination with a PCSK9 inhibitor is recommended.320,323
ACE inhibitors
ACE inhibitors (or ARBs) are recommended if a patient has other conditions (e.g. heart failure, hypertension, or
I A
diabetes).328330
ACE inhibitors should be considered in CCS patients at very high risk of cardiovascular events.331,332,335,336 IIa A
Other drugs
Beta-blockers are recommended in patients with LV dysfunction or systolic HF.211,212,214 I A
In patients with a previous STEMI, long-term oral treatment with a beta-blocker should be considered.213,220222,225,343 IIa B

ACE = angiotensin-converting enzyme; ARB = angiotensin-receptor blocker; CCS = chronic coronary syndrome; HF = heart failure; LV = left ventricular; PCSK9 = proprotein
convertase subtilisin-kexin type 9; STEMI = ST-elevation myocardial infarction.
a
Class of recommendation.
b
Level of evidence.
c
The treatment goals are shown in the European Society of Cardiology/European Atherosclerosis Society Guidelines for the management of dyslipidaemias.315

..
3.3.5 Hormone replacement therapy .. with PCI.262 The study highlights a significant placebo component to
The results from large randomized trials have shown that hormone .. the clinical effects, and alerts us to the pitfalls of interpreting end-
..
replacement therapy provides no prognostic benefit and increases .. points subject to bias in the absence of sham control and blinding.
the risk of CVD in women aged >60 years.344 .. However, the ORBITA results cannot inform Guidelines due to the
..
.. limited trial size, short-term observation time until crossover, and
.. insufficient power to assess clinical endpoints.
..
3.4 Revascularization .. Revascularization by either PCI or CABG also aims to effectively
In patients with CCS, optimal medical therapy is key for reducing .. eliminate myocardial ischaemia and its adverse clinical manifestations
..
symptoms, halting the progression of atherosclerosis, and preventing .. among patients with significant coronary stenosis, and to reduce the
atherothrombotic events. Myocardial revascularization plays a cen-
.. risk of major acute cardiovascular events including MI and cardiovas-
..
tral role in the management of CCS on top of medical treatment, but .. cular death. Numerous meta-analyses comparing a strategy of PCI
always as an adjunct to medical therapy without supplanting it. The
.. with initial medical therapy among patients with CCS have found
..
two objectives of revascularization are symptom relief in patients .. no348,349 or a modest104,350,351 benefit, in terms of survival or MI for
with angina and/or improvement of prognosis.
.. an invasive strategy. In this regard, previous Guidelines identified spe-
..
Previous Guidelines support indications for revascularization .. cific subgroups of patients (based on the anatomy of the coronary
mainly in patients with CCS who receive Guideline-recommended
.. tree, LV function, risk factors, etc.) in whom revascularization may
..
optimal medical therapy and continue to be symptomatic, and/or in .. improve prognosis, indicating that in other groups it may not.88
..
whom revascularization may ameliorate prognosis.88 These recom- .. A meta-analysis by Windecker et al. reported an incremental
mendations suggested that revascularization in patients with angina .. reduction of death and MI by revascularization vs. medical therapy
..
and significant stenosis was often a second-line therapy after medical .. only in CCS patients when revascularization was performed with
therapy had been unsuccessful. However, angina is associated with .. CABG or new-generation drug-eluting stents (DES), as opposed to
..
balloon angioplasty, bare-metal stents, or early DES.351 Data
impaired quality of life, reduced physical endurance, mental depres-
...
sion, and recurrent hospitalizations and office visits, with impaired .. reported in 2018 indicate a potentially broader prognostic impact of
clinical outcomes.345,346 .. revascularization strategies. The 5 year follow-up of the FAME 2 trial
..
Revascularization by PCI or CABG may effectively relieve angina, .. confirmed a sustained clinical benefit in patients treated with PCI spe-
reduce the use of antianginal drugs, and improve exercise capacity .. cifically targeting the ischaemia-producing stenoses (i.e. FFR <0.80)
..
and quality of life compared with a strategy of medical therapy .. plus optimal medical therapy vs. optimal medical therapy alone in
alone. In the 5 year follow-up of the FAME 2 (Fractional Flow .. terms of a significantly lower rate of urgent revascularization (hazard
..
Reserve versus Angiography for Multivessel Evaluation 2) trial, revas- .. ratio 0.27, 95% CI 0.180.41), and a lower rate of spontaneous MI
cularization improved quality of life, and reduced the use of antiangi- .. (hazard ratio 0.62, 95% CI 0.390.99).347 In contrast to some of the
..
nal drugs and associated side effects.347 The ORBITA (Objective .. earlier meta-analyses, this signal was confirmed in a patient-level
Randomised Blinded Investigation with optimal medical Therapy or
.. meta-analysis including 2400 subjects, all of whom underwent inva-
..
Angioplasty in stable angina) study, entailing a sham procedure in the .. sive physiological guidance, showing a significant reduction in cardiac
control group, found no significant improvement in exercise capacity
.. death and MI after a median follow-up of 33 months with FFR-guided
36 ESC Guidelines

PCI vs. medical therapy (hazard ratio 0.74, 95% CI 0.560.989;


.. two strategies, including the DAPT-related bleeding risks in cases of
..
P=0.041).352 Together, these new data support a less restrictive indi- .. revascularization by PCI. For the discussion of the best choice
cation for revascularization in CCS, in addition to specific anatomy
.. between revascularization modalitiesPCI or CABGfor individual
..
[e.g. left main (LM)] or extended ischaemia (>10%), when PCI is .. patients, we refer readers to the 2018 ESC myocardial revasculariza-
..
restricted to angiographic stenoses on large vessels causing a signifi- tion Guidelines.88
...
cant intracoronary pressure gradient. Figure 9 summarizes a practical ..
approach to the indications of revascularization in CCS according to ..
.. 4 Patients with new onset of heart

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the presence or absence of symptoms, and documentation of non- ..
invasive ischaemia. However, the individual risk-benefit ratio should .. failure or reduced left ventricular
..
always be evaluated and revascularization considered only if its .. function
expected benefit outweighs its potential risk. Also, the aspect of ..
..
shared decision-making is key, with full information given to the .. CAD is the most common cause of HF in Europe, and most of the
patient about the anticipated advantages and disadvantages of the .. trial evidence supporting management recommendations is based on

Angina symptoms

Yes No

Documented Documented
ischaemia ischaemia

Yes No Yes No

• Diameter stenosis • Diameter stenosis


MVD >90% >90%
• FFR ≤0.80 or iwFR Large area • FFR ≤0.80 or iwFR
≤0.89 in major of ischaemia ≤0.89 in major
Yes No vessel (>10% of LV) vessel
Identify lesions with • LVEF ≤35% due • LVEF ≤35% due
FFR ≤0.80 or to CAD to CAD
iwFR ≤0.89
©ESC 2019

Consider revascularization on top of medical therapy

Figure 9 Decision tree for patients undergoing invasive coronary angiography. Decisions for revascularization by percutaneous coronary intervention
or coronary artery bypass grafting are based on clinical presentation (symptoms present or absent), and prior documentation of ischaemia (present or
absent). In the absence of prior documentation of ischaemia, indications for revascularization depend on invasive evaluation of stenosis severity or prog-
nostic indications. Patients with no symptoms and ischaemia include candidates for transcatheter aortic valve implantation, valve, and other surgery. CAD
= coronary artery disease; FFR = fractional flow reserve; iwFR = instantaneous wave-free ratio; LV = left ventricle; LVEF = left ventricular ejection fraction;
MVD = multivessel disease.
ESC Guidelines 37

research conducted in patients with ischaemic cardiomyopathy. The


.. performed to establish the presence and extent of CAD, and evalu-
..
pathophysiology results in systolic dysfunction due to myocardial .. ate the potential for revascularization.52,53
injury and ischaemia, and most patients with symptomatic HF have
.. Laboratory investigations should measure natriuretic peptide levels to
..
reduced ejection fraction (<40%), although patients with CCS .. rule-out the diagnosis of suspected HF. When present, the severity of
..
may also have symptomatic HF and a preserved ejection fraction HF can be assessed.25,49 Renal function along with serum electrolytes
...
(>_50%). Patients with symptomatic HF should be managed clinically .. should be measured routinely to detect the development of renal
according to the 2016 ESC heart failure Guidelines.340 .. insufficiency, hyponatraemia, or hyperkalaemia, especially at the initia-
..

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History should include the assessment of symptoms suggestive of .. tion and during up-titration of pharmacological therapy.
HF, especially exercise intolerance and dyspnoea on exertion. All .. The management of patients with symptomatic HF requires
..
major past events related to CAD including MI and revascularization .. adequate diuretic therapy, preferably with a loop diuretic, to relieve
procedures are recorded, as well as all major cardiovascular comor- .. signs and symptoms of pulmonary and systemic congestion.
..
bidity requiring treatment such as AF, hypertension, or valvular dys- .. Inhibitors of both the RAS system (ACE inhibitors, ARBs, angiotensin
function, and non-cardiovascular comorbidity such as CKD, diabetes, .. receptor-neprilysin inhibitor) and the adrenergic nervous system
..
anaemia, or cancer. Current medical therapy, adherence, and toler- .. (beta-blockers) are indicated in all symptomatic patients with HF.340
ance should be reviewed. .. In patients with persistent symptoms, an MRA is also indicated. Up-
..
Physical examination should assess the nutritional status of patients, .. titration of these drugs should be gradual to avoid symptomatic sys-
and estimate biological age and cognitive ability. Recorded physical .. tolic hypotension, renal insufficiency, or hyperkalaemia.
..
signs include heart rate, heart rhythm, supine BP, murmurs suggestive .. Patients who remain symptomatic, with LV systolic dysfunction
of aortic stenosis or mitral insufficiency, signs of pulmonary conges-
.. and evidence of ventricular dysrhythmia or bundle branch block, may
..
tion with basal rales or pleural effusion, signs of systemic congestion .. be eligible for a device [cardiac resynchronization therapy (CRT)/
with dependant oedema, hepatomegaly, and elevated jugular venous
.. implantable cardioverter-defibrillator]. Such devices may provide
..
pressure. .. symptomatic relief, reduce morbidity, and improve survival.353356
A routine ECG provides information on heart rate and rhythm,
.. Patients with HF may decompensate rapidly following the onset of
..
extrasystole, signs of ischaemia, pathological Q waves, hypertrophy, .. atrial or ventricular dysrhythmia, and should be treated according to
conduction abnormalities, and bundle branch block.
.. current Guidelines. Patients with HF, and haemodynamically signifi-
..
Imaging should include an echocardiographic examination with .. cant aortic stenosis or mitral insufficiency, may require percutaneous
..
Doppler to evaluate evidence of ischaemic cardiomyopathy with HF .. or surgical intervention.
with reduced ejection fraction, HF with mid-range ejection fraction, .. Myocardial revascularization should be considered in eligible
..
or HF with preserved ejection fraction, focal/diffuse LV or right ven- .. patients with HF based on their symptoms, coronary anatomy, and
tricular systolic dysfunction, evidence of diastolic dysfunction, hyper- .. risk profile. Successful revascularization in patients with HF due to
..
trophy, chamber volumes, valvular function, and evidence of .. ischaemic cardiomyopathy may improve LV dysfunction and progno-
pulmonary hypertension. Chest X-ray can detect signs of pulmonary .. sis by reducing ischaemia to viable, hibernating myocardium. If avail-
..
congestion, interstitial oedema, infiltration, or pleural effusion. If not .. able, cooperation with a multidisciplinary HF team is strongly
known, coronary angiography (or coronary CTA) should be .. advised.348,357,358
.

General recommendations for the management of patients with chronic coronary syndromes and symptomatic heart
failure due to ischaemic cardiomyopathy and left ventricular systolic dysfunction

Recommendations for drug therapy Classa Levelb

Diuretic therapy is recommended in symptomatic patients with signs of pulmonary or systemic congestion to relieve HF
I B
symptoms.359,360
Beta-blockers are recommended as essential components of treatment due to their efficacy in both relieving angina, and
I A
reducing morbidity and mortality in HF.214,361367
ACE inhibitor therapy is recommended in patients with symptomatic HF or asymptomatic LV dysfunction following MI, to
I A
improve symptoms and reduce morbidity and mortality.333,368
An ARB is recommended as an alternative in patients who do not tolerate ACE inhibition, or an angiotensin recep-
I B
tor-neprilysin inhibitor in patients with persistent symptoms despite optimal medical therapy.337,369
An MRA is recommended in patients who remain symptomatic despite adequate treatment with an ACE inhibitor and
I A
beta-blocker, to reduce morbidity and mortality.360,370
A short-acting oral or transcutaneous nitrate should be considered (effective antianginal treatment, safe in HF).371 IIa A
Ivabradine should be considered in patients with sinus rhythm, an LVEF <_35% and a resting heart rate >70 b.p.m. who
remain symptomatic despite adequate treatment with a beta-blocker, ACE inhibitor, and MRA, to reduce morbidity and IIa B
238,372,373
mortality.
Amlodipine may be considered for relief of angina in patients with HF who do not tolerate beta-blockers, and is consid-
IIb B
ered safe in HF.374,375
Continued
38 ESC Guidelines

For devices, comorbidities, and revascularization


In patients with HF and bradycardia with high-degree atrioventricular block who require pacing, a CRT with a pacemaker
I A
rather than right ventricular pacing is recommended.353
An implantable cardioverter-defibrillator is recommended in patients with documented ventricular dysrhythmia causing
haemodynamic instability (secondary prevention), as well as in patients with symptomatic HF and an LVEF <_35%, to I A
reduce the risk of sudden death and all-cause mortality.354,376382

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CRT is recommended for symptomatic patients with HF in sinus rhythm with a QRS duration >_150 ms and LBBB QRS
morphology, and with LVEF <_35%, despite optimal medical therapy to improve symptoms, and reduce morbidity and I A
mortality.355,356,383392
CRT is recommended for symptomatic patients with HF in sinus rhythm with a QRS duration 130 - 149 ms and LBBB
QRS morphology, and with LVEF <_35%, despite optimal medical therapy to improve symptoms, and reduce morbidity I B
and mortality.355,356,383392
Comprehensive risk profiling and multidisciplinary management, including treatment of major comorbidities such as
hypertension, hyperlipidaemia, diabetes, anaemia, and obesity, as well as smoking cessation and lifestyle modification, are I A
recommended.393396
Myocardial revascularization is recommended when angina persists despite treatment with antianginal drugs.348,357,397 I A

ACE inhibitor = angiotensin-converting enzyme; ARB = angiotensin receptor blocker; b.p.m. = beats per minute; CCS = chronic coronary syndromes; CRT = cardiac resynch-
ronization therapy; HF = heart failure; LBBB = left bundle branch block; LV = left ventricular; LVEF = left ventricular ejection fraction; MI = myocardial infarction; MRA = miner-
alocorticoid receptor antagonist.
a
Class of recommendation.
b
Level of evidence.

..
5 Patients with a long-standing .. such as recovery from myocardial stunning or hibernation, which
.. may be reversed by revascularization.52,53 Conversely, cardiac func-
diagnosis of chronic coronary ..
.. tion may have deteriorated given other concomitant CVD (e.g. valvu-
syndromes .. lar disease, infection or inflammation, arrhythmia, etc.). In such cases,
..
.. these other damaging factors need to be identified and treated.
In patients with a long-standing diagnosis of CCS, lifelong treatment .. Likewise, non-invasive assessment of myocardial ischaemia may be
.
and surveillance are required (Figure 10). The clinical course of .. considered after revascularization to rule-out residual ischaemia or
.
patients with CCS may be benign over the course of time. However, .. to document the residual ischaemia as reference for subsequent
.
patients with CCS may develop a variety of cardiovascular complica- .. assessments over time.
.
tions or undergo therapeutic measures, some directly related to the ..
.
underlying CAD, and some having therapeutic or prognostic interac- .. 5.2 Patients >1 year after initial diagnosis
.
tions with the underlying disease. Risk for complications may occur in ..
. or revascularization
an otherwise asymptomatic patient, and thus the assessment of risk ..
.. To assess a patient’s risk, an annual evaluation by a cardiovascular
status applies to symptomatic and asymptomatic patients. .. practitioner (cardiologist, general physician, or nurse) is warranted,
Periodic assessment of the patient’s individual risk may be consid- ..
. even if the patient is asymptomatic. It is recommended that the
ered (Figure 10). Scores that apply clinical parameters have been ..
. annual evaluation should assess the patient’s overall clinical status and
shown to predict outcomes among patients with CCS. Moreover, if ...
medication compliance, as well as the risk profile (as reflected by risk
the clinical parameters are complemented by biomarkers, such a risk ...
score may be even more accurate. In 2017, a biomarker-based risk ...
scores). Laboratory tests—which include a lipid profile, renal func-
model to predict cardiovascular mortality in patients with CCS was ...
tion, a complete blood count, and possibly biomarkers—should be
developed and externally validated.398 .. performed every 2 years.45 A patient with a worsening risk score
.. over time may warrant more intense therapy or diagnostic measures,
..
. although risk score-guided therapy has not yet been proved to ameli-
5.1 Patients with stabilized symptoms <1 ... orate outcomes.
year after an acute coronary syndrome ..
.. A 12 lead ECG should be a part of every such visit to delineate
or patients with recent revascularization ... heart rate and heart rhythm, to detect changes suggestive of silent
After revascularization and/or after stabilized ACS (<1 year), patients ... ischaemia/infarction, and to discern abnormalities in the specific elec-
should be monitored more vigilantly, because they are at greater risk ... trocardiographic segments (e.g. PR, QRS, and QT intervals). It may
for complications and because they are subject to changes in pharma- ... be beneficial to assess LV function (diastolic and systolic), valvular sta-
cological treatment.45 Thus, we recommend at least two visits in the ... tus, and cardiac dimensions in apparently asymptomatic patients
first year of follow-up. In a patient who had LV systolic dysfunction ... every 35 years.52,53 In cases of unexplained reduction in systolic LV
.
before the revascularization procedure or after the ACS, a reassess- .. function, especially if regional, imaging of coronary artery anatomy is
.
ment of LV function must be considered 812 weeks after the inter- .. recommended. Likewise, it may be beneficial to assess non-invasively
.
vention. Cardiac function may have improved, owing to mechanisms . for silent ischaemia in an apparently asymptomatic patient every 35
ESC Guidelines 39

..
years, preferably applying stress imaging. Coronary CTA should not .. to support recommendations for the frequency of reassessment of
be used for follow-up of patients with established CAD given its .. these risk factors, but consensus suggests annual evaluation.
..
strength on morphological insight, but lack of functional information .. Elevated inflammatory markers, particularly of high-sensitivity C-
related to ischaemia. However, coronary CTA may be used for .. reactive protein, have also been associated with an increased event
..
unique cases, such as delineation of patency of coronary artery .. risk in patients with and without CAD in multiple studies,25 although
bypass grafts. .. the robustness of the association has been questioned because of
..
The lipid profile and glycaemia status should be reassessed periodi- .. reporting and publication bias.399 In addition, von Willebrand factor,

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cally to determine efficacy of treatment and, in patients without dia- .. interleukin-6, and N-terminal pro-B-type natriuretic peptide (NT-
..
betes, to detect new development of diabetes. There is no evidence . proBNP) have identified as been predictors of outcome.25 Other

9
9
9

Cardiovascular Risk score(s) Resting


caregivera visit stratification ECG

Recent CCS diagnosis


Destabilization

or revascularization

Baseline
initial evaluation
of recent CCS
Time from

3 months

6 months

12 months
ACS
Destabilization
Stabilization

Long-standing diagnosis
of CCS (>1 year)

Yearly

Post-ACS CCS
(e.g. >1 year after MI)

Baseline

3 months
of post-ACS CCS
initial evaluation

6 months
Time from

12 months

18 months

24 months

Yearly

Legend Time for decision-making on Advisable timepoint


DAPT continuation in PCI patients

Time for decision-making on Optional timepoint


optional dual antithrombotic therapy
(see table 9)
a
cardiologist, internist, general practitioner, or cardiovascular nurse

Echocardiography Early (e.g. 1-3 months) after revascularization to set as a reference and/or
at rest periodically (e.g. at 1 year if previously abnormal and/or every 3-5 years) to
evaluate LV function, valvular status and haemodynamic status.

Stress test for As necessary, to investigate changes in symptoms level, and/or early
inducible ischaemia (e.g. 1-3 months) after revascularization to set as a reference
and/or periodically (e.g. every 3-5 years) to reassess ischaemia.

Invasive coronary As necessary, for patients at high risk based on noninvasive ischaemia
©ESC 2019

angiography testing, or severe angina symptoms (e.g. CCS class 3-4).


Not recommended solely for risk stratification.

Figure 10 Proposed algorithm according to patient types commonly observed at chronic coronary syndrome outpatient clinics. The frequency of fol-
low-up may be subject to variation based on clinical judgement. ACS = acute coronary syndromes; CCS = chronic coronary syndromes; DAPT = dual anti-
platelet therapy; ECG = electrocardiogram; LV = left ventricular; MI = myocardial infarction; PCI = percutaneous coronary intervention. aCardiologist,
internist, general practitioner, or cardiovascular nurse.
40 ESC Guidelines

..
readily available biomarkers shown to predict prognosis in patients ..
..
6 Angina without obstructive
with CCS include heart rate, haemoglobin, and white cell count.400
.. disease in the epicardial coronary
Scores based on aggregated biomarkers may have greater success ..
than individual biomarkers. A multiple biomarker score combining .. arteries
..
high-sensitivity C-reactive protein, heat shock protein 70, and fibrin ..
degradation products significantly improved C-statistics and the net .. In clinical practice, a marked discrepancy between findings regarding
.. coronary anatomy, the presence of symptoms, and the results of
reclassification index compared with a basic model using clinical ..

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data.401 Similar results were reported for a combination of high- .. non-invasive tests frequently occurs.13 These patients deserve atten-
.. tion, as angina and non-obstructive disease are associated with an
sensitivity cardiac troponin T, NT-proBNP, and LDL-C.398 In several ..
studies, genetic risk scores have been shown to improve risk predic- .. increased risk of adverse clinical events.14 Low diagnostic yield of ICA
.. can be explained by the presence of: (i) stenoses with mild or moder-
tion above traditional risk factors in general population samples402,403 ..
and to predict recurrent events in populations with known
.. ate angiographic severity, or diffuse coronary narrowing, with under-
.. estimated functional significance identified by ICA; (ii) disorders
CCS.404407 Although there is additional prognostic value in using ..
several individual and aggregated biomarkers, there is currently no
.. affecting the microcirculatory domain that escape the resolution of
..
evidence that routine use leads to improved care. Nevertheless, .. angiographic techniques; and (iii) dynamic stenoses of epicardial ves-
these measurements may have a role in selected patients (e.g. when
.. sels caused by coronary spasm or intramyocardial bridges that are
..
testing for haemostatic abnormalities in those with previous MI with- .. not evident during CTA or ICA. Intracoronary pressure measure-
out conventional risk factors or a strong family history of CAD).
.. ments are useful in circumventing the first of these scenarios. For
..
Patients with unequivocal symptoms suggestive of ACS should be .. diagnostic workup, patients with angina and/or myocardial ischaemia
.. showing coronary stenoses with non-ischaemic FFR or iwFR values
expeditiously referred for evaluation, applying current Guidelines for ..
diagnosis and management. Among patients with more equivocal .. may also be labelled as having non-obstructive epicardial disease.
.. The presence of clear-cut anginal symptoms and abnormal non-
symptoms, stress imaging is recommended408 and, if not available and ..
the ECG is amenable to identification of ischaemia, exercise stress .. invasive tests in patients with non-obstructed epicardial vessels
.. should lead to the suspicion of a non-obstructive cause of ischaemia.
electrocardiography can be used as an alternative. In patients with ..
severe angina and a high-risk clinical profile, direct referral for ICA is .. Quite often, and mainly as a result of persistence of symptoms,
.. patients with angina and no obstructive disease undergo multiple
recommended, provided that ad hoc physiological assessment of hae- ..
modynamic stenosis significance is readily available in the catheteriza- .. diagnostic tests, including repeated coronary CTA or ICA, that con-
.. tribute to increased healthcare costs.409 Because diagnostic pathways
tion laboratory [e.g. instantaneous wave-free ratio (iwFR) or FFR]. ..
Likewise, ICA is recommended for patients with evidence of signifi- .. to investigate microcirculatory or vasomotor coronary disorders are
.. often not implemented, a final diagnosis supported by objective
cant ischaemia obtained by non-invasive testing. ..

Recommendations for patients with a long-standing diagnosis of chronic coronary syndromes

Recommendations for asymptomatic patients Classa Levelb

A periodic visit to a cardiovascular healthcare professional is recommended to reassess any potential change in the risk
status of patients, entailing clinical evaluation of lifestyle-modification measures, adherence to targets of cardiovascular I C
risk factors, and the development of comorbidities that may affect treatments and outcomes.
In patients with mild or no symptoms receiving medical treatment in whom non-invasive risk stratification indicates a high
risk, and for whom revascularization is considered for improvement of prognosis, invasive coronary angiography (with I C
FFR when necessary) is recommended.
Coronary CTA is not recommended as a routine follow-up test for patients with established CAD. III C
Invasive coronary angiography is not recommended solely for risk stratification. III C
Symptomatic patients
Reassessment of CAD status is recommended in patients with deteriorating LV systolic function that cannot be attributed
I C
to a reversible cause (e.g. long-standing tachycardia or myocarditis).
Risk stratification is recommended in patients with new or worsening symptom levels, preferably using stress imaging or,
I B
alternatively, exercise stress ECG.408
It is recommended to expeditiously refer patients with significant worsening of symptoms for evaluation. I C
Invasive coronary angiography (with FFR/iwFR when necessary) is recommended for risk stratification in patients with
I C
severe CAD, particularly if the symptoms are refractory to medical treatment or if they have a high-risk clinical profile.

CAD = coronary artery disease; CTA = computed tomography angiography; ECG = electrocardiogram; FFR = fractional flow reserve; iwFR = instantaneous wave-free ratio;
LV = left ventricular.
a
Class of recommendation.
b
Level of evidence.
ESC Guidelines 41

..
evidence is seldom reached. Owing to this, patient dismay and .. the challenges in performing a comprehensive assessment of micro-
depression are not rare in this clinical population.410,411 Of note, the .. vascular function is testing the two main mechanisms of dysfunction
..
use of a structured, systematic approach to explore microcirculatory .. separately: impaired microcirculatory conductance and arteriolar
and vasomotor disorders in patients with non-obstructive CAD, as .. dysregulation.424426 Yet, outlining which of these two pathways is
..
delineated below, has been shown to increase diagnostic yield.412,413 .. affected is critically relevant in setting medical treatment to relieve
Furthermore, an RCT, which reported in 2018, found that in patients
.. patient symptoms.414
..
with non-obstructive coronary disease, tailored treatment guided by .. Impaired microcirculatory conductance can be diagnosed by measuring

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the results of intracoronary testing [coronary flow reserve (CFR),
.. CFR or minimal microcirculatory resistance (the inverse of conduc-
..
microcirculatory resistance, and acetylcholine testing] resulted in a .. tance). CFR can be measured non-invasively with transthoracic
significant reduction of anginal symptoms, compared with conven-
.. Doppler echocardiography [by imaging left anterior descending
..
tional, non-guided medical treatment.414 .. (LAD) flow],427 magnetic resonance imaging (myocardial perfusion
.. index),428430 or PET.431 Microcirculatory resistance can be measured
..
6.1 Microvascular angina .. in the catheterization laboratory by combining intracoronary pressure
..
Patients with microvascular angina typically have exercise-related .. with thermodilution-based data (to calculate the IMR) or Doppler
angina, evidence of ischaemia in non-invasive tests, and either no .. flow velocity (to calculate hyperaemic microvascular resistance or
..
stenoses or mild-to-moderate stenoses (4060%), revealed by .. HMR).432,433 Both intracoronary thermodilution and Doppler allow
ICA or CTA, that are deemed functionally non-relevant.415 Given
.. the calculation of CFR. For decision-making purposes, values of IMR
..
the similarity of angina symptoms, a microvascular origin of angina .. >_25 units or CFR <2.0 are indicative of abnormal microcirculatory
is typically suspected, after excluding obstructive epicardial coro-
.. function.414 Both CFR and IMR are typically measured while using
..
nary stenoses, during diagnostic workup of patients with suspected .. intravenous vasodilators, such as adenosine or regadenoson.
myocardial ischaemia. Regional LV wall motion abnormalities rarely
.. In contrast, the diagnosis of arteriolar dysregulation requires the
..
develop during exercise or stress in patients with microvascular .. assessment of endothelial function in the coronary microcirculation
angina.412,416 Some patients may also have a mixed pattern of
.. by selective intracoronary acetylcholine infusion (see section 6.5). In
..
angina, with occasional episodes at rest, particularly associated with .. the presence of dysfunctional vascular endothelium or abnormal
.. function of smooth muscle cells, acetylcholine (an endothelium-
exposure to cold. ..
Secondary microvascular angina, in the absence of epicardial .. dependent vasodilator that also acts directly on smooth muscle cells)
.. triggers paradoxical arteriolar vasoconstriction.434 Thus, in patients
obstruction, may result from cardiac or systemic conditions, including ..
those that cause LV hypertrophy (such as hypertrophic cardiomyop- .. with microvascular angina and arteriolar dysregulation, acetylcholine
.. challenge is likely to trigger microvascular spasm. This arteriolar
athy, aortic stenosis, and hypertensive heart disease) or inflammation ..
(such as myocarditis or vasculitis).417 .. response to acetylcholine causes anginal symptoms with or without
.. concomitant ischaemic ECG changes, and a decrease in coronary
..
.. blood flow velocity if concomitant Doppler measurements are per-
6.1.1 Risk stratification .. formed. Peripheral pulse tonometry during reactive hyperaemia may
The presence of microcirculatory dysfunction in patients with CCS ..
.. also reveal abnormal systemic endothelial function in patients with
entails a worse prognosis than originally thought, probably because .. angina and non-obstructive CAD.435
most recent evidence has been based on follow-up of patients in ..
..
whom abnormalities in the microcirculation have been objectively ..
documented with invasive or non-invasive techniques.418423 ..
.. 6.1.3 Treatment
Microcirculatory dysfunction precedes the development of epicar- .. Treatment of microvascular angina should address the dominant
dial lesions, particularly in women,419 and is associated with impaired ..
.. mechanism of microcirculatory dysfunction. In patients with abnor-
outcomes. Among patients with diabetes undergoing diagnostic .. mal CFR <2.0 or IMR >_25 units, and a negative acetylcholine provo-
workup, those without obstructive epicardial disease but with an ..
.. cation test, beta-blockers, ACE inhibitors, and statins, along with
abnormal CFR have similarly poor long-term prognosis as those with .. lifestyle changes and weight loss, are indicated.436,437 Patients devel-
obstructive epicardial disease.421 In patients with non-significant cor- ..
.. oping ECG changes and angina in response to acetylcholine testing
onary stenoses by FFR, the presence of abnormal CFR is associated .. but without severe epicardial vasoconstriction (all suggestive of
with an excess of events in the long-term,418,422,423 particularly when
..
.. microvascular spasm) may be treated like vasospastic angina patients.
the index of microcirculatory resistance (IMR) is also abnormal.422 .. The effectiveness of a tailored treatment strategy was investigated in
..
.. the CorMiCa trial, which randomized 151 patients to a stratified
6.1.2 Diagnosis .. medical treatment (based on the results of CFR, IMR, and acetylcho-
..
The possibility of a microcirculatory origin of angina should be con- .. line testing) vs. a standard-care group (including a sham interventional
sidered in patients with clear-cut angina, abnormal non-invasive func-
.. diagnostic procedure). At 1 year, there was a significant difference in
..
tional tests, and coronary vessels that are either normal or have mild .. angina scores favouring patients assigned to the stratified medical
stenosis deemed functionally non-significant on ICA or CTA. One of
.. treatment arm.414
42 ESC Guidelines

..
Investigations in patients with suspected coronary micro- .. coronary stenosis. Angiographic documentation of coronary spasm
vascular angina .. requires the use of a provocation test in the catheterization laboratory.
..
.. Given the low sensitivity of hyperventilation and the cold pressor test,
Recommendations Classa Levelb .. intracoronary administration of acetylcholine or ergonovine during
..
Guidewire-based CFR and/or microcirculatory .. ICA are the preferred provocation tests.442 Both pharmacological
resistance measurements should be consid-
.. agents are safe, provided that they are selectively infused into the left
..
ered in patients with persistent symptoms, but .. or right coronary artery, and that triggered spasm is readily controlled

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coronary arteries that are either angiographi-
IIa B .. with intracoronary nitrates. A low percentage of patients may develop
..
cally normal or have moderate stenoses with .. ventricular tachycardia/ventricular fibrillation or bradyarrhythmias dur-
preserved iwFR/FFR.412,413
.. ing the provocation test (3.2 and 2.7%, respectively), similar to that
..
Intracoronary acetylcholine with ECG moni- .. reported during spontaneous spasm attacks (7%).446 Intravenous
.. administration of ergonovine for non-invasive tests should be discour-
toring may be considered during angiography, ..
if coronary arteries are either angiographically .. aged due to the risk of triggering prolonged spasm in multiple vessels,
IIb B .. which may be very difficult to manage and can be fatal.447
normal or have moderate stenoses with pre- ..
served iwFR/FFR, to assess microvascular .. A provocation test for coronary spasm is considered positive when
.. it triggers: (i) anginal symptoms, (ii) ischaemic ECG changes, and (iii)
vasospasm.412,438440 ..
Transthoracic Doppler of the LAD, CMR, and
.. severe vasoconstriction of the epicardial vessel. Should the test fail in
.. triggering all three components, it should be considered equivocal.442
PET may be considered for non-invasive IIb B ..
assessment of CFR.430432,441
.. The development of angina in response to acetylcholine injections in
... the absence of angiographically evident spasm, with or without accom-
CFR = coronary flow reserve; CMR = cardiac magnetic resonance; ECG = elec- ..
trocardiogram; FFR = fractional flow reserve; iwFR = instantaneous wave-free
.. panying ST-segment changes, may indicate microvascular spasm and is
.. seen frequently in patients presenting with microvascular angina.445
ratio; LAD = left anterior descending; PET = positron emission tomography. ..
a
Class of recommendation. ..
b
Level of evidence. ..
..
.. 6.2.2 Treatment
.. In patients with epicardial or microcirculatory vasomotor disorders,
..
6.2 Vasospastic angina .. CCBs and long-acting nitrates constitute the treatment of choice, in
.. addition to the control of cardiovascular risk factors and lifestyle
Vasospastic angina should be suspected in patients with anginal ..
symptoms occurring predominantly at rest, with maintained effort .. changes.437,445 Nifedipine has been shown to be effective in reducing
.. coronary spasm associated with stent implantation.444
tolerance. The likelihood of vasospastic angina increases when
attacks follow a circadian pattern, with more episodes at night and
in the early morning hours. Patients are frequently younger and
have fewer cardiovascular risk factors than patients with effort Recommendations for investigations in patients with
angina, except for cigarette smoking.442 Coronary vasospasm suspected vasospastic angina
should be also suspected in patients with patent coronary stents
Recommendations Classa Levelb
and persistent angina.443,444
An ECG is recommended during angina if
I C
possible.
6.2.1 Diagnosis Invasive angiography or coronary CTA is rec-
The diagnosis of vasospastic angina is based on detecting transient ommended in patients with characteristic epi-
ischaemic ST-segment changes during an angina attack (usually at sodic resting angina and ST-segment changes,
rest). Patients with Prinzmetal angina represent a special subset in I C
which resolve with nitrates and/or calcium
whom resting angina is accompanied by transient ST-segment eleva- antagonists, to determine the extent of under-
tion.442,445 These ECG changes correlate with proximal vessel occlu- lying coronary disease.
sion and diffuse, distal subocclusive narrowing of epicardial vessels.
Ambulatory ST-segment monitoring should be
As most attacks of vasospastic angina are self-limiting, documentation IIa C
considered to identify ST-segment deviation in
of these ECG changes is challenging. Ambulatory ECG monitoring,
the absence of increased heart rate.
preferably with 12 lead recording, may be helpful in patients in whom
An intracoronary provocation test should be
vasospastic angina is suspected. The occurrence of ST-segment shifts
considered to identify coronary spasm in
at normal heart rate supports the likelihood of myocardial ischaemia
patients with normal findings or non-obstruc-
caused by spasm. Extended Holter monitoring (for >1 week) may be IIa B
tive lesions on coronary arteriography and a
required for successful documentation of transient ST-segment
clinical picture of coronary spasm, to diagnose
changes in these patients. Ambulatory ECG monitoring may also be
the site and mode of spasm.412,414,438440
used to assess the results of medical therapy in controlling the fre-
quency of vasospastic events. CTA = computed tomography angiography; ECG = electrocardiogram.
a
Class of recommendation.
In patients with suspected vasospastic angina and documented ECG b
Level of evidence.
changes, CTA or ICA is indicated to rule-out the presence of fixed
ESC Guidelines 43

..
7 Screening for coronary artery ..
..
asymptomatic subjects who receive testing and have a positive test
.. result beyond the recommendations listed in these Guidelines.
disease in asymptomatic subjects .. However, the principles of risk stratification, as described above for
.. symptomatic patients, also apply to these individuals.450 It is impor-
In an effort to lower the high burden of coronary deaths in asympto- ..
matic adults, numerous measurements of risk factors and risk markers, .. tant to remember that data demonstrating improved prognosis fol-
.. lowing appropriate management based on new biomarkers are still
as well as stress tests, are often performed as screening investigations. ..
.. lacking.

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The 2016 European Guidelines on CVD prevention in clinical practice ..
have focused on these issues in detail.15 These recommendations have .. It is important to note that patients with cancer and undergoing
been adapted for the purpose of these Guidelines.
.. cancer treatment, or chronic inflammatory diseases such as inflam-
..
In general, the use of risk-estimation systems such as SCORE is .. matory bowel diseases, rheumatoid arthritis, and systemic lupus
recommended (see also Figure 6). Subjects with a family history of
.. erythematosus, may deserve more intensive risk screening, counsel-
..
premature CAD should be screened for familial hypercholesterolae- .. ling, and management.451454
mia. Coronary calcium score, ankle-brachial index, and carotid ultra-
.. Persons whose occupations involve public safety (e.g. airline
..
sound for plaque detection may provide useful information about the .. pilots, or lorry or bus drivers), or who are professional or high-
atherosclerotic risk in selected patients, but routine use of bio-
.. profile athletes, commonly undergo periodic testing for the assess-
..
markers or other imaging tests for CAD are not recommended. The .. ment of exercise capacity and evaluation of possible heart disease,
.. including CAD. Although there are insufficient data to justify this
new biomarkers have incremental predictive value over classical ..
ones,448 but the net reclassification improvement is still only modest .. approach, these evaluations may be done for medicolegal reasons.
..
(718%) compared, for example, with the coronary calcium score, .. The threshold for performing an imaging test in such persons may
which has a net reclassification improvement of 66%.449 .. be lower than in the average patient. Otherwise, the same consid-
..
Only subjects at high event risk should be considered for further .. erations as discussed above for other asymptomatic persons apply
non-invasive or invasive testing. There are no data on how to manage .. to these individuals.
.

Recommendations for screening for coronary artery disease in asymptomatic subjects

Recommendations Classa Levelb

Total risk estimation using a risk-estimation system such as SCORE is recommended for asymptomatic adults >40 years
I C
of age without evidence of CVD, diabetes, CKD, or familial hypercholesterolaemia.
Assessment of family history of premature CVD (defined as a fatal or non-fatal CVD event, or/and established diagnosis of
CVD in first-degree male relatives before 55 years of age or female relatives before 65 years of age) is recommended as I C
part of cardiovascular risk assessment.
It is recommended that all individuals aged <50 years with a family history of premature CVD in a first-degree relative
(<55 years of age in men or <65 years of age in women) or familial hypercholesterolaemia are screened using a validated I B
clinical score.455,456
Assessment of coronary artery calcium score with computed tomography may be considered as a risk modifierc in the
IIb B
cardiovascular risk assessment of asymptomatic subjects.449,457
Atherosclerotic plaque detection by carotid artery ultrasound may be considered as a risk modifierc in the cardiovascular
IIb B
risk assessment of asymptomatic subjects.458
ABI may be considered as a risk modifierc in cardiovascular risk assessment.459 IIb B
In high-risk asymptomatic adults (with diabetes, a strong family history of CAD, or when previous risk-assessment tests
IIb C
suggest a high risk of CAD), functional imaging or coronary CTA may be considered for cardiovascular risk assessment.
In asymptomatic adults (including sedentary adults considering starting a vigorous exercise programme), an exercise ECG
may be considered for cardiovascular risk assessment, particularly when attention is paid to non-ECG markers such as IIb C
exercise capacity.
Carotid ultrasound IMT for cardiovascular risk assessment is not recommended.460 III A
In low-risk non-diabetic asymptomatic adults, coronary CTA or functional imaging for ischaemia are not indicated for fur-
III C
ther diagnostic assessment.
Routine assessment of circulating biomarkers is not recommended for cardiovascular risk stratification.448,449,461,462 III B

ABI = ankle-brachial index; CAD = coronary artery disease; CKD = chronic kidney disease; CTA = computed tomography angiography; CVD = cardiovascular disease; ECG =
electrocardiogram; IMT = intima-media thickness; SCORE = Systematic COronary Risk Evaluation.
a
Class of recommendation.
b
Level of evidence.
c
Reclassifies patients better into low- or high-risk groups.
44 ESC Guidelines

..
8 Chronic coronary syndromes in ..
..
8.1.2 Valvular heart disease (including planned
transcatheter aortic valve implantation)
specific circumstances ..
.. Coronary angiography for the assessment of CAD is recommended
.. before valve surgery or when percutaneous valvular intervention is
8.1 Cardiovascular comorbidities ..
.. planned, to determine if revascularization is required. Coronary CTA
8.1.1 Hypertension .. may be considered in patients with low risk for CAD, or in patients in
Hypertension is the most prevalent cardiovascular risk factor and is ..
.. whom conventional ICA is technically not feasible or associated with

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closely associated with CCS. Thresholds for the definition of hyperten- .. increased risk. The combination of PCI and transcatheter aortic valve
sion are provided in Table 10. BP lowering can significantly reduce major ..
.. implantation appears feasible and safe, but more data are needed
cardiovascular risk, including CHD. Meta-analysis suggests that for every .. before definite recommendations can be provided.473,474 The routine
10 mmHg reduction in systolic BP, CAD can be reduced by 17%.463 ..
.. use of stress testing to detect CAD associated with severe sympto-
More intensive BP targets (office BP <130 mmHg) have been associated .. matic valvular disease is not recommended because of low diagnostic
with favourable outcomes and are endorsed by the 2018 ESC/ESH ..
.. value and potential risk. Symptom-limited stress testing in patients
Guidelines for the management of arterial hypertension.464 It is recom- ..
.. with valvular heart disease appears safe, and may be useful to unmask
mended treat hypertensive patients with CCS are treated to office tar- .. symptoms in asymptomatic patients or in patients with equivocal
gets of 130/80 mmHg, because an increased systolic BP of >_140 mmHg .. symptoms.475
and diastolic BP of >_80 mmHg, but also a systolic BP of <120 mmHg ..
and diastolic BP of <70 mmHg, are associated with increased risk465,466
(Table 10). Whether the J-curve phenomenon exists in patients with Recommendations for valvular disease in chronic coro-
nary syndromes476
revascularized CAD remains uncertain. In hypertensive patients with
CHD, beta-blockers and RAS blockers may improve post-MI out- Recommendations Classa Levelb
comes.467 In patients with symptomatic angina, beta-blockers and cal-
cium antagonists are the preferred components of the drug-treatment ICA is recommended before valve surgery and
strategy. The combination of ACE inhibitors and ARBs is not recom- for any of the following: history of CVD, sus-
mended for the treatment of hypertension because of increased renal pected myocardial ischaemia, LV systolic dys-
I C
adverse events without beneficially influencing outcome.468,469 function, in men >40 years of age and post-
menopausal women, or one or more cardio-
Table 10 Blood pressure thresholds for the definition of vascular risk factors.
hypertension with different types of blood pressure ICA is recommended in the evaluation of
measurement470472 moderate-to-severe functional mitral I C
Category Systolic BP Diastolic BP regurgitation.
(mmHg) (mmHg) Coronary CTA should be considered as an
Office BP >_140 and/or >_90 alternative to coronary angiography before
>_80 years of age >_160 and/or >_90 IIa C
valve intervention in patients with severe valv-
Ambulatory BP ular heart disease and low probability of CAD.
Daytime (or awake) >_135 and/or >_85
PCI should be considered in patients under-
Night-time (or asleep) >_120 and/or >_70
going transcatheter aortic valve implantation
24 h >_130 and/or >_80 IIa C
and coronary artery diameter stenosis >70%
Home BP >_135 and/or >_85 in proximal segments.
BP = blood pressure. In severe valvular heart disease, stress testing
should not be routinely used to detect CAD
III C
because of the low diagnostic yield and poten-
Recommendations for hypertension treatment in chronic
coronary syndromes tial risks.

CAD = coronary artery disease; CTA = computed tomography angiography;


Recommendations Classa Levelb CVD = cardiovascular disease; ICA = invasive coronary angiography; LV = left
ventricular; PCI = percutaneous coronary intervention.
It is recommended that office BP is controlled a
Class of recommendation.
b
to target values: systolic BP 120 - 130 mmHg in Level of evidence.
I A
general and systolic BP 130 - 140 mmHg in
older patients (aged >65 years).463467,470472
In hypertensive patients with a recent MI, beta- 8.1.3 After heart transplantation
I A The follow-up and assessment of long-term heart transplant survi-
blockers and RAS blockers are recommended.467
vors requires specific know-how. Transplant CAD is largely an immu-
In patients with symptomatic angina, beta-
I A nological phenomenon, and remains a significant cause of morbidity
blockers and/or CCBs are recommended.467
and mortality.477 ICA is recommended for the assessment of trans-
The combination of ACE inhibitors and ARBs is
III A plant CAD and should be performed annually for 5 years after trans-
not recommended.468,469
plantation. If there are no significant abnormalities, angiograms can be
ACE = angiotensin converting enzyme; ARB = angiotensin receptor blocker; BP = performed biannually thereafter. Intravascular ultrasound
blood pressure; CCB = calcium channel blocker; RAS = renin-angiotensin system.
a
Class of recommendation.
b
Level of evidence.
ESC Guidelines 45

..
examinations may be useful in assessing cardiac allograft vasculopathy .. >_50% if the baseline LCL-C is between 1.8 and 3.5 mmol/L (70 and
and plaque stability.478 Treatment options for CAD in transplant .. 135 mg/dL).15 For the majority of patients with diabetes and CAD, a
..
recipients include pharmacotherapy and revascularization. PCI in the .. target glycated HbA1c level of <7% (<53 mmol/L) is recom-
transplanted heart has become an established therapy.479 .. mended.483,484 Large safety studies on new glucose-lowering drugs,
..
.. namely sodium-glucose co-transporter-2 and glucagon-like peptide-1
.. receptor agonists, have demonstrated significant reductions in cardi-
..
.. ovascular events. Indications for their clinical use are described in the

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8.2 Non-cardiovascular comorbidities .. 2019 ESC/European Association for the Study of Diabetes
8.2.1 Cancer ..
.. Guidelines on diabetes mellitus, pre-diabetes, and cardiovascular
Occurrence of CAD in patients with active cancer is increasing451,452 .. diseases.16
as a side effect of cancer therapy (i.e. radiotherapy to the thorax/ ..
.. A 12 lead ECG is recommended as part of the routine assessment
mediastinum, cardiotoxic chemotherapy, or immunotherapies) or a .. for screening for conduction abnormalities, LV hypertrophy, and
result of extended cancer therapies in elderly individuals. CAD in
..
.. arrhythmias. The high prevalence of significant CAD and prohibitively
patients with active cancer is associated with challenges for clinicians .. high cardiovascular mortality may suggest the usefulness of routine
as treatment decisions should be the subject of individualized discus-
..
.. screening for CAD (with functional imaging testing or coronary
sions based on life expectancy, additional comorbidities such as .. CTA) in asymptomatic patients with diabetes, but no data have
thrombocytopenia, increased thrombosis and bleeding propensity,
..
.. shown an improvement in outcomes so far. Routine use of CTA in
and potential interactions between drugs used in CCS management .. asymptomatic patients with diabetes is therefore not recommended.
..
and antineoplastic drugs. In cancer patients with increased frailty, the
least invasive revascularization procedures are recommended. For
further information, see the ESC position paper on cancer treat- Recommendations for diabetes mellitus in chronic coro-
ments and cardiovascular toxicity.480 nary syndromes

Recommendations Classa Levelb


Recommendations for active cancer in chronic coronary
syndromes Risk factor (BP, LDL-C, and HbA1c) control
to targets is recommended in patients with I A
Recommendations Classa Levelb
CAD and diabetes mellitus.482484
Treatment decisions should be based on life In asymptomatic patients with diabetes melli-
expectancy, additional comorbidities such as tus, a periodic resting ECG is recommended
I C
thrombocytopenia, increased thrombosis pro- for cardiovascular detection of conduction
I C
pensity, and potential interactions between abnormalities, AF, and silent MI.
drugs used in CCS management and antineo- ACE inhibitor treatment is recommended in
plastic agents. CCS patients with diabetes for event I B
If revascularization is indicated in highly symp- prevention.482
tomatic patients with active cancer and The sodium-glucose co-transporter 2 inhibi-
I C
increased frailty, the least invasive procedure tors empagliflozin, canagliflozin, or dapagliflo-
I A
is recommended. zin are recommended in patients with
c 485487
CCS = chronic coronary syndromes.
diabetes and CVD.
a
Class of recommendation. A glucagon-like peptide-1 receptor agonist
b
Level of evidence. I A
(liraglutide or semaglutide) is recommended in
patients with diabetes and CVD.c 488490
8.2.2 Diabetes mellitus In asymptomatic adults (age >40 years) with
Diabetes mellitus confers about a two-fold increased risk for CAD481 diabetes, functional imaging or coronary CTA
IIb B
and, consequently, control of risk factors is recommended for the may be considered for advanced cardiovascu-
prevention of CVD. Systolic BP in patients with diabetes should be lar risk assessment.491,492
targeted to <_130 mmHg, if tolerated, but not <120 mmHg, and dia- ACE = angiotensin-converting enzyme; AF = atrial fibrillation; BP = blood pres-
stolic BP to <80 mmHg, but not <70 mmHg.482 Initial antihyperten- sure; CAD = coronary artery disease; CCS = chronic coronary syndromes; CTA
sion treatment should consist of a combination of a RAS blocker with = computed tomography angiography; CVD = cardiovascular disease; ECG =
electrocardiogram; HbA1c = glycated haemoglobin; LDL-C = low-density lipo-
a CCB or thiazide/thiazide-like diuretic. ACE inhibitors reduce albu- protein cholesterol; MI = myocardial infarction.
a
minuria, and the appearance or progression of diabetic nephropathy, Class of recommendation.
b
more effectively than other drug classes.482 Patients with diabetes c
Level of evidence.
Treatment algorithm is available in the 2019 European Society of Cardiology/
and CAD are considered to be at very high risk; consequently, LDL- European Association for the Study of Diabetes Guidelines on diabetes mellitus,
C should be lowered to <1.8 mmol/L (<70 mg/dL) or reduced by pre-diabetes, and cardiovascular diseases.16
46 ESC Guidelines

8.2.3 Chronic kidney disease .. access-site complications, when choosing an invasive strategy for
..
CAD is highly prevalent in patients with CKD and a growing number .. patient management.506,507 The use of DES, compared with bare-
of patients undergoing PCI have concomitant CKD.493 There is a lin-
.. metal stents, in combination with a short duration of DAPT is associ-
..
ear increase in the risk of cardiovascular mortality with decreasing .. ated with significant safety and efficacy benefits in elderly
GFR.494 Medical treatment for risk-factor control (lipids, BP, and glu-
.. patients.508,509
..
cose) can improve outcomes. Special attention during the workup .
for CKD patients with suspected obstructive CAD should be paid to

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the fact that angina is less common and silent ischaemia more com- Recommendations for elderly patients with chronic coro-
mon.495 Additionally, non-invasive stress testing shows reduced accu- nary syndromes
racy in patients with CKD.496 The use of an iodinated contrast agent
Recommendations Classa Levelb
should be minimized to prevent further deterioration of renal func-
tion. Decisions regarding diagnostic and treatment modalities should It is recommended that particular attention is
be made accordingly. Interestingly, patients with CKD are less likely paid to side effects of drugs, intolerance, and I C
to receive invasive management for treatment of CAD compared overdosing in elderly patients.
with those without, although benefits of invasive management have The use of DES is recommended in elderly
been reported.497 Revascularization options in patients with CKD I A
patients.508,509
include CABG and PCI. Meta-analyses suggest that CABG is associ- Radial access is recommended in elderly
ated with higher short-term risk of death, stroke, and repeat revascu- patients to reduce access-site bleeding I B
larization, whereas PCI with a new-generation DES is associated with complications.506,507
a higher long-term risk of repeat revascularization.498,499 Data on
It is recommended that diagnostic and revas-
patients on haemodialysis are very limited, making generalizable
cularization decisions are based on symptoms,
treatment recommendations difficult. I C
the extent of ischaemia, frailty, life expectancy,
and comorbidities.

DES = drug-eluting stents.


Recommendations for chronic kidney disease in chronic a
Class of recommendation.
coronary syndromes b
Level of evidence.

Recommendations Classa Levelb

It is recommended that risk factors are


I A
8.3 Sex
controlled to target values.500502 Making up <_30% of study populations, women are widely under-
It is recommended that special attention is represented in cardiovascular studies.510 This recruitment bias causes
paid to potential dose adjustments of renally I C an evidence gap, as sex-based randomized controlled studies are
excreted drugs used in CCS. lacking, and most data are extracted from meta-analyses and post hoc
It is recommended that the use of iodinated analyses of trials in ACS patients. Differences in symptom presenta-
contrast agents is minimized in patients with tion, the accuracy of diagnostic tests for CAD, and other factors that
I B
severe CKD and preserved urine production lead to differential triage, evaluation, or early treatment of women
to prevent further deterioration.503,504 with myocardial ischaemia compared with men could contribute to
their worse outcomes.511514 Whether there are true sex-related
CKD = chronic coronary disease; CCS = chronic coronary syndromes.
a
Class of recommendation. differences in mortality after myocardial ischaemia, or whether they
b
Level of evidence. owing to older age or a higher prevalence of coexisting diseases in
women, remains incompletely understood. It has become evident
that sex-related mortality differences are particularly apparent in
8.2.4 Elderly younger patients, typically those aged <60 years.511,512,515 The rea-
Ageing predisposes patients to a high incidence and prevalence of sons for this age-dependent disparity in mortality remain unclear.
CAD, in both men and women. Elderly patients (age >75 years) have Women tend to be treated less aggressively than men.515 However,
the greatest mortality and morbidity risk attributable to CCS, which patient characteristics and treatments do not entirely account for sex
is enriched by the high prevalence of comorbidities (e.g. hyperten- differences in outcomes, even after PCI.512 It is therefore recom-
sion, diabetes mellitus, CKD, etc.).505 Although the prevalence of eld- mended that women who present with signs suggestive of cardiac
erly patients with CAD is increasing, this population is usually ischaemia undergo careful investigation, as clinical symptoms might
undertreated, underdiagnosed, and under-represented in clinical tri- be atypical. The diagnostic accuracy of the exercise ECG is even
als. Elderly patients often present with atypical symptoms, which may lower in women than in men, which is in part related to functional
delay proper diagnosis. The treatment of CCS in the elderly is com- impairment, precluding some women from achieving an adequate
plicated by a higher vulnerability to complications for both conserva- workload. Stress echocardiography with exercise or dobutamine
tive and invasive strategies, such as bleeding, renal failure, and stress is an accurate, non-invasive technique for the detection of
neurological impairments, all of which require special attention. It is obstructive CAD and risk among women with suspected CCS.516
recommended that radial access is used whenever possible to reduce Both women and men have experienced improvements in mortality
ESC Guidelines 47

..
when new-generation DES were used.517519 The mortality reduc- .. obviously needed, along with safety metrics. To confirm treatment
tions were similar among women and men leaving sex disparities in .. efficacy, trials with a sham-controlled design are desirable, a significant
..
outcomes unchanged.512 Women have higher complication rates fol- .. placebo effect being part of the therapeutic effect. Patients with
lowing CABG and may also have higher mortality risk,520,521 espe- .. refractory angina are best treated in dedicated ‘angina clinics’ by mul-
..
cially in elderly patients. Hormone replacement therapy in post- .. tidisciplinary teams experienced in selecting the most suitable thera-
menopausal women does not reduce the risk of ischaemic myocar- .. peutic approach in the individual patient based on an accurate
..
dial disease (see section 3.3.5), and is therefore not recommended for .. diagnosis of the mechanisms of the pain syndrome. Once conven-

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primary and secondary prevention.344,522,523 .. tional anti-ischaemic targets have been exhausted (through an
..
.. increase in nutrient blood flow delivery and/or reduction in oxygen
.. consumption), novel therapies can be ranked by mechanism of
Recommendation for sex issues and chronic coronary ..
syndromes
.. action: promotion of collateral growth, transmural redistribution of
.. blood flow, and neuromodulation of the cardiac pain syndrome
..
Recommendation Classa Levelb .. (Table 11).
.. Both the STARTSTIM and RENEW (Efficacy and Safety of
..
Hormone replacement therapy is not recom- .. Targeted Intramyocardial Delivery of Auto CD34þ Stem Cells for
mended for risk reduction in post-menopausal III C .. Improving Exercise Capacity in Subjects With Refractory Angina) tri-
..
women. .. als were underpowered due to premature study termination. Of
.. note, a patient-level pooled analysis of 304 patients included in three
a
Class of recommendation. ..
b
Level of evidence. .. double-blind, cell therapy, placebo-controlled trials, among which
..
.. was the RENEW trial, showed that active treatment with autologous
.. haematopoietic cells had significant effects on exercise time and
..
.. angina frequency.528
8.4 Patients with refractory angina .. Based on positive results from two RCTs in small groups of
..
Refractory angina refers to long-lasting symptoms (for >_3 months) .. patients, both enhanced external counterpulsation and the coronary
due to established reversible ischaemia in the presence of obstructive .. sinus reducer device represent alternative options in patients with
..
CAD, which cannot be controlled by escalating medical therapy with .. refractory angina, which is resistant after having exhausted all options
the use of second- and third-line pharmacological agents, bypass .. for medical therapy and mechanical revascularization. Controlled
..
grafting, or stenting including PCI of chronic total coronary occlusion. .. coronary sinus narrowing with the implantation of a large stainless-
Incidence is growing with more advanced CAD, multiple comorbid- .. steel device increases coronary sinus pressure, leading to improved
..
ities, and ageing of the population. The quality of life of patients with .. perfusion in the LAD territory.
refractory angina is poor, with frequent hospitalization and a high .. Total reported experience with all novel therapeutic options
..
level of resource utilization. The number of potential treatment .. remains limited, both regarding the number of treated patients and
options is increasing, but the level of evidence in support of their .. the duration of follow-up. Larger RCTs are required to define the
..
safety and efficacy varies from non-existent (in the case of transmyo- .. role of each treatment modality for specific subgroups, to decrease
cardial laser application) to promising. RCTs with endpoints such as
.. non-responder rates and ascertain benefit beyond potential placebo
..
the severity and frequency of angina, as well as quality of life, are .. effects.

Table 11 Potential treatment options for refractory angina and summary of trial data
Therapy Type of therapy RCT Type of control group Number of
patients enrolled
External counterpulsation Enhanced external counterpulsation MUST524 Sham 139
Extracorporeal shockwave Low-energy extracorporeal shockwave therapy Not available Not available —
Coronary sinus constriction Reducer device COSIRA525 Sham 104
Neuromodulation Spinal cord stimulation STARTSTIM526 Not available 68
Transcutaneous electrical neural stimulation Not available Not available —
Subcutaneous electrical neural stimulation Not available Not available —
Sympathectomy Denby et al.527 Placebo 65
Gene therapy Adenovirus fibroblast growth factor 5 Not available Not available —
Autologous cell therapy Mononuclear bone marrow-derived RENEW528 Placebo 112
haematopoietic progenitor cells
RCT = randomized clinical trial.
48 ESC Guidelines

Recommendations for treatment options for refractory angina

Recommendations Classa Levelb

Enhanced external counterpulsation may be considered for symptom relief in patients with debilitating angina refractory
IIb B
to optimal medical and revascularization strategies.524
A reducer device for coronary sinus constriction may be considered to ameliorate symptoms of debilitating angina refrac-

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IIb B
tory to optimal medical and revascularization strategies.525
Spinal cord stimulation may be considered to ameliorate symptoms and quality of life in patients with debilitating angina
IIb B
refractory to optimal medical and revascularization strategies.526
Transmyocardial revascularization is not recommended in patients with debilitating angina refractory to optimal medical
III A
and revascularization strategies.529
a
Class of recommendation.
b
Level of evidence.

..
9 Key messages ..
..
(10) Anti-ischaemic treatment must be adapted to the individual patient
based on comorbidities, co-administered therapies, expected tol-
(1) Careful evaluation of patient history, including the characterization
..
.. erance and adherence, and patient preferences. The choice of
of anginal symptoms, and evaluation of risk factors and manifesta- .. anti-ischaemic drugs to treat CCS should be adapted to the
..
tions of CVD, as well as proper physical examination and basic .. patient’s heart rate, BP, and LV function.
testing, are crucial for the diagnosis and management of CCS. .. (11) Beta-blockers and/or CCBs remain the first-line drugs in patients
..
(2) Unless obstructive CAD can be excluded based on clinical evalua- .. with CCS. Beta-blockers are recommended in patients with LV
tion alone, either non-invasive functional imaging or anatomical .. dysfunction or HF with reduced ejection fraction.
..
imaging using coronary CTA may be used as the initial test to rule- .. (12) Long-acting nitrates provoke tolerance with loss of efficacy. This
out or establish the diagnosis of CCS. .. requires prescription of a daily nitrate-free or nitrate-low interval
..
(3) Selection of the initial non-invasive diagnostic test is based on the .. of 1014 h.
PTP, the test’s performance in ruling-in or ruling-out obstructive .. (13) Antithrombotic therapy is a key part of secondary prevention in
..
CAD, patient characteristics, local expertise, and the availability of .. patients with CCS and warrants careful consideration. Patients
the test. .. with a previous MI, who are at high risk of ischaemic events and
..
(4) For revascularization decisions, both anatomy and functional eval- .. low risk of fatal bleeding, should be considered for long-term
uation are to be considered. Either non-invasive or invasive func- .. DAPT with aspirin and either a P2Y12 inhibitor or very low-dose
..
tional evaluation is required for the assessment of myocardial .. rivaroxaban, unless they have an indication for an OAC such as
ischaemia associated with angiographic stenosis, unless very high .. AF.
..
grade (>90% diameter stenosis). .. (14) Statins are recommended in all patients with CCS. ACE inhibitors
(5) Assessment of risk serves to identify CCS patients at high event risk
.. (or ARBs) are recommended in the presence of HF, diabetes, or
..
who are projected to derive prognostic benefit from revasculariza- .. hypertension and should be considered in high-risk patients.
tion. Risk stratification includes the assessment of LV function.
.. (15) Proton pump inhibitors are recommended in patients receiving
(6) Patients at high event risk should undergo invasive investigation for
...
.. aspirin or combination antithrombotic therapy who are at high
consideration of revascularization, even if they have mild or no .. risk of gastrointestinal bleeding.
symptoms.
..
.. (16) Efforts should be made to explain to patients the importance of
(7) Implementation of healthy lifestyle behaviours decreases the risk .. evidence-based prescriptions to increase adherence to treatment,
..
of subsequent cardiovascular events and mortality, and is addi- .. and repeated therapeutic education is essential in every clinical
tional to appropriate secondary prevention therapy. Clinicians .. encounter.
..
should advise on and encourage necessary lifestyle changes in .. (17) Patients with a long-standing diagnosis of CCS should undergo
every clinical encounter. .. periodic visits to assess potential changes in risk status, adherence
..
(8) Cognitive behavioural interventions such as supporting patients to .. to treatment targets, and the development of comorbidities.
set realistic goals, self-monitor, plan how to implement changes .. Repeat stress imaging or ICA with functional testing is recom-
..
and deal with difficult situations, set environmental cues, and .. mended in the presence of worsening symptoms and/or increased
engage social support are effective interventions for behaviour .. risk status.
..
change. .. (18) Assessment of myocardial and valvular function and dimensions, as
(9) Multidisciplinary teams can provide patients with support to make .. well as a functional test to rule-out significant myocardial silent
..
healthy lifestyle changes, and address challenging aspects of behav- .. ischaemia, may be contemplated every 35 years in asymptomatic
iour and risk. .. patients with a long-standing diagnosis of CCS.
..
ESC Guidelines 49

..
(19) An assessment of coronary vasomotor function should be consid- .. of aspirin þ P2Y12 inhibitor with aspirin þ factor Xa inhibitor are
ered in patients with non-significant epicardial CAD and objective .. warranted to determine which subgroups may be preferentially
..
evidence of ischaemia. .. treated with one or other strategy. The potential clinical benefit of
.. ticagrelor monotherapy, while stopping aspirin, remains unproved at
..
.. present.
10 Gaps in the evidence ..
.. The role of biomarkers in stratifying patients’ risk of ischaemic
.. events and bleeding requires clarification, including the role of growth

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10.1 Diagnosis and assessment .. differentiation factor-15 in guiding the risk of bleeding with DAPT. It
More information on the effects of various risk factors, biomarkers,
..
.. is uncertain what effect novel lipid-lowering strategies will have on
and comorbidities on the PTP of obstructive CAD is needed. .. the net clinical benefit of DAPT, with similar implications of other
..
Adequately powered RCTs are needed to compare the effectiveness .. strategies such as intensive BP lowering and, potentially in the future,
of different diagnostic strategies, and to evaluate how to best inte- .. selective anti-inflammatory therapies.
..
grate diagnostic tests in patient care in terms of clinical outcomes and ..
the use of healthcare resources. ..
.. 10.5 Revascularization
.. Further studies, including RCTs, are needed to assess the value of
10.2 Assessment of risk ..
.. functional vs. anatomical guidance for CABG. The concept of com-
Studies should address whether an initial invasive strategy, in addition .. plete revascularization and its effect on prognosis needs to be re-
to optimal medical therapy in patients with CCS and inducible ischae- ..
.. evaluated by prospective comparisons of functional vs. anatomical
mia by non-invasive testing, improves outcomes. Larger trials are .. guidance for stenting on the one hand, and bypass on the other. Of
needed to verify the utility of systematic assessment of biomarkers in
..
.. note, none of the RCTs comparing PCI with CABG to date have
patients with suspected obstructive CAD. .. used combined anatomical and functional guidance for PCI, a strategy
..
.. that is suggested to significantly improve outcomes of PCI (Syntax II
10.3 Lifestyle management ..
.. registry).
Research regarding the most effective methods to support healthy ..
lifestyle behaviours in brief or very brief clinical encounters, and sus- ..
.. 10.6 Heart failure and left ventricular
tain medication and lifestyle behaviour adherence over time, is ..
needed. The cardiovascular effects of newer e-cigarettes over the .. dysfunction
.. Most of the evidence from RCTs supporting the recommendations
long-term remain unknown, as does their effectiveness in smoking ..
cessation. .. for the use of drugs and devices in patients with chronic heart failure
.. is based on cohorts with stable ischaemic heart disease and reduced
The relative benefits of high-intensity interval training vs. ..
moderate-intensity exercise in patients with CCS should be further .. LV function. However, patients with CCS requiring acute or chronic
.. mechanical support are largely excluded from clinical trials, and the
evaluated. The benefits of decreasing sedentary behaviour, and the ..
most appropriate ‘dose’ and type of physical activity in patients with .. optimal management of such patients with drugs and devices during
.. episodes of acute decompensation has not been adequately
CCS, are unknown, as are the effectiveness and cost-effectiveness of ..
increasing cardiac rehabilitation participation among patients with .. addressed.
..
CCS. ..
.. 10.7 Patients with long-standing diagno-
..
10.4 Pharmacological management .. sis of chronic coronary syndromes
The need for and duration of beta-blocker therapy following MI to
..
.. The incremental value of using risk scores to serially evaluate
maintain a protective effect on cardiac events in the absence of LV .. patients’ risks, and more importantly to adjust the intensity of treat-
..
systolic dysfunction are unknown. .. ment, remains to be determined.
In patients with CCS and without a previous MI, it remains to be .. The optimal time intervals for serial visits remain to be
..
determined whether current anti-ischaemic drugs improve .. determined.
prognosis. ..
..
Whether the initial use of second-line anti-ischaemic therapy (i.e. .. 10.8 Angina without obstructive
long-acting nitrates, ranolazine, nicorandil, ivabradine, or trimetazi- ..
.. coronary artery disease
dine) alone or in combination with a first-line drug (i.e. beta-blocker ..
or CCB) is superior to the combination of a beta-blocker with a CCB .. Development of safe and efficacious novel pharmacological agents
.. for this indication remains an unmet need.
to control anginal symptoms and myocardial ischaemia in patients ..
with CCS remains to be proven. ..
..
The efficacy and safety of aspirin or an alternative antithrombotic .. 10.9 Screening in asymptomatic subjects
therapy in patients with a mild extent of atherosclerotic disease, such .. Further studies on biomarkers and imaging tests for screening of
..
as that discovered by coronary CTA, requires further assessment, .. CAD in asymptomatic subjects are needed. Furthermore, there are
including the effect on cancer rates as well as cardiovascular events. .. limited data on how to manage asymptomatic subjects who receive
..
The optimal long-term antithrombotic therapy, and strategies for .. testing and have a positive test result, as evidence demonstrating
individualizing this, in patients at high risk of ischaemic events is uncer-
.. improved prognosis following appropriate management is still
..
tain. Consequently, clinical studies comparing the efficacy and safety . lacking.
50 ESC Guidelines

..
10.10 Comorbidities .. 10.11 Patients with refractory angina
..
The role of PCI in patients with aortic stenosis remains undetermined .. Larger RCTs and registries are required to define the role of additional
with respect to the indication for coronary revascularization and tim- .. treatment modalities for specific subgroups, to decrease non-
..
ing vs. valve intervention. Further information is needed on how to .. responder rates and ascertain benefit beyond potential placebo effects.
adapt cardiovascular therapies in patients with chronic inflammatory ..
..
diseases.

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11 ‘What to do’ and ‘what not to do’ messages from the Guidelines

Recommendations: ‘what to do’ and ‘what not to do’ Classa Levelb

Basic biochemistry testing in the initial diagnostic management of patients with suspected CAD
If evaluation suggests clinical instability or ACS, repeated measurements of troponin, preferably using high-sensitivity or
I A
ultrasensitive assays, are recommended to rule-out myocardial injury associated with ACS.
The following blood tests are recommended in all patients:
• Full blood count (including haemoglobin); I B
• Creatinine measurement and estimation of renal function; I A
• A lipid profile (including LDL-C). I A
It is recommended that screening for type 2 diabetes mellitus in patients with suspected and established CCS is imple-
mented with HbA1c and fasting plasma glucose measurements, and that an oral glucose tolerance test is added if HbA1c I B
and fasting plasma glucose results are inconclusive.
Assessment of thyroid function is recommended in cases where there is clinical suspicion of thyroid disorders. I C
Resting ECG in the initial diagnostic management of patients with suspected CAD
A resting 12 lead ECG is recommended in all patients with chest pain without obvious non-cardiac cause. I C
A resting 12 lead ECG is recommended in all patients during or immediately after an episode of angina suspected to indi-
I C
cate clinical instability of CAD.
ST-segment alterations recorded during supraventricular tachyarrhythmias should not be used as evidence of CAD. III C
Ambulatory ECG monitoring in the initial diagnostic management of patients with suspected CAD
Ambulatory ECG monitoring is recommended in patients with chest pain and suspected arrhythmias. I C
Ambulatory ECG monitoring should not be used as routine examination in patients with suspected CCS. III C
Resting echocardiography and CMR in the initial diagnostic management of patients with suspected CAD
A resting transthoracic echocardiogram is recommended in all patients for:
• Exclusion of alternative causes of angina;
• Identification of regional wall motion abnormalities suggestive of CAD; I B
• Measurement of LVEF for risk-stratification purposes;
• Evaluation of diastolic function.
Chest X-ray in the initial diagnostic management of patients with suspected CAD
Chest X-ray is recommended for patients with an atypical presentation, signs and symptoms of heart failure, or suspicion
I C
of pulmonary disease.
Use of diagnostic imaging tests in the initial diagnostic management of symptomatic patients with suspected CAD
Non-invasive functional imaging for myocardial ischaemia or coronary CTA is recommended as the initial test for diagnos-
I B
ing CAD in symptomatic patients in whom obstructive CAD cannot be excluded by clinical assessment alone.
It is recommended that selection of the initial non-invasive diagnostic test is done based on the clinical likelihood of CAD
I C
and other patient characteristics that influence test performance, local expertise, and the availability of tests.
Functional imaging for myocardial ischaemia is recommended if coronary CTA has shown CAD of uncertain functional sig-
I B
nificance or is not diagnostic.
Invasive angiography is recommended as an alternative test to diagnose CAD in patients with a high clinical likelihood and
severe symptoms refractory to medical therapy, or typical angina at a low level of exercise and clinical evaluation that indi-
I B
cates high event risk. Invasive functional assessment must be available and used to evaluate stenoses before revasculariza-
tion, unless very high grade (>90% diameter stenosis).
Continued
ESC Guidelines 51

Coronary CTA is not recommended when extensive coronary calcification, irregular heart rate, significant obesity, inabil-
III C
ity to cooperate with breath-hold commands, or any other conditions makes good image quality unlikely.
Coronary calcium detection by computed tomography is not recommended to identify individuals with obstructive CAD. III C
Performing exercise ECG in the initial diagnostic management of patients with suspected CAD
Exercise ECG is recommended for the assessment of exercise tolerance, symptoms, arrhythmias, BP response, and event
I C
risk in selected patients.

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Recommendations for risk assessment
Risk stratification is recommended based on clinical assessment and the result of the diagnostic test initially employed to
I B
make a diagnosis of CAD.
Resting echocardiography is recommended to quantify LV function in all patients with suspected CAD. I C
Risk stratification, preferably using stress imaging or coronary CTA (if local expertise and availability permit), or alterna-
tively exercise stress ECG (if significant exercise can be performed and the ECG is amenable to the identification of I B
ischaemic changes), is recommended in patients with suspected or newly diagnosed CAD.
In symptomatic patients with a high-risk clinical profile, ICA complemented by invasive physiological guidance (FFR) is rec-
ommended for cardiovascular risk stratification, particularly if the symptoms are inadequately responding to medical treat- I A
ment and revascularization is considered for improvement of prognosis.
In patients with mild or no symptoms, ICA complemented by invasive physiological guidance (FFR/iwFR) is recommended
for patients undergoing medical treatment in whom non-invasive risk stratification indicates a high event risk and revascu- I A
larization is considered for the improvement of prognosis.
ICA is not recommended solely for risk stratification. III C
Recommendations on lifestyle management
Improvement of lifestyle factors in addition to appropriate pharmacological management is recommended. I A
Cognitive behavioural interventions are recommended to help individuals achieve a healthy lifestyle. I A
Exercise-based cardiac rehabilitation is recommended as an effective means for patients with CCS to achieve a healthy
I A
lifestyle and manage risk factors.
Involvement of multidisciplinary healthcare professionals (cardiologists, GPs, nurses, dieticians, physiotherapists, psycholo-
I A
gists, and pharmacists) is recommended.
Psychological interventions are recommended to improve symptoms of depression in patients with CCS. I B
Annual influenza vaccination is recommended for patients with CCS, especially in the elderly. I B
Recommendations on anti-ischaemic drugs in patients with CCS
General considerations
Medical treatment of symptomatic patients requires one or more drug(s) for angina/ischaemia relief in association with
I C
drug(s) for event prevention.
It is recommended that patients are educated about the disease, risk factors, and treatment strategy. I C
Timely review of the patient’s response to medical therapies (e.g. 24 weeks after drug initiation) is recommended. I C
Angina/ischaemia relief
Short-acting nitrates are recommended for immediate relief of effort angina. I B
First-line treatment is indicated with beta-blockers and/or CCBs to control heart rate and symptoms. I A
Nitrates are not recommended in patients with hypertrophic obstructive cardiomyopathy or co-administration of phos-
III B
phodiesterase inhibitors.
Recommendations for event prevention
Antithrombotic therapy in patients with CCS and in sinus rhythm
Aspirin 75100 mg daily is recommended in patients with a previous MI or revascularization. I A
Clopidogrel 75 mg daily is recommended as an alternative to aspirin in patients with aspirin intolerance. I B
Antithrombotic therapy post-PCI in patients with CCS and in sinus rhythm
Aspirin 75100 mg daily is recommended following stenting. I A
Clopidogrel 75 mg daily following appropriate loading (e.g. 600 mg, >5 days, or maintenance therapy) is recommended, in
addition to aspirin, for 6 months following coronary stenting, irrespective of stent type, unless a shorter duration (13 I A
months) is indicated due to the risk or occurrence of life-threatening bleeding.
Antithrombotic therapy in patients with CCS and AF
When oral anticoagulation is initiated in a patient with AF who is eligible for a NOAC, a NOAC is recommended in pref-
I A
erence to a VKA.
Long-term OAC therapy (a NOAC or VKA with time in therapeutic range >70%) is recommended in patients with AF
I A
and a CHA2DS2-VASc score >_2 in males and >_3 in females.
Continued
52 ESC Guidelines

Antithrombotic therapy in post-PCI patients with AF or another indication for an OAC


It is recommended that peri-procedural aspirin and clopidogrel are administered to patients undergoing coronary stent
I C
implantation.
In patients who are eligible for a NOAC, it is recommended that a NOAC (apixaban 5 mg b.i.d., dabigatran 150 mg b.i.d.,
I A
edoxaban 60 mg o.d., or rivaroxaban 20 mg o.d.) is used in preference to a VKA in combination with antiplatelet therapy.
The use of ticagrelor or prasugrel is not recommended as part of triple antithrombotic therapy with aspirin and an OAC. III C

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Use of proton pump inhibitors
Concomitant use of a proton pump inhibitor is recommended in patients receiving aspirin monotherapy, DAPT, or OAC
I A
monotherapy who are at high risk of gastrointestinal bleeding.
Lipid-lowering drugs
Statins are recommended in all patients with CCS. I A
If the goals are not achieved with the maximum tolerated dose of a statin, combination with ezetimibe is recommended. I B
For patients at very high risk who do not achieve their goal on a maximum tolerated dose of statin and ezetimibe, combi-
I A
nation with a PCSK9 inhibitor is recommended.
ACE inhibitors
ACE inhibitors (or ARBs) are recommended in the presence of other conditions (e.g. HF, hypertension, or diabetes). I A
Other drugs
Beta-blockers are recommended in patients with LV dysfunction or systolic HF. I A
General recommendations for the management of patients with CCS and symptomatic HF due to ischaemic cardiomyopathy and LV
systolic dysfunction
Recommendations for drug therapy
Diuretic therapy is recommended in symptomatic patients with signs of pulmonary or systemic congestion to relieve HF
I B
symptoms.
Beta-blockers are recommended as an essential component of treatment due to their efficacy in both relieving angina, and
I A
reducing morbidity and mortality in HF.
ACE inhibitor therapy is recommended in patients with symptomatic HF or asymptomatic LV dysfunction following MI, to
I A
improve symptoms and reduce morbidity and mortality.
An ARB is recommended as an alternative in patients who do not tolerate ACE inhibition or an angiotensin recep-
I B
tor-neprilysin inhibitor in patients with persistent symptoms despite optimal medical therapy.
An MRA is recommended in patients who remain symptomatic despite adequate treatment with an ACE inhibitor and
I A
beta-blocker to reduce morbidity and mortality.
For devices, comorbidities, and revascularization
In patients with HF and bradycardia with high-degree atrioventricular block who require pacing, a CRT with a pacemaker
I A
rather than right ventricular pacing is recommended.
An implantable cardioverter-defibrillator is recommended in patients with documented ventricular dysrhythmia causing
haemodynamic instability (secondary prevention), as well as in patients with symptomatic HF and an LVEF <_35%, to I A
reduce the risk of sudden death and all-cause mortality.
CRT is recommended for symptomatic patients with HF in sinus rhythm with a QRS duration >_150 ms and LBBB QRS
morphology, and with LVEF <_35% despite optimal medical therapy to improve symptoms and reduce morbidity and mor- I A
tality. 355,356,383392,353,354,381390
CRT is recommended for symptomatic patients with HF in sinus rhythm with a QRS duration 130149 ms and LBBB
QRS morphology, and with LVEF <_35% despite optimal medical therapy to improve symptoms and reduce morbidity and I B
mortality. 355,356,383392,353,354,381390
Comprehensive risk profiling and multidisciplinary management, including treatment of major comorbidities such as
hypertension, hyperlipidaemia, diabetes, anaemia, and obesity, as well as smoking cessation and lifestyle modification, are I A
recommended.
Myocardial revascularization is recommended when angina persists despite treatment with antianginal drugs. I A
Recommendations for patients with a long-standing diagnosis of CCS
Asymptomatic patients
A periodic visit to a cardiovascular healthcare professional is recommended to reassess potential changes in the risk status
of patients, entailing clinical evaluation of lifestyle-modification measures, adherence to targets of cardiovascular risk fac- I C
tors, and the development of comorbidities that may affect treatments and outcomes.
Continued
ESC Guidelines 53

In patients with mild or no symptoms receiving medical treatment, in whom non-invasive risk stratification indicates a high
risk, and for whom revascularization is considered for improvement of prognosis, ICA (with FFR when necessary) is I C
recommended.
Coronary CTA is not recommended as a routine follow-up test for patients with established CAD. III C
ICA is not recommended solely for risk stratification. III C
Symptomatic patients

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Reassessment of CAD status is recommended in patients with deteriorating LV systolic function that cannot be attributed
I C
to a reversible cause (e.g. long-standing tachycardia or myocarditis).
Risk stratification is recommended for patients with new or worsening symptom levels, preferably using stress imaging or,
I B
alternatively, exercise stress ECG.
It is recommended that patients with significant worsening of symptoms be expeditiously referred for evaluation. I C
ICA (with FFR/iwFR when necessary) is recommended for risk stratification in patients with severe CAD, particularly if
I C
the symptoms are refractory to medical treatment or if they have a high-risk clinical profile.
Investigations in patients with suspected vasospastic angina
An ECG is recommended during angina if possible. I C
Invasive angiography or coronary CTA is recommended in patients with characteristic episodic resting angina and ST-seg-
ment changes, which resolve with nitrates and/or calcium antagonists, to determine the extent of underlying coronary I C
disease.
Screening for CAD in asymptomatic subjects
Total risk estimation using a risk-estimation system such as SCORE is recommended for asymptomatic adults aged >40
I C
years without evidence of CVD, diabetes, CKD, or familial hypercholesterolaemia.
Assessment of family history of premature CVD (defined as a fatal or non-fatal CVD event, and/or established diagnosis of
CVD in first-degree male relatives before 55 years of age or female relatives before 65 years of age) is recommended as I C
part of cardiovascular risk assessment.
It is recommended that all individuals aged <50 years with a family history of premature CVD in a first-degree relative
(<55 years of age in men, <65 years of age in women) are screened for familial hypercholesterolaemia using a validated I B
clinical score.
Carotid ultrasound IMT for cardiovascular risk assessment is not recommended. III A
In low-risk non-diabetic asymptomatic adults, coronary CTA or functional imaging for ischaemia is not indicated for fur-
III C
ther diagnostic assessment.
Routine assessment of circulating biomarkers is not recommendedfor cardiovascular risk stratification. III B
Recommendations for hypertension treatment in CCS
It is recommended that office BP be controlled to target values: systolic BP 120130 mmHg in general and systolic BP
I A
130140 mmHg in older patients (aged >65 years).
In hypertensive patients with a recent MI, beta-blockers and RAS blockers are recommended. I A
In patients with symptomatic angina, beta-blockers and/or CCBs are recommended. I A
The combination of ACE inhibitors and an ARB is not recommended. III A
Recommendations for valvular disease in CCS
ICA is recommended before valve surgery and any of the following: history of CVD, suspected myocardial ischaemia, LV
I C
systolic dysfunction, in men aged >40 years and post-menopausal women, or one or more cardiovascular risk factors.
ICA is recommended in the evaluation of moderate-to-severe functional mitral regurgitation. I C
In severe valvular heart disease, stress testing should not be routinely used to detect CAD because of the low diagnostic
III C
yield and potential risks.
Recommendations for active cancer in CCS
Treatment decisions should be based on life expectancy, additional comorbidities such as thrombocytopenia, increased
I C
thrombosis propensity, and potential interactions between drugs used in CCS management and antineoplastic agents.
If revascularization is indicated in highly symptomatic patients with active cancer and increased frailty, the least invasive
I C
procedure is recommended.
Recommendations for diabetes mellitus in CCS
Risk factor (BP, LDL-C, and HbA1c) control to targets is recommended in patients with CAD and diabetes mellitus. I A
In asymptomatic patients with diabetes mellitus, a periodic resting ECG is recommended for cardiovascular detection of
I C
conduction abnormalities, AF, and silent MI.
Continued
54 ESC Guidelines

Treatment with ACE inhibitors is recommended in CCS patients with diabetes for event prevention. I B
The sodium-glucose co-transporter 2 inhibitors empagliflozin, canagliflozin, or dapagliflozin are recommended in patients
I A
with diabetes and CVD.
A glucagon-like peptide-1 receptor agonist (liraglutide or semaglutide) is recommended in patients with diabetes and
I A
CVD.
Recommendations for CKD in CCS

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It is recommended that risk factors are controlled to target values. I A
It is recommended that special attention be paid to potential dose adjustments of renally excreted drugs used in CCS. I C
It is recommended that the use of iodinated contrast agents is minimized in patients with severe CKD and preserved urine
I B
production to prevent further deterioration.
Recommendations for elderly patients with CCS
It is recommended that particular attention is paid to side effects of drugs, intolerance, and overdosing in elderly patients. I C
The use of DES is recommended in elderly patients. I A
Radial access is recommended in elderly patients to reduce access-site bleeding complications. I B
It is recommended that diagnostic and revascularization decisions are based on symptoms, the extent of ischaemia, frailty,
I C
life expectancy, and comorbidities.
Recommendation for sex issues and CCS
Hormone replacement therapy is not recommended for risk reduction in post-menopausal women. III C
Treatment options in refractory angina
Transmyocardial revascularization is not recommended in patients with debilitating angina refractory to optimal medical
III A
and revascularization strategies.

ACE = angiotensin-converting enzyme; ACS = acute coronary syndromes; AF = atrial fibrillation; ARB = angiotensin receptor blocker; b.i.d. = bis in die (twice a day); BP =
blood pressure; CHA2DS2-VASc = Cardiac failure, Hypertension, Age >_75 [Doubled], Diabetes, Stroke [Doubled]  Vascular disease, Age 6574 and Sex category [Female];
CAD = coronary artery disease; CCB = calcium channel blocker; CCS = chronic coronary syndromes; CKD = chronic kidney disease; CMR = cardiac magnetic resonance;
CRT = cardiac resynchronization therapy; CTA = computed tomography angiography; CVD = cardiovascular disease; DAPT = dual antiplatelet therapy; DES = drug-eluting
stent; ECG = electrocardiogram; FFR = fractional flow reserve; GPs = general practitioners; HbA1C = glycated haemoglobin; HF = heart failure; ICA = invasive coronary
angiography; IMT = intima-media thickness; iwFR = instantaneous wave-free ratio (instant flow reserve); LBBB = left bundle branch block; LDL-C = low-density lipoprotein cho-
lesterol; LV = left ventricular; LVEF = left ventricular ejection fraction; MI = myocardial infarction; MRA = mineralocorticoid receptor antagonist; NOAC = non-vitamin K antag-
onist oral anticoagulant; OAC = oral anticoagulant; o.d. = omni die (once a day); PCI = percutaneous coronary intervention; PCSK9 = proprotein convertase subtilisin-kexin
type 9; RAS = renin-angiotensin system; VKA = vitamin K antagonist.
a
Class of recommendation.
b
Level of evidence.

..
12 Supplementary data ..
..
University of Bergen, Stavanger, Norway; Thor Edvardsen,
.. Cardiology, Oslo University Hospital, Oslo, Norway; Javier Escaned,
Supplementary Data with additional Supplementary Tables and Figures .. Interventional Cardiology Unit, Hospital Clinico San Carlos, Madrid,
complementing the full text—as well as section 3 on patients with angina .. Spain; Christian Funck-Brentano, Department of Clinical
and/or dyspnoea, and suspected coronary artery disease—are available
..
.. Pharmacology, Sorbonne Université, AP-HP, ICAN and INSERM CIC
on the European Heart Journal website and via the ESC website at www. .. Paris-Est, Paris, France; Bernard J. Gersh, Department of
escardio.org/guidelines. ..
.. Cardiovascular Medicine, Mayo Clinic, Rochester, MN, United States of
.. America; Martine Gilard, Cardiology, Brest University, Brest, France;
..
.. David Hasdai, Cardiology, Rabin Medical Center Petah Tikva, Israel;
13 Appendix .. Robert Hatala, Department of Cardiology and Angiology, Slovak
..
Author/Task Force Member affiliations: .. Cardiovascular Institute, Slovak Medical University, Bratislava, Slovakia;
.. Felix Mahfoud, Internal Medicine III, Saarland University, Homburg,
Stephan Achenbach, Department of Cardiology, Friedrich- ..
Alexander-Universit€at Erlangen-Nürnberg, Erlangen, Germany; Stefan .. Germany; Josep Masip, Cardiology Department /Intensive Care
.. Department, Hospital CIMA-Sanitas/Consorci Sanitari Integral/
Agewall, Department of Medicine, Clinical Science, Oslo, Norway; ..
Emanuele Barbato, Advanced Biomedical Sciences, University .. University of Barcelona, Barcelona, Spain; Claudio Muneretto,
..
Federico II, Naples, Italy; Jeroen J. Bax, Cardiology, Leiden University .. Cardiovascular Surgery, University of Brescia Medical School, Brescia,
Medical Center, Leiden, Netherlands; Davide Capodanno, .. Italy; Eva Prescott, Department of Cardiology, Bispebjerg University
..
CardioThoracic-Vascular and Transplant Department, A.O.U. .. Hospital, Copenhagen, Denmark; Antti Saraste, Heart Center, Turku
‘Policlinico-Vittorio Emanuele’, University of Catania, Catania, Italy; .. University Hospital, Turku, Finland; Robert F. Storey, Department of
..
Thomas Cuisset, Cardiology, CHU Timone, Marseille, France; .. Infection, Immunity and Cardiovascular Disease, University of Sheffield,
Christi Deaton, Public Health and Primary Care, University of
.. Sheffield, United Kingdom; Pavel Svitil, Cardiologic Practice, Practice
..
Cambridge School of Clinical Medicine, Cambridge, United Kingdom; .. of General Cardiology, Jihlava, Czech Republic; Marco Valgimigli,
Kenneth Dickstein, Cardiology, Stavanger University Hospital,
.. Inselspital, University of Bern, Bern, Switzerland.
ESC Guidelines 55

..
ESC Committee for Practice Guidelines (CPG): Stephan .. Dikic; Slovakia: Slovak Society of Cardiology, Martin Studencan;
Windecker (Chairperson) (Switzerland), Victor Aboyans (France), .. Slovenia: Slovenian Society of Cardiology, Matjaz Bunc; Spain:
..
Colin Baigent (United Kingdom), Jean-Philippe Collet (France), .. Spanish Society of Cardiology, Fernando Alfonso; Sweden:
Veronica Dean (France), Victoria Delgado (Netherlands), Donna .. Swedish Society of Cardiology, Magnus B€ack; Switzerland: Swiss
..
Fitzsimons (United Kingdom), Christopher P. Gale (United .. Society of Cardiology, Michael Zellweger; Tunisia: Tunisian
Kingdom), Diederick E. Grobbee (Netherlands), Sigrun Halvorsen .. Society of Cardiology and Cardio-Vascular Surgery, Faouzi Addad;
..
(Norway), Gerhard Hindricks (Germany), Bernard Iung (France), .. Turkey: Turkish Society of Cardiology, Aylin Yildirir; Ukraine:

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Peter Jüni (Canada), Hugo A. Katus (Germany), Ulf Landmesser .. Ukrainian Association of Cardiology, Yuriy Sirenko; United
..
(Germany), Christophe Leclercq (France), Maddalena Lettino (Italy), .. Kingdom of Great Britain and Northern Ireland: British
Basil S. Lewis (Israel), Bela Merkely (Hungary), Christian Mueller .. Cardiovascular Society, Brian Clapp.
..
(Switzerland), Steffen Petersen (United Kingdom), Anna Sonia ..
Petronio (Italy), Dimitrios J. Richter (Greece), Marco Roffi ..
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European Heart Journal (2016) 37, 267–315 ESC GUIDELINES
doi:10.1093/eurheartj/ehv320

2015 ESC Guidelines for the management


of acute coronary syndromes in patients
presenting without persistent ST-segment
elevation

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Task Force for the Management of Acute Coronary Syndromes
in Patients Presenting without Persistent ST-Segment Elevation
of the European Society of Cardiology (ESC)
Authors/Task Force Members: Marco Roffi* (Chairperson) (Switzerland),
Carlo Patrono* (Co-Chairperson) (Italy), Jean-Philippe Collet† (France),
Christian Mueller† (Switzerland), Marco Valgimigli† (The Netherlands),
Felicita Andreotti (Italy), Jeroen J. Bax (The Netherlands), Michael A. Borger
(Germany), Carlos Brotons (Spain), Derek P. Chew (Australia), Baris Gencer
(Switzerland), Gerd Hasenfuss (Germany), Keld Kjeldsen (Denmark),
Patrizio Lancellotti (Belgium), Ulf Landmesser (Germany), Julinda Mehilli (Germany),
Debabrata Mukherjee (USA), Robert F. Storey (UK), and Stephan Windecker
(Switzerland)
Document Reviewers: Helmut Baumgartner (CPG Review Coordinator) (Germany), Oliver Gaemperli (CPG Review
Coordinator) (Switzerland), Stephan Achenbach (Germany), Stefan Agewall (Norway), Lina Badimon (Spain),
Colin Baigent (UK), Héctor Bueno (Spain), Raffaele Bugiardini (Italy), Scipione Carerj (Italy), Filip Casselman
(Belgium), Thomas Cuisset (France), Çetin Erol (Turkey), Donna Fitzsimons (UK), Martin Halle (Germany),

* Corresponding authors: Marco Roffi, Division of Cardiology, University Hospital, Rue Gabrielle Perret-Gentil 4, 1211 Geneva 14, Switzerland, Tel: +41 22 37 23 743, Fax: +41 22 37
27 229, E-mail: Marco.Roffi@hcuge.ch
Carlo Patrono, Istituto di Farmacologia, Università Cattolica del Sacro Cuore, Largo F. Vito 1, IT-00168 Rome, Italy, Tel: +39 06 30154253, Fax: +39 06 3050159, E-mail: carlo.
patrono@rm.unicatt.it

Section Coordinators affiliations listed in the Appendix.
ESC Committee for Practice Guidelines (CPG) and National Cardiac Societies document reviewers listed in the Appendix.
ESC entities having participated in the development of this document:
Associations: Acute Cardiovascular Care Association (ACCA), European Association for Cardiovascular Prevention & Rehabilitation (EACPR), European Association of Cardiovas-
cular Imaging (EACVI), European Association of Percutaneous Cardiovascular Interventions (EAPCI), Heart Failure Association (HFA).
Councils: Council on Cardiovascular Nursing and Allied Professions (CCNAP), Council for Cardiology Practice (CCP), Council on Cardiovascular Primary Care (CCPC).
Working Groups: Working Group on Cardiovascular Pharmacotherapy, Working Group on Cardiovascular Surgery, Working Group on Coronary Pathophysiology and Microcir-
culation, Working Group on Thrombosis.
The content of these European Society of Cardiology (ESC) Guidelines has been published for personal and educational use only. No commercial use is authorized. No part of the
ESC Guidelines may be translated or reproduced in any form without written permission from the ESC. Permission can be obtained upon submission of a written request to Oxford
University Press, the publisher of the European Heart Journal and the party authorized to handle such permissions on behalf of the ESC.
Disclaimer: The ESC Guidelines represent the views of the ESC and were produced after careful consideration of the scientific and medical knowledge and the evidence available at
the time of their publication. The ESC is not responsible in the event of any contradiction, discrepancy and/or ambiguity between the ESC Guidelines and any other official recom-
mendations or guidelines issued by the relevant public health authorities, in particular in relation to good use of healthcare or therapeutic strategies. Health professionals are encour-
aged to take the ESC Guidelines fully into account when exercising their clinical judgment, as well as in the determination and the implementation of preventive, diagnostic or
therapeutic medical strategies; however, the ESC Guidelines do not override, in any way whatsoever, the individual responsibility of health professionals to make appropriate and
accurate decisions in consideration of each patient’s health condition and in consultation with that patient and, where appropriate and/or necessary, the patient’s caregiver. Nor
do the ESC Guidelines exempt health professionals from taking into full and careful consideration the relevant official updated recommendations or guidelines issued by the competent
public health authorities, in order to manage each patient’s case in light of the scientifically accepted data pursuant to their respective ethical and professional obligations. It is also the
health professional’s responsibility to verify the applicable rules and regulations relating to drugs and medical devices at the time of prescription.
& The European Society of Cardiology 2015. All rights reserved. For permissions please email: journals.permissions@oup.com.
268 ESC Guidelines

Christian Hamm (Germany), David Hildick-Smith (UK), Kurt Huber (Austria), Efstathios Iliodromitis (Greece),
Stefan James (Sweden), Basil S. Lewis (Israel), Gregory Y. H. Lip (UK), Massimo F. Piepoli (Italy), Dimitrios Richter
(Greece), Thomas Rosemann (Switzerland), Udo Sechtem (Germany), Ph. Gabriel Steg (France), Christian Vrints
(Belgium), and Jose Luis Zamorano (Spain)
The disclosure forms of all experts involved in the development of these guidelines are available on the ESC website
http://www.escardio.org/guidelines

Online publish-ahead-of-print 29 August 2015

- - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - -- - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - -
Keywords Acute cardiac care † Acute coronary syndromes † Angioplasty † Anticoagulation † Apixaban † Aspirin †
Atherothrombosis † Beta-blockers † Bivalirudin † Bypass surgery † Cangrelor † Chest pain unit †

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Clopidogrel † Dabigatran † Diabetes † Early invasive strategy † Enoxaparin † European Society of
Cardiology † Fondaparinux † Glycoprotein IIb/IIIa inhibitors † Guidelines † Heparin † High-sensitivity
troponin † Myocardial ischaemia † Nitrates † Non-ST-elevation myocardial infarction † Platelet inhibition †
Prasugrel † Recommendations † Revascularization † Rhythm monitoring † Rivaroxaban † Statin † Stent †
Ticagrelor † Unstable angina † Vorapaxar

Table of Contents
Abbreviations and acronyms . . . . . . . . . . . . . . . . . . . . . . . . 270 5.1.1 General supportive measures . . . . . . . . . . . . . . . 281
1. Preamble . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 271 5.1.2 Nitrates . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 281
2. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 273 5.1.3 Beta-blockers . . . . . . . . . . . . . . . . . . . . . . . . . . 281
2.1 Definitions, pathophysiology and epidemiology . . . . . . . 273 5.1.4 Other drug classes (see Web addenda) . . . . . . . . . 282
2.1.1 Universal definition of myocardial infarction . . . . . . 273 5.1.5 Recommendations for anti-ischaemic drugs in
2.1.1.1 Type 1 MI . . . . . . . . . . . . . . . . . . . . . . . . . 273 the acute phase of non-ST-elevation acute coronary
2.1.1.2 Type 2 MI . . . . . . . . . . . . . . . . . . . . . . . . . 273 syndromes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 282
2.1.2 Unstable angina in the era of high-sensitivity cardiac 5.2 Platelet inhibition . . . . . . . . . . . . . . . . . . . . . . . . . . 282
troponin assays . . . . . . . . . . . . . . . . . . . . . . . . . . . . 273 5.2.1 Aspirin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 282
2.1.3 Pathophysiology and epidemiology 5.2.2 P2Y12 inhibitors . . . . . . . . . . . . . . . . . . . . . . . . 282
(see Web addenda) . . . . . . . . . . . . . . . . . . . . . . . . . 273 5.2.2.1 Clopidogrel . . . . . . . . . . . . . . . . . . . . . . . . 282
3. Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 273 5.2.2.2 Prasugrel . . . . . . . . . . . . . . . . . . . . . . . . . . 282
3.1 Clinical presentation . . . . . . . . . . . . . . . . . . . . . . . . 273 5.2.2.3 Ticagrelor . . . . . . . . . . . . . . . . . . . . . . . . . 283
3.2 Physical examination . . . . . . . . . . . . . . . . . . . . . . . . 274 5.2.2.4 Cangrelor . . . . . . . . . . . . . . . . . . . . . . . . . 284
3.3 Diagnostic tools . . . . . . . . . . . . . . . . . . . . . . . . . . . 274 5.2.3 Timing of P2Y12 inhibitor administration . . . . . . . . 285
3.3.1 Electrocardiogram . . . . . . . . . . . . . . . . . . . . . . 274 5.2.4 Monitoring of P2Y12 inhibitors
3.3.2 Biomarkers . . . . . . . . . . . . . . . . . . . . . . . . . . . 275 (see Web addenda) . . . . . . . . . . . . . . . . . . . . . . . . . 285
3.3.3 ‘Rule-in’ and ‘rule-out’ algorithms . . . . . . . . . . . . . 276 5.2.5 Premature discontinuation of oral antiplatelet
3.3.4 Non-invasive imaging . . . . . . . . . . . . . . . . . . . . . 277 therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 285
3.3.4.1 Functional evaluation . . . . . . . . . . . . . . . . . . 277 5.2.6 Duration of dual antiplatelet therapy . . . . . . . . . . . 285
3.3.4.2 Anatomical evaluation . . . . . . . . . . . . . . . . . 277 5.2.7 Glycoprotein IIb/IIIa inhibitors . . . . . . . . . . . . . . . 286
3.4 Differential diagnosis . . . . . . . . . . . . . . . . . . . . . . . . 278 5.2.7.1 Upstream versus procedural initiation
4. Risk assessment and outcomes . . . . . . . . . . . . . . . . . . . . . 278 (see Web addenda) . . . . . . . . . . . . . . . . . . . . . . . . 286
4.1 Clinical presentation, electrocardiogram and biomarkers 278 5.2.7.2 Combination with P2Y12 inhibitors
4.1.1 Clinical presentation . . . . . . . . . . . . . . . . . . . . . 278 (see Web addenda) . . . . . . . . . . . . . . . . . . . . . . . . 286
4.1.2 Electrocardiogram . . . . . . . . . . . . . . . . . . . . . . 278 5.2.7.3 Adjunctive anticoagulant therapy
4.1.3 Biomarkers . . . . . . . . . . . . . . . . . . . . . . . . . . . 279 (see Web addenda) . . . . . . . . . . . . . . . . . . . . . . . . 286
4.2 Ischaemic risk assessment . . . . . . . . . . . . . . . . . . . . . 279 5.2.8 Vorapaxar (see Web addenda) . . . . . . . . . . . . . . 286
4.2.1 Acute risk assessment . . . . . . . . . . . . . . . . . . . . 279 5.2.9 Recommendations for platelet inhibition in
4.2.2 Cardiac rhythm monitoring . . . . . . . . . . . . . . . . . 279 non-ST-elevation acute coronary syndromes . . . . . . . . . 286
4.2.3 Long-term risk . . . . . . . . . . . . . . . . . . . . . . . . . 280 5.3 Anticoagulation . . . . . . . . . . . . . . . . . . . . . . . . . . . 287
4.3 Bleeding risk assessment . . . . . . . . . . . . . . . . . . . . . 280 5.3.1 Anticoagulation during the acute phase . . . . . . . . . 287
4.4 Recommendations for diagnosis, risk stratification, imaging 5.3.1.1 Unfractionated heparin . . . . . . . . . . . . . . . . 287
and rhythm monitoring in patients with suspected non-ST- 5.3.1.2 Low molecular weight heparin . . . . . . . . . . . . 288
elevation acute coronary syndromes . . . . . . . . . . . . . . . . 280 5.3.1.3 Fondaparinux . . . . . . . . . . . . . . . . . . . . . . . 288
5. Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 281 5.3.1.4 Bivalirudin . . . . . . . . . . . . . . . . . . . . . . . . . 288
5.1 Pharmacological treatment of ischaemia . . . . . . . . . . . 281 5.3.2 Anticoagulation following the acute phase . . . . . . . 289
ESC Guidelines 269

5.3.3 Recommendations for anticoagulation in acute coronary syndrome patients requiring coronary
non-ST-elevation acute coronary syndromes . . . . . . . . . 289 artery bypass surgery . . . . . . . . . . . . . . . . . . . . . . . 299
5.4 Managing oral antiplatelet agents in patients requiring 5.6.6.3 Technical aspects and outcomes
long-term oral anticoagulants . . . . . . . . . . . . . . . . . . . . . 290 (see Web addenda) . . . . . . . . . . . . . . . . . . . . . . . . 299
5.4.1 Patients undergoing percutaneous coronary 5.6.7 Percutaneous coronary intervention vs. coronary
intervention . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 290 artery bypass surgery . . . . . . . . . . . . . . . . . . . . . . . . 299
5.4.2 Patients medically managed or requiring coronary 5.6.8 Management of patients with cardiogenic shock . . . 300
artery bypass surgery . . . . . . . . . . . . . . . . . . . . . . . . 292 5.6.9 Recommendations for invasive coronary angiography
5.4.3 Recommendations for combining antiplatelet agents and revascularization in non-ST-elevation acute coronary
and anticoagulants in non-ST-elevation acute coronary syndromes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 300
syndrome patients requiring chronic oral anticoagulation . 292 5.7 Gender specificities (see Web addenda) . . . . . . . . . . . 301
5.5 Management of acute bleeding events 5.8 Special populations and conditions (see Web addenda) . 301

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(see Web addenda) . . . . . . . . . . . . . . . . . . . . . . . . . . . 293 5.8.1 The elderly and frail patients (see Web addenda) . . 301
5.5.1 General supportive measures (see Web addenda) . . 293 5.8.1.1 Recommendations for the management of
5.5.2 Bleeding events on antiplatelet agents elderly patients with non-ST-elevation acute coronary
(see Web addenda) . . . . . . . . . . . . . . . . . . . . . . . . . 293 syndromes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 301
5.5.3 Bleeding events on vitamin K antagonists 5.8.2 Diabetes mellitus (see Web addenda) . . . . . . . . . . 301
(see Web addenda) . . . . . . . . . . . . . . . . . . . . . . . . . 293 5.8.2.1 Recommendations for the management of
5.5.4 Bleeding events on non-vitamin K antagonist oral diabetic patients with non-ST-elevation acute coronary
anticoagulants (see Web addenda) . . . . . . . . . . . . . . . . 293 syndromes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 301
5.5.5 Non-access-related bleeding events 5.8.3 Chronic kidney disease (see Web addenda) . . . . . . 302
(see Web addenda) . . . . . . . . . . . . . . . . . . . . . . . . . 293 5.8.3.1 Dose adjustment of antithrombotic agents
5.5.6 Bleeding events related to percutaneous coronary (see Web addenda) . . . . . . . . . . . . . . . . . . . . . . . . 302
intervention (see Web addenda) . . . . . . . . . . . . . . . . . 293 5.8.3.2 Recommendations for the management of
5.5.7 Bleeding events related to coronary artery bypass patients with chronic kidney disease and non-ST-
surgery (see Web addenda) . . . . . . . . . . . . . . . . . . . . 293 elevation acute coronary systems . . . . . . . . . . . . . . . 302
5.5.8 Transfusion therapy (see Web addenda) . . . . . . . . 293 5.8.4 Left ventricular dysfunction and heart failure (see
5.5.9 Recommendations for bleeding management and Web addenda) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 302
blood transfusion in non-ST-elevation acute coronary 5.8.4.1 Recommendations for the management of
syndromes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 293 patients with acute heart failure in the setting of non-ST-
5.6 Invasive coronary angiography and revascularization . . . 294 elevation acute coronary syndromes . . . . . . . . . . . . . 302
5.6.1 Invasive coronary angiography . . . . . . . . . . . . . . . 294 5.8.4.2 Recommendations for the management of
5.6.1.1 Pattern of coronary artery disease . . . . . . . . . 294 patients with heart failure following non-ST-elevation
5.6.1.2 Identification of the culprit lesion . . . . . . . . . . 294 acute coronary syndromes . . . . . . . . . . . . . . . . . . . 303
5.6.1.3 Fractional flow reserve . . . . . . . . . . . . . . . . . 295 5.8.5 Atrial fibrillation (see Web addenda) . . . . . . . . . . 303
5.6.2 Routine invasive vs. selective invasive approach . . . . 295 5.8.5.1 Recommendations for the management of atrial
5.6.3 Timing of invasive strategy . . . . . . . . . . . . . . . . . 295 fibrillation in patients with non-ST-elevation acute
5.6.3.1 Immediate invasive strategy (,2 h) . . . . . . . . . 295 coronary syndromes . . . . . . . . . . . . . . . . . . . . . . . 303
5.6.3.2 Early invasive strategy (,24 h) . . . . . . . . . . . 295 5.8.6 Anaemia (see Web addenda) . . . . . . . . . . . . . . . 304
5.6.3.3 Invasive strategy (,72 h) . . . . . . . . . . . . . . . 296 5.8.7 Thrombocytopenia (see Web addenda) . . . . . . . . 304
5.6.3.4 Selective invasive strategy . . . . . . . . . . . . . . . 297 5.8.7.1 Thrombocytopenia related to GPIIb/IIIa
5.6.4 Conservative treatment . . . . . . . . . . . . . . . . . . . 297 inhibitors (Web addenda) . . . . . . . . . . . . . . . . . . . . 304
5.6.4.1 In patients with coronary artery disease . . . . . . 297 5.8.7.2 Heparin-induced thrombocytopenia (Web
5.6.4.1.1 Non-obstructive CAD . . . . . . . . . . . . . . 297 addenda) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 304
5.6.4.1.2 CAD not amenable to revascularization . . . 297 5.8.7.3 Recommendations for the management of
5.6.4.2 In patients with normal coronary angiogram thrombocytopenia in non-ST-elevation acute coronary
(see Web addenda) . . . . . . . . . . . . . . . . . . . . . . . . 297 syndromes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 304
5.6.5 Percutaneous coronary intervention . . . . . . . . . . . 297 5.8.8 Patients requiring chronic analgesic or anti-
5.6.5.1 Technical aspects and challenges . . . . . . . . . . 297 inflammatory treatment (see Web addenda) . . . . . . . . . 304
5.6.5.2 Vascular access . . . . . . . . . . . . . . . . . . . . . . 298 5.8.9 Non-cardiac surgery (see Web addenda) . . . . . . . . 304
5.6.5.3 Revascularization strategies and outcomes . . . . 298 5.9 Long-term management . . . . . . . . . . . . . . . . . . . . . . 304
5.6.6 Coronary artery bypass surgery . . . . . . . . . . . . . . 298 5.9.1 Medical therapy for secondary prevention . . . . . . . 304
5.6.6.1 Timing of surgery and antithrombotic drug 5.9.1.1 Lipid-lowering treatment . . . . . . . . . . . . . . . 304
discontinuation (see Web addenda) . . . . . . . . . . . . . 299 5.9.1.2 Antithrombotic therapy . . . . . . . . . . . . . . . . 304
5.6.6.2 Recommendations for perioperative 5.9.1.3 ACE inhibition . . . . . . . . . . . . . . . . . . . . . . 304
management of antiplatelet therapy in non-ST-elevation 5.9.1.4 Beta-blockers . . . . . . . . . . . . . . . . . . . . . . . 304
270 ESC Guidelines

5.9.1.5 Mineralocorticoid receptor antagonist therapy . 304 CKD chronic kidney disease
5.9.1.6 Antihypertensive therapy . . . . . . . . . . . . . . . 304 CK-MB creatine kinase myocardial band
5.9.1.7 Glucose-lowering therapy in diabetic patients . . 304 COX cyclooxygenase
5.9.2 Lifestyle changes and cardiac rehabilitation . . . . . . . 305 CMR cardiac magnetic resonance
5.9.3 Recommendations for long-term management after CPG Committee for Practice Guidelines
non-ST-elevation acute coronary syndromes . . . . . . . . . 305 CREDO Clopidogrel for the Reduction of Events
6. Performance measures . . . . . . . . . . . . . . . . . . . . . . . . . . 305 During Observation
7. Summary of management strategy . . . . . . . . . . . . . . . . . . . 306 CRUSADE Can Rapid risk stratification of Unstable an-
8. Gaps in evidence . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 307 gina patients Suppress ADverse outcomes
9. To do and not to do messages from the guidelines . . . . . . . . 308 with Early implementation of the ACC/AHA
10. Web addenda and companion documents . . . . . . . . . . . . . 309 guidelines
11. Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . 309 CT computed tomography

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12. Appendix . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 309 CURE Clopidogrel in Unstable Angina to Prevent
13. References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 309 Recurrent Events
CURRENT-OASIS Clopidogrel and Aspirin Optimal Dose Usage
7 to Reduce Recurrent Events –Seventh Organ-
ization to Assess Strategies in Ischaemic
Abbreviations and acronyms Syndromes
CV cardiovascular
ACC American College of Cardiology CYP cytochrome P450
ACCOAST Comparison of Prasugrel at the Time of DAPT dual(oral) antiplatelet therapy
Percutaneous Coronary Intervention or as DES drug-eluting stent
Pretreatment at the Time of Diagnosis in EARLY-ACS Early Glycoprotein IIb/IIIa Inhibition in
Patients with Non-ST Elevation Myocardial Non-ST-Segment Elevation Acute Coronary
Infarction Syndrome
ACE angiotensin-converting enzyme ECG electrocardiogram
ACS acute coronary syndromes eGFR estimated glomerular filtration rate
ACT activated clotting time EMA European Medicines Agency
ACTION Acute Coronary Treatment and Intervention ESC European Society of Cardiology
Outcomes Network FDA Food and Drug Administration
ACUITY Acute Catheterization and Urgent Interven- FFR fractional flow reserve
tion Triage strategY FREEDOM Future Revascularization Evaluation in
ADAPT-DES Assessment of Dual AntiPlatelet Therapy with Patients with Diabetes Mellitus: Optimal
Drug-Eluting Stents Management of Multivessel Disease
ADP adenosine diphosphate GPIIb/IIIa glycoprotein IIb/IIIa
AHA American Heart Association GRACE 2.0 Global Registry of Acute Coronary Events 2.0
APPRAISE Apixaban for Prevention of Acute Ischaemic GUSTO Global Utilization of Streptokinase and TPA
Events for Occluded Arteries
aPTT activated partial thromboplastin time GWTG Get With The Guidelines
ARB angiotensin receptor blocker HAS-BLED hypertension, abnormal renal and liver func-
ATLAS ACS Anti-Xa Therapy to Lower Cardiovascular tion (1 point each), stroke, bleeding history
2-TIMI 51 Events in Addition to Aspirin With or With- or predisposition, labile INR, elderly (.65
out Thienopyridine Therapy in Subjects with years), drugs and alcohol (1 point each)
Acute Coronary Syndrome – Thrombolysis HIT heparin-induced thrombocytopenia
in Myocardial Infarction 51 HORIZONS Harmonizing Outcomes with Revasculariza-
ATP adenosine triphosphate tiON and Stents in Acute Myocardial Infarction
BARC Bleeding Academic Research Consortium HR hazard ratio
BMS bare-metal stent IABP-Shock II Intra-Aortic Balloon Pump in Cardiogenic
CABG coronary artery bypass graft Shock II
CAD coronary artery disease IMPROVE-IT IMProved Reduction of Outcomes: Vytorin
CHA2DS2-VASc Cardiac failure, Hypertension, Age ≥75 Efficacy International Trial
(2 points), Diabetes, Stroke (2 points)– INR international normalized ratio
Vascular disease, Age 65 –74, Sex category ISAR-CLOSURE Instrumental Sealing of ARterial puncture
CHAMPION Cangrelor versus Standard Therapy to site – CLOSURE device versus manual
Achieve Optimal Management of Platelet compression
Inhibition ISAR-REACT Intracoronary stenting and Antithrombotic
CI confidence interval Regimen – Rapid Early Action for Coronary
CK creatine kinase Treatment
ESC Guidelines 271

ISAR-TRIPLE Triple Therapy in Patients on Oral Anticoagula- TIA transient ischaemic attack
tion After Drug Eluting Stent Implantation TIMACS Timing of Intervention in Patients with Acute
i.v. intravenous Coronary Syndromes
LDL low-density lipoprotein TIMI Thrombolysis In Myocardial Infarction
LMWH low molecular weight heparin TRA 2P-TIMI 50 Thrombin Receptor Antagonist in Secondary
LV left ventricular Prevention of Atherothrombotic Ischemic
LVEF left ventricular ejection fraction Events – Thrombolysis in Myocardial Infarc-
MACE major adverse cardiovascular event tion 50
MATRIX Minimizing Adverse Haemorrhagic Events by TRACER Thrombin Receptor Antagonist for Clinical
TRansradial Access Site and Systemic Imple- Event Reduction in Acute Coronary
mentation of angioX Syndrome
MDCT multidetector computed tomography TRILOGY ACS Targeted Platelet Inhibition to Clarify the Op-

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MERLIN Metabolic Efficiency With Ranolazine for Less timal Strategy to Medically Manage Acute
Ischaemia in Non-ST-Elevation Acute Coron- Coronary Syndromes
ary Syndromes TRITON-TIMI 38 TRial to Assess Improvement in Therapeutic
MI myocardial infarction Outcomes by Optimizing Platelet InhibitioN
MINAP Myocardial Infarction National Audit Project with Prasugrel – Thrombolysis In Myocardial
NOAC non-vitamin K antagonist oral anticoagulant Infarction 38
NSAID non-steroidal anti-inflammatory drug TVR target vessel revascularization
NSTE-ACS non-ST-elevation acute coronary syndromes UFH unfractionated heparin
NSTEMI non-ST-elevation myocardial infarction VKA vitamin K antagonist
NYHA New York Heart Association WOEST What is the Optimal antiplatElet and anti-
OAC oral anticoagulation/anticoagulant coagulant therapy in patients with OAC and
OASIS Organization to Assess Strategies for Ischae- coronary StenTing
mic Syndromes ZEUS Zotarolimus-eluting Endeavor Sprint Stent in
OR odds ratio Uncertain DES Candidates
PARADIGM-HF Prospective comparison of ARNI with ACEI
to Determine Impact on Global Mortality
and morbidity in Heart Failure 1. Preamble
PCI percutaneous coronary intervention
PEGASUS-TIMI 54 Prevention of Cardiovascular Events in Pa- Guidelines summarize and evaluate all available evidence on a par-
tients with Prior Heart Attack Using Ticagre- ticular issue at the time of the writing process, with the aim of assist-
lor Compared to Placebo on a Background of ing health professionals in selecting the best management strategies
Aspirin-Thrombolysis in Myocardial Infarction for an individual patient with a given condition, taking into account
54 the impact on outcome, as well as the risk– benefit ratio of particu-
PLATO PLATelet inhibition and patient Outcomes lar diagnostic or therapeutic means. Guidelines and recommenda-
POISE PeriOperative ISchemic Evaluation tions should help health professionals to make decisions in their
RCT randomized controlled trial daily practice. However, the final decisions concerning an individual
RIVAL RadIal Vs femorAL access for coronary patient must be made by the responsible health professional(s) in
intervention consultation with the patient and caregiver as appropriate.
RR relative risk A great number of Guidelines have been issued in recent years by
RRR relative risk reduction the European Society of Cardiology (ESC) as well as by other soci-
SAFE-PCI Study of Access Site for Enhancement of PCI eties and organisations. Because of the impact on clinical practice,
for Women quality criteria for the development of guidelines have been estab-
s.c. subcutaneous lished in order to make all decisions transparent to the user. The re-
STEMI ST-segment elevation myocardial infarction commendations for formulating and issuing ESC Guidelines can be
SWEDEHEART Swedish Web-system for Enhancement and found on the ESC website (http://www.escardio.org/Guidelines-
Development of Evidence-based care in &-Education/Clinical-Practice-Guidelines/Guidelines-development/
Heart disease Evaluated According to Recom- Writing-ESC-Guidelines). ESC Guidelines represent the official pos-
mended Therapies ition of the ESC on a given topic and are regularly updated.
SYNERGY Superior Yield of the New Strategy of Enoxa- Members of this Task Force were selected by the ESC to re-
parin, Revascularization and Glycoprotein IIb/ present professionals involved with the medical care of patients
IIIa Inhibitors trial with this pathology. Selected experts in the field undertook a com-
SYNTAX SYNergy between percutaneous coronary prehensive review of the published evidence for management
intervention with TAXus and cardiac surgery (including diagnosis, treatment, prevention and rehabilitation) of a
TACTICS Treat angina with Aggrastat and determine given condition according to ESC Committee for Practice Guide-
Cost of Therapy with an Invasive or Conser- lines (CPG) policy. A critical evaluation of diagnostic and therapeutic
vative Strategy procedures was performed, including assessment of the
272 ESC Guidelines

Table 1 Classes of recommendations

Classes of Suggested wording to use


recommendations

Class I Evidence and/or general Is recommended/is


agreement that a given treatment indicated
or procedure is beneficial, useful,
effective.

Class II Conflicting evidence and/or a


divergence of opinion about the
usefulness/efficacy of the given
treatment or procedure.

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Class IIa Weight of evidence/opinion is in Should be considered
favour of usefulness/efficacy.

Class IIb Usefulness/efficacy is less well May be considered


established by evidence/opinion.

Class III Evidence or general agreement Is not recommended


that the given treatment or
procedure is not useful/effective,
and in some cases may be harmful.

risk –benefit ratio. Estimates of expected health outcomes for larger


populations were included, where data exist. The level of evidence Table 2 Levels of evidence
and the strength of the recommendation of particular management
options were weighed and graded according to predefined scales, as Level of Data derived from multiple randomized
evidence A clinical trials or meta-analyses.
outlined in Tables 1 and 2.
The experts of the writing and reviewing panels provided declar- Data derived from a single randomized
Level of
clinical trial or large non-randomized
ation of interest forms for all relationships that might be perceived as evidence B
studies.
real or potential sources of conflicts of interest. These forms were
compiled into one file and can be found on the ESC website (http:// Consensus of opinion of the experts and/
Level of
or small studies, retrospective studies,
www.escardio.org/guidelines). Any changes in declarations of evidence C
registries.
interest that arise during the writing period must be notified to
the ESC and updated. The Task Force received its entire financial
support from the ESC without any involvement from the healthcare
industry.
The ESC CPG supervises and coordinates the preparation of new The National Societies of the ESC are encouraged to endorse,
Guidelines produced by task forces, expert groups or consensus pa- translate and implement all ESC Guidelines. Implementation pro-
nels. The Committee is also responsible for the endorsement pro- grammes are needed because it has been shown that the outcome
cess of these Guidelines. The ESC Guidelines undergo extensive of disease may be favourably influenced by the thorough applica-
review by the CPG and external experts. After appropriate revi- tion of clinical recommendations.
sions the Guidelines are approved by all the experts involved in Surveys and registries are needed to verify that real-life daily prac-
the Task Force. The finalized document is approved by the CPG tice is in keeping with what is recommended in the guidelines, thus
for publication in the European Heart Journal. The Guidelines completing the loop between clinical research, writing of guidelines,
were developed after careful consideration of the scientific disseminating them and implementing them into clinical practice.
and medical knowledge and the evidence available at the time of Health professionals are encouraged to take the ESC Guidelines
their dating. fully into account when exercising their clinical judgment, as well as
The task of developing ESC Guidelines covers not only in the determination and the implementation of preventive, diagnos-
integration of the most recent research, but also the creation of tic or therapeutic medical strategies. However, the ESC Guidelines
educational tools and implementation programmes for the recom- do not override in any way whatsoever the individual responsibility
mendations. To implement the guidelines, condensed pocket of health professionals to make appropriate and accurate decisions
guidelines versions, summary slides, booklets with essential mes- in consideration of each patient’s health condition and in consult-
sages, summary cards for non-specialists and an electronic version ation with that patient and the patient’s caregiver where appropriate
for digital applications (smartphones, etc.) are produced. These and/or necessary. It is also the health professional’s responsibility to
versions are abridged and thus, if needed, one should always refer verify the rules and regulations applicable to drugs and devices at the
to the full text version which is freely available on the ESC website. time of prescription.
ESC Guidelines 273

2. Introduction myocardial blood flow and/or distal embolization and subsequent


myocardial necrosis. The patient may have underlying severe coron-
2.1 Definitions, pathophysiology and ary artery disease (CAD) but, on occasion (i.e. 5 – 20% of cases),
there may be non-obstructive coronary atherosclerosis or no angio-
epidemiology
graphic evidence of CAD, particularly in women.2 – 5
The leading symptom that initiates the diagnostic and therapeutic
cascade in patients with suspected acute coronary syndromes 2.1.1.2 Type 2 MI
(ACS) is chest pain. Based on the electrocardiogram (ECG), two Type 2 MI is myocardial necrosis in which a condition other than cor-
groups of patients should be differentiated: onary plaque instability contributes to an imbalance between myo-
(1) Patients with acute chest pain and persistent (.20 min) cardial oxygen supply and demand.2 Mechanisms include coronary
ST-segment elevation. artery spasm, coronary endothelial dysfunction, tachyarrhythmias,
This condition is termed ST-elevation ACS and generally re- bradyarrhythmias, anaemia, respiratory failure, hypotension and se-

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flects an acute total coronary occlusion. Most patients will ultim- vere hypertension. In addition, in critically ill patients and in patients
ately develop an ST-elevation myocardial infarction (STEMI). The undergoing major non-cardiac surgery, myocardial necrosis may be
mainstay of treatment in these patients is immediate reperfusion related to injurious effects of pharmacological agents and toxins.6
by primary angioplasty or fibrinolytic therapy.1 The universal definition of MI also includes type 3 MI (MI resulting
(2) Patients with acute chest pain but no persistent ST-segment in death when biomarkers are not available) and type 4 and 5 MI
elevation. (related to percutaneous coronary intervention [PCI] and coronary
ECG changes may include transient ST-segment elevation, artery bypass grafting [CABG], respectively).
persistent or transient ST-segment depression, T-wave inver-
2.1.2 Unstable angina in the era of high-sensitivity cardiac
sion, flat T waves or pseudo-normalization of T waves or the
troponin assays
ECG may be normal.
Unstable angina is defined as myocardial ischaemia at rest or minimal
The clinical spectrum of non-ST-elevation ACS (NSTE-ACS) may exertion in the absence of cardiomyocyte necrosis. Among unse-
range from patients free of symptoms at presentation to individuals lected patients presenting with suspected NSTE-ACS to the emer-
with ongoing ischaemia, electrical or haemodynamic instability or gency department, the introduction of high-sensitivity cardiac
cardiac arrest. The pathological correlate at the myocardial level is troponin measurements in place of standard troponin assays resulted
cardiomyocyte necrosis [NSTE-myocardial infarction (NSTEMI)] in an increase in the detection of MI (4% absolute and 20% relative
or, less frequently, myocardial ischaemia without cell loss (unstable increase) and a reciprocal decrease in the diagnosis of unstable an-
angina). A small proportion of patients may present with ongoing gina.7 – 10 Compared with NSTEMI patients, individuals with unstable
myocardial ischaemia, characterized by one or more of the follow- angina do not experience myocardial necrosis, have a substantially
ing: recurrent or ongoing chest pain, marked ST depression on lower risk of death and appear to derive less benefit from intensified
12-lead ECG, heart failure and haemodynamic or electrical instabil- antiplatelet therapy as well as early invasive strategy.2 – 4,6 – 13
ity. Due to the amount of myocardium in jeopardy and the risk of
malignant ventricular arrhythmias, immediate coronary angiography 2.1.3 Pathophysiology and epidemiology
and, if appropriate, revascularization are indicated. (see Web addenda)

2.1.1 Universal definition of myocardial infarction


Acute myocardial infarction (MI) defines cardiomyocyte necrosis in 3. Diagnosis
a clinical setting consistent with acute myocardial ischaemia.2
A combination of criteria is required to meet the diagnosis of acute 3.1 Clinical presentation
MI, namely the detection of an increase and/or decrease of a cardiac Anginal pain in NSTE-ACS patients may have the following
biomarker, preferably high-sensitivity cardiac troponin, with at least presentations:
one value above the 99th percentile of the upper reference limit and † Prolonged (.20 min) anginal pain at rest;
at least one of the following: † New onset (de novo) angina (class II or III of the Canadian Car-
diovascular Society classification);21
(1) Symptoms of ischaemia.
† Recent destabilization of previously stable angina with at least
(2) New or presumed new significant ST-T wave changes or left
Canadian Cardiovascular Society Class III angina characteristics
bundle branch block on 12-lead ECG.
(crescendo angina); or
(3) Development of pathological Q waves on ECG.
† Post-MI angina.
(4) Imaging evidence of new or presumed new loss of viable myo-
cardium or regional wall motion abnormality. Prolonged and de novo/crescendo angina are observed in 80%
(5) Intracoronary thrombus detected on angiography or autopsy. and 20% of patients, respectively. Typical chest pain is character-
ized by a retrosternal sensation of pressure or heaviness (‘angina’)
2.1.1.1 Type 1 MI radiating to the left arm (less frequently to both arms or to the right
Type 1 MI is characterized by atherosclerotic plaque rupture, ulcer- arm), neck or jaw, which may be intermittent (usually lasting several
ation, fissure, erosion or dissection with resulting intraluminal minutes) or persistent. Additional symptoms such as sweating, nau-
thrombus in one or more coronary arteries leading to decreased sea, abdominal pain, dyspnoea and syncope may be present. Atypical
274 ESC Guidelines

presentations include epigastric pain, indigestion-like symptoms and stenosis (mimicking ACS).25 Rarely, a systolic murmur may indicate a
isolated dyspnoea. Atypical complaints are more often observed in mechanical complication (i.e. papillary muscle rupture or ventricular
the elderly, in women and in patients with diabetes, chronic renal septal defect) of a subacute and possibly undetected MI. Physical
disease or dementia.22 – 24 The exacerbation of symptoms by phys- examination may identify signs of non-coronary causes of chest
ical exertion and their relief at rest increase the probability of myo- pain (e.g. pulmonary embolism, acute aortic syndromes, myoperi-
cardial ischaemia. The relief of symptoms after nitrates carditis, aortic stenosis) or extracardiac pathologies (e.g. pneumo-
administration is not specific for anginal pain as it is reported also thorax, pneumonia or musculoskeletal diseases). In this setting,
in other causes of acute chest pain.24 In patients presenting with sus- the presence of a chest pain that can be reproduced by exerting
pected MI to the emergency department, overall, the diagnostic per- pressure on the chest wall has a relatively high negative predictive
formance of chest pain characteristics for MI is limited.24 Older age, value for NSTE-ACS.24,26 According to the presentation, abdominal
male gender, family history of CAD, diabetes, hyperlipidaemia, disorders (e.g. oesophageal spasm, oesophagitis, gastric ulcer, chole-
hypertension, renal insufficiency, previous manifestation of CAD cystitis, pancreatitis) may also be considered in the differential diag-

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as well as peripheral or carotid artery disease increase the likelihood nosis. Differences in blood pressure between the upper and lower
of NSTE-ACS. Conditions that may exacerbate or precipitate limbs or between the arms, irregular pulse, jugular vein distension,
NSTE-ACS include anaemia, infection, inflammation, fever, and heart murmurs, friction rub and pain reproduced by chest or ab-
metabolic or endocrine (in particular thyroid) disorders. dominal palpation are findings suggestive of alternative diagnoses.
Pallor, sweating or tremor may point towards precipitating condi-
tions such as anaemia and thyrotoxicosis.27
3.2 Physical examination
Physical examination is frequently unremarkable in patients with
suspected NSTE-ACS. Signs of heart failure or haemodynamic or 3.3 Diagnostic tools
electrical instability mandate a quick diagnosis and treatment. Car- 3.3.1 Electrocardiogram
diac auscultation may reveal a systolic murmur due to ischaemic mi- The resting 12-lead ECG is the first-line diagnostic tool in the assess-
tral regurgitation, which is associated with poor prognosis, or aortic ment of patients with suspected ACS (Figure 1). It is recommended to

Low Likelihood
Likelihoo
od High Likelihood
Likelihoo

1. Presentation

2. ECG

3. Troponin

4. Diagnosis Non-cardiac UA Other NSTEMI STEMI


Cardiac

STEMI = ST-elevation myocardial infarction; NSTEMI = non-ST-elevation myocardial infarction; UA = unstable angina.

Figure 1 Initial assessment of patients with suspected acute coronary syndromes. The initial assessment is based on the integration of low-
likelihood and/or high-likelihood features derived from clinical presentation (i.e., symptoms, vital signs), 12-lead ECG, and cardiac troponin. The pro-
portion of the final diagnoses derived from the integration of these parameters is visualized by the size of the respective boxes. “Other cardiac”
includes, among other, myocarditis, Tako-Tsubo cardiomyopathy, or tachyarrhythmias. “Non-cardiac” refers to thoracic diseases such as pneumonia
or pneumothorax. Cardiac troponin should be interpreted as a quantitative marker: the higher the level, the higher the likelihood for the presence of
myocardial infarction. In patients presenting with cardiac arrest or haemodynamic instability of presumed cardiovascular origin, echocardiography
should be performed/interpreted by trained physicians immediately following a 12-lead ECG. If the initial evaluation suggests aortic dissection or
pulmonary embolism, D-dimers and multi-detector computed tomography angiography are recommended according to dedicated algorithms.42,43
ESC Guidelines 275

Table 3 Clinical implications of high-sensitivity Table 4 Conditions other than acute myocardial
cardiac troponin assays infarction type 1 associated with cardiac troponin
elevation
Compared with standard cardiac troponin assays, high-sensitivity assays:
• Have higher negative predictive value for acute MI. Tachyarrhythmias
• Reduce the “troponin-blind” interval leading to earlier detection of acute MI. Heart failure
• Result in a ~4% absolute and ~20% relative increase in the detection of type 1 MI and a Hypertensive emergencies
corresponding decrease in the diagnosis of unstable angina.
Critical illness (e.g. shock/ sepsis/ burns)
• Are associated with a 2-fold increase in the detection of type 2 MI.
Myocarditisa
Levels of high-sensitivity cardiac troponin should be interpreted as quantitative
markers of cardiomyocyte damage (i.e. the higher the level, the greater the Tako-Tsubo cardiomyopathy
likelihood of MI): Structural heart disease (e.g. aortic stenosis)
• Elevations beyond 5-fold the upper reference limit have high (>90%) positive predictive

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Aortic dissection
value for acute type 1 MI.
Pulmonary embolism, pulmonary hypertension
• Elevations up to 3-fold the upper reference limit have only limited (50–60%) positive
predictive value for acute MI and may be associated with a broad spectrum of conditions. Renal dysfunction and associated cardiac disease
• It is common to detect circulating levels of cardiac troponin in healthy individuals. Coronary spasm
Rising and/or falling cardiac troponin levels differentiate acute from chronic Acute neurological event (e.g. stroke or subarachnoid haemorrhage)
cardiomyocyte damage (the more pronounced the change, the higher the Cardiac contusion or cardiac procedures (CABG, PCI, ablation, pacing, cardioversion, or
likelihood of acute MI).
endomyocardial biopsy)
Hypo- and hyperthyroidism
MI ¼ myocardial infarction.

venoms)
Extreme endurance efforts
obtain it within 10 min of the patient’s arrival in the emergency room
Rhabdomyolysis
or, ideally, at first contact with emergency medical services in the pre-
hospital setting and to have it immediately interpreted by a qualified
Bold = most frequent conditions; CABG ¼ coronary artery bypass surgery; PCI ¼
physician.28 While the ECG in the setting of NSTE-ACS may be nor- percutaneous coronary intervention.
mal in more than one-third of patients, characteristic abnormalities a
includes myocardial extension of endocarditis or pericarditis.
include ST depression, transient ST elevation and T-wave changes.1,18
If the standard leads are inconclusive and the patient has signs or
symptoms suggestive of ongoing myocardial ischaemia, additional
leads should be recorded; left circumflex artery occlusion or right the vast majority of cardiac troponin assays run on automated plat-
ventricular MI may be detected only in V7 – V9 and V3R and V4R, re- forms and are sensitive (i.e. allow for detection of cardiac troponin in
spectively.2 In patients with suggestive signs and symptoms, the 20 – 50% of healthy individuals) or high-sensitivity (detection in
finding of persistent ST elevation indicates STEMI, which mandates 50– 90% of healthy individuals) assays. High-sensitivity assays are
immediate reperfusion.1 Comparison with previous tracings is recommended over less sensitive ones.2,6,8 The majority of currently
valuable, particularly in patients with pre-existing ECG abnormal- used point-of-care assays cannot be considered sensitive or high-
ities. It is recommended to obtain additional 12-lead ECGs in the sensitivity assays.8,35 Therefore the obvious advantage of
case of persistent or recurrent symptoms or diagnostic uncer- point-of-care tests, namely the shorter turnaround time, is counter-
tainty. In patients with bundle branch block or paced rhythm, balanced by lower sensitivity, lower diagnostic accuracy and lower
ECG is of no help for the diagnosis of NSTE-ACS. negative predictive value. Overall, automated assays have been
more thoroughly evaluated as compared with point-of-care tests.2,6,8
As these techniques continue to improve and performance charac-
3.3.2 Biomarkers teristics are both assay and hospital dependent, no recommendation
Biomarkers complement clinical assessment and 12-lead ECG in the regarding the site of measurement (central laboratory vs. bedside)
diagnosis, risk stratification and treatment of patients with suspected can be given.2,6,8,38 Data from large multicentre studies have consist-
NSTE-ACS. Measurement of a biomarker of cardiomyocyte injury, ently shown that sensitive and high-sensitivity cardiac troponin as-
preferably high-sensitivity cardiac troponin, is mandatory in all pa- says increase diagnostic accuracy for MI at the time of presentation
tients with suspected NSTE-ACS.2,6,8 Cardiac troponins are more as compared with conventional assays, especially in patients present-
sensitive and specific markers of cardiomyocyte injury than creatine ing early after chest pain onset, and allow for a more rapid ‘rule-in’
kinase (CK), its MB isoenzyme (CK-MB) and myoglobin.6 If the clin- and ‘rule-out’ of MI (see section 3.3.3 and Table 3).2,6,8,29 – 34
ical presentation is compatible with myocardial ischaemia, then a dy- In most patients with renal dysfunction, elevations in cardiac tropo-
namic elevation of cardiac troponin above the 99th percentile of nin should not be primarily attributed to impaired clearance and con-
healthy individuals indicates MI.2 In patients with MI, levels of cardiac sidered harmless, as cardiac conditions such as chronic coronary or
troponin rise rapidly (i.e. usually within 1 h if using high-sensitivity as- hypertensive heart disease seem to be the most important contribu-
says) after symptom onset and remain elevated for a variable period tor to troponin elevation in this setting.41 Other life-threatening con-
of time (usually several days).2,6 Advances in technology have led to a ditions presenting with chest pain, such as aortic dissection and
refinement in cardiac troponin assays and have improved the ability pulmonary embolism, may also result in elevated troponin levels
to detect and quantify cardiomyocyte injury.2,6,8,10,29 – 37 In Europe, and should be considered as differential diagnoses (Table 4).
276 ESC Guidelines

Acute Chest Pain

hs-cTn
hs-cTn<ULN
<ULN hs-cTn
hs-cTn>ULN
>ULN

Pain
Pain>6h
>6h Pain
Pain<6h
<6h

Re-test hs-cTn: 3h

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Highly abnormal hs-cTn
+ clinical presentation
hs-cTn
hs-cTnno
nochange
change ΔΔ change
changeaa
hs-cTn
hs-cTnno
nochange
change
(1(1 value
value >>ULN)
ULN)

Painfree,
Painfree,GRACE
GRACE<140,
<140,
Work-up
Work-updifferential
differential
differential
differentialdiagnoses
diagnosesexcluded
excluded
diagnoses
diagnoses

Discharge/Stresstesting
Discharge/Stress testing Invasivemanagement
Invasive management

GRACE = Global Registry of Acute Coronary Events score; hs-cTn = high sensitivity cardiac troponin; ULN = upper limit of normal, 99th percentile of healthy controls.
a

Figure 2 0 h/3 h rule-out algorithm of non-ST-elevation acute coronary syndromes using high-sensitivity cardiac troponin assays.

Among the multitude of additional biomarkers evaluated for the


diagnosis of NSTE-ACS, only CK-MB and copeptin seem to have
clinical relevance.2,6,8,10,44 – 50 CK-MB shows a more rapid decline Suspected NSTEMI
after MI as compared with cardiac troponin and may provide added
value for the timing of myocardial injury and the detection of early
0h B ng/l 0h D ng/l
reinfarction.2,6,8,10 Assessment of copeptin, the C-terminal part of 0h <A*ng/l or and Other or
the vasopressin prohormone, may quantify the endogenous stress 0-1h C ng/l 0-1h E ng/l

level in multiple medical conditions including MI. As the level of en-


dogenous stress appears to be invariably high at the onset of MI, the Rule-out Observe Rule-in
added value of copeptin to conventional (less sensitive) cardiac
troponin assays is substantial.44 – 50 Therefore the routine use of A B C D E
copeptin as an additional biomarker for the early rule-out of MI hs-cTnT (Elecsys) 5 12 3 52 5
is recommended whenever sensitive or high-sensitivity cardiac hs-cTnl (Architect) 2 5 2 52 6
hs-cTnl (Dimension Vista)+ 0.5 5 2 107 19
troponin assays are not available. Copeptin may have some added
value even over high-sensitivity cardiac troponin in the early rule-
out of MI.44 – 48 Figure 3 0 h/1 h rule-in and rule-out algorithms using high-
sensitivity cardiac troponins (hs-cTn) assays in patients presenting
3.3.3 ‘Rule-in’ and ‘rule-out’ algorithms with suspected non-ST-elevation myocardial infarction (NSTEMI)
Due to the higher sensitivity and diagnostic accuracy for the detec- to the emergency department. 0 h and 1 h refer to the time from
first blood test. NSTEMI can be ruled-out already at presentation,
tion of acute MI at presentation, the time interval to the second car-
if the hs-cTn concentration is very low. NSTEMI can also be ruled-
diac troponin assessment can be shortened with the use of
out by the combination of low baseline levels and the lack of a rele-
high-sensitivity assays. This may reduce substantially the delay to vant increase within 1 h. Patients have a high likelihood for NSTEMI
diagnosis, translating into shorter stays in the emergency depart- if the hs-cTn concentration at presentation is at least moderately
ment and lower costs.2,6,8,10,29 – 36 It is recommended to use the elevated or hs-cTn concentrations show a clear rise within the first
0 h/3 h algorithm (Figure 2). As an alternative, 0 h/1 h assessments hour. Cut-off levels are assay-specific. Cut-off levels for other
are recommended when high-sensitivity cardiac troponin assays hs-cTn assays are in development. *Only applicable if chest pain
with a validated algorithm are available (Figure 3). The 0 h/1 h algo- onset .3h, +At the time of the publication of the guideline not
rithms rely on two concepts: first, high-sensitivity cardiac troponin is yet commercially available.
a continuous variable and the probability of MI increases with in-
creasing high-sensitivity cardiac troponin values;39 second, early ab- value to the cardiac troponin assessment at presentation.39 The cut-
solute changes of the levels within 1 h can be used as surrogates for off levels within the 0 h/1 h algorithm are assay specific.36,39,51 – 55
absolute changes over 3 h or 6 h and provide incremental diagnostic Those algorithms should always be integrated with a detailed
ESC Guidelines 277

clinical assessment and 12-lead ECG and repeat blood sampling is NSTE-ACS. This imaging modality is useful to identify abnormalities
mandatory in case of ongoing or recurrent chest pain (Table 5, suggestive of myocardial ischaemia or necrosis (i.e. segmental hypo-
see Web addenda). kinesia or akinesia). In the absence of significant wall motion abnor-
Table 5 (see Web addenda) Characteristics of the 0 h/3 h malities, impaired myocardial perfusion detected by contrast
and 0 h/1 h algorithms echocardiography or reduced regional function using strain and
strain rate imaging might improve the diagnostic and prognostic va-
The negative predictive value for MI in patients assigned ‘rule-out’
lue of conventional echocardiography.60,61 Moreover, echocardiog-
exceeded 98% in several large validation cohorts.30 – 34,36,39,51 – 55
raphy can help in detecting alternative pathologies associated with
Used in conjunction with clinical and ECG findings, the 0 h/1 h
chest pain, such as acute aortic dissection, pericardial effusion, aortic
algorithm may allow the identification of candidates for early dis-
valve stenosis, hypertrophic cardiomyopathy or right ventricular
charge and outpatient management. The positive predictive value
dilatation suggestive of acute pulmonary embolism. Similarly, echo-
for MI in those patients meeting the ‘rule-in’ criteria was 75 –
cardiography is the diagnostic tool of choice for patients with
80%.30 – 34,39,53 – 55 Most of the ‘rule-in’ patients with diagnoses other

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haemodynamic instability of suspected cardiac origin.62 Evaluation
than MI did have conditions that usually require inpatient coronary
of left ventricular (LV) systolic function, at the latest by the time
angiography for accurate diagnosis, including Tako– Tsubo cardio-
of hospital discharge, is important to estimate prognosis, and echo-
myopathy and myocarditis.39,53 – 55 Patients who do not qualify for
cardiography (as well as other imaging modalities) can provide this
‘rule-out’ or ‘rule-in’ represent a heterogeneous group that may re-
information.
quire further investigations if no alternative explanation for the car-
In patients without ischaemic changes on 12-lead ECGs and nega-
diac troponin elevation is identified. A large proportion of these
tive cardiac troponins (preferably high-sensitivity) who are free of
patients may require a further high-sensitivity cardiac troponin as-
chest pain for several hours, stress imaging can be performed during
sessment (e.g. at 3 h). Coronary angiography should be considered
admission or shortly after discharge. Stress imaging is preferred over
in patients for whom there is a high degree of clinical suspicion of
exercise ECG due to its greater diagnostic accuracy.63 Various stud-
NSTE-ACS, while in patients with low to intermediate likelihood
ies have shown that normal exercise, dobutamine or dipyridamole
for this condition, computed tomography (CT) coronary angiog-
stress echocardiograms have high negative predictive value for ischae-
raphy should be considered. No further diagnostic testing in the
mia and are associated with excellent patient outcomes.64,65 More-
emergency department is indicated when alternative conditions
over, stress echocardiography demonstrated superior prognostic
such as rapid ventricular rate response to atrial fibrillation or hyper-
value over exercise ECG.64,66 The addition of contrast may improve
tensive emergency have been identified.
endocardial border detection, which may facilitate detection of
For rapid rule-out, two alternative approaches to the 0 h/1 h
ischaemia.67
or 0 h/3 h algorithms have been adequately validated and may be
Cardiac magnetic resonance (CMR) can assess both perfusion
considered. First, a 2 h rule-out protocol combining the Thromboly-
and wall motion abnormalities, and patients presenting with acute
sis in Myocardial Infarction (TIMI) risk score with ECG and high-
chest pain with a normal stress CMR have an excellent short- and
sensitivity cardiac troponin at presentation allowed a safe rule-out
midterm prognosis.68 CMR also permits detection of scar tissue
in up to 40% of patients.56 – 58 Second, a dual-marker strategy com-
(using late gadolinium enhancement) and can differentiate this
bining normal levels of cardiac troponin together with low levels of
from recent infarction (using T2-weighted imaging to delineate myo-
copeptin (,10 pmol/L) at presentation showed very high negative
cardial oedema).69,70 Moreover, CMR can facilitate the differential
predictive value for MI, obviating the need for serial testing in se-
diagnosis between infarction and myocarditis or Tako–Tsubo car-
lected patients.44 – 50 When using any algorithm, three main caveats
diomyopathy.71 Similarly, nuclear myocardial perfusion imaging has
apply: (i) algorithms should only be used in conjunction with all avail-
been shown to be useful for risk stratification of patients with acute
able clinical information, including detailed assessment of chest pain
chest pain suggestive for ACS. Resting myocardial scintigraphy, by
characteristics and ECG; (ii) in patients presenting very early (e.g.
detecting fixed perfusion defects suggestive of myocardial necrosis,
within 1 h from chest pain onset), the second cardiac troponin level
can be helpful for initial triage of patients presenting with chest pain
should be obtained at 3 h, due to the time dependency of troponin
without ECG changes or elevated cardiac troponins.72 Combined
release; (iii) as late increases in cardiac troponin have been de-
stress –rest imaging may further enhance assessment of ischaemia,
scribed in 1% of patients, serial cardiac troponin testing should
while a normal study is associated with excellent outcome.73,74
be pursued if the clinical suspicion remains high or whenever the pa-
Stress – rest imaging modalities are usually not widely available on
tient develops recurrent chest pain.52,54 High-sensitivity cardiac
24 h service.
troponin assays also maintain high diagnostic accuracy in patients
with renal dysfunction. To ensure the best possible clinical use,
3.3.4.2 Anatomical evaluation
assay-specific optimal cut-off levels, which are higher in patients
Multidetector computed tomography (MDCT) allows for visualiza-
with renal dysfunction, should be used.59
tion of the coronary arteries and a normal scan excludes CAD. A
meta-analysis of nine studies (n ¼ 1349 patients) has reported over-
3.3.4 Non-invasive imaging all high negative predictive values to exclude ACS (by excluding
3.3.4.1 Functional evaluation CAD) and excellent outcome in patients presenting to the emer-
Transthoracic echocardiography should be routinely available in gency department with low to intermediate pre-test probability
emergency rooms and chest pain units and performed/interpreted for ACS and a normal coronary CT angiogram.75 Four randomized
by trained physicians in all patients during hospitalization for controlled trials (RCTs) have tested MDCT (n ¼ 1869 patients) vs.
278 ESC Guidelines

usual care (n ¼ 1397) in the triage of low- to intermediate-risk pa- and coronary artery spasm are briefly described in section 5.6.4.2,
tients presenting with acute chest pain to emergency departments Web addenda. Stroke may be accompanied by ECG changes, myo-
without signs of ischaemia on ECG and/or inconclusive cardiac tro- cardial wall motion abnormalities and an increase in cardiac troponin
ponins.76 – 79 At a follow-up of 1–6 months, there were no deaths, levels.2,6 The majority of patients presenting with acute chest pain to
and a meta-analysis demonstrated comparable outcomes with the the emergency department have non-cardiac conditions causing the
two approaches (i.e. no difference in the incidence of MI, post- chest discomfort. In many instances the pain is musculoskeletal, and
discharge emergency department visits or rehospitalizations) and therefore benign, self-limiting and does not require hospitalization.
showed that MDCT was associated with a reduction in emergency de- Chest pain characteristics help to some extent in the early identifica-
partment costs and length of stay.80 However, none of these studies tion of those patients.24
used high-sensitivity cardiac troponin assays, which also may reduce
hospital stay. It was also noted that MDCT was associated with an in-
crease in the use of invasive angiography {8.4% vs. 6.3%; odds ratio 4. Risk assessment and outcomes

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[OR] 1.36 [95% confidence interval (CI) 1.03, 1.80], P ¼ 0.030}.80 Ac-
cordingly, MDCT coronary angiography can be used to exclude CAD 4.1 Clinical presentation,
(and MDCT is thus not useful in patients with known CAD). Other electrocardiogram and biomarkers
factors limiting MDCT coronary angiography include severe calcifica- 4.1.1 Clinical presentation
tions (high calcium score) and elevated or irregular heart rate; in add- In addition to some universal clinical markers of risk, such as ad-
ition, a sufficient level of expertise is needed and 24 h service is vanced age, diabetes and renal insufficiency, the initial clinical pres-
currently not widely available. Finally, the use of MDCT coronary angi- entation is highly predictive of early prognosis.82 Chest pain at rest
ography in the acute setting in patients with stents or previous CABG carries a worse prognosis than symptoms elicited during physical
has not been validated. Importantly, CT imaging can effectively exclude exertion. In patients with intermittent symptoms, an increasing
other causes of acute chest pain that, if untreated, are associated with number of episodes preceding the index event also adversely affects
high mortality, namely pulmonary embolism, aortic dissection and ten- prognosis. Tachycardia, hypotension, heart failure and new mitral
sion pneumothorax.81 regurgitation at presentation predict poor prognosis and call for ra-
pid diagnosis and management.25,82 – 84
3.4 Differential diagnosis
Among unselected patients presenting with acute chest pain to the 4.1.2 Electrocardiogram
emergency department, disease prevalence can be expected to be The initial ECG is predictive of early risk.18 Patients with ST depres-
the following: 5 – 10% STEMI, 15 – 20% NSTEMI, 10% unstable an- sion have a worse prognosis than patients with a normal ECG.85,86
gina, 15% other cardiac conditions and 50% non-cardiac dis- The number of leads showing ST depression and the magnitude of
eases.48,51,52,56 – 58 Several cardiac and non-cardiac conditions may ST depression are indicative of the extent of ischaemia and correlate
mimic NSTE-ACS (Table 6). with prognosis on the one hand, and benefit from an invasive treat-
Conditions that should always be considered in the differential ment strategy on the other.87 ST depression ≥0.05 mV in two or
diagnosis of NSTE-ACS, because they are potentially life- more contiguous leads, in the appropriate clinical context, is sug-
threatening but also treatable, include aortic dissection, pulmonary gestive of NSTE-ACS and linked to adverse prognosis.85 ST depres-
embolism and tension pneumothorax. Echocardiography should be sion combined with transient ST elevation identifies a high-risk
performed urgently in all patients with haemodynamic instability of subgroup,88 while associated T-wave inversion does not alter the
suspected cardiovascular (CV) origin.62 prognostic value of ST depression. While isolated T-wave inversion
Chest X-ray is recommended in all patients in whom NSTE-ACS is on admission has not been associated with worse prognosis com-
considered unlikely in order to detect pneumonia, pneumothorax, rib pared with the absence of ECG abnormalities, it frequently triggers
fractures or other thoracic disorders. Tako–Tsubo cardiomyopathy a more rapid diagnosis and treatment.86

Table 6 Differential diagnoses of acute coronary syndromes in the setting of acute chest pain

Cardiac Pulmonary Vascular Gastro-intestinal Orthopaedic Other


Myopericarditis Pulmonary embolism Aortic dissection Oesophagitis, reflus or spasm Musculoskeletal disorders Anxiety disorders
Cardiomyopathiesa
Tachyarrhythmias (Tension)-Pneumothorax Symptomatic aortic aneurysm Peptic
Pepticulcer,
ulcer,gastritis
gastritis Chest trauma Herpes zoster
Acute heart failure Bronchitis, pneumonia Stroke Pancreatitis
Pancreatitis Anaemia
Hypertensive emergencies Pleuritis Cholecystitis
Cholecystitis Costochondritis
Aortic valve stenosis Cervical spine pathologies
Tako-Tsubo cardiomyopathy
Coronary spasm
Cardiac trauma

Bold ¼ common and/or important differential diagnoses.


a
Dilated, hypertrophic and restrictive cardiomyopathies may cause angina or chest discomfort.
ESC Guidelines 279

4.1.3 Biomarkers out. The greatest challenge is the integration of clinical presentation
Beyond diagnostic utility, cardiac troponin levels add prognostic in- with information derived from ECG, troponin assessment and imaging
formation in terms of short- and long-term mortality to clinical and modalities into a standardised management strategy.97 Assessment of
ECG variables. While high-sensitivity cardiac troponin T and I seem acute risk guides initial evaluation, selection of the site of care (i.e. cor-
to have comparable diagnostic accuracy, high-sensitivity cardiac onary or intensive care unit, intermediate care unit, inpatient moni-
troponin T has greater prognostic accuracy.89,90 The higher the tored unit or regular unit) and therapy, including antithrombotic
high-sensitivity troponin levels at presentation, the greater the risk treatment and timing of coronary angiography. Risk is highest at the
of death.6,8,10,39 Multiple biomarkers have been associated with time of presentation and may remain elevated for several days, al-
mortality in NSTE-ACS, several of them conferring additive though rapidly declining over time, depending on clinical presentation,
prognostic value to cardiac troponin.8,48 – 50 Serum creatinine and comorbidities, coronary anatomy and revascularization.98 The esti-
estimated glomerular filtration rate (eGFR) should also be deter- mated risk should be communicated to the patient and their family.
mined in all patients with NSTE-ACS because they affect prognosis

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and are key elements of the Global Registry of Acute Coronary
Events (GRACE 2.0) risk calculation (see section 4.2). The exten- 4.2.2 Cardiac rhythm monitoring
sively validated natriuretic peptides (i.e. B-type natriuretic peptide, Early revascularization as well as the use of antithrombotic agents
N-terminal pro-B-type natriuretic peptide and midregional and beta-blockers have markedly reduced the incidence of life-
pro-A-type natriuretic peptide) provide prognostic information on threatening arrhythmias in the acute phase to ,3%, with most of
top of cardiac troponin.91 To some extent, the same applies to high- the arrhythmic events occurring within 12 h of symptom on-
sensitivity C-reactive protein and novel biomarkers such as midre- set.99,100 Patients with life-threatening arrhythmias more frequently
gional pro-adrenomedullin, growth differentiation factor 15 and had prior heart failure, LV ejection fraction (LVEF) ,30% and triple-
copeptin. However, the assessment of these markers has so far not vessel CAD. A patient with NSTE-ACS who presents early after
been shown to improve patient management and their added value symptom onset, has no or mild to moderate cardiac biomarker ele-
in risk assessment on top of the GRACE 2.0 risk calculation seems vation, normal LV function and single-vessel CAD successfully trea-
marginal. Therefore the routine use of these biomarkers for prognos- ted with PCI may be discharged the next day. At the other end of the
tic purposes cannot be recommended at the present time. spectrum are NSTE-ACS patients with multivessel CAD in whom
complete revascularization may not be achieved in one session
4.2 Ischaemic risk assessment (or at all); these patients may have a complicated course (e.g. heart
In NSTE-ACS, quantitative assessment of ischaemic risk by means of failure) or prior cardiac disease, major comorbidities, advanced age
scores is superior to the clinical assessment alone. The GRACE risk or recent extensive myocardial necrosis.101,102 Cardiac troponin-
score provides the most accurate stratification of risk both on ad- negative (i.e. unstable angina) patients without recurrent or ongoing
mission and at discharge.92,93 The GRACE 2.0 risk calculator (http:// symptoms and with normal ECG do not necessarily require rhythm
www.gracescore.org/WebSite/default.aspx?ReturnUrl=%2f) pro- monitoring or hospital admission.
vides a direct estimation, bypassing the calculation of a score, of NSTEMI patients at low risk for cardiac arrhythmias require
mortality while in hospital, at 6 months, at 1 year and at 3 years. rhythm monitoring for ≤24 h or until coronary revascularization
The combined risk of death or MI at 1 year is also provided.94 (whichever comes first) in an intermediate or coronary care unit,
Variables used in the GRACE 2.0 risk calculation include age, systolic while individuals at intermediate to high risk for cardiac arrhythmia
blood pressure, pulse rate, serum creatinine, Killip class at presenta- may require rhythm monitoring for .24 h in an intensive or
tion, cardiac arrest at admission, elevated cardiac biomarkers and ST coronary care unit or in an intermediate care unit, depending on
deviation. If the Killip class or serum creatinine values are not avail- the clinical presentation, degree of revascularization and early
able, a modified score can be calculated by adding renal failure and post-revascularization course (Table 7). It is recommended that per-
use of diuretics, respectively. The TIMI risk score uses seven vari- sonnel adequately equipped and trained to manage life-threatening
ables in an additive scoring system: age ≥65 years, three or more
CAD risk factors, known CAD, aspirin use in the past 7 days, severe Table 7 Recommended unit and duration of cardiac
angina (two or more episodes within 24 h), ST change ≥0.5 mm and rhythm monitoring according to clinical presentation
positive cardiac marker (http://www.timi.org/index.php?page= after established NSTE-ACS diagnosis
calculators).82 It is simple to use, but its discriminative accuracy is in-
Rhythm
ferior to that of the GRACE risk score and the GRACE 2.0 risk cal- Clinical Presentation Unit
monitoring
culation. While the value of risk scores as prognostic assessment Unstable angina Regular ward or discharge None
tools is undisputed, the impact of risk score implementation on pa- NSTEMI at low risk for cardiac Intermediate care unit
≤24 h
tient outcomes has not been adequately investigated.95,96 arrhythmiasa or coronary care unit
NSTEMI at intermediate to high Intensive/coronary care units or
>24 h
risk for cardiac arrhythmiasb intermediate care unit
4.2.1 Acute risk assessment
Patients with suspected NSTE-ACS must be evaluated rapidly in order
NSTEMI ¼ Non-ST-elevation myocardial infarction.
to identify individuals with ongoing myocardial ischaemia who are at a
If none of the following criteria: haemodynamically unstable, major arrhythmias,
risk of life-threatening arrhythmias and need close surveillance as left ventricular ejection fraction ,40%, failed reperfusion, additional critical
coronary stenoses of major vessels or complications related to percutaneous
well as immediate coronary angiography. Patients with suspected
revascularization.
NSTE-ACS should be observed in interdisciplinary emergency depart- b
If one or more of the above criteria are present.
ments or chest pain units until the diagnosis of MI is confirmed or ruled
280 ESC Guidelines

arrhythmias and cardiac arrest accompany patients who are trans- coronary angiography, with CRUSADE found to be the most discrim-
ferred between facilities during the time window in which they re- inatory.107 However, in patients medically treated or on oral anticoa-
quire continuous rhythm monitoring. gulants, the predictive value of these scores is not established.
Moreover, the impact on patient outcomes of integrating these
4.2.3 Long-term risk scores has not been investigated. Given these limitations, use of the
In addition to short-term risk factors, a number of conditions are as- CRUSADE bleeding risk score may be considered in patients under-
sociated with long-term risk, including a complicated clinical course, going coronary angiography to quantify bleeding risk.
LV systolic dysfunction, atrial fibrillation, severity of CAD, revascu-
larization status, evidence of residual ischaemia on non-invasive test- 4.4 Recommendations for diagnosis,
ing and non-cardiac comorbidities. At 1 year, the rates of death, MI risk stratification, imaging and rhythm
and recurrent ACS in contemporary NSTE-ACS registries are
.10%. While early events are related to ruptured coronary plaques
monitoring in patients with suspected
non-ST-elevation acute coronary

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and associated thrombosis, the majority of later events may be the
result of coronary and systemic atherosclerosis progression.98,103 syndromes

4.3 Bleeding risk assessment Recommendations for diagnosis, risk stratification,


Major bleeding events are associated with increased mortality in imaging and rhythm monitoring in patients with
NSTE-ACS.104,105 Bleeding risk scores have been developed suspected non-ST-elevation acute coronary
from registry or trial cohorts in the setting of ACS and PCI. syndromes
The Can Rapid risk stratification of Unstable angina patients Suppress
ADverse outcomes with Early implementation of the ACC/
Recommendations Classa Levelb Ref.c
AHA guidelines (CRUSADE) bleeding risk score (http://www.
Diagnosis and risk stratification
crusadebleedingscore.org) was developed from a cohort of 71 277
NSTE-ACS patients (derivation cohort) and further validated in a co- It is recommended to base diagnosis
hort of 17 857 patients (validation cohort) from the same registry.106 and initial short-term ischaemic and
28,
bleeding risk stratification on a
The CRUSADE bleeding risk score considered baseline patient char- I A 109–
combination of clinical history,
acteristics (i.e. female gender, history of diabetes, history of peripheral 112
symptoms, vital signs, other physical
vascular disease or stroke), admission clinical variables (i.e. heart rate, findings, ECG and laboratory results.
systolic blood pressure, signs of heart failure) and admission labora- It is recommended to obtain a 12-lead
tory values (i.e. haematocrit, calculated creatinine clearance) to esti- ECG within 10 min after first medical
mate the patient’s likelihood of an in-hospital major bleeding event. contact and to have it immediately
However, model performance for the risk score was modest interpreted by an experienced
I B 28
physician. It is recommended to obtain
(C-statistic 0.68 in patients treated conservatively and 0.73 in patients
an additional 12-lead ECG in case of
undergoing invasive approach). recurrent symptoms or diagnostic
The Acute Catheterization and Urgent Intervention Triage strat- uncertainty.
egY (ACUITY) bleeding risk score was derived from a pooled cohort Additional ECG leads (V3R, V4R,
of 17 421 patients with ACS (both NSTE-ACS and STEMI) recruited V7 –V9) are recommended if ongoing
I C
in the ACUITY and Harmonizing Outcomes with RevasculariZatiON ischaemia is suspected when standard
and Stents in Acute Myocardial Infarction (HORIZONS-AMI) leads are inconclusive.
trials.104 Six independent baseline predictors (i.e. female gender, It is recommended to measure cardiac 6,30–
advanced age, elevated serum creatinine, white blood cell count, troponins with sensitive or 36,
high-sensitivity assays and obtain the I A 39,
anaemia and presentation as NSTEMI or STEMI) and one treat-
results within 60 min. 51– 59,
ment-related variable [use of unfractionated heparin (UFH) and a 108
glycoprotein IIb/IIIa (GPIIb/IIIa) inhibitor rather than bivalirudin alone]
A rapid rule-out protocol at 0 h and 6,
were identified. This risk score identified patients at increased risk for 3 h is recommended if high-sensitivity 30– 36,
non-CABG-related major bleeds at 30 days and subsequent 1 year cardiac troponin tests are available. I B 39,
mortality. However, it has not been validated in an independent co- 51– 59,
hort, no risk calculator is available and model performance for the risk 108
score is modest (C-statistic 0.74). Changes in interventional practice, A rapid rule-out and rule-in protocol at
such as increasing use of radial access, reduction in the dose of UFH, 0 h and 1 h is recommended if a
use of bivalirudin, diminished use of GPIIb/IIIa inhibitors and adminis- high-sensitivity cardiac troponin test
30– 34,
with a validated 0 h/1 h algorithm is
tration of more effective inhibitors of the platelet adenosine diphos- 36,
available. Additional testing after 3–6 h I B
phate (ADP) receptor P2Y12 (P2Y12 inhibitors), may all modify the 39,
is indicated if the first two troponin
51–55
predictive value of risk scores. Ischaemic and bleeding risks need to measurements are not conclusive and
be weighed in the individual patient, although many of the predictors the clinical condition is still suggestive of
of ischaemic events are also associated with bleeding complica- ACS.
tions.104,106 Overall, CRUSADE and ACUITY scores have reasonable It is recommended to use established
I B
84,94,
predictive value for major bleeding in ACS patients undergoing risk scores for prognosis estimation. 106
ESC Guidelines 281

The use of the CRUSADE score may be 5. Treatment


considered in patients undergoing 106,
IIb B
coronary angiography to quantify 107 5.1 Pharmacological treatment of
bleeding risk.
ischaemia
Imaging 5.1.1 General supportive measures
In patients with no recurrence of The goal of pharmacological anti-ischaemic therapy is to decrease
chest pain, normal ECG findings and myocardial oxygen demand (secondary to a decrease in heart rate,
normal levels of cardiac troponin blood pressure, preload or myocardial contractility) or to increase
(preferably high-sensitivity), but 64,74,
myocardial oxygen supply (by administration of oxygen or through
suspected ACS, a non-invasive stress I A 113,
test (preferably with imaging) for 114 coronary vasodilation). If, following treatment, the patient does not
inducible ischaemia is recommended rapidly become free of ischaemic signs or symptoms, immediate cor-

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before deciding on an invasive onary angiography is recommended independently of ECG findings
strategy. and cardiac troponin levels. While data in NSTE-ACS are lacking, a ran-
Echocardiography is recommended to domized comparison of oxygen vs. air administration in 441 normox-
evaluate regional and global LV aemic patients with STEMI showed no benefit and possibly harm
I C
function and to rule in or rule out
associated with oxygen administration. Oxygen should be adminis-
differential diagnoses.d
tered when blood oxygen saturation is ,90% or if the patient is in re-
MDCT coronary angiography should
spiratory distress.115 In patients whose ischaemic symptoms are not
be considered as an alternative to
invasive angiography to exclude ACS relieved by nitrates and beta-blockers, opiate administration is reason-
when there is a low to intermediate IIa A 80 able while waiting for immediate coronary angiography, with the caveat
likelihood of CAD and when cardiac that morphine may slow intestinal absorption of oral platelet inhibitors.
troponin and/or ECG are
inconclusive.
Monitoring 5.1.2 Nitrates
Continuous rhythm monitoring is Intravenous nitrates are more effective than sublingual nitrates with
recommended until the diagnosis regard to symptom relief and regression of ST depression. Under
I C 101
of NSTEMI is established or ruled careful blood pressure monitoring, the dose should be titrated up-
out. wards until symptoms are relieved, and in hypertensive patients until
It is recommended to admit NSTEMI blood pressure is normalized, unless side effects (notably headache
I C 99,100
patients to a monitored unit. or hypotension) occur. Beyond symptom control, there is no indi-
Rhythm monitoring up to 24 h or PCI cation for nitrate treatment.116 In patients with recent intake of a
(whichever comes first) should be phosphodiesterase type 5 inhibitor (i.e. within 24 h for sildenafil
IIa C
considered in NSTEMI patients at low or vardenafil and 48 h for tadalafil), nitrates should not be adminis-
risk for cardiac arrhythmias.e
tered due to the risk of severe hypotension.117
Rhythm monitoring for .24 h should
be considered in NSTEMI patients at 5.1.3 Beta-blockers
IIa C
intermediate to high-risk for cardiac Beta-blockers competitively inhibit the myocardial effects of circu-
arrhythmias.f
lating catecholamines and reduce myocardial oxygen consumption
In the absence of signs or symptoms of by lowering heart rate, blood pressure and myocardial contractility.
ongoing ischaemia, rhythm monitoring
The evidence for the beneficial effects of beta-blockers in
in unstable angina may be considered
in selected patients (e.g. suspicion of IIb C NSTE-ACS is derived from a meta-analysis of 27 early studies show-
coronary spasm or associated ing that beta-blocker treatment was associated with a significant
symptoms suggestive of arrhythmic 13% relative risk reduction (RRR) of mortality in the first week fol-
events). lowing MI.118 In addition, a later meta-analysis comprising 73 396 pa-
tients with ACS showed an 8% RRR (P ¼ 0.04) for in-hospital
ACS ¼ acute coronary syndromes; CAD ¼ coronary artery disease; ECG ¼ mortality associated with beta-blockade, with no increase in cardio-
electrocardiogram; LV ¼ left ventricular; MDCT ¼ multidetector computed
tomography; NSTEMI ¼ non-ST-elevation myocardial infarction; PCI ¼
genic shock.119 A registry study of 21 822 NSTEMI patients found
percutaneous coronary intervention. 0 h ¼ time of first blood test; 1 h, 3 h ¼ 1 that in patients at risk of developing cardiogenic shock (i.e. age
or 3 h after the first blood test. .70 years, heart rate .110 beats/min, systolic blood pressure
a
Class of recommendation.
b
Level of evidence.
,120 mmHg) the observed shock or death rate was significantly in-
c
References supporting level of evidence. creased in patients receiving beta-blockers within 24 h of hospital
d
Does not apply to patients discharged the same day in whom NSTEMI has been admission.120 Therefore early administration of beta-blockers
ruled out.
e
If none of the following criteria: haemodynamically unstable, major arrhythmias,
should be avoided in these patients if the ventricular function is un-
left ventricular ejection fraction ,40%, failed reperfusion, additional critical known. Beta-blockers should not be administered in patients with
coronary stenoses of major vessels or complications related to percutaneous symptoms possibly related to coronary vasospasm or cocaine use,
revascularization.
f
If one or more of the above criteria are present.
as they might favour spasm by leaving alpha-mediated vasoconstric-
tion unopposed by beta-mediated vasodilation.
282 ESC Guidelines

5.1.4 Other drug classes (see Web addenda) cytochrome P450 (CYP) system to generate an active metabolite (Ta-
5.1.5 Recommendations for anti-ischaemic drugs in the ble 8). An estimated 85% of the prodrug is hydrolysed by esterases
acute phase of non-ST-elevation acute coronary syndromes into an inactive form, leaving only 15% of clopidogrel available for
transformation to the active metabolite, which selectively and irre-
Recommendations for anti-ischaemic drugs in the versibly inactivates platelet P2Y12 receptors and thus inhibits
acute phase of non-ST-elevation acute coronary ADP-induced platelet aggregation.135,136 Dual antiplatelet therapy
syndromes (DAPT) comprising aspirin and clopidogrel has been shown to reduce
recurrent ischaemic events in the NSTE-ACS setting compared with
aspirin alone.137,138 However, up to 10% of patients treated with the
Recommendations Classa Levelb Ref.c combination of aspirin and clopidogrel will have a recurrent ischaemic
Early initiation of beta-blocker event in the first year after an ACS, with a rate of stent thrombosis of
treatment is recommended in patients up to 2%.139 This residual risk may be partly explained by suboptimal

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I B 119
with ongoing ischaemic symptoms and platelet inhibition due to inadequate response to clopidogrel. Indeed,
without contraindications.
pharmacodynamic and pharmacokinetic studies have described sub-
It is recommended to continue stantial interindividual variability in the antiplatelet response to this
chronic beta-blocker therapy, unless I B 126
drug and an increased risk of ischaemic and bleeding events in clopi-
the patient is in Killip class III or higher.
dogrel hypo- and hyper-responders, respectively.140 – 143 There is evi-
Sublingual or i.v. nitrates are
dence that key gene polymorphisms are involved in both the
recommended to relieve angina;d i.v.
treatment is recommended in patients I C variability of active metabolite generation and clinical efficacy of clo-
with recurrent angina, uncontrolled pidogrel.144 – 147
hypertension or signs of heart failure.
In patients with suspected/confirmed 5.2.2.2 Prasugrel
vasospastic angina, calcium channel Prasugrel (60 mg loading and 10 mg/day maintenance dose) is a pro-
IIa B 127
blockers and nitrates should be drug that irreversibly blocks platelet P2Y12 receptors with a faster
considered and beta-blockers avoided. onset and a more profound inhibitory effect than clopidogrel
(Table 8). This compound has been tested against the 300 mg load-
i.v. ¼ intravenous. ing and 75 mg/day maintenance dose of clopidogrel in the TRial to
a
Class of recommendation.
b
Level of evidence. Assess Improvement in Therapeutic Outcomes by Optimizing
c
References supporting level of evidence. Platelet InhibitioN with Prasugrel – Thrombolysis In Myocardial
d
Should not be administered in patients with recent intake of sildenafil or Infarction (TRITON-TIMI 38), in which ACS patients (STEMI and
vardenafil (,24 h) or tadalafil (,48 h).
NSTE-ACS) scheduled for PCI received the drugs during or after
the procedure.148 In the 10 074 NSTE-ACS patients included, recur-
5.2 Platelet inhibition rent CV events were reduced in prasugrel-treated patients at the
5.2.1 Aspirin 15-month follow-up [from 11.2% to 9.3%; relative risk (RR) 0.82
Aspirin (acetylsalicylic acid) irreversibly inactivates the cyclooxygen- (95% CI 0.73, 0.93), P ¼ 0.002], driven by a significant reduction
ase (COX) activity of platelet prostaglandin endoperoxide (PGH) in MI [from 9.2% to 7.1%; RRR 23.9% (95% CI 12.7, 33.7), P ,
synthase 1 (COX-1), thereby suppressing thromboxane A2 pro- 0.001]. Severe bleeding complications were more common with
duction throughout the platelet lifespan.128 Aspirin has been prasugrel [TIMI non-CABG major bleeds 2.4% vs. 1.8%; hazard ratio
shown to be effective in patients with unstable angina; the incidence (HR) 1.40 (95% CI 1.05, 1.88), P ¼ 0.02], due to an increase in spon-
of MI or death was consistently reduced in four RCTs in the taneous bleeds [1.6% vs. 1.1%; HR 1.51 (95% CI 1.09, 2.08), P ¼
pre-PCI era.129 – 132 A meta-analysis of these trials suggests that 0.01] and fatal bleeds [0.4% vs. 0.1%; HR 4.19 (95% CI 1.58,
aspirin administration (up to 2 years) is associated with a highly sig- 11.11), P ¼ 0.002].149 Bleeding events were increased by more
nificant 46% odds reduction in major vascular events.133 The Clopi- than four-fold in prasugrel-treated patients referred for early
dogrel and Aspirin Optimal Dose Usage to Reduce Recurrent CABG. Based on the marked reduction in definite or probable stent
Events– Seventh Organization to Assess Strategies in Ischaemic Syn- thrombosis observed in the TRITON-TIMI 38 overall [1.13% in the
dromes (CURRENT-OASIS 7), which enrolled 25 086 ACS (both prasugrel arm vs. 2.35% in the clopidogrel arm; HR 0.48 (95% CI
NSTE-ACS and STEMI) patients undergoing invasive strategy, found 0.36, 0.64), P , 0.0001] and in patients with drug-eluting stents
no difference between higher-dose (300 –325 mg/day) and lower- (DESs) [0.84% vs. 2.31%, respectively; HR 0.36 (95% CI 0.22,
dose (75 – 100 mg/day) aspirin.134 An oral loading dose (150 – 0.58), P , 0.0001], prasugrel should be considered in patients
300 mg) of plain aspirin (non-enteric-coated formulation) is recom- who present with stent thrombosis despite compliance with clo-
mended, while the recommended intravenous (i.v.) dose is 150 mg. pidogrel therapy.150,151 Prasugrel is contraindicated in patients
No monitoring of its effects is required. The mechanisms of action with prior stroke/transient ischaemic attack (TIA) due to evidence
of antiplatelet and anticoagulant agents are described in Figure 4. of net harm in this group in TRITON-TIMI 38. In addition, the
study showed no apparent benefit in patients .75 years of age
5.2.2 P2Y12 inhibitors or with low bodyweight (,60 kg).148 The Targeted Platelet Inhib-
5.2.2.1 Clopidogrel ition to Clarify the Optimal Strategy to Medically Manage Acute
Clopidogrel (300–600 mg loading and 75 mg/day maintenance dose) Coronary Syndromes (TRILOGY ACS) trial is discussed in section
is an inactive prodrug that requires oxidation by the hepatic 5.6.4.1.1.
ESC Guidelines 283

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ADP = adenosine diphosphate; AT = antithrombin; GP = glycoprotein; LMWH = low molecular weight heparin; Tx = thromboxane;
UFH = Unfractionated heparin. Vorapaxar is a protease-activated receptor 1 (PAR1) blocker.

Figure 4 Antithrombotic drugs for non-ST-elevation acute coronary syndromes. The figure depicts the targets of available antithrombotic
drugs that can be used to inhibit blood coagulation and platelet aggregation during and after thrombus formation.

5.2.2.3 Ticagrelor drugs metabolized through CYP3A, such as simvastatin, while mod-
Ticagrelor is an oral, reversibly binding P2Y12 inhibitor with a plasma erate CYP3A inhibitors, such as diltiazem, increase ticagrelor plasma
half-life of 6 – 12 h. Ticagrelor also inhibits adenosine reuptake via levels and might delay the offset of effect. In the PLATelet inhibition
equilabrative nucleoside transporter 1 (ENT1) (Table 8). Like prasu- and patient Outcomes (PLATO) trial, 18 624 patients with
grel, ticagrelor has a more rapid and consistent onset of action com- moderate- to high-risk NSTE-ACS (planned for either conservative
pared with clopidogrel, as well as a faster offset of action with more or invasive management) or STEMI were randomized to either clo-
rapid recovery of platelet function.152 Ticagrelor increases levels of pidogrel 75 mg/day, with a loading dose of 300 – 600 mg, or
284 ESC Guidelines

Table 8 P2Y12 inhibitors

Clopidogrel Prasugrel Ticagrelor Cangrelor


Chemical class Thienopyridine Thienopyridine Cyclopentyl-triazolopyrimidine Stabilized ATP analogue
Administration Oral Oral Oral Intravenous
300–600 mg orally 60 mg orally then 180 mg orally then 30 µg/kg bolus and
Dose
then 75 mg a day 10 mg a day 90 mg twice a day 4 µg/kg/min infusion

Dosing in CKD

• Stage 3
No dose adjustment No dose adjustment No dose adjustment No dose adjustment
(eGFR 30–59 mL/min/1.73m2)
• Stage 4
No dose adjustment No dose adjustment No dose adjustment No dose adjustment
(eGFR 15–29 mL/min/1.73m2)

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• Stage 5 Use only for selected indications
Not recommended Not recommended No dose adjustment
(eGFR <15 mL/min/1.73m2) (e.g. stent thrombosis prevention)
Binding reversibility Irreversible Irreversible Reversible Reversible
Prodrug, with variable Prodrug, with predictable Active drug, with additional
Activation Active drug
liver metabolism liver metabolism active metabolite
a
Onset of loading dose effect 2–6 hoursb 30 minb 30 minb 2 min

Duration of effect 3–10 days 7–10 days 3–5 days 1–2 hours

Withdrawal before surgery 5 daysc 7 daysc 5 daysc 1 hour


d e
Plasma half-life of active P2Y12 inhibitor 30–60 min 30–60 min 6–12 hours 5–10 min

Inhibition of adenosine reuptake No No Yes Yes (‘inactive’ metabolite only)

ADP ¼ adenosine diphosphate; ATP ¼ adenosine triphosphate; CKD ¼ chronic kidney disease; eGFR ¼ estimated glomerular filtration rate.
a
50% inhibition of ADP-induced platelet aggregation.
b
Onset of effect may be delayed if intestinal absorption is delayed (e.g. by opiate).
c
Shortening may be considered if indicated by platelet function tests and low bleeding risk.
d
Affecting the response to platelet transfusion.
e
The distribution phase half-life is reported since it most likely reflects duration of clinically-relevant plasma levels, while the corresponding elimination phase half-life is
approximately 7 hours.

ticagrelor 180 mg loading dose followed by 90 mg twice a day.153 5.2.2.4 Cangrelor


Patients undergoing PCI were allowed to receive an additional Cangrelor is an i.v. adenosine triphosphate (ATP) analogue that binds
blinded 300 mg loading dose of clopidogrel (total loading dose reversibly and with high affinity to the platelet P2Y12 receptor and has
600 mg) or its placebo. Treatment was continued for up to 12 a short plasma half-life (,10 min) (Table 8). It produces a highly ef-
months, with a median duration of drug exposure of 9 months.153 fective inhibition of ADP-induced platelet aggregation immediately
In the NSTE-ACS subgroup (n ¼ 11 080), the primary composite ef- after i.v. bolus administration and allows for restoration of platelet
ficacy endpoint (death from CV causes, MI or stroke) was signifi- function within 1–2 h of infusion discontinuation in NSTE-ACS pa-
cantly reduced with ticagrelor compared with clopidogrel [10.0% tients.157 Cangrelor (30 mg/kg bolus and 4 mg/kg/min infusion) in-
vs. 12.3%; HR 0.83 (95% CI 0.74, 0.93), P ¼ 0.0013] with similar re- itiated at the commencement of PCI has been examined in three
ductions for CV death [3.7% vs. 4.9%; HR 0.77 (95% CI 0.64, 0.93), clinical trials including a total of 24 910 patients: one with clopidogrel
P ¼ 0.0070] and all-cause mortality [4.3% vs. 5.8%; HR 0.76 (95% CI (600 mg) given at the beginning of PCI [Cangrelor versus Standard
0.64, 0.90), P ¼ 0.0020].154 Differences in bleeding event rates were Therapy to Achieve Optimal Management of Platelet Inhibition
also similar in the NSTE-ACS subgroup compared with the overall (CHAMPION)-PCI], one with clopidogrel (600 mg) initiated at the
study, with increased risk of non-CABG-related PLATO-defined end of PCI (CHAMPION-PLATFORM), and one with clopidogrel
major bleeds with ticagrelor compared with clopidogrel [4.8% vs. (300 or 600 mg) initiated either before or after PCI based on local
3.8%; HR 1.28 (95% CI 1.05, 1.56), P ¼ 0.0139] but no difference clinical practice (CHAMPION-PHOENIX) among patients without
in life-threatening or fatal bleeds.154 The benefits of ticagrelor com- prior P2Y12 or GPIIb/IIIa inhibition.158 – 160 A meta-analysis of these
pared with clopidogrel in NSTE-ACS were independent of whether studies, in which 69% of patients were undergoing PCI for ACS, ob-
or not revascularization was performed in the first 10 days after ran- served a 19% RRR in periprocedural death, MI, ischaemia-driven re-
domization.154 The reduction in definite stent thrombosis with tica- vascularization and stent thrombosis [cangrelor 3.8% vs. clopidogrel
grelor in the NSTE-ACS subgroup [1.1% vs. 1.4%; HR 0.71 (95% CI 4.7%; OR 0.81 (95% CI 0.71, 0.91), P ¼ 0.007], with a 39% RRR in
0.43, 1.17] was consistent with that seen in the trial overall [1.4% vs. stent thrombosis alone [cangrelor 0.5% vs. clopidogrel 0.8%; OR
1.9%; HR 0.67 (95% CI 0.50, 0.90), P ¼ 0.0091].155 In addition to in- 0.61 (95% CI 0.43, 0.80), P ¼ 0.008].161 The combination of TIMI ma-
creased rates of minor or non-CABG-related major bleeding events jor and minor bleeds was increased [cangrelor 0.9% vs. clopidogrel
with ticagrelor, adverse effects included dyspnoea (without 0.6%; OR 1.38 (95% CI 1.03, 1.86), P ¼ 0.007], but there was no in-
bronchospasm), increased frequency of asymptomatic ventricular crease in the rate of transfusions. The European Commission issued
pauses and increases in uric acid.153,156 marketing authorization for this compound in March 2015.
ESC Guidelines 285

5.2.3 Timing of P2Y12 inhibitor administration In patients undergoing elective non-cardiac surgery, ticagrelor
Initiation of P2Y12 inhibitors soon after the diagnosis of NSTE-ACS and clopidogrel should be discontinued 5 days before surgery, while
irrespective of management strategy has been recommended.162,163 the interval should be increased to 7 days in patients on prasugrel,
This implies pretreatment, defined as P2Y12 inhibitor administration unless the patient is at high risk of stent thrombosis.179 In the latter
before coronary angiography, in patients scheduled for an invasive case, a multidisciplinary decision is required to determine the best
approach. Subsequently the results of the only RCT on P2Y12 inhibi- strategy. Longer discontinuation times (e.g. 7 days for ticagrelor
tor pretreatment in NSTE-ACS, the Comparison of Prasugrel at the and 10 days for clopidogrel or prasugrel) may be appropriate for
Time of Percutaneous Coronary Intervention or as Pretreatment at surgery at extreme risk of bleeding (e.g. some types of neurosur-
the Time of Diagnosis in Patients with Non-ST Elevation Myocardial gery). For NSTE-ACS patients, the risk of bleeds related to surgery
Infarction (ACCOAST) trial, were published.164 The ACCOAST must be balanced against the risk of recurrent ischaemic events
study compared pretreatment with prasugrel 30 mg and a further related to discontinuation of therapy. The type of surgery, the is-
30 mg dose prior to PCI with a regimen of prasugrel 60 mg after chaemic risk and extent of CAD, the time since the acute episode

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diagnostic angiography but prior to PCI among 4033 patients with and, for patients who have undergone PCI, the time since the pro-
NSTEMI scheduled for early invasive strategy. The median duration cedure and the type of stent implanted are key elements of the dis-
of pretreatment was 4.3 h. Sixty-nine per cent of the patients under- cussion. Selected patients who require non-cardiac surgery after
went PCI, 6% required surgical revascularization and the remainder recently implanted stents may benefit from bridging therapy with
were treated conservatively.164 At 7 days, patients randomized to small molecule GPIIb/IIIa inhibitors (i.e. tirofiban or eptifibatide)
the pretreatment arm experienced no reduction in the primary end- after discontinuation of the P2Y12 inhibitor, while cangrelor has so
point (i.e. CV death, recurrent MI, stroke, urgent revascularization far been tested as bridging therapy to CABG.181,182 In patients on
and bailout use of GPIIb/IIIa inhibitors) [HR 1.02 (95% CI 0.84, DAPT following an episode of NSTE-ACS that was treated conser-
1.25), P ¼ 0.81], and no benefits emerged at 30 days.164 TIMI major vatively, the P2Y12 inhibitor may be discontinued. In surgical proce-
bleeds were significantly increased in the pretreatment group at dures with low to moderate bleeding risk, surgeons should be
7 days [pretreatment 2.6% vs. no pretreatment 1.4%; HR 1.90, encouraged to operate on patients on DAPT. Adherence to
(95% CI 1.19, 3.02), P ¼ 0.006]. Arguments for and against pretreat- DAPT should be improved through education of patients, relatives
ment with P2Y12 inhibitors in NSTE-ACS patients have been dis- and physicians in order to prevent avoidable CV events.
cussed extensively and the topic remains controversial.165,166 As
the optimal timing of ticagrelor or clopidogrel administration in 5.2.6 Duration of dual antiplatelet therapy
NSTE-ACS patients scheduled for an invasive strategy has not been In patients with NSTE-ACS, DAPT with aspirin and clopidogrel has
adequately investigated, no recommendation for or against pretreat- been recommended for 1 year over aspirin alone, irrespective of re-
ment with these agents can be formulated. Based on the ACCOAST vascularization strategy and stent type, according to the Clopidogrel
results, pretreatment with prasugrel is not recommended. In in Unstable Angina to Prevent Recurrent Events (CURE) study,
NSTE-ACS patients planned for conservative management, P2Y12 in- while the TRITON-TIMI 38 and PLATO studies have demonstrated
hibition (preferably with ticagrelor) is recommended, in the absence the superiority of a prasugrel- and ticagrelor-based regimen, re-
of contraindications, as soon as the diagnosis is confirmed. spectively, over a clopidogrel-based one.138,148,153 A 1-year duration
of DAPT with clopidogrel was associated with a 26.9% RRR of
5.2.4 Monitoring of P2Y12 inhibitors (see Web addenda)
death, MI or stroke (8.6% vs. 11.8%; 95% CI 3.9, 44.4; P ¼ 0.02)
5.2.5 Premature discontinuation of oral antiplatelet vs. 1-month DAPT in the Clopidogrel for the Reduction of Events
therapy During Observation (CREDO) trial, which enrolled 2116 pa-
Withdrawal of oral antiplatelet therapy may lead to an increased risk tients.183 The study population comprised patients with stable
of recurrent events, particularly when the recommended course of CAD and low-risk NSTE-ACS undergoing PCI (each 50%), and no
therapy has not yet been completed.176 – 178 Interruption of DAPT interaction between ACS status and DAPT was observed.
soon after stent implantation increases the risk of stent thrombosis, Evidence to support the extension of DAPT after DES beyond
especially within the first month after cessation.178 While discontinu- 1 year in NSTE-ACS patients is limited (Table 9, see Web addenda).
ation of DAPT prior to cardiac surgery is discussed in sections 5.6.6.1
Web addenda and 5.6.6.2, in the case of a non-cardiac surgical proced- Table 9 (see Web addenda) Main features of published
ure that cannot be postponed, a minimum of 1 and 3 months DAPT randomized studies investigating various durations of
for bare-metal stents (BMSs) and new-generation DESs, respectively, dual antiplatelet therapy following percutaneous coronary
might be acceptable.179 In this setting, surgery should be performed in intervention (PCI)
hospitals having continuous catheterization laboratory availability, so The DAPT trial randomized patients who did not experience ad-
as to treat patients immediately in case of perioperative MI.179 If inter- verse events in the first year after PCI to an additional 18 months of
ruption of DAPT becomes mandatory because of urgent high-risk thienopyridine (clopidogrel/prasugrel) or placebo.184 Continued
surgery (e.g. neurosurgery) or in the case of a major bleed that cannot treatment with thienopyridine, as compared with placebo, reduced
be controlled by local treatment, no alternative therapy can be pro- the rates of stent thrombosis [0.4% vs. 1.4%; HR 0.29 (95% CI 0.17,
posed as a substitute to DAPT to prevent stent thrombosis. Low mo- 0.48), P , 0.001] and major adverse cardiovascular and cerebrovas-
lecular weight heparin (LMWH) has been advocated, but the proof of cular events [4.3% vs. 5.9%; HR 0.71 (95% CI 0.59, 0.85), P , 0.001].
efficacy for this indication is lacking.180 Whenever possible, aspirin The rate of MI was lower with thienopyridine treatment than with
should be continued because early discontinuation of both antiplate- placebo (2.1% vs. 4.1%; HR 0.47, P , 0.001). The rate of death from
let drugs will further increase the risk of stent thrombosis. any cause was 2.0% in the group that continued thienopyridine
286 ESC Guidelines

therapy and 1.5% in the placebo group [HR 1.36 (95% CI 1.00, 1.85), appeared consistent among patients receiving and not receiving
P ¼ 0.05]. The rate of moderate or severe bleeding was increased GPIIb/IIIa inhibitors, the efficacy and safety of GPIIb/IIIa inhibitors
with continued thienopyridine treatment [2.5% vs. 1.6%; HR 1.61 on top of these P2Y12 inhibitors have not been prospectively ad-
(95% CI 1.21, 2.16), P ¼ 0.001]. 184 A meta-analysis including dressed.153,197 In patients treated with prasugrel or ticagrelor,
32 287 patients enrolled in 10 RCTs compared different DAPT GPIIb/IIIa inhibitors should be limited to bailout situations or
durations.185 Nearly 50% of the patients had stable CAD. Studies thrombotic complications during PCI. Dosing in patients with
were stratified according to the DAPT duration in the control group impaired renal function is reported in Table 10. Additional informa-
in order to avoid having 12-month DAPT duration included in both tion on GPIIb/IIIa inhibitors may be found in sections 5.2.7.1 –
study arms. As a consequence, it allowed comparison of outcomes 5.2.7.3, while GPIIb/IIIa inhibitor-related thrombocytopenia is
of either short-term or extended (i.e. beyond 12 months) DAPT described in section 5.8.7.1 (all in the Web addenda).
duration vs. 12-month therapy. Compared with 12-month DAPT,
a shorter course of treatment was associated with a significant re- 5.2.7.1 Upstream versus procedural initiation (see Web addenda)

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duction in major bleeds [OR 0.58 (95% CI 0.36, 0.92), P ¼ 0.02], 5.2.7.2 Combination with P2Y12 inhibitors (see Web addenda)
while no statistically significant differences in ischaemic outcomes 5.2.7.3 Adjunctive anticoagulant therapy (see Web addenda)
or stent thrombosis risks were observed, although a small to mod-
5.2.8 Vorapaxar (see Web addenda)
erate increase could not be excluded. Extended DAPT, compared
5.2.9 Recommendations for platelet inhibition in
with 12-month treatment, yielded a significant reduction in MI
non-ST-elevation acute coronary syndromes
[OR 0.53 (95% CI 0.42, 0.66), P , 0.001] and stent thrombosis
[OR 0.33 (95% CI 0.21, 0.51), P , 0.001] while more major bleeds
occurred [OR 1.62 (95% CI 1.26, 2.09), P , 0.001]. In addition, all-
Recommendations for platelet inhibition in non-ST-
cause death was significantly increased in the extended DAPT group
elevation acute coronary syndromes
[OR 1.30 (95% CI 1.02, 1.66), P ¼ 0.03] while CV death did not dif-
fer among the groups.185
The Prevention of Cardiovascular Events in Patients with Prior Recommendations Classa Levelb Ref.c
Heart Attack Using Ticagrelor Compared to Placebo on a Back-
Oral antiplatelet therapy
ground of Aspirin-Thrombolysis in Myocardial Infarction 54
Aspirin is recommended for all
(PEGASUS-TIMI 54) trial randomized 21 162 patients who had had
patients without contraindications at
an MI 1–3 years earlier to ticagrelor at a dose of 90 mg twice daily, an initial oral loading dosed of 150 –
ticagrelor at a dose of 60 mg twice daily or placebo.186 At a median 129–
300 mg (in aspirin-naive patients) and I A
132
follow-up of 33 months, the study demonstrated a reduced rate of a maintenance dose of 75 – 100 mg/
CV death, MI or stroke with ticagrelor [HR 0.85 (95% CI 0.75, day long-term regardless of treatment
strategy.
0.96), P ¼ 0.008 and HR 0.84 (95% CI 0.74, 0.95), P ¼ 0.004 for
90 mg and 60 mg of ticagrelor vs. placebo, respectively) and increased A P2Y12 inhibitor is recommended, in
137,
rates of major bleeding events (2.60% with 90 mg, 2.30% with 60 mg addition to aspirin, for 12 months
I A 148,
unless there are contraindications such
and 1.06% with placebo, P , 0.001).186 All-cause mortality did not as excessive risk of bleeds.
153
differ between the groups. Of importance, most patients began treat-
† Ticagrelor (180 mg loading dose,
ment with ticagrelor after an interruption in DAPT and all had prior 90 mg twice daily) is recommended,
MI (context of secondary prevention in high-risk patients), while in the absence of contraindications,e
patients with a history of ischaemic stroke were excluded. In conclu- for all patients at moderate-to-high
sion, while a 1-year duration of DAPT in NSTE-ACS patients is re- risk of ischaemic events (e.g. elevated
commended, based on individual patient ischaemic and bleeding cardiac troponins), regardless of I B 153
initial treatment strategy and
risk profiles, DAPT duration may be shortened (i.e. 3 – 6 months) including those pretreated with
or extended (i.e. up to 30 months) in selected patients if required. clopidogrel (which should be
discontinued when ticagrelor is
5.2.7 Glycoprotein IIb/IIIa inhibitors started).
Intravenous GPIIb/IIIa inhibitors block platelet aggregation by † Prasugrel (60 mg loading dose,
inhibiting fibrinogen binding to a conformationally activated 10 mg daily dose) is recommended 148,
I B
form of the GPIIb/IIIa receptor on two adjacent platelets.128 A in patients who are proceeding to 164
meta-analysis of six RCTs involving 29 570 NSTE-ACS patients, PCI if no contraindication.e
mainly medically managed, showed a 9% RRR in death or non-fatal † Clopidogrel (300–600 mg loading
dose, 75 mg daily dose) is
MI with GPIIb/IIIa inhibitors (10.7% vs. 11.5%, P ¼ 0.02) when
recommended for patients who
added to heparin.196 The greatest benefit was observed in patients cannot receive ticagrelor or
I B 137
undergoing PCI while on these agents [10.5% vs. 13.6%; OR 0.74 prasugrel or who require oral
(95% CI 0.57, 0.96), P ¼ 0.02]. The use of GPIIb/IIIa inhibitors anticoagulation.
was associated with an increase in major bleeding complications P2Y12 inhibitor administration for a
187–
without a significant increase in intracranial haemorrhage. Many shorter duration of 3–6 months after
IIb A 189,
of these trials predated the routine use of P2Y12 inhibitors. While DES implantation may be considered in
192
the relative efficacy of prasugrel and ticagrelor in the trials patients deemed at high bleeding risk.
ESC Guidelines 287

It is not recommended to administer Table 10 Dosing of glycoprotein IIb/IIIa inhibitors in


prasugrel in patients in whom coronary III B 164 patients with normal and impaired renal function
anatomy is not known.
Intravenous antiplatelet therapy Drug Recommendations
Normal renal Stage 3 CKD Stage 4 CKD Stage 5 CKD
GPIIb/IIIa inhibitors during PCI should function or stage (eGFR (eGFR (eGFR
be considered for bailout situations or IIa C 1–2 CKD 30–59 mL/ 15–29 mL/ <15 mL/
(eGFR min/1.73m2) min/1.73m2) min/1.73m2)
thrombotic complications. ≥60 mL/
min/1.73m 2)
Cangrelor may be considered in P2Y12 158–
IIb A No adjustment
inhibitor–naive patients undergoing PCI. 161 Bolus of bolus, reduce
180 µg/kg i.v., infusion rate to Not Not
It is not recommended to administer infusion 1 µg/kg/min if recommended recommended
198,
GPIIb/IIIa inhibitors in patients in whom III A 2 µg/kg/min eGFR
199 <50 mL/min/1.73m2
coronary anatomy is not known.

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Bolus 25 µg/kg No adjustment
Long-term P2Y12 inhibition or 10 µg/kg i.v, No dose of bolus, reduce Not
infusion adjustment infusion to recommended
P2Y12 inhibitor administration 0.15 µg/kg/min 0.05 µg/kg/min
in addition to aspirin beyond 1 year Bolus
184, 0.25 mg/kg i.v.,
may be considered after careful IIb A
186 infusion or for dose adjustment in the case of renal failure.
assessment of the ischaemic and 0.125 µg/kg/min Careful evaluation of haemorrhagic risk is needed.
bleeding risks of the patient. (max.10 µg/min)

General recommendations
CKD ¼ chronic kidney disease; eGFR ¼ estimated glomerular filtration rate; i.v. ¼
A proton pump inhibitor in intravenous; kg ¼ kilograms bodyweight.
combination with DAPT is Recommendations for the use of drugs listed in this table may vary depending on
recommended in patients at higher the exact labeling of each drug in the country where it is used.
than average risk of gastrointestinal
bleeds (i.e. history of gastrointestinal
ulcer/haemorrhage, anticoagulant 208,
I B
therapy, chronic NSAID/ 209 5.3 Anticoagulation
corticosteroid use or two or more of
the following: age ≥65 years,
5.3.1 Anticoagulation during the acute phase
dyspepsia, gastro-oesophageal reflux Anticoagulants are used to inhibit thrombin generation and/or activ-
disease, Helicobacter pylori infection, ity, thereby reducing thrombus-related events. There is evidence
chronic alcohol use). that anticoagulation is effective in reducing ischaemic events in
In patients on P2Y12 inhibitors who NSTE-ACS and that the combination with platelet inhibitors is
need to undergo non-emergency more effective than either treatment alone.210 Several anticoagu-
major non-cardiac surgery,f lants, acting at different levels of the coagulation cascade, have
postponing surgery for at least 5 days
been approved or are under investigation for this indication
after cessation of ticagrelor or IIa C
clopidogrel, and for 7 days for (Figure 4). Anticoagulant doses in patients with impaired renal func-
prasugrel, should be considered if tion are reported in Table 11.
clinically feasible and unless the patient
is at high risk of ischaemic events.
5.3.1.1 Unfractionated heparin
In case of a non-cardiac surgical
UFH has a pharmacokinetic profile with large interindividual variabil-
procedure that cannot be postponed
or of a bleeding complication, ity and a narrow therapeutic window. Weight-adjusted i.v. administra-
discontinuation of the P2Y12 inhibitor IIb C tion with an initial bolus of 60–70 IU/kg up to a maximum of 5000 IU,
may be considered after a minimum of 1 followed by an infusion of 12 – 15 IU/kg/h up to a maximum of
and 3 months from PCI with BMS and 1000 IU/h, is recommended. Anticoagulation level is usually moni-
new-generation DES, respectively.
tored in the cardiac catheterization laboratory with activated clotting
time (ACT) and elsewhere with the activated partial thromboplastin
BMS ¼ bare-metal stent; CABG ¼ coronary artery bypass graft; DAPT ¼ dual time (aPTT; therapeutic window is 50–75 s, corresponding to 1.5–
(oral) antiplatelet therapy; DES ¼ drug-eluting stent; GPIIb/IIIa ¼ glycoprotein IIb/
IIIa; NSAID ¼ non-steroidal anti-inflammatory drug; NSTE-ACS ¼ non-ST- 2.5 times the upper limit of normal). UFH remains a widely used anti-
elevation acute coronary syndromes; PCI ¼ percutaneous coronary intervention. coagulant in NSTE-ACS in the context of short delays to coronary
a
Class of recommendation. angiography and short hospital stays despite consistent evidence for
b
Level of evidence.
c
References supporting level of evidence. greater bleeding risk compared with other strategies.211 In the PCI
d
Non-enteric coated formulation; 75–150 mg intravenously if oral ingestion is not setting, UFH is given as an i.v. bolus either under ACT guidance (in
possible. the range of 250–350 s, or 200–250 s if a GPIIb/IIIa inhibitor is given)
e
Contraindications for ticagrelor: previous intracranial haemorrhage or ongoing
bleeds. Contraindications for prasugrel: previous intracranial haemorrhage, previous or in a weight-adjusted manner (usually 70–100 IU/kg, or 50–70 IU/
ischaemic stroke or transient ischaemic attack or ongoing bleeds; prasugrel is kg in combination with a GPIIb/IIIa inhibitor).212,213 UFH should be
generally not recommended for patients ≥75 years of age or with a bodyweight stopped after PCI unless there is an established indication related
,60 kg.
f
Recommendations for cardiac surgery are listed in section 5.6.6.2. to the procedure or to the patient’s condition. For heparin-induced
thrombocytopenia (HIT) see section 5.8.7.2.
288 ESC Guidelines

antithrombin with high affinity, thereby preventing thrombin gener-


Table 11 Dosing of anticoagulants in patients with ation (Figure 4). The compound has 100% bioavailability after s.c. injec-
normal and impaired renal function tion, with an elimination half-life of 17 h, allowing once-daily dosing.
No monitoring of anti-Xa activity and no dose adjustments are re-
Drug Recommendations
Normal renal function Stage 4 CKD (eGFR Stage 5 CKD (eGFR
quired and the compound does not induce HIT. In NSTE-ACS, the
or stage 1–3 CKD 15–29 mL/min/1.73m2) <15 mL/min/1.73m2) recommended dose is 2.5 mg/day. Due to its renal elimination, fonda-
(eGFR ≥30 mL/min/1.73m )2

• Prior to coronary
parinux is contraindicated if eGFR is ,20 mL/min/1.73m2. In the fifth
angiography: 60–70 IU/kg Organization to Assess Strategies in Acute Ischaemic Syndromes
i.v. (max 5000 IU) and
infusion (12–15 IU/kg/h) (OASIS-5) study, which enrolled 20 078 patients with NSTE-ACS,
Unfractionated (max 1000 IU/h), target No dose No dose fondaparinux 2.5 mg s.c. once daily was non-inferior to enoxaparin
heparin aPTT 1.5–2.5x control adjustment adjustment
• During PCI according to with respect to ischaemic events [death, MI or refractory ischaemia
ACT or 70–100 IU/kg i.v. in at 9 days; HR 1.01 (95% CI 0.90, 1.13), P ¼ 0.007], but halved in-

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patients not anticoagulated
(50–70 IU/kg if concomitant hospital major bleeds [HR 0.52 (95% CI 0.44, 0.61), P , 0.001] and
with GPIIb/IIIa inhibitors)
Enoxaparin 1 mg/kg s.c. twice a day 1 mg/kg s.c. once a day Not recommended
significantly reduced mortality at 30 days [2.9% vs. 3.5%; HR 0.83
Not recommended if (95% CI 0.71, 0.97), P , 0.02] and 6 months [5.8% vs. 6.5%; HR
Fondaparinux 2.5 mg s.c. once a day eGFR Not recommended 0.89 (95% CI 0.80, 1.00), P , 0.05].218 In the subgroup of patients
<20 mL/min/1.73m2
who underwent PCI (n ¼ 6239), a significantly lower rate of major
Bolus 0.75 mg/kg i.v.,
Bivalirudin Not recommended Not recommended bleeding complications (including access site complications) was ob-
infusion 1.75 mg/kg/h*
served at 9 days in the fondaparinux group vs. enoxaparin [2.3% vs.
5.1%; HR 0.45 (95% CI 0.34, 0.59), P , 0.001].203 The rate of major
ACT ¼ activated clotting time; aPTT ¼ activation partial thromboplastin time; bleeds was not influenced by the timing of the intervention after in-
CKD ¼ chronic kidney disease; eGFR ¼ estimated glomerular filtration rate; IU ¼
international units; i.v. ¼ intravenous; kg ¼ kilograms bodyweight; s.c. ¼ jection of the last dose of fondaparinux (1.6% vs. 1.3% for ,6 h vs.
subcutaneous; *Infusion dose 1.4 mg/kg/h if eGFR ≥30 and ≤ 60 mL/min/1.73m2. .6 h, respectively). Catheter thrombus was observed more fre-
Recommendations for the use of drugs listed in this table may vary depending on quently with fondaparinux (0.9%) than with enoxaparin (0.4%), but
the exact labeling of each drug in the country where it is used.
this complication was abolished by injection of an empirically deter-
mined bolus of UFH at the time of PCI. Subsequent studies have
5.3.1.2 Low molecular weight heparin shown that a standard UFH bolus is recommended at the time of
LMWH has a more predictable dose–effect relationship than UFH PCI in patients pretreated with fondaparinux.219 An analysis exploring
and causes HIT less frequently. The most widely used agent in the uptake of fondaparinux compared with LMWH among 40 616
NSTE-ACS is enoxaparin, 1 mg/kg administered subcutaneously NSTEMI patients from a large-scale Scandinavian registry described
twice daily, while the dose is reduced to 1 mg/kg once a day if a reduction in in-hospital mortality [OR 0.75 (95% CI 0.63, 0.89)]
eGFR , 30 mL/min/1.73m2. LMWH should not be administered and in bleeding events [OR 0.54 (95% CI 0.42, 0.70)] associated
in patients with eGFR , 15 mL/min/1.73m2. Monitoring of anti-Xa with the use of fondaparinux, but the advantage disappeared at 30
activity is not necessary except in patients in whom the eGFR is days and 6 months, respectively.220 Overall, fondaparinux is consid-
15 – 30 mL/min/1.73m2 or bodyweight is .100 kg. In NSTE-ACS ered to be the parenteral anticoagulant with the most favourable ef-
patients pretreated with enoxaparin, no additional enoxaparin is re- ficacy – safety profile and is recommended regardless of the
commended during PCI if the last subcutaneous (s.c.) enoxaparin in- management strategy, unless the patient is scheduled for immediate
jection was administered ,8 h before PCI, whereas an additional coronary angiography.
0.3 mg/kg i.v. bolus is recommended if the last s.c. enoxaparin injec-
tion was administered ≥8 h before PCI.214,215 Crossing over to an- 5.3.1.4 Bivalirudin
other anticoagulant during PCI is strongly discouraged. 216 A Bivalirudin binds directly to thrombin and thereby inhibits the
meta-analysis of all trials testing enoxaparin vs. UFH in ACS showed thrombin-induced conversion of fibrinogen to fibrin. It inactivates
a marginally significant reduction in the combined endpoint of death fibrin-bound as well as fluid-phase thrombin (Figure 4). As the
or MI at 30 days in favour of enoxaparin [10.0% vs. 11.0%; OR 0.90 drug does not bind to plasma proteins, its anticoagulant effect is
(95% CI 0.81, 0.996), P ¼ 0.043] but no statistically significant differ- more predictable than that of UFH. Bivalirudin is eliminated by
ences in major bleeds [6.3% with enoxaparin vs. 5.4% with UFH; OR the kidney and has a half-life of 25 min after cessation of the infusion.
1.13 (95% CI 0.84, 1.54)] at 7 days.217 A meta-analysis including The anticoagulant activity of bivalirudin correlates well with aPTT
23 trials and 30 966 patients documented the favourable safety and ACT values. In NSTE-ACS patients, a bivalirudin dose of
and efficacy profile of enoxaparin compared with UFH during PCI, 0.1 mg/kg i.v. bolus followed by an infusion of 0.25 mg/kg/h was
with significant reductions in death [RR 0.66 (95% CI 0.57, 0.76), P , tested in the ACUITY trial in 13 819 moderate- to high-risk
0.001], the composite of death or MI [RR 0.68 (95% CI 0.57, 0.81), NSTE-ACS patients planned for an invasive strategy.205 In patients
P , 0.001], complications of MI [RR 0.75 (95% CI 0.6, 0.85), P , undergoing PCI, an additional i.v. bolus of 0.5 mg/kg bivalirudin
0.001] and major bleeds [RR 0.80 (95% CI 0.68, 0.95), P ¼ 0.009].211 was added before the procedure and the infusion dose was in-
creased to 1.75 mg/kg/h before PCI and stopped at the end of the
5.3.1.3 Fondaparinux procedure. Patients were randomized to one of three unblinded
The parenteral selective factor Xa inhibitor fondaparinux is a synthet- treatments: UFH or LMWH plus GPIIb/IIIa inhibitor, bivalirudin
ic pentasaccharide that binds reversibly and non-covalently to plus GPIIb/IIIa inhibitor or bivalirudin with bailout use of GPIIb/IIIa
ESC Guidelines 289

inhibitor. There was no significant difference between UFH/LMWH rivaroxaban 5 mg (4.0%). Non-CABG major bleeds occurred in
plus GPIIb/IIIa inhibitor vs. bivalirudin plus GPIIb/IIIa inhibitor for the 1.8% and 2.4% with 2.5 and 5 mg rivaroxaban, respectively, compared
composite ischaemia endpoint at 30 days [death, MI or unplanned re- with 0.6% with placebo [HR 3.46 for rivaroxaban 2.5 mg (95% CI 2.08,
vascularization for ischaemia 7.3% vs. 7.7%, respectively; RR 1.07 5.77), P , 0.001; HR 4.47 for rivaroxaban 5 mg (95% CI 2.71, 7.36),
(95% CI 0.92, 1.23), P ¼ 0.39] or for major bleeds [5.7% vs. 5.3%; P , 0.001]. Intracranial haemorrhage rates were 0.4% with 2.5 mg
RR 0.93 (95% CI 0.78, 1.10), P ¼ 0.38]. Bivalirudin with bailout use and 0.7% with 5 mg rivaroxaban vs. 0.2% with placebo [HR 2.83
of GPIIb/IIIa inhibitor was non-inferior to UFH/LMWH combined (95% CI 1.02, 7.86), P ¼ 0.04 for 2.5 mg; HR 3.74 (95% CI 1.39,
with a GPIIb/IIIa inhibitor with respect to the composite ischaemia 10.07), P ¼ 0.005 for 5 mg].226 The use of rivaroxaban 2.5 mg twice
endpoint [7.8% vs. 7.3%; RR 1.08 (95% CI 0.93, 1.24), P ¼ 0.32], daily, while not recommended in patients treated with ticagrelor or
but with a significantly lower rate of major bleeds [3.0% vs. 5.7%; prasugrel, might be considered in combination with aspirin and clopi-
RR 0.53 (95% CI 0.43, 0.65), P , 0.001]. In patients not pretreated dogrel if ticagrelor and prasugrel are not available for NSTEMI patients
with clopidogrel prior to PCI, a significant excess in ischaemic events who have high ischaemic and low bleeding risks. It is contraindicated in

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was observed in bivalirudin-treated patients vs. those receiving UFH/ patients with a prior history of ischaemic stroke/TIA and its use is cau-
LMWH plus GPIIb/IIIa inhibitor [9.1% vs. 7.1%; RR 1.29 (95% CI 1.03, tioned in patients .75 years of age or ,60 kg bodyweight.
1.63)].221,222 Comparable findings were observed in a trial with a simi-
lar design, the Intracoronary Stenting and Anti-thrombotic Regimen–
Rapid Early Action for Coronary Treatment (ISAR-REACT) 4 5.3.3 Recommendations for anticoagulation in
study.223 The ISAR-REACT 3 study, the only head-to-head compari- non-ST-elevation acute coronary syndromes
son between bivalirudin and UFH alone (140 IU/kg) published so far,
was performed in 4570 stable CAD patients as well as biomarker- Recommendations for anticoagulation in non-ST-
negative NSTE-ACS patients undergoing PCI; the study found com- elevation acute coronary syndromes
parable rates of death, MI and urgent revascularization at 30 days
[5.9% in the bivalirudin arm vs. 5.0% in the UFH arm; OR 1.16
Recommendations Classa Levelb Ref.c
(95% CI 0.91, 1.49), P ¼ 0.23] but a reduction in bleeding events
[3.1% vs. 4.6%; OR 0.66 (95% CI 0.49, 0.90), P ¼ 0.008].224 Parenteral anticoagulation is
recommended at the time of diagnosis
I B 227
according to both ischaemic and
5.3.2 Anticoagulation following the acute phase bleeding risks.
Two phase III trials have compared non-vitamin K antagonist (VKA)
Fondaparinux (2.5 mg s.c. daily) is
oral anticoagulants (NOACs) (for mode of action, see Figure 4) to recommended as having the most 218,
placebo in patients with recent ACS treated with aspirin and clopi- favourable efficacy–safety profile I B 228,
dogrel who did not have atrial fibrillation or other indications for regardless of the management 229
oral anticoagulation (OAC). The Apixaban for Prevention of Acute strategy.
Ischaemic Events (APPRAISE) 2 study assessed the effects of the oral Bivalirudin (0.75 mg/kg i.v. bolus,
factor Xa inhibitor apixaban 5 mg twice daily compared with pla- followed by 1.75 mg/kg/h for up to 4 h 205,
after the procedure) is recommended I A 222,
cebo, in addition to standard-of-care antiplatelet therapy following
as an alternative to UFH plus GPIIb/IIIa 223
ACS; it was terminated early (median 8 months) due to a markedly inhibitors during PCI.
increased risk of severe bleeds, including intracranial haemorrhage,
UFH 70–100 IU/kg i.v. (50–70 IU/kg if
without any apparent benefit in terms of ischaemic events.225 The concomitant with GPIIb/IIIa inhibitors)
study Anti-Xa Therapy to Lower Cardiovascular Events in Addition 219,
is recommended in patients I B
229
to Aspirin with or without Thienopyridine Therapy in Subjects with undergoing PCI who did not receive
Acute Coronary Syndrome–Thrombolysis in Myocardial Infarction any anticoagulant.
(ATLAS ACS 2-TIMI 51) has led to the European Medicines In patients on fondaparinux (2.5 mg
Agency’s (EMA’s) approval of rivaroxaban (2.5 mg twice daily) for s.c. daily) undergoing PCI, a single i.v.
NSTEMI and STEMI patients after the acute phase.226 The trial com- bolus of UFH (70– 85 IU/kg, or 50–
I B 219
60 IU/kg in the case of concomitant
pared rivaroxaban 2.5 mg or 5 mg twice daily (unlike the 20 mg use of GPIIb/IIIa inhibitors) is
once-daily dose for atrial fibrillation) with placebo in 15 526 patients recommended during the procedure.
following ACS; 50% had NSTE-ACS and 93% received clopidogrel in
Enoxaparin (1 mg/kg s.c. twice daily)
addition to aspirin at randomization. Patients with prior ischaemic 218,
or UFH are recommended when I B
230
stroke/TIA were excluded. At a mean follow-up of 13 months, the fondaparinux is not available.
primary efficacy endpoint of CV death, MI or stroke was 10.7% with Enoxaparin should be considered as an
placebo, 9.1% with rivaroxaban 2.5 mg [HR 0.84 (95% CI 0.72, 0.97), anticoagulant for PCI in patients IIa B 211
P ¼ 0.02] and 8.8% with rivaroxaban 5 mg [HR 0.85 (95% CI 0.73, pretreated with s.c. enoxaparin.
0.98), P ¼ 0.03], with no interaction by ACS subtype. Rates of def- Additional ACT-guided i.v. boluses of
inite, probable or possible stent thrombosis were 2.2% and 2.3% UFH during PCI may be considered IIb B 231
with 2.5 and 5 mg rivaroxaban, respectively, vs. 2.9% with placebo following initial UFH treatment.
(P ¼ 0.02 and P ¼ 0.04, respectively). Rates of CV death were signifi- Discontinuation of anticoagulation
cantly lower with rivaroxaban 2.5 mg compared with placebo [2.7% should be considered after PCI, unless IIa C
vs. 4.1%; HR 0.66 (95% CI 0.51, 0.86), P ¼ 0.002] but not with otherwise indicated.
290 ESC Guidelines

Crossover between UFH and LMWH Table 12 Suggested strategies to reduce bleeding risk
III B 216
is not recommended. related to PCI
In NSTEMI patients with no prior
stroke/TIA and at high ischaemic risk • Anticoagulant doses adjusted to bodyweight and renal function,
as well as low bleeding risk receiving especially in women and elderly patients.
aspirin and clopidogrel, low-dose
IIb B 226 • Radial approach preferred.
rivaroxaban (2.5 mg twice daily for
approximately 1 year) may be • Proton pump inhibitors in patients on DAPT at higher than average risk of
gastrointestinal bleeds (i.e. history of gastrointestinal ulcer/haemorrhage,
considered after discontinuation of
anticoagulant therapy, chronic NSAIDs/corticosteroid use, or two or
parenteral anticoagulation. more among age ≥65 years, dyspepsia, gastrooesophageal reflux disease,
Helicobacter pylori infection, and chronic alcohol use).

ACT ¼ activated clotting time; GPIIb/IIIa ¼ glycoprotein IIb/IIIa; i.v. ¼ • In patients on OAC
o PCI performed without interruption of VKAs or NOACs.

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intravenous; LMWH ¼ low molecular weight heparin; NSTEMI ¼ non-ST-
elevation myocardial infarction; PCI ¼ percutaneous coronary intervention; o In patients on VKAs, do not administer UFH if INR value >2.5.
s.c. ¼ subcutaneous; TIA ¼ transient ischaemic attack; UFH ¼ unfractionated o In patients on NOACs, regardless of the timing of the last
heparin. administration of NOACs, add additional low-dose parenteral
a
Class of recommendation.
anticoagulation (e.g. enoxaparin 0.5 mg/kg i.v. or UFH 60 IU/kg).
b
Level of evidence. o Aspirin indicated but avoid pretreatment with P2Y12 inhibitors.
c
References supporting level of evidence. o GPIIb/IIIa inhibitors only for bailout of periprocedural complications.

DAPT ¼ dual (oral) antiplatelet therapy; GPIIb/IIIa ¼ glycoprotein IIb/IIIa; INR ¼


international normalised ratio; NOACs ¼ non-vitamin K antagonist oral
anticoagulants; NSAIDs ¼ non-steroidal anti-inflammatory drugs; OACs ¼ oral
5.4 Managing oral antiplatelet agents in anticoagulants; PCI ¼ percutaneous coronary intervention; UFH ¼ unfractionated
patients requiring long-term oral heparin; VKAs ¼ vitamin K antagonists.

anticoagulants
5.4.1 Patients undergoing percutaneous coronary
intervention abnormal renal and liver function (1 point each), stroke, bleeding
Approximately 6 – 8% of patients undergoing PCI have an indica- history or predisposition, labile INR, elderly (.65 years), drugs
tion for long-term OAC with VKA or NOACs due to various con- and alcohol (1 point each)] score} risks (Figure 5).234 In the absence
ditions such as atrial fibrillation, mechanical heart valves or venous of safety and efficacy data, the use of prasugrel or ticagrelor as
thromboembolism. In the periprocedural phase it should be con- part of triple therapy should be avoided. Gastric protection with a
sidered to perform coronary angiography on OAC, because inter- proton pump inhibitor is recommended. The dose intensity
ruption of OAC and bridging with parenteral anticoagulants may of OAC should be carefully monitored with a target INR of
lead to an increase in both thromboembolic episodes and 2.0 – 2.5 in patients treated with VKA (with the exception of
bleeds.232 – 234 The safety of PCI on NOACs without additional individuals with mechanical prosthetic valves in the mitral position).
parenteral anticoagulation is unknown, while no parenteral antic- In patients treated with NOACs, the lowest tested dose for stroke
oagulation is needed if the international normalized ratio (INR) is prevention should be applied.
.2.5 in VKA-treated patients. 235 – 237 Strategies to minimise The choice of stent type (newer-generation DES vs. BMS) in pa-
PCI-related complications in patients on oral anticoagulants are tients requiring long-term anticoagulation is controversial in the
listed in Table 12. setting of NSTE-ACS. In the absence of conclusive data, the deci-
With respect to long-term antithrombotic treatment after PCI, sion for the individual patient should also take into account the es-
a cohort study including 82 854 patients with atrial fibrillation timated probability of subsequent target vessel revascularization
showed that long-term exposure of patients to triple therapy, de- (TVR) due to restenosis. Although in stable CAD patients DAPT
fined as the combination of aspirin, clopidogrel and OAC, was as- is recommended for at least 1 month after BMS and for 6 months
sociated with an increased risk of 1-year major [14.3% vs. 6.9%; HR after DES, the risk of stent thrombosis (and other ischaemic compli-
2.08 (95% CI 1.64, 2.65)] and fatal bleeds [0.9% vs. 0.3%; HR 4.8 cations) during the period beyond 1 month and long-term appears
(95% CI 1.62, 14.02)] as compared with DAPT.238 In the setting similar with both stent types.240 – 242 Data from the DAPT trial indi-
of NSTE-ACS, evidence to guide the management of patients cate a similar impact of prolonged DAPT administration irrespective
undergoing PCI and requiring long-term OAC is limited. 234,239 of stent type (BMS vs. DES).243 In addition, analyses on the risk of
The indication for OAC should be reassessed and treatment con- adverse events among patients with DAPT cessation and patients
tinued only if a compelling indication exists {e.g. paroxysmal, per- undergoing non-cardiac surgery indicate no differences between
sistent or permanent atrial fibrillation with a CHA 2 DS 2 -VASc BMS and DES.177,244 Until data from RCTs become available, new-
[Cardiac failure, Hypertension, Age ≥ 75 (2 points), Diabetes, generation DESs are recommended over BMSs in patients requiring
Stroke (2 points) – Vascular disease, Age 65 – 74, Sex category] OAC at low bleeding risk (HAS-BLED ≤2). For patients at high
score ≥2; mechanical heart valve; recent or a history of recurrent bleeding risk (HAS-BLED ≥3) undergoing PCI who require OAC,
deep venous thrombosis or pulmonary embolism}. Duration of tri- the choice between a BMS and a new-generation DES needs to be
ple therapy should be as limited as possible, depending on the clin- individualised.
ical setting as well as the thromboembolic (CHA2DS2-VASc score) In the Zotarolimus-eluting Endeavor Sprint Stent in Uncertain
and bleeding {e.g. based on the HAS-BLED [hypertension, DES Candidates (ZEUS) trial, 1606 patients at either high bleeding
ESC Guidelines 291

NSTE-ACS patients with non-valvular atrial fibrillation

Management strategy PCI Medically managed / CABG

Low to intermediate High


Bleeding risk
(e.g. HAS-BLED = 0–2) (e.g. HAS-BLED 3)

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0
Triple or dual
Triple therapy a
therapy
Time from PCI/ACS

O A C
4 weeks
O A C
6 months Dual
therapy b
Dual
therapy b
Dual
therapy b

O C or A O C or A O C or A
12 months

Lifelong O Monotherapy c

O Oral anticoagulation A Aspirin 75–100 mg daily C Clopidogrel 75 mg daily


(VKA or NOACs)

ACS = acute coronary syndrome; CABG = coronary artery bypass graft; CHA2DS2-VASc = Cardiac failure, Hypertension, Age ≥75 [2 points], Diabetes, Stroke [2 points] –
Vascular disease, Age 65–74, Sex category; DAPT = dual antiplatelet therapy; NOACs = non-vitamin K antagonist oral anticoagulants; NSTE-ACS = non-ST-elevation acute
coronary syndrome; PCI = percutaneous coronary intervention;VKAs = vitamin K antagonists. Adapted from Lip et al.234
a
Dual therapy with oral anticoagulation and clopidogrel may be considered in selected patients (low ischaemic risk).
b
Aspirin as an alternative to clopidogrel may be considered in patients on dual therapy (i.e., oral anticoagulation plus single antiplatelet); triple therapy may be considered up to
12 months in very selected patients at high risk of ischaemic events (e.g. prior stent thrombosis on adequate antiplatelet therapy, stenting in the left main or last remaining patent
coronary artery, multiple stenting in proximal coronary segments, two stents bifurcation treatment, or diffuse multivessel disease, especially in diabetic patients).
c
Dual therapy with oral anticoagulation and an antiplatelet agent (aspirin or clopidogrel) beyond one year may be considered in patients at very high risk of coronary events.
In patients undergoing coronary stenting, dual antiplatelet therapy may be an alternative to triple or a combination of anticoagulants and single antiplatelet therapy if the
CHA2DS2-VASc score is 1 (males) or 2 (females).

Figure 5 Antithrombotic strategies in patients with non-ST-elevation acute coronary syndromes (NSTE-ACS) and non-valvular atrial
fibrillation.

risk (52%), high thrombotic risk (17%) or low restenosis risk (31%) and, in particular, in patients at high bleeding risk. While there were
were randomized to implantation with either the zotarolimus- no significant differences in any bleeding events between treatment
eluting stent (n ¼ 802) or a BMS (n ¼ 804).245 Overall, 4.6% of groups, the limited size of the trial does not allow potential differ-
the population never received DAPT, 43.6% and 62.5% discontin- ences in major bleeds to be reliably detected. As an additional limi-
ued it at 1 and 2 months, respectively, with 24.7% remaining on tation, the zotarolimus-eluting stent is no longer marketed in
DAPT beyond 6 months. At 1 year, major adverse cardiovascular Europe. This study suggests that a newer-generation DES may be
events (MACEs) were lower for those implanted with a preferred in patients who cannot tolerate long-term exposure to
zotarolimus-eluting stent compared with a BMS [17.5% vs. 22.1%; DAPT, such as those needing chronic OAC.
HR 0.76 (95% CI 0.61, 0.95), P ¼ 0.011], driven by reductions in Omission of aspirin while maintaining clopidogrel has been eval-
TVR [5.9% vs. 10.7%; HR 0.53 (95% CI 0.37, 0.75), P ¼ 0.001], MI uated in the What is the Optimal antiplatElet and anticoagulant ther-
[2.9% vs. 8.1%; HR 0.35 (95% CI 0.22, 0.56), P , 0.001] and defin- apy in patients with OAC and coronary StenTing (WOEST) trial,
ite/probable stent thrombosis [2.0% vs. 4.1%; HR 0.48 (95% CI which randomized 573 patients to dual therapy with OAC and clo-
0.27, 0.88), P ¼ 0.019]. The benefit of the zotarolimus-eluting stent pidogrel (75 mg/day) or to triple therapy with OAC, clopidogrel and
over the BMS remained consistent across all prespecified subgroups aspirin 80 mg/day.246 Treatment was continued for 1 month after
292 ESC Guidelines

BMS placement (35% of patients) and for 1 year after DES place- recommended in non-emergent cases. In emergency surgery, a com-
ment (65% of patients); follow-up was for 1 year.246 PCI was per- bination of prothrombin complex concentrate of four inactivated fac-
formed on VKA in half of the patients and one-third of them tors (25 IU/kg) and oral vitamin K is required to obtain fast and
presented with NSTE-ACS. The primary endpoint of any TIMI sustained restoration of haemostasis at the time of surgery.180 While
bleeds was significantly reduced in the dual-therapy arm [19.5% experience with urgent major surgery in patients treated with
vs. 44.9%; HR 0.36 (95% CI 0.26, 0.50), P , 0.001], while no signifi- NOACs is limited, it has been suggested to use prothrombin complex
cant differences in major bleeds were observed. The rates of MI, concentrate of activated factors to restore haemostasis.250 In the set-
stroke, TVR or stent thrombosis did not differ significantly, but all- ting of planned CABG, a 48 h interruption of NOACs is recom-
cause mortality was lower in the dual group (2.5% vs. 6.4%, P ¼ mended. In ACS patients with an established indication for OAC,
0.027) at 1 year. Femoral access was used in the majority of patients the antiplatelet agent (commonly aspirin) and then anticoagulation
(74%). While the trial was too small to reliably assess ischaemic out- should be resumed after CABG as soon as the bleeding is controlled,
comes and potential differences in major bleeds, dual therapy with while triple therapy should be avoided. For antithrombotic therapy

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clopidogrel and OAC may be considered as an alternative to triple and CABG see sections 5.6.6.1 and 5.6.6.2.
therapy in patients at high bleeding risk. In the Triple Therapy in Pa-
tients on Oral Anticoagulation After Drug Eluting Stent Implant- 5.4.3 Recommendations for combining antiplatelet
ation (ISAR-TRIPLE) trial, 614 patients (one-third with ACS) agents and anticoagulants in non-ST-elevation acute
undergoing stenting and requiring OAC were randomly assigned coronary syndrome patients requiring chronic oral
to receive either 6-week or 6-month clopidogrel therapy in addition anticoagulation
to aspirin and VKA. The primary endpoint of death, MI, stent
thrombosis, ischaemic stroke or TIMI major bleeding at 9 months Recommendations for combining antiplatelet agents
did not differ between the 6-week and 6-month triple therapy and anticoagulants in non-ST-elevation acute coronary
[9.8% vs. 8.8%; HR 1.14 (95% CI 0.68, 1.91), P ¼ 0.63]; the same syndrome patients requiring chronic oral
was true for the combined incidence of death, MI, stent thrombosis anticoagulation
and ischaemic stroke [4.0% vs. 4.3%; HR 0.93 (95% CI 0.43, 2.05),
P ¼ 0.87]. Furthermore, no difference in TIMI major bleeding
[5.3% vs. 4.0%; HR 1.35 (95% CI 0.64, 2.84), P ¼ 0.44] was ob- Recommendations Classa Levelb Ref.c
served.247 Finally, there are no data on the optimal timing of cessa- In patients with a firm indication for
tion of any antiplatelet agent in stabilized NSTE-ACS patients who OAC (e.g. atrial fibrillation with a
underwent coronary stenting and require chronic OAC. Specifical- CHA2DS2-VASc score ≥2, recent
venous thromboembolism, LV I C
ly, it is not known whether there are differences according to the thrombus or mechanical valve
type of OAC (NOACs versus VKA) or stent platform. In accord- prosthesis), OAC is recommended in
ance with a joint consensus document, discontinuation of any anti- addition to antiplatelet therapy.
platelet agent at 1 year is encouraged in this patient population An early invasive coronary
irrespective of stent type, while dual therapy with oral anticoagula- angiography (within 24 h) should be
tion and one antiplatelet agent (aspirin or clopidogrel) may be con- considered in moderate- to high-risk
sidered in very selected patients at high risk of ischaemic events patients,d irrespective of
IIa C
OAC exposure, to expedite treatment
(Figure 5).234
allocation (medical vs. PCI vs. CABG)
and to determine the optimal
antithrombotic regimen.
5.4.2 Patients medically managed or requiring coronary
Initial dual antiplatelet therapy with
artery bypass surgery
aspirin plus a P2Y12 inhibitor in
With respect to NSTE-ACS patients who are medically managed, III C
addition to OAC before coronary
in an analysis of the nationwide Danish registry, 90-day bleeding angiography is not recommended.
risk was increased on triple therapy compared with OAC plus a Patients undergoing coronary stenting
single antiplatelet agent [HR 1.47 (95% CI 1.04, 2.08)], with a non-
Anticoagulation
significant increase at 360 days [HR 1.36 (95% CI 0.95, 1.95)], with-
out differences in ischaemic events [HR 1.15 (95% CI 0.95, During PCI, additional parenteral
anticoagulation is recommended,
1.40)].248 The same registry suggests that warfarin plus clopidogrel irrespective of the timing of the last I C
resulted in a non-significant reduction in major bleeds [HR 0.78 dose of all NOACs and if INR is ,2.5 in
(95% CI 0.55, 1.12)] compared with triple therapy, with a non- VKA-treated patients.
significant reduction in MI or coronary death [HR 0.69 (95% CI Uninterrupted therapeutic
0.55, 1.12)].249 anticoagulation with VKA or NOACs
IIa C
Coronary surgery in fully anticoagulated patients is associated with should be considered during the
an increased bleeding risk, thus interruption of VKA prior to CABG is periprocedural phase.
ESC Guidelines 293

Antiplatelet treatment
5.5 Management of acute bleeding events
Following coronary stenting, DAPT
(see Web addenda)
including new P2Y12 inhibitors should 5.5.1 General supportive measures (see Web
be considered as an alternative to addenda)
triple therapy for patients with NSTE- IIa C
ACS and atrial fibrillation with a 5.5.2 Bleeding events on antiplatelet agents (see Web
CHA2DS2-VASc score of 1 (in males) addenda)
or 2 (in females).
5.5.3 Bleeding events on vitamin K antagonists (see Web
If at low bleeding risk (HAS-BLED ≤2), addenda)
triple therapy with OAC, aspirin
(75–100 mg/day) and clopidogrel 5.5.4 Bleeding events on non-vitamin K antagonist
75 mg/day should be considered for 6 IIa C oral anticoagulants (see Web addenda)

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months, followed by OAC and aspirin 5.5.5 Non-access-related bleeding events (see Web
75–100 mg/day or clopidogrel (75 mg/
addenda)
day) continued up to 12 months.
If at high bleeding risk (HAS-BLED ≥3), 5.5.6 Bleeding events related to percutaneous coronary
triple therapy with OAC, aspirin (75– intervention (see Web addenda)
100 mg/day) and clopidogrel 75 mg/day 5.5.7 Bleeding events related to coronary artery bypass
should be considered for a duration of
surgery (see Web addenda)
1 month, followed by OAC and aspirin IIa C
75–100 mg/day or clopidogrel (75 mg/ 5.5.8 Transfusion therapy (see Web addenda)
day) continued up to 12 months
irrespective of the stent type (BMS or
5.5.9 Recommendations for bleeding management and
new-generation DES). blood transfusion in non-ST-elevation acute coronary
syndromes
Dual therapy with OAC
and clopidogrel 75 mg/day may
be considered as an alternative 246, Recommendations for bleeding management and
IIb B
to triple antithrombotic therapy in 248 blood transfusion in non-ST-elevation acute coronary
selected patients (HAS-BLED ≥3 and syndromes
low risk of stent thrombosis).
The use of ticagrelor or prasugrel as part
III C
of triple therapy is not recommended. Recommendations Classa Levelb Ref.c
Vascular access and stent type In patients with VKA-associated
life-threatening bleeding events, rapid
Radial over femoral access is
reversal of anticoagulation with
recommended for coronary I A 251
four-factor prothrombin complex
angiography and PCI.
concentrate rather than with fresh
The use of new-generation DES over frozen plasma or recombinant IIa C
245,
BMS should be considered among IIa B activated factor VII should be
252
patients requiring OAC. considered. In addition, repetitive
Medically managed patients 10 mg i.v. doses of vitamin K
should be administered by slow
One antiplatelet agent in addition to OAC injection.
IIa C
should be considered for up to 1 year.
In patients with NOAC-associated
ongoing life-threatening bleeds, the
ACS ¼ acute coronary syndromes; BMS ¼ bare-metal stent; CHA2DS2-VASc ¼ administration of prothrombin
Cardiac failure, Hypertension, Age ≥75 (2 points), Diabetes, Stroke (2 points) – IIa C
complex concentrate or activated
Vascular disease, Age 65 –74, Sex category; DAPT ¼ dual (oral) antiplatelet
prothrombin complex concentrates
therapy; DES ¼ drug-eluting stent; INR ¼ international normalized ratio; LV ¼
should be considered.
left ventricular; NOAC ¼ non-vitamin K antagonist oral anticoagulant;
NSTE-ACS ¼ non-ST-elevation acute coronary syndromes; OAC ¼ oral In patients with anaemia and no
anticoagulant/anticoagulation (it refers to both vitamin K and non-vitamin K evidence of active bleed, blood
antagonist oral anticoagulants); PCI ¼ percutaneous coronary intervention; transfusion may be considered
VKA ¼ vitamin K antagonist.
in the case of compromised IIb C
Triple therapy refers to aspirin, clopidogrel and OAC.
haemodynamic status or
HAS-BLED bleeding score includes hypertension, abnormal renal and liver function,
stroke, bleeding history or predisposition, labile INR (international normalized haematocrit ,25% or
ratio), elderly (.65 years) and drugs increasing bleeding risk or alcohol abuse. haemoglobin level ,7 g/dL.
When NOACs are combined with antiplatelet drugs, the lowest effective dose for
stroke prevention should be used. When VKAs are combined with antiplatelet
i.v. ¼ intravenous; NOAC ¼ non-vitamin K antagonist oral anticoagulant;
drugs, INR should not exceed 2.5.
a NSTE-ACS ¼ non-ST-elevation acute coronary syndromes; VKA ¼ vitamin K
Class of recommendation.
b antagonist.
Level of evidence. a
c Class of recommendation.
References supporting level of evidence. b
d Level of evidence.
Risk criteria are listed in Table 13. c
References supporting level of evidence.
294 ESC Guidelines

5.6.1 Invasive coronary angiography


Table 13 Risk criteria mandating invasive strategy in Invasive coronary angiography maintains its central role in the man-
NSTE-ACS agement of patients with NSTE-ACS. In the vast majority of cases it
allows clinicians to
Very-high-risk criteria
• Haemodynamic instability or cardiogenic shock † confirm the diagnosis of ACS related to obstructive epicardial
CAD (or to rule out a coronary origin of chest pain) and, as a con-
• Recurrent or ongoing chest pain refractory to medical treatment
sequence, to guide antithrombotic treatment and avoid unneces-
• Life-threatening arrhythmias or cardiac arrest
sary exposure to antithrombotic agents;
• Mechanical complications of MI † identify the culprit lesion(s);
• Acute heart failure † establish the indication for coronary revascularization and assess
• Recurrent dynamic ST-T wave changes, particularly with intermittent the suitability of coronary anatomy for PCI and CABG and
ST-elevation

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† stratify the patient’s short- and long-term risk.
High-risk criteria
• Rise or fall in cardiac troponin compatible with MI 5.6.1.1 Pattern of coronary artery disease
Angiographic patterns of CAD in NSTE-ACS patients are diverse,
• Dynamic ST- or T-wave changes (symptomatic or silent)
ranging from normal epicardial coronary arteries to a severely and
• GRACE score >140
diffusely diseased coronary artery tree. Up to 20% of patients with
Intermediate-risk criteria
NSTE-ACS have no lesions or non-obstructive lesions of epicardial
• Diabetes mellitus coronary arteries, while among patients with obstructive CAD, 40–
• 80% have multivessel disease.164,224,303,304 Bypass graft failures and
• LVEF <40% or congestive heart failure left main coronary artery disease may be the underlying condition
• Early post-infarction angina in 5% and up to 10% of patients presenting with NSTE-ACS, re-
• Prior PCI
spectively. The left anterior descending coronary artery is the
most frequent culprit vessel in both STEMI and NSTEMI-ACS
• Prior CABG
(in up to 40% of patients).164,224,303 – 306 Regarding the distribution
• GRACE risk score >109 and <140
within the infarct-related artery, culprit lesions in NSTE-ACS are
Low-risk criteria more often located within the proximal and mid segments, with
• Any characteristics not mentioned above approximately the same frequency in the two segments.305,306

CABG ¼ coronary artery bypass graft; eGFR ¼ estimated glomerular filtration


5.6.1.2 Identification of the culprit lesion
rate; GRACE ¼ Global Registry of Acute Coronary Events; LVEF ¼ left ventricular In order to characterize a coronary lesion as culprit on angiography,
ejection fraction; PCI ¼ percutaneous coronary intervention; MI ¼ myocardial at least two of the following morphological features suggestive of
infarction.
acute plaque rupture should be present:306 – 308 intraluminal filling
defects consistent with thrombus (i.e. acute occlusion abruptly end-
ing with a squared-off or convex upstream termination or an intra-
luminal filling defect in a patent vessel within or adjacent to a
stenotic region with surrounding homogeneous contrast opacifica-
5.6 Invasive coronary angiography and tion), plaque ulceration (i.e. presence of contrast and hazy contour
revascularization beyond the vessel lumen), plaque irregularity (i.e. irregular margins
Invasive coronary angiography, followed if indicated by coronary or overhanging edges), dissection or impaired flow. Pathological and
revascularization, is performed in the majority of patients hospita- intracoronary imaging studies have documented the simultaneous
lised with NSTE-ACS in regions with well-developed healthcare occurrence of multiple vulnerable plaques, mostly as thin-cap fi-
systems. The decision for an invasive strategy should carefully broatheroma.309 – 311 Angiographic studies have confirmed these
weigh the risks of invasive diagnostics and the benefits in terms findings, showing that in up to 40% of NSTEMI-ACS patients with
of diagnostic accuracy, risk stratification and assessment of the obstructive CAD, multiple complex plaques fulfilling the criteria
risks related to revascularization. The decision for revasculariza- of a culprit lesion may be observed.306,308,312,313 Nearly one-quarter
tion takes into account the risk in terms of morbidity and mortality of NSTEMI patients present with an acute occluded coronary artery
associated with the proposed modality (PCI or CABG) and the and two-thirds of the occlusions are already collateralised at the
benefits in terms of short- and long-term prognosis, symptom re- time of angiographic examination.223,310 As a consequence, differen-
lief, quality of life and duration of hospital stay. The indication for an tiation between an acute/subacute and chronic occlusion may
invasive approach, the timing for myocardial revascularization and sometimes be challenging and identification of the culprit lesion
the selection of the revascularization modality depend on numer- based solely on angiography may not be possible.
ous factors, including clinical presentation, comorbidities, risk Diffuse precordial ST depression more pronounced in leads V4 –
stratification (as outlined in section 4), presence of high-risk fea- V6 may indicate a culprit lesion located in the mid left anterior des-
tures specific for a revascularization modality, frailty, cognitive sta- cending coronary artery, while changes more evident in leads V2 –V3
tus, estimated life expectancy and functional and anatomic severity may be more suggestive of a culprit lesion located in the left circum-
as well as pattern of CAD. flex artery.314 Diffuse ST depression including both precordial and
ESC Guidelines 295

extremity leads associated with ST-elevation ≥1 mm in lead aVR patients deteriorated while on medical therapy (crossover), the trials
may indicate either left main coronary artery as the culprit lesion did not include consecutive patients and excluded those with
or proximal occlusion of the left anterior descending coronary ar- very-high-risk features and advances in percutaneous treatment
tery in the presence of severe three-vessel CAD.315,316 The correl- such as single-stent strategy for bifurcation lesions, radial approach,
ation of ECG changes with the culprit lesion is weakened in the new-generation DES as well as more effective P2Y12 inhibitors
presence of left coronary artery dominance, multivessel disease were not available or broadly implemented in the trials. Despite these
and distal location of the culprit lesion.317 Echocardiography or limitations, the results of RCTs and their meta-analyses support the
left ventriculography may also help to identify the culprit lesion cor- broad implementation of a routine invasive strategy and highlight
responding to a regional wall motion abnormality. Finally, approxi- the role of risk stratification in the decision process. Specific sub-
mately 25% of NSTEMI patients have angiographically normal groups of high-risk patients that, while benefiting from an early inva-
epicardial coronary arteries or non-obstructive CAD.164,303,304 A sive management, pose additional challenges in terms of treatment
provocative test, such as with acetylcholine or ergonovine, and newer (e.g. diabetic patients, the elderly, frail patients or those with renal in-

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intracoronary imaging methods (i.e. optical coherence tomography) sufficiency) are discussed in their respective sections.
may sometimes help to identify the culprit lesion or the underlying
pathology, such as medial thickness due to abnormal media contrac- 5.6.3 Timing of invasive strategy
tion in coronary spasm or superficial erosions of non-obstructive 5.6.3.1 Immediate invasive strategy (,2 h)
thin-cap fibroatheroma.318 – 320 Very-high-risk NSTE-ACS patients (i.e. with at least one very-high-risk
criterion according to Table 13) have been generally excluded from
5.6.1.3 Fractional flow reserve RCTs. Owing to a poor short- and long-term prognosis if left untreat-
The achievement of maximal hyperaemia may be unpredictable in ed, an immediate (i.e. ,2 h from hospital admission, analogous to
NSTEMI because of the dynamic nature of coronary lesions and STEMI management) invasive strategy with intent to perform revascu-
the associated acute microvascular dysfunction. As a result, fraction- larization is recommended, irrespective of ECG or biomarker find-
al flow reserve (FFR) may be overestimated and the haemodynamic ings. Centres without STEMI programmes should transfer the
relevance of a coronary stenosis underestimated.320 So far, the value patient immediately (Figure 6). The management of patients with
of FFR-guided PCI in this setting has not been properly addressed. out-of-hospital cardiac arrest and no ST elevation on ECG needs to
be individualized and requires multidisciplinary consultation in the
5.6.2 Routine invasive vs. selective invasive approach emergency department. While conscious survivors should undergo
While PCI associated with antithrombotic therapy results in culprit immediate coronary angiography, comatose survivors should first
lesion stabilization, thereby reducing the risk of target lesion – be investigated for non-coronary conditions, if appropriate, and cor-
associated (re)infarction, CABG provides protection against compli- onary angiography should be performed directly after in the absence
cations (i.e. occlusion/subocclusion, but possibly not distal embol- of an obvious non-coronary cause of the cardiac arrest.325
ization) originating from culprit lesions as well as from disease
progression in the vessel segments proximal to the anastomotic 5.6.3.2 Early invasive strategy (,24 h)
sites.321 Compared with a selective invasive strategy, a routine inva- Early invasive strategy is defined as coronary angiography performed
sive strategy in NSTE-ACS has been shown to improve clinical within 24 h of hospital admission. The optimal timing of invasive cor-
outcomes and reduce recurrent ACS episodes, subsequent rehospi- onary angiography and revascularization in NSTE-ACS patients
talization and revascularization. A meta-analysis of seven RCTs in has been investigated in multiple RCTs and meta-analyses. A
8375 NSTE-ACS patients with frequent use of thienopyridines, meta-analysis of four RCTs with 4013 NSTE-ACS patients com-
GPIIb/IIIa inhibitors and stents showed that a routine invasive strat- pared an early (i.e. time to angiography 1.16– 14 h) with a delayed
egy was associated with a lower risk of death [4.9% vs. 6.5%; RR 0.75 (i.e. time to angiography 20.8 –86 h) invasive strategy. While there
(95% CI 0.63, 0.90), P ¼ 0.001], MI [7.6% vs. 9.1%; RR 0.83 (95% CI were no significant differences in terms of death or MI, the early in-
0.72, 0.96), P ¼ 0.012] and rehospitalization for recurrent ACS vasive strategy was associated with a statistically significant lower
[19.9% vs. 28.7%; RR 0.69 (95% CI 0.65, 0.74), P , 0.0001] at a risk of recurrent ischaemia [RR 0.59 (95% CI 0.38, 0.92), P ¼
mean follow-up of 2 years.322 A meta-analysis of eight RCTs in 0.02] and shorter duration of hospital stay [by 28% (95% CI 22,
10 150 NSTE-ACS patients showed that the benefit in favour of a 35), P , 0.001] and a trend towards fewer major bleeds [RR 0.78
routine invasive strategy for the composite endpoint of death or (95% CI 0.57, 1.07), P ¼ 0.13] and major adverse cardiac events
MI was confined to biomarker-positive patients [OR 0.68 (95% [RR 0.91 (95% CI 0.82, 1.01), P ¼ 0.09]. 326 An updated
CI 0.56, 0.82) vs. OR 1.01 (95% CI 0.79, 1.28) in biomarker-negative meta-analysis of seven RCTs in 5370 NSTE-ACS patients and of
patients, interaction P ¼ 0.03]. 323 An individual patient data four observational studies in 77 499 patients compared an early
meta-analysis of three RCTs with long-term follow-up data through- (,24 h) with a delayed invasive strategy.327 The results of the
out 5 years in 5467 NSTE-ACS patients reported a lower risk of CV pooled analysis of RCTs showed no significant benefit for death
death or MI [14.7% vs. 17.9%; HR 0.81 (95% CI 0.71, 0.93), P ¼ [3.9% vs. 4.7%; OR 0.83 (95% CI 0.64, 1.09), P ¼ 0.18], MI [7.5%
0.002] in favour of a routine over a selective invasive strategy; the vs. 7.8%; OR 1.15 (95% CI 0.65, 2.01), P ¼ 0.63] or major bleeds
most pronounced difference was observed in high-risk patients [2.8% vs. 3.7%; OR 0.76 (95% CI 0.56, 1.04), P ¼ 0.09], and similar
(according to a risk score developed by the authors based on clinical outcomes were reported in the observational studies. Yet an early
characteristics), with an absolute risk reduction of 2.0%, 3.8% and invasive strategy was associated with a lower risk of refractory
11.1% among low-, intermediate- and high-risk patients, respective- ischaemia [3.8% vs. 7.3%; OR 0.55 (95% CI 0.35, 0.86), P ¼ 0.008].
ly.324 Of note, the benefit of revascularization in the RCT was likely Three of the trials included in the mentioned meta-analyses com-
underestimated because revascularization was allowed when pared a strategy of immediate (e.g. primary PCI-like approach) vs.
296 ESC Guidelines

Symptoms Onset

First medical contact NSTE-ACS diagnosis

PCI center EMS or Non–PCI center

Immediate transfer to PCI center

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Very high Very high
Risk stratification

Same-day transfer
High High

Transfer
Intermediate Intermediate

Transfer
optional
Low Low
Therapeutic
strategy

Immediate Early Non-invasive


Invasive
Invasive invasive testing if
(<72 hr)
(<2 hr) (<24 hr) appropriate

EMS = emergency medical services; PCI = percutaneous coronary intervention.

Figure 6 Selection of non-ST-elevation acute coronary syndrome (NSTE-ACS) treatment strategy and timing according to initial risk
stratification.

early and/or delayed intervention in NSTE-ACS patients.304,328,329 analysis of high-risk patients (i.e. one-third of patients with a GRACE
There were no differences with respect to the primary endpoints risk score .140), an early invasive strategy lowered the risk of
based on biomarker elevation after intervention or with respect death, MI or stroke [13.9% vs. 21.0%; HR 0.65 (95% CI 0.48, 0.89),
to secondary clinical outcomes (except for a higher rate of MI in P ¼ 0.006], whereas the difference was not significant for patients
the immediate invasive approach in one of the studies).328 However, with a GRACE risk score ≤140 [7.6% vs. 6.7%; HR 1.12 (95% CI
the design and interpretation of these studies is challenging from a 0.81, 1.56), P ¼ 0.48; P ¼ 0.01 for heterogeneity].303 Importantly,
methodological point of view, because in cases of early intervention, an early invasive strategy did not trigger any safety issue in this trial.
biomarkers had not returned to normal values or were still in the In a post hoc analysis of the ACUITY trial, a delay to PCI .24 h was
ascending phase of the curve. Therefore it may be difficult, if not im- an independent predictor of 30-day and 1-year mortality.330 The ex-
possible, to differentiate between the evolution of the index MI and cess of ischaemic events associated with the PCI .24 h strategy was
an ischaemic complication of the revascularization procedure. most apparent among moderate- and high-risk patients (according
There is evidence to suggest a benefit of an early invasive strategy to the TIMI risk score). Overall, an early invasive strategy is recom-
in patients with a high-risk profile. The largest individual RCT to mended in patients with at least one high-risk criterion (Table 13).
date, Timing of Intervention in Acute Coronary Syndromes (TI- This implies timely transfer for patients admitted to hospitals with-
MACS), randomly assigned 3031 NSTE-ACS patients to an early out onsite catheterization facilities (Figure 6).
(,24 h, median time 14 h) or delayed (median time 50 h) interven-
tion. At 6 months, the primary composite endpoint of death, MI or 5.6.3.3 Invasive strategy (,72 h)
stroke was not different between the early and delayed invasive This is the recommended maximal delay for angiography in patients
strategy [9.6% vs. 11.3%; HR 0.85 (95% CI 0.68, 1.06), P ¼ 0.15]. with at least one intermediate risk criterion, recurrent symptoms or
The secondary endpoint of death, MI, stroke or refractory ischaemia known ischaemia on non-invasive testing.324,327 Even if hospital
was reduced by 28% in favour of the early invasive strategy [9.5% vs. transfer is required, the 72 h window for coronary angiography
12.9%; HR 0.72 (95% CI 0.58, 0.89), P ¼ 0.003]. In the pre-specified should be complied with.
ESC Guidelines 297

5.6.3.4 Selective invasive strategy NSTEMI.333 In 36% of the patients, clopidogrel was prescribed within
Patients with no recurrence of symptoms and none of the criteria 7 days of discharge. In 8562 propensity score–matched patients, pa-
listed in Table 13 are to be considered at low risk of ischaemic tients who were prescribed clopidogrel had lower rates of all-cause
events. In these patients, a non-invasive stress test (preferably mortality [8.3% vs. 13.0%; adjusted HR 0.63 (95% CI 0.54, 0.72), P ,
with imaging) for inducible ischaemia is recommended before decid- 0.01] and the composite of death or MI [13.5% vs. 17.4%; HR 0.74
ing on an invasive strategy.331 (95% CI 0.66, 0.84), P , 0.01], but not MI alone [6.7% vs. 7.2%; HR
0.93 (95% CI 0.78, 1.11), P ¼ 0.30], compared with non-users of clopi-
In summary, available data indicate that an early as opposed to a dogrel. The association between clopidogrel use and the composite of
delayed invasive strategy is safe and associated with a lower risk of death or MI was significant among patients presenting with NSTEMI [HR
refractory ischaemia and a shorter duration of hospital stay. The se- 0.67 (95% CI 0.59, 0.76)] compared with those presenting with unstable
lection of the optimal timing of invasive coronary angiography and angina [HR 1.25 (95% CI 0.94, 1.67), P for interaction ,0.01].
revascularization should be guided by individual risk stratification. The TRILOGY ACS trial randomized 7243 patients with NSTE-

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It is recommended that patients at very high risk (i.e. with at least ACS ,75 years of age selected for medical management to clopido-
one very-high-risk criterion) undergo an immediate invasive strategy grel or prasugrel for a median duration of 17 months.334 Allocation
(,2 h). In patients at high risk (i.e. with at least one high-risk criter- to prasugrel was not associated with a statistically significant reduc-
ion), an early invasive strategy (,24 h) is recommended. In patients tion in the primary endpoint of death from CV causes, MI or stroke
with at least one intermediate-risk criterion, the invasive strategy [13.9% in the prasugrel group and 16.0% in the clopidogrel group;
may be delayed but a maximum 72 h window from admission to HR 0.91 (95% CI 0.79, 1.05), P ¼ 0.21]. While non-CABG TIMI ma-
coronary angiography is recommended. In low-risk patients, a jor bleeding rates did not differ among the groups, TIMI major and
non-invasive stress test (preferably with imaging) for inducible is- minor bleeding events were more frequent in the prasugrel group
chaemia is recommended before deciding on an invasive strategy. [1.9% vs. 1.3%; HR 1.54 (95% CI 1.06, 2.23), P ¼ 0.02]. In the PLATO
study, 5216 patients (28% of the total PLATO population) admitted
5.6.4 Conservative treatment to hospital for ACS were specified as planned for non-invasive man-
agement, although by the end of follow-up, 3143 (60.3%) patients
5.6.4.1 In patients with coronary artery disease
had been managed non-invasively. In the population intended for
5.6.4.1.1 Non-obstructive CAD. A pooled data analysis from eight non-invasive management, the incidence of the primary endpoint,
NSTE-ACS RCTs showed that 9.6% of the patients had non- a composite of CV death, MI and stroke, was lower with ticagrelor
obstructive CAD. Compared with patients with obstructive CAD,
than with clopidogrel [12.0% vs. 14.3%; HR 0.85 (95% CI 0.73, 1.00,
those individuals were younger and more often female, while fewer
P ¼ 0.04]. Overall mortality was also lower [6.1% vs. 8.2%; HR 0.75
had diabetes mellitus, previous MI or prior PCI. Thirty-day death or
MI was less frequent among patients with non-obstructive CAD (95% CI 0.61, 0.93), P ¼ 0.01]. The incidence of non-CABG TIMI
(2.2%) vs. obstructive CAD (13.3%) [adjusted OR 0.15 (95% CI major bleeds was numerically higher in the ticagrelor-treated pa-
0.11, 0.20)]. Thirty-day death or MI and 6-month mortality were tients [2.8% vs. 2.2%; HR 1.33 (95% CI 0.91, 1.94), P ¼ 0.142].335
also lower among patients with non-obstructive CAD [adjusted
5.6.4.1.2 CAD not amenable to revascularization. Data regarding pa-
OR 0.19 (95% CI 0.14, 0.25) and adjusted OR 0.37 (95% CI 0.28,
tients with ACS who are not amenable to revascularization due
0.49), respectively].332 While invasive evaluation and, if appropriate
to severe/diffuse CAD are sparse. The available observational stud-
and feasible, revascularization are indicated in patients at high is-
ies included mainly patients with stable CAD and refractory an-
chaemic risk, in a proportion of them this strategy is not offered be-
gina.336,337 Although the prognosis differs according to patient
cause of the perception that patients might not benefit in terms of
characteristics (e.g. age, prior CABG or PCI, LV dysfunction, con-
event reduction—due to the estimated increased risk related to
gestive heart failure), overall, patients not amenable to revasculari-
coronary angiography and/or revascularization—or quality of life.
zation have higher mortality compared with patients who are
Patients in whom an invasive strategy may be withheld by the treat-
revascularized.336 The main objective of pharmacological treatment
ing physicians may include very elderly or frail patients (section
is relief from refractory angina, as detailed in the 2013 ESC guide-
5.8.1); patients with comorbidities such as dementia, severe chronic
lines on the management of stable CAD.63
renal insufficiency (section 5.8.3) or cancer and patients at high risk
of bleeding complications (section 4.3). Usually these patient cat- 5.6.4.2 In patients with normal coronary angiogram (see Web addenda)
egories have been excluded from RCTs. Tako – Tsubo cardiomyopathy, non-CAD-associated coronary
With respect to oral antiplatelet therapy in the context of medic- thromboembolism, vasospasm and microvascular disease may all
ally managed NSTE-ACS, the CURE study randomized 12 562 pa- cause NSTE-ACS. While these conditions have been extensively cov-
tients to clopidogrel or placebo in addition to aspirin for 3 – 12 ered in the 2013 ESC guidelines on the management of stable CAD,
months (mean duration of treatment 9 months). The majority of pa- the most relevant features are summarised in the Web addenda.63
tients were treated conservatively, while ,40% underwent coronary
revascularization during the study period. The primary outcome, a
composite of death from CV causes, non-fatal MI or stroke at 1 5.6.5 Percutaneous coronary intervention
year, occurred in 9.3% of the patients in the clopidogrel group and 5.6.5.1 Technical aspects and challenges
11.4% of the patients in the placebo group [RR 0.80 (95% CI 0.72, Although suspected or confirmed NSTE-ACS represents the most
0.90), P , 0.001]. There were significantly more patients with major frequent indication for coronary angiography and PCI worldwide,
bleeds in the clopidogrel group than in the placebo group [3.7% vs. few studies focus on the technical aspects of PCI in this setting. Hence
2.7%; RR 1.38 (95% CI 1.13, 1.67), P ¼ 0.001].137 A registry looked information on PCI techniques and outcomes has to be derived large-
at the comparative effectiveness of clopidogrel vs. no clopidogrel in ly from PCI studies or from trials and registries encompassing ACS pa-
16 365 medically managed patients with unstable angina and tients. As for all other manifestations of CAD, stent implantation in
298 ESC Guidelines

the setting of NSTE-ACS helps to reduce abrupt vessel closure and ACS patients implement a transition from transfemoral to transradial
restenosis associated with balloon angioplasty and it should be con- access. However, proficiency in the femoral approach should be
sidered the standard treatment strategy. Based on at least compar- maintained, as this access is indispensable in a variety of procedures,
able safety and superior efficacy (i.e. prevention of restenosis including intra-aortic balloon counterpulsation implantation, struc-
and need for repeat revascularization), new-generation DESs are tural heart disease interventions and peripheral revascularization pro-
recommended over BMSs in NSTE-ACS.345 – 347 DAPT is recom- cedures. A consensus document has proposed a stepwise approach
mended for 12 months irrespective of stent type, while in patients to favour the transition from a femoral to a radial approach.351
at high ischaemic risk not experiencing bleeding events, DAPT may
be extended (see section 5.2.6). The impact of thrombectomy has 5.6.5.3 Revascularization strategies and outcomes
not been established by adequately sized RCTs in NSTE-ACS. This There is a lack of prospective randomized investigations addressing
treatment modality cannot be recommended considering the lack the type (i.e. complete vs. incomplete) and timing (i.e. simultaneous
of benefit observed in STEMI.348 While FFR is considered the inva- vs. staged) of revascularization in NSTE-ACS. A complete revascular-

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sive gold standard for the functional assessment of lesion severity ization strategy of significant lesions should be pursued in multivessel
in stable CAD, its role in NSTE-ACS still needs to be defined. Strat- disease patients with NSTE-ACS based on two considerations. First,
egies to reduce bleeding risk related to PCI are listed in Table 12. several studies showing the benefit of early intervention when com-
pared with the conservative approach in patients with NSTE-ACS
5.6.5.2 Vascular access mandated a complete revascularization strategy, irrespective of the
The RadIal Vs femorAL access for coronary intervention (RIVAL) trial possibility to identify and/or treat the culprit lesion.352 – 354 Second,
randomized 7021 ACS patients (both STEMI and NSTE-ACS) to ra- multiple PCI and NSTE-ACS trials have shown a detrimental prognos-
dial or femoral artery access.349 The primary outcome, a composite tic effect of incomplete revascularization. Accordingly, a residual
of death, MI, stroke or non-CABG-related major bleeds at 30 days, SYNergy between percutaneous coronary intervention with TAXus
occurred in 3.7% of patients in the radial access group compared and cardiac surgery (SYNTAX) score .8 has been shown to be in-
with 4.0% of patients in the femoral access group [HR 0.92 (95% CI dependently associated with a poor 30-day and 1-year prognosis, in-
0.72, 1.17), P ¼ 0.50]. The Study of Access Site for Enhancement of cluding higher mortality after PCI in patients with moderate- and
PCI for Women (SAFE-PCI) trial randomized women undergoing high-risk ACS.355,356 However, the presence of important unmeas-
coronary angiography, and if required PCI, to radial or femoral access. ured confounding factors in retrospective studies showing worse out-
The study was stopped early due to a lower than expected event rate. comes in patients who did not receive complete revascularization
Among the 1787 patients enrolled (.50% presented with cannot be excluded. Since pursuing completeness of revascularization
NSTE-ACS), 691 underwent PCI. There was no significant difference for some patients with complex coronary anatomy may mean in-
in the primary efficacy endpoint of bleeding or vascular complications creasing the risk of PCI (e.g. in the presence of complex chronic total
between radial and femoral access among women undergoing PCI occlusions) or requiring CABG, it is reasonable, in the absence of
[radial 1.2% vs. 2.9% femoral; OR 0.39 (95% CI 0.12, 1.27), P ¼ compelling clinical data, to tailor the need for complete revasculariza-
0.12], while in the overall cohort of women undergoing coronary tion to age, general patient condition and comorbidities. The decision
angiography a benefit was detected [0.6% in the radial group vs. to treat all the significant lesions in the same setting or to stage the
1.7% in the femoral group; OR 0.32 (95% CI 0.12, 0.90), P ¼ procedures should be based on clinical presentation, comorbidities,
0.03].350 In the Minimizing Adverse Haemorrhagic Events by TRans- complexity of coronary anatomy, ventricular function, revasculariza-
radial Access Site and Systemic Implementation of angioX (MATRIX) tion modality and patient preference.
trial, 8404 ACS patients were randomly allocated to radial or femoral With respect to outcomes, periprocedural complications of PCI as
access. The first co-primary outcome of 30-day MACE, defined as well as the long-term ischaemic risk remain higher in NSTE-ACS than
death, MI or stroke, occurred in 8.8% of patients with radial access in stable patients, despite contemporary management. Accordingly,
and 10.3% of patients with femoral access [RR 0.85 (95% CI 0.74, the risk of CV death, MI or stroke in NSTE-ACS patients in recent
0.99), two-sided P ¼ 0.031; formally non-significant at the pre- trials was approximately 10% and 15% at 1 and 2 years follow-up, re-
specified a of 0.025).251 The second co-primary outcome of spectively.154,206 For ACS patients who underwent PCI, revasculariza-
30-day net adverse clinical events [MACE or non-CABG Bleeding tion procedures represent the most frequent, most costly and earliest
Academic Research Consortium (BARC) major bleeding] was experi- cause for rehospitalization.357,358 This reflects both planned (i.e.
enced in 9.8% and 11.7% of patients {RR 0.83 (95% CI 0.73, 0.96), P ¼ staged) as well as unplanned revascularization procedures due to
0.009]. Radial access was associated with a lower risk of all-cause symptoms or CV event recurrence.357,358
mortality [1.6% vs. 2.2%; RR 0.72 (95% CI 0.53, 0.99), P ¼ 0.045],
while the rates of cardiac mortality, MI and stroke were not signifi- 5.6.6 Coronary artery bypass surgery
cantly different. The two groups had similar rates of urgent TVR Approximately 10% of NSTE-ACS patients may require CABG during
and stent thrombosis. Major BARC 3 or 5 bleeding was significantly their index hospitalization.359 A Danish nationwide cohort study
reduced in the radial group [1.6% vs. 2.3%; RR 0.67 (95% CI 0.49, showed that the proportion of patients undergoing CABG
0.92), P ¼ 0.013]. Radial access was associated with significantly lower for NSTE-ACS decreased from 2001 to 2009, while the proportion
rates of surgical access site repair or transfusion of blood products. of patients undergoing coronary angiography and PCI markedly
An updated meta-analysis including MATRIX found a significant re- increased.360 NSTE-ACS patients requiring CABG represent a
duction in major bleeds; death, MI or stroke and in all-cause mortality challenging group of patients, mainly because of the difficulties in bal-
associated with radial as compared with femoral access.251 Radial ac- ancing ischaemic and bleeding risks in relation to the timing of surgery
cess, performed by experienced operators, is recommended over the and perioperative antithrombotic therapy. In addition, NSTE-ACS pa-
transfemoral access in ACS. It is recommended that centres treating tients present with a higher proportion of surgical high-risk
ESC Guidelines 299

characteristics, including older age, female gender, left main coronary 5.6.6.3 Technical aspects and outcomes (see Web addenda)
disease and LV dysfunction compared with patients undergoing elect- 5.6.7 Percutaneous coronary intervention vs. coronary
ive CABG.361 In the absence of randomized data, optimal timing for artery bypass surgery
non-emergent CABG in NSTE-ACS patients should be determined While the main advantages of PCI in the setting of NSTE-ACS are
individually, as detailed in section 5.6.6.1, Web addenda. faster revascularization of the culprit lesion, a lower risk of stroke
and the absence of deleterious effects of cardiopulmonary bypass
on the ischaemic myocardium, CABG may more frequently offer
5.6.6.1 Timing of surgery and antithrombotic drug discontinuation
(see Web addenda) complete revascularization in advanced multivessel CAD. However,
no contemporary RCT comparing PCI with CABG in patients with
5.6.6.2 Recommendations for perioperative management of antiplatelet NSTE-ACS and multivessel CAD is available. Accordingly, in nearly
therapy in non-ST-elevation acute coronary syndrome patients requiring
all trials comparing an early with a delayed invasive strategy, or a
coronary artery bypass surgery
routine invasive with a selective invasive strategy, the decision to

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perform PCI or CABG was left to the discretion of the investigator.
Recommendations for perioperative management of A post hoc analysis of 5627 NSTE-ACS patients with multivessel
antiplatelet therapy in non-ST-elevation acute CAD included in the ACUITY trial showed that 78% underwent
coronary syndrome patients requiring coronary artery PCI while the remaining patients were treated surgically.374 After
bypass surgery propensity-score matching, there were no differences among
1056 patients in mortality at 1 month (CABG 2.5% vs. PCI 2.1%;
Recommendations Classa Levelb Ref.c P ¼ 0.69) and 1 year (CABG 4.4% vs. PCI 5.7%; P ¼ 0.58). PCI-
treated patients experienced lower rates of stroke (0% vs. 1.1%;
Irrespective of the revascularization
strategy, a P2Y12 inhibitor is P ¼ 0.03), MI (8.8%% vs. 13.3%; P ¼ 0.03), major bleeds (9.1% vs.
137, 45.5%; P , 0.001) and renal injury (14.2% vs. 31.7%; P , 0.001),
recommended in addition to aspirin
I A 148,
and maintained over 12 months unless but had significantly higher rates of unplanned revascularization
153
there are contraindications such as than CABG (3.1% vs. 0.2%; P , 0.001) during the periprocedural
excessive risk of bleeding events.
period. At 1 year, the risk of stroke remained lower among PCI-
It is recommended that the Heart treated patients (0% vs. 1.1%; P ¼ 0.03), whereas unplanned revas-
Team estimate the individual bleeding cularization (12% vs. 0.2%; P , 0.001) and MACE tended to be
and ischaemic risks and guide the I C
more common (25.0% vs. 19.2%; P ¼ 0.053). A subgroup analysis
timing of CABG as well as
management of DAPT. of an individual patient data meta-analysis of 10 RCTs comparing
CABG and PCI reported similar mortality after a median follow-up
It is recommended to perform CABG
without delay in patients with
of 5.9 years among 2653 stabilised NSTE-ACS patients with multi-
haemodynamic instability, ongoing vessel CAD [9.6% in the CABG group vs. 11.1% in the PCI group;
I C
myocardial ischaemia or very-high-risk HR 0.95 (95% CI 0.80, 1.12)].377
coronary anatomy, regardless of As both the SYNergy Yield of the New Strategy of Enoxaparin,
antiplatelet treatment. Revascularization and Glycoprotein IIb/IIIa Inhibitors (SYNERGY)
Aspirin is recommended 6–24 h and Future Revascularization Evaluation in Patients with Diabetes
365,
post-CABG in the absence of ongoing I A Mellitus: Optimal Management of Multivessel Disease (FREEDOM)
366
bleeding events.
trials compared PCI and CABG in patients with multivessel CAD
It is recommended to continue 367– and included up to one-third of patients with unstable angina or
I B
low-dose aspirin until CABG. 369
NSTE-ACS, it is reasonable to use the criteria applied in patients
In stabilised patients requiring CABG with stable CAD to guide the choice of revascularization modality
who are on DAPT, discontinuation of 285,
among stabilised patients with NSTE-ACS.378 – 380 While the major-
ticagrelor and clopidogrel 5 days IIa B 370,
before and prasugrel 7 days prior to 371 ity of patients with single-vessel CAD should undergo ad hoc PCI of
surgery should be considered. the culprit lesion, the revascularization strategy in an individual
After CABG, resuming P2Y12 inhibitor
NSTE-ACS patient with multivessel CAD should be discussed in
therapy should be considered as soon IIa C the context of a Heart Team and be based on the clinical status
as deemed safe. as well as the severity and distribution of the CAD and the lesion
Platelet function testing may be characteristics. The SYNTAX score was found to be useful in the
considered in shortening the time prediction of death, MI and revascularization among NSTE-ACS pa-
IIb B 372
window to CABG following P2Y12 tients undergoing PCI and may help guide the choice between revas-
inhibitor discontinuation. cularization strategies.381 PCI of the culprit lesion does not require a
case-by-case review by the Heart Team when an ad hoc interven-
ACS ¼ acute coronary syndromes; CABG ¼ coronary artery bypass graft; tion is indicated based on clinical or angiographic grounds, such as
DAPT ¼ dual (oral) antiplatelet therapy.
a
Class of recommendation.
ongoing ischaemia, haemodynamic instability, pulmonary oedema,
b
Level of evidence. recurrent ventricular arrhythmias or total occlusion of the culprit
c
References supporting level of evidence. coronary artery requiring urgent revascularization. Following PCI
of the culprit lesion, stabilised NSTE-ACS patients with multivessel
300 ESC Guidelines

CAD may be discussed within the Heart Team if delayed CABG of


An invasive strategy (<72 h) is
the non-culprit vessels is an option. recommended in patients with at least
one of the following intermediate-risk
5.6.8 Management of patients with cardiogenic shock criteria:
Cardiogenic shock may develop in up to 3% of NSTE-ACS patients – diabetes mellitus
during hospitalization and has become the most frequent cause of – renal insufficiency (eGFR

in-hospital mortality in this setting.382 – 384 One or more partial or ,60 mL/min/1.73 m2)
– LVEF ,40% or congestive heart 322,
complete vessel occlusions may result in severe heart failure, espe- failure
I A
324
cially in cases of pre-existing LV dysfunction, reduced cardiac output – early post-infarction angina
and ineffective peripheral organ perfusion. More than two-thirds of – recent PCI
patients have three-vessel CAD. Cardiogenic shock may also be re- – prior CABG
– GRACE risk score .109 and
lated to mechanical complications of NSTEMI, including mitral re-

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,140,
gurgitation related to papillary muscle dysfunction or rupture and or recurrent symptoms or known
ventricular septal or free wall rupture. In patients with cardiogenic ischaemia on non-invasive testing.
shock, immediate coronary angiography is indicated and PCI is the
In patients with none of the above
most frequently used revascularization modality. If the coronary mentioned risk criteria and no
anatomy is not suitable for PCI, patients should undergo emergent recurrent symptoms, non-invasive
113,
CABG. The value of intra-aortic balloon counterpulsation in MI testing for ischaemia (preferably I A
114
complicated by cardiogenic shock has been challenged.385 Extra- with imaging) is recommended
before deciding on an invasive
corporeal membrane oxygenation and/or implantable LV assist
evaluation.
devices may be considered in selected patients.
In centres experienced with radial
5.6.9 Recommendations for invasive coronary access, a radial approach is
I A 251
angiography and revascularization in non-ST-elevation recommended for coronary
angiography and PCI.
acute coronary syndromes
In patients undergoing PCI, 242,
new-generation DESs are 252,
Recommendations for invasive coronary angiography I A
recommended. 386–
and revascularization in non-ST-elevation acute 390
coronary syndromes
In patients with multivessel CAD,
it is recommended to base the
revascularization strategy (e.g. ad
Recommendations Classa Levelb Ref.c
hoc culprit-lesion PCI, multivessel
An immediate invasive strategy PCI, CABG) on the clinical status
(<2 h) is recommended in patients with and comorbidities as well as the I C
at least one of the following disease severity (including
very-high-risk criteria: distribution, angiographic lesion
– haemodynamic instability or characteristics, SYNTAX score),
cardiogenic shock according to the local Heart Team
– recurrent or ongoing chest protocol.
pain refractory to medical
In patients in whom a short DAPT
treatment I C
duration (30 days) is planned because
– life-threatening arrhythmias or
of an increased bleeding risk, a new- IIb B 245
cardiac arrest
generation DES may be considered
– mechanical complications of MI
over a BMS.
– acute heart failure with refractory
angina or ST deviation
– recurrent dynamic ST- or T-wave BMS ¼ bare-metal stent; CABG ¼ coronary artery bypass grafting;
changes, particularly with CAD ¼ coronary artery disease; DAPT ¼ dual (oral) antiplatelet therapy;
intermittent ST-elevation. DES ¼ drug-eluting stent; eGFR ¼ estimated glomerular filtration rate;
GRACE ¼ Global Registry of Acute Coronary Events; LVEF ¼ left ventricular
An early invasive strategy (<24 h) ejection fraction; MI ¼ myocardial infarction; NSTE-ACS ¼ non-ST-elevation
is recommended in patients with at acute coronary syndromes; PCI ¼ percutaneous coronary intervention;
least one of the following high-risk SYNTAX ¼ SYNergy between percutaneous coronary intervention with
criteria: 303, TAXus and cardiac surgery.
– rise or fall in cardiac troponin I A 326, Timing to coronary angiography is calculated from hospital admission.
a
Class of recommendation.
compatible with MI 327 b
Level of evidence.
– dynamic ST- or T-wave changes c
References supporting level of evidence.
(symptomatic or silent)
– GRACE score .140.
ESC Guidelines 301

5.7 Gender specificities (see Web addenda)


Recommendations for the management of diabetic
5.8 Special populations and conditions patients with non-ST-elevation acute coronary
(see Web addenda) syndromes

5.8.1 The elderly and frail patients (see Web addenda)


Recommendations Classa Levelb Ref.c
5.8.1.1 Recommendations for the management of elderly patients with
non-ST-elevation acute coronary syndromes Blood glucose control
It is recommended to screen all
Recommendations for the management of elderly patients with NSTE-ACS for diabetes
and to monitor blood glucose levels I C
patients with non-ST-elevation acute coronary
frequently in patients with known
syndromes diabetes or admission hyperglycaemia.

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Glucose-lowering therapy should
Recommendations Classa Levelb Ref.c be considered in ACS patients with
blood glucose .10 mmol/L
It is recommended to tailor (.180 mg/dL), with the target IIa C
antithrombotic treatment according I C adapted to comorbidities, while
to bodyweight and renal function. episodes of hypoglycaemia should be
Elderly patients should be considered avoided.
for an invasive strategy and, if Less stringent glucose control
appropriate, revascularization after 408, should be considered both in the
careful evaluation of potential risks IIa A 414– acute phase and at follow-up in
and benefits, estimated life expectancy, 418 patients with more advanced IIa C
comorbidities, quality of life, frailty and cardiovascular disease, older age,
patient values and preferences. longer diabetes duration and more
Adjusted dosing regimens of comorbidities.
beta-blockers, ACE inhibitors, ARBs Antithrombotic treatment and invasive strategy
IIa C
and statins should be considered to
It is recommended to administer
prevent side effects.
the same antithrombotic treatment
I C
in diabetic and non-diabetic
ACE ¼ angiotensin-converting enzyme; ARB ¼ angiotensin receptor blocker; patients.
NSTE-ACS ¼ non-ST-elevation acute coronary syndromes.
a
Class of recommendation. An invasive strategy is recommended 352,
b
Level of evidence. over non-invasive management. I A 441,
c
References supporting level of evidence. 442
It is recommended to monitor renal
function for 2– 3 days after coronary
angiography or PCI in patients with I C
5.8.2 Diabetes mellitus (see Web addenda) baseline renal impairment or on
5.8.2.1 Recommendations for the management of diabetic patients with metformin.
non-ST-elevation acute coronary syndromes In patients undergoing PCI, 240,
new-generation DESs are I A 241,
recommended over BMSs. 443
In patients with stabilised multivessel
379,
CAD and an acceptable surgical
I A 436,
risk, CABG is recommended over
444
PCI.
In patients with stabilised multivessel
CAD and a SYNTAX score ≤22, PCI 435,
IIa B
should be considered as an alternative 445
to CABG.

ACS ¼ acute coronary syndromes; BMS ¼ bare-metal stent; CABG ¼ coronary


artery bypass grafting; CAD ¼ coronary artery disease; DES ¼ drug-eluting
stent; NSTE-ACS ¼ non-ST-elevation acute coronary syndromes;
PCI ¼ percutaneous coronary intervention; SYNTAX ¼ SYNergy
between percutaneous coronary intervention with TAXus and
cardiac surgery.
a
Class of recommendation.
b
Level of evidence.
c
References supporting level of evidence.
302 ESC Guidelines

5.8.3 Chronic kidney disease (see Web addenda) 5.8.4 Left ventricular dysfunction and heart failure
5.8.3.1 Dose adjustment of antithrombotic agents (see Web addenda) (see Web addenda)
5.8.3.2 Recommendations for the management of patients with chronic 5.8.4.1 Recommendations for the management of patients with
kidney disease and non-ST-elevation acute coronary syndromes acute heart failure in the setting of non-ST-elevation acute
coronary syndromes

Recommendations for the management of patients Recommendations for the management of patients
with chronic kidney disease and non-ST-elevation with acute heart failure in the setting of non-ST-
acute coronary syndromes elevation acute coronary syndromes

Recommendations Classa Levelb Ref.c Recommendations Classa Levelb Ref.c

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It is recommended to assess kidney It is recommended to perform
I C
function by eGFR in all patients. emergency echocardiography to
It is recommended to administer the assess LV and valvular function I C
same first-line antithrombotic and exclude mechanical
453, complications.
treatment as in patients with normal I B
454
kidney function, with appropriate dose Immediate coronary angiography is
adjustment if indicated. recommended in patients with 1,
Depending on the degree of renal acute heart failure with refractory I B 475,
dysfunction, it is recommended to angina, ST deviation or cardiogenic 476
switch parenteral anticoagulation to shock.
453,
UFH or to adjust the doses of I B Immediate PCI is recommended for
454
fondaparinux, enoxaparin and patients with cardiogenic shock if I B 475
bivalirudin, as well as the dose of small coronary anatomy is suitable.
molecule GPIIb/IIIa inhibitors.
Emergency CABG is recommended
It is recommended to switch s.c. or i.v. for patients with cardiogenic shock if
anticoagulation to UFH infusion adjusted I B 475
the coronary anatomy is not amenable
to the aPTT when eGFR is ,30 mL/min/ I C to PCI.
1.73 m2 (for fondaparinux, when eGFR is
,20 mL/min/1.73 m2). It is recommended that patients with
mechanical complications of NSTE-
In patients undergoing an invasive I C
ACS are immediately discussed by the
strategy, hydration with isotonic saline Heart Team.
455–
and low- or iso-osmolar contrast I A
460 IABP insertion should be considered in
media (at lowest possible volume) are
recommended. patients with haemodynamic
IIa C
instability/cardiogenic shock due to
Coronary angiography and, if needed, mechanical complications.
revascularization are recommended
after careful assessment of the risk – I B 448 Short-term mechanical circulatory
benefit ratio, in particular with respect support in patients with cardiogenic IIb C
to the severity of renal dysfunction. shock may be considered.

In patients undergoing PCI, Routine use of IABP in patients with


461, 385,
new-generation DESs are I B cardiogenic shock is not III B
462 477
recommended over BMSs. recommended.

CABG should be considered over PCI


in patients with multivessel CAD 463, CABG ¼ coronary artery bypass grafting; IABP ¼ intra-aortic balloon pump;
IIa B LV ¼ left ventricular; NSTE-ACS = non-ST-elevation acute coronary syndromes;
whose surgical risk profile is acceptable 464
PCI ¼ percutaneous coronary intervention.
and life expectancy is .1 year.
With respect to detailed medical management of acute heart failure, we refer the
PCI should be considered over reader to dedicated guidelines.469
a
CABG in patients with multivessel 465, Class of recommendation.
IIa B b
Level of evidence.
CAD whose surgical risk profile 466 c
References supporting level of evidence.
is high or life expectancy is ,1 year.

aPTT ¼ activated partial thromboplastin time; BMS ¼ bare metal stent; CABG ¼
coronary artery bypass graft; CAD ¼ coronary artery disease; CKD ¼ chronic
kidney disease; DES ¼ drug-eluting stent; eGFR ¼ estimated glomerular filtration
rate; GP ¼ glycoprotein; i.v. ¼ intravenous; PCI ¼ percutaneous coronary
intervention; s.c. ¼ subcutaneous; UFH ¼ unfractionated heparin.
a
Class of recommendation.
b
Level of evidence.
c
References supporting level of evidence.
ESC Guidelines 303

5.8.4.2 Recommendations for the management of patients with 5.8.5 Atrial fibrillation (see Web addenda)
heart failure following non-ST-elevation acute coronary syndromes
5.8.5.1 Recommendations for the management of atrial fibrillation in
patients with non-ST-elevation acute coronary syndromes
Recommendations for the management of patients
with heart failure following non-ST-elevation acute Recommendations for the management of atrial
coronary syndromes fibrillation in patients with non-ST-elevation acute
coronary syndromes

Recommendations Classa Levelb Ref.c


An ACE inhibitor (or ARB, if an ACE Recommendations Classa Levelb Ref.c
inhibitor is not tolerated) is In the absence of contraindications, it
469,
recommended in patients with LVEF is recommended to administer

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I A 478– I A 497
≤40% after stabilization, to reduce anticoagulant drugs to all patients at
481
the risk of death, recurrent MI and presentation.
hospitalization for heart failure.
Investigations to detect ischaemia should
A beta-blocker is recommended be considered in patients with atrial
IIa C
in patients with an LVEF ≤40% 469, fibrillation and elevated cardiac troponin
after stabilization, to reduce the I A 482– levels.
risk of death, recurrent MI and 486
Patients with rapid ventricular rate
hospitalization for heart failure.
Electrical cardioversion is
Mineralocorticoid receptor
recommended in haemodynamically I C
antagonists are recommended to
unstable patients.
reduce the risk of heart failure
hospitalization and death in all Electrical or pharmacological
patients with persistent symptoms 487, cardioversion with amiodarone is
I A
(NYHA class II –IV) and LVEF ≤35% 488 recommended in patients when a
despite treatment with an ACE decision is made to restore sinus
inhibitor (or an ARB, if an ACE rhythm non-urgently (rhythm control
inhibitor is not tolerated) and a strategy). This strategy should only be
beta-blocker. employed in patients with the first I C
episode of atrial fibrillation of ,48 h
Mineralocorticoid receptor
duration (or in patients with no
antagonists, preferably eplerenone,
469, evidence of left atrial appendage
are recommended to reduce the risk I B
525 thrombus on TOE) or if the patient
of cardiovascular hospitalization and
was anticoagulated in the therapeutic
death in patients with LVEF ≤40%.
range for at least 3 weeks.
Device therapy (CRT-D or ICD,
Intravenous beta-blockers are
depending on QRS duration) is
recommended to slow the rapid
recommended in symptomatic
ventricular response to atrial I C
patients with severe LV dysfunction
fibrillation in haemodynamically stable
(LVEF ≤35%) despite optimal 489,
I A patients.
medical therapy .40 days after the 490
acute event and without options of Intravenous administration of cardiac
revascularization. Patients should be glycosides may be considered for
expected to survive .1 year with ventricular rate control if the IIb C
good functional status. response to beta-blockers is not
sufficient.
In patients with CAD and LVEF
≤35%, testing for residual ischaemia Intravenous administration of
and subsequent revascularization non-dihydropyridine calcium
should be considered prior to antagonists (verapamil, diltiazem) may
primary prophylactic ICD/CRT-D 491, be considered to slow a rapid IIb C
IIa B
implantation. After revascularization, 492 ventricular response to atrial fibrillation
assessment of reverse LV remodelling in patients not on beta-blockers and
up to 6 months should be considered with no signs of heart failure.
prior to primary prophylactic ICD/
Administration of class I
CRT-D implantation.
antiarrhythmic agents (e.g. encainide, III B 498
flecainide) is not recommended.
ACE ¼ angiotensin-converting enzyme; ARB ¼ angiotensin receptor blocker;
Vernakalant is not recommended. III C 493
CAD ¼ coronary artery disease; CRT-D ¼ cardiac resynchronization therapy
defibrillator; ICD ¼ implantable cardioverter defibrillator; LV ¼ left
ventricular; LVEF ¼ left ventricular ejection fraction; MI ¼ myocardial TOE ¼ transoesophageal echocardiography.
infarction; NYHA ¼ New York Heart Association. a
Class of recommendation.
a
Class of recommendation. b
Level of evidence.
b
Level of evidence. c
References supporting level of evidence.
c
References supporting level of evidence.
304 ESC Guidelines

5.8.6 Anaemia (see Web addenda) should be increased in those receiving a low- or moderate-intensity
5.8.7 Thrombocytopenia statin treatment at presentation, unless they have a history of in-
tolerance to high-intensity statin therapy or other characteristics
5.8.7.1 Thrombocytopenia related to GPIIb/IIIa inhibitors (Web addenda)
that may influence safety.522,527,528 In this regard, the IMProved Re-
5.8.7.2 Heparin-induced thrombocytopenia (Web addenda) duction of Outcomes: Vytorin Efficacy International Trial
5.8.7.3 Recommendations for the management of thrombocytopenia in (IMPROVE-IT) randomized a total of 18 144 patients with recent
non-ST-elevation acute coronary syndromes ACS (NSTEMI 47%, STEMI 29% and unstable angina 24%) and
LDL cholesterol ,125 mg/dL (,2.5 mmol/L) to either ezetimibe
Recommendations for the management of 10 mg/simvastatin 40 mg or simvastatin 40 mg (simvastatin was
thrombocytopenia in non-ST-elevation acute up-titrated to 80 mg if LDL cholesterol was .79 mg/dL or
coronary syndromes 2.04 mmol/L). Over a period of 7 years, the composite primary end-
point of CV death, MI, hospital admission for unstable angina, coronary

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revascularization or stroke was significantly lower in the combined
Recommendations Classa Levelb Ref.c treatment arm compared with the statin-only arm [32.7% vs. 34.7%;
Immediate interruption of GPIIb/IIIa HR 0.94 (95% CI 0.89, 0.99), P ¼ 0.016].529 IMPROVE-IT was the first
inhibitor and/or heparin (UFH, study powered for clinical outcomes to show a modest benefit with a
LMWH, other heparin products) is non-statin agent added to a statin. As a limitation, not all patients in the
recommended in case of
I C control arm were on a high-intensity statin regimen. Based on the re-
thrombocytopenia ,100 000/mL (or
.50% relative drop from baseline sults of the trial, further LDL cholesterol lowering with a non-statin
platelet count) occurring during agent should be considered in patients with LDL cholesterol
treatment. ≥70 mg/dL (≥1.8 mmol/L) after NSTE-ACS despite a maximally
In patients treated with GP IIb/IIIa tolerated dose of statin. At the time of finalizing the guidelines, this
inhibitors, platelet transfusion is recommendation applies only to ezetimibe.
recommended in case of major active
I C
bleeding events or in the presence of
5.9.1.2 Antithrombotic therapy
severe (,10 000/mL) asymptomatic
thrombocytopenia. Duration of antiplatelet treatment and anticoagulation during the
chronic phase are discussed in sections 5.2.6 and 5.3.2, respectively.
Treatment with a non-heparin
anticoagulant is recommended in case I C
of documented or suspected HIT. 5.9.1.3 ACE inhibition
ACE inhibitors are recommended in patients with systolic LV dys-
Use of anticoagulants with low or no
risk of HIT or brief administration of function or heart failure, hypertension or diabetes (agents and doses
UFH or LMWH, when these are I C of proven efficacy should be employed). ARBs are indicated in pa-
chosen, are recommended to prevent tients who are intolerant of ACE inhibitors.478 – 480,530,531
the occurrence of HIT.
5.9.1.4 Beta-blockers
GP ¼ glycoprotein; HIT ¼ heparin-induced thrombocytopenia; LMWH ¼ low Beta-blockers are recommended, in the absence of contraindications,
molecular weight heparin; UFH ¼ unfractionated heparin. in patients with reduced systolic LV function (LVEF ≤40%). Agents
a
Class of recommendation.
b
Level of evidence. and doses of proven efficacy should be administered.482 – 486 Beta-
c
References supporting level of evidence. blocker therapy has not been investigated in contemporary RCTs
in patients after NSTE-ACS and no reduced LV function or heart fail-
5.8.8 Patients requiring chronic analgesic or ure. In a large-scale observational propensity-matched study in pa-
anti-inflammatory treatment (see Web addenda) tients with known prior MI, beta-blocker use was not associated
with a lower risk of CV events or mortality.532
5.8.9 Non-cardiac surgery (see Web addenda)
5.9 Long-term management 5.9.1.5 Mineralocorticoid receptor antagonist therapy
5.9.1 Medical therapy for secondary prevention Aldosterone antagonist therapy is recommended in patients with LV
Secondary prevention of CV events, including optimal medical therapy, dysfunction (LVEF ≤40%) and heart failure or diabetes after
other strategies for risk factor modification and lifestyle changes such as NSTE-ACS. Eplerenone therapy has been shown to reduce morbid-
diet, exercise and smoking cessation, is of paramount importance be- ity and mortality in these patients after ACS.487,488,525
cause after an ACS episode, patients remain at high risk for recurrent
5.9.1.6 Antihypertensive therapy
ischaemic events.521 Secondary prevention has been shown to have a
Antihypertensive therapy (blood pressure goal ,140/90 mmHg)
major impact on long-term outcome in these patients.478,479,482,521 – 526
is recommended according to the European Society of
Hypertension/ESC guidelines on the management of arterial
5.9.1.1 Lipid-lowering treatment hypertension.533
It is recommended to initiate high-intensity statin therapy [i.e. statin
regimens that reduce low-density lipoprotein (LDL) cholesterol by 5.9.1.7 Glucose-lowering therapy in diabetic patients
50%] as early as possible after admission in all NSTE-ACS patients This topic is beyond the scope of the present document and was dis-
(in the absence of contraindications). The intensity of statin therapy cussed in recent guidelines.433 As a general rule, the more advanced
ESC Guidelines 305

the CV disease, the older the patient, the longer the diabetes dur-
Participation in a well-structured cardiac
ation and the more comorbidities that are present, the less stringent rehabilitation programme to modify
535,
the glucose control should be. IIa A 541–
lifestyle habits and increase adherence
546
Core components and goals of cardiac rehabilitation, including to treatment should be considered.
physical activity counselling, diet/nutrition counselling, smoking ces- In patients with LDL cholesterol
sation, weight control and goals for lipid and blood pressure man- ≥70 mg/dL (≥1.8 mmol/L) despite a
agement should be stated in the discharge letter.534 maximally tolerated statin dose, further IIa B 529
reduction in LDL cholesterol with a
5.9.2 Lifestyle changes and cardiac rehabilitation non-statin agente should be considered.
Enrolment in a well-structured cardiac rehabilitation/secondary pre- A systolic blood pressure goal 547–
IIa B
vention programme after NSTE-ACS should be considered, as it can of ,140 mmHg should be considered. 549
enhance patient compliance with the medical regimen and promote

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lifestyle changes, including regular physical exercise and smoking ces- ACE ¼ angiotensin-converting enzyme; ARB ¼ angiotensin receptor blocker;
sation, and allows for dietary counselling.521,535 Aerobic exercise train- LDL ¼ low-density lipoprotein; LVEF ¼ left ventricular ejection fraction;
NSTE-ACS ¼ non-ST-elevation acute coronary syndromes.
ing within a cardiac rehabilitation programme should be offered to a
Class of recommendation.
b
patients after NSTE-ACS, with the need for an evaluation of both ex- Level of evidence.
c
ercise capacity and exercise-associated risk. If feasible, regular exercise References supporting level of evidence.
d
Serum creatinine ,221 mmol/L (2.5 mg/dL) for men and ,177 mmol/L
training three or more times a week and 30 min per session is recom- (2.0 mg/dL) for women; serum potassium concentration ,5.0 mmol/L.
e
mended. Sedentary patients should be strongly encouraged to start At the time of finalizing the guidelines, this recommendation applies only to ezetimibe.
light-intensity exercise programmes after adequate exercise-related
risk stratification. Smoking cessation is a highly effective measure to re-
duce morbidity and mortality in patients after ACS.521,536
6. Performance measures
5.9.3 Recommendations for long-term management after
non-ST-elevation acute coronary syndromes Variations in the application of evidence-based strategies are associated
with significant differences in outcome. Several large registries have
shown deficiencies in the treatment of NSTE-ACS patients when com-
Recommendations for long-term management after
pared with recommendations from contemporary guidelines. Under-
non-ST-elevation acute coronary syndromes
utilization of evidence-based treatments is common. Adherence to
guidelines has been correlated with improvements in patient outcomes
Recommendations (for the Classa Levelb Ref.c in ACS, including reduced mortality.550,551 Thus priority needs to be gi-
recommendations on antithrombotic ven to improving the utilization of evidence-based guidelines. Continu-
treatment, see sections 5.2.9 and 5.3.3) ous monitoring of performance indicators is strongly encouraged to
It is recommended to advise all enhance the quality of treatment and minimize unwarranted variations
patients on lifestyle changes (including 536, in evidence-based care. Consistent application of therapies based on
I A
smoking cessation, regular physical 537
activity and a healthy diet).
Table 14 Performance measures in NSTE-ACS
It is recommended to start
high-intensity statin therapy as early as
522, patients
I A 527,
possible, unless contraindicated, and
528
maintain it long term. • Use of aspirin

An ACE inhibitor is recommended in • Use of ticagrelor/prasugrel/clopidogrel


478–
patients with LVEF ≤40% or heart • Use of fondaparinux/bivalirudin/UFH/enoxaparin
481,
failure, hypertension or diabetes,
I A 530, • Use of beta-blocker at discharge in patients with LV dysfunction
unless contraindicated. An ARB
531, • Use of statins
provides an alternative, particularly if
538
ACE inhibitors are not tolerated. • Use of ACE-inhibitor or ARB in patients with systolic LV dysfunction
Beta-blocker therapy is recommended or heart failure, hypertension or diabetes
482–
in patients with LVEF ≤40%, unless I A • Use of early invasive procedures in intermediate- to high-risk patients
486
contraindicated. • Smoking cessation advice/counselling
Mineralocorticoid receptor • Enrolment in a secondary prevention/ cardiac rehabilitation
antagonists, preferably eplerenone, are programme
recommended in patients with LVEF 487,
≤35% and either heart failure or I A 488, • Development of regional and/or national programmes to measure
performance indicators systematically and provide feedback to
diabetes after NSTE-ACS but no 525
individual hospitals
significant renal dysfunction or
hyperkalaemia.d
ACE ¼ angiotensin-converting enzyme; ARB ¼ angiotensin receptor blocker;
A diastolic blood pressure goal of ,90
539, LV ¼ left ventricular; NSTEMI ¼ non-ST-elevation myocardial infarction;
mmHg is recommended (,85 mmHg I A UFH ¼ unfractionated heparin.
540
in diabetic patients).
306 ESC Guidelines

robust evidence may have larger effects on real-life CV health than pain, hypertension or heart failure. Oxygen therapy should be applied
those seen in selected trial populations, especially with the combined in the presence of a blood oxygen saturation ,90% or respiratory
implementation of several effective treatment modalities. Such pro- distress. Morphine (i.v. or s.c.) or alternative opiates are reserved
grammes have been implemented successfully in several countries, in- for patients with persisting severe chest pain. In patients with ongoing
cluding Sweden [the Swedish Web-system for Enhancement and chest pain and inconclusive ECG, consider immediate echocardiog-
Development of Evidence-based care in Heart disease Evaluated Ac- raphy to exclude alternative diagnoses (if appropriate in conjunction
cording to Recommended Therapies (SWEDEHEART)], the UK with CT angiography) such as pulmonary embolism, pericarditis or
[Myocardial Infarction National Audit Project (MINAP) registry], aortic dissection and at the same time to reinforce the suspicion of
Germany, Italy and Israel on a regional basis, or in intermittent pro- NSTE-ACS (i.e. by identifying a focal wall motion abnormality). In
grammes in many other countries. These performance measure the setting of ongoing myocardial ischaemia or haemodynamic com-
programmes are also proposed and developed by the ESC through promise (the clinical suspicion should be corroborated by the echo-
the continuous ACS Registry within the Euro Heart Survey Program. cardiographic finding of regional wall motion abnormality) the patient

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The most useful performance indicators for monitoring and improv- should undergo immediate coronary angiography irrespective of ECG
ing the standards of care in NSTEMI are listed in Table 14. or biomarker findings to prevent life-threatening ventricular arrhyth-
mias and limit myocardial necrosis. Blood work on admission should
include at least (preferably high-sensitivity) cardiac troponin T or I,
7. Summary of management serum creatinine, haemoglobin, haematocrit, platelet count, blood
strategy glucose and INR in patients on VKA. The results of the troponin mea-
This section summarises the diagnostic and therapeutic steps dis- surements should be available within 60 min and troponin measure-
cussed in the previous sections. The goal is to outline the most import- ment should be repeated at 1–3 h if high-sensitivity troponin assays
ant steps in the management of patients with NSTE-ACS. In each are used. Vital signs should be assessed on a regular basis. In case of
individual patient, decision making should take into account the pa- hospital admission, guidance in the choice of the unit is described in
tient’s history (e.g. age, comorbidities), clinical presentation (e.g. on- Table 7. Patients with suspected NSTE-ACS should be observed in
going myocardial ischaemia, haemodynamic or electrical instability), interdisciplinary emergency departments or chest pain units until
findings obtained during the initial assessment (i.e. ECG, cardiac tropo- the diagnosis of MI is confirmed or ruled out. If the diagnosis of
nin), timing and expected risk–benefit ratio of available therapies (i.e. NSTE-ACS is confirmed, the lipid profile should be assessed in the
pharmacological, invasive assessment, revascularization). early phase of admission. In case of ongoing ischaemia, defibrillator
patches should be placed until urgent revascularization is performed.
Step 1: Initial evaluation and pathway It is recommended that medical and paramedical personnel caring for
Chest pain or other atypical symptoms prompt the patient to seek suspected NSTE-ACS patients have access to defibrillator equipment
medical attention. All patients with suspected NSTE-ACS must be and are trained in advanced cardiac life support.
admitted to an emergency department and evaluated rapidly by a
qualified physician. The delay between first medical contact and
Step 2: Diagnosis validation, risk
ECG should be ≤10 min. The cardiac rhythm of the patient should assessment and rhythm monitoring
be monitored (Table 7). Once the initial clinical assessment, complemented by the 12-lead
The working diagnosis of NSTE-ACS and the initial management ECG and the first cardiac troponin measurement, has substan-
should be based on the following parameters: tiated the diagnosis of NSTE-ACS, antithrombotic treatment (as
described in step 3) as well as anti-anginal treatment (i.e. beta-
† Chest pain characteristics, duration and persistence as well as a blockers and nitrates) should be started. Further management of
symptom-oriented physical examination (e.g. systolic blood pressure, the patient is based on responsiveness to anti-anginal treatment
heart rate, cardiopulmonary auscultation, Killip classification) and risk assessment, as quantified by the GRACE 2.0 risk score
† Assessment of the probability of CAD based on chest pain char- (http://www.gracescore.org/WebSite/default.aspx?ReturnUrl=%
acteristics, age, gender, CV risk factors, known CAD and non- 2f), as well as on results of the subsequent troponin measurement
cardiac manifestations of atherosclerosis (at 1 – 3 h, if high-sensitivity assays are used). Echocardiography is
† 12-lead ECG (to detect ST deviation or other abnormalities sug- useful to identify abnormalities suggestive of myocardial ischaemia
gestive of myocardial ischaemia or necrosis) or necrosis (i.e. segmental hypokinesia or akinesia) and should be
On the basis of these findings, the patient can be assigned to one of performed immediately in patients with haemodynamic instability
four working diagnoses: of suspected CV origin. If aortic dissection or pulmonary embolism
is suspected, echocardiography, D-dimer assessment and CT
† STEMI
angiography should be implemented according to the respective
† NSTE-ACS with ongoing ischaemia or haemodynamic instability
ESC guidelines. 42,43 Rhythm monitoring up to 24 hours or
† NSTE-ACS without ongoing ischaemia or haemodynamic instability
PCI (whichever comes first) should be considered in NSTEMI pa-
† NSTE-ACS unlikely
tients at low risk for cardiac arrhythmias (i.e. with none of the fol-
The treatment of patients with STEMI is covered in the respective lowing criteria: haemodynamically unstable, major arrhythmias,
ESC guidelines.1 The assignment to the category ‘unlikely’ must be LVEF ,40%, failed reperfusion, additional critical coronary sten-
done with caution, especially in patients with a specific condition, oses or complications related to PCI). Rhythm monitoring for
such as the elderly and those with diabetes mellitus, and only .24 hours should be considered in NSTEMI patients at intermedi-
when another explanation is obvious. The initial treatment measure ate to high-risk for cardiac arrhythmias (i.e. if one or more of the
should include nitrates (sublingual or i.v.) if there is persisting chest above criteria are present).
ESC Guidelines 307

Step 3: Antithrombotic treatment and should not be changed during PCI. In patients pretreated with fon-
The choice of the antithrombotic regimen in NSTE-ACS should be daparinux, UFH must be added before PCI. In anticoagulant-naive pa-
based on the selected management strategy (i.e. conservative vs. in- tients, consider bivalirudin. If CABG is planned and the patient is on a
vasive) as well as the chosen revascularization modality (PCI vs. P2Y12 inhibitor, this should be stopped and surgery deferred if the clin-
CABG). Dosing of antithrombotic agents (Tables 8, 10 and 11) should ical condition and the angiographic findings permit. If coronary angiog-
take into account patient age and renal function. Aspirin and paren- raphy shows no options for revascularization, owing to the extent of
teral anticoagulation are recommended. In patients intended for a the lesions and/or poor distal run-off, freedom from angina should be
conservative treatment and not at high bleeding risk, ticagrelor (pre- aimed for by intensifying medical therapy.
ferred over clopidogrel) is recommended once the NSTEMI diagno-
Step 6: Hospital discharge and
sis is established. In patients intended for an invasive strategy, the
optimal timing of the administration of ticagrelor (preferred over clo-
post-discharge management
Although in NSTE-ACS most adverse events occur in the early

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pidogrel) has not been adequately investigated, while prasugrel is re-
commended only after coronary angiography prior to PCI. phase, the risk for MI or death remains elevated over several
months. Intense risk factor modification and lifestyle changes are
Step 4: Invasive strategy warranted in all patients following NSTE-ACS, and enrolment in a
cardiac rehabilitation programme after discharge can enhance pa-
Radial access for coronary angiography and, if needed, revasculariza-
tient adherence to the medical regimen, may be supportive of risk
tion is recommended. Strategies to reduce bleeding complications
factor modification and is associated with improved outcomes.
related to PCI are summarised in Table 12. The timing of angiog-
raphy (calculated from first medical contact) can be classified into
four categories based on the risk profile of the individual patient ac- 8. Gaps in evidence
cording to Table 13 and Figure 6.
† The role of genetic testing to individualize treatment and ultim-
† Immediate invasive strategy (<2 h). Paralleling the STEMI ately improve patient outcomes remains to be established.
pathway, this strategy should be undertaken for patients with on- † While both sensitive and high-sensitivity cardiac troponin assays
going ischaemia, characterized by at least one very-high-risk cri- show superior diagnostic accuracy compared with conventional
terion. Centres without ongoing STEMI programmes should assays, it is unknown whether high-sensitivity assays provide a
transfer the patient immediately. clinically meaningful advantage over sensitive assays and whether
† Early invasive strategy (<24 h). Most patients in this category there are clinically relevant differences among various high-
respond to the initial pharmacological treatment but are at in- sensitivity assays. The incremental value of copeptin over high-
creased risk and need early angiography followed by revascular- sensitivity cardiac troponin assays remains to be fully elucidated.
ization. Patients qualify if they have at least one high-risk criterion. † The performance of the 1 h algorithm to rule in and rule out
This implies timely transfer for patients admitted to hospitals acute MI in patients presenting with chest pain to the emergency
without onsite catheterization facilities. department has not been tested within an RCT. The best man-
† Invasive strategy (<72 h). This is the recommended maximal agement of patients assigned to the ‘observational zone’ accord-
delay for coronary angiography in patients without recurrence of ing to the 1 h algorithm remains to be defined.
symptoms but with at least one intermediate-risk criterion. Ur- † The role of CT angiography as a rule-out tool for acute MI in the
gent transfer to a hospital with onsite catheterization facilities emergency department needs to be reassessed in the context of
is not necessary, but the 72 h window for coronary angiography high-sensitivity cardiac troponin assays.
should be complied with. † The development of a single clinical risk score that assesses both
† Selective invasive strategy. Patients with no recurrence of chest ischaemic and bleeding risks would be desirable.
pain, no signs of heart failure, no abnormalities in the initial or subse- † The role of beta-blockers during and after an NSTE-ACS episode
quent ECG and no increase in (preferably high-sensitivity) cardiac in patients with normal or mildly depressed LV function needs to
troponin level are at low risk of subsequent CV events. In this setting, be investigated.
a non-invasive stress test (preferably with imaging) for inducible is- † The optimal timing of ticagrelor administration in patients in-
chaemia is recommended before deciding on an invasive strategy. tended for an invasive strategy needs to be defined.
† Additional data are necessary to establish the optimal duration of
Step 5: Revascularization modalities dual antiplatelet therapy following stent implantation.
In the absence of dedicated trials, recommendations for PCI and † The development of antidotes to normalise haemostasis in pa-
CABG in stabilised NSTE-ACS are similar to those for stable CAD. tients with ongoing major bleeding events while on P2Y12 inhibi-
In patients with single-vessel disease, PCI with stenting of the culprit tors or NOACs should be accelerated.
lesion is the first choice. In patients with multivessel disease, the deci- † The safety, effectiveness and optimal duration of combined
sion for PCI or CABG should be individualized through consultation oral anticoagulant and antiplatelet therapy in patients requiring
with the Heart Team. A sequential approach, consisting of treating chronic oral anticoagulation deserves further investigation.
the culprit lesion with PCI followed by elective CABG with proof of † While several RCTs have compared CABG and PCI in popula-
ischaemia and/or FFR of the non-culprit lesions, may be advantageous tions comprising mainly stable CAD patients with multivessel dis-
in selected patients. In patients on a single antiplatelet agent (aspirin) ease, contemporary comparative investigations in the NSTE-ACS
undergoing PCI, the addition of a P2Y12 inhibitor (prasugrel or ticagre- setting are lacking.
lor preferred over clopidogrel) is recommended. The anticoagulant † The value of FFR-guided PCI in NSTE-ACS requires adequate
should be selected based on both the ischaemic and bleeding risks investigation.
308 ESC Guidelines

† The burden of late CV events despite optimal pharmacological


Invasive strategy
treatment, including effective P2Y12 inhibitors and statins, calls
for reappraisal of the pathophysiology of these adverse outcomes 5 An immediate invasive strategy (,2 h) is
recommended in patients with at least one
and innovative preventive strategies.
of the following very-high-risk criteria:
† Clinical trials are under way to examine whether a profound LDL haemodynamic instability or cardiogenic
cholesterol – lowering or immune-modulating therapy (e.g. shock; recurrent or ongoing chest pain
PCSK-9 inhibition, intense CETP inhibition, methotrexate or refractory to medical treatment;
I C
monoclonal anti-IL-1b antibodies) in addition to maximally toler- life-threatening arrhythmias or cardiac
arrest; mechanical complications of MI;
ated statin treatment may improve long-term prognosis.
acute heart failure with refractory angina
† The optimal haemoglobin/haematocrit threshold that should trig- or ST deviation; recurrent dynamic ST- or
ger blood transfusion in anaemic patients with NSTE-ACS needs T-wave changes, particularly with
to be determined. intermittent ST elevation.

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6 An early invasive strategy (,24 h) is
recommended in patients with at least one
of the following high-risk criteria: rise or
fall in cardiac troponin compatible with MI; I A
9. To do and not to do messages dynamic ST- or T-wave changes
from the guidelines (symptomatic or silent); GRACE score
.140.
7 An invasive strategy (,72 h) is
recommended in patients with at least one
of the following intermediate-risk criteria:
W diabetes mellitus

Recommendations Classa Levelb W renal insufficiency (eGFR ,60 mL/


min/1.73 m2)
Diagnosis W LVEF ,40% or congestive heart
I A
1 Similarly to the 0 h and 3 h protocol, a rapid failure
rule-out and rule-in protocol at 0 h and 1 h W early post-infarction angina
is recommended if a high-sensitivity cardiac W recent PCI
troponin test with a validated 0 h/1 h W prior CABG
I B W GRACE risk score .109 and ,140,
algorithm is available. Additional testing after
3–6 h is indicated if the first two troponin or recurrent symptoms or known
measurements are not conclusive and the ischaemia on non-invasive testing.
clinical condition is still suggestive of ACS.
Coronary revascularization
2 Echocardiography is recommended to 8 In centres experienced with radial access,
evaluate regional and global LV function and I C a radial approach is recommended for I A
to rule in or rule out differential diagnoses. coronary angiography and PCI.
Antiplatelet treatment 9 In patients with multivessel CAD, it is
3 A P2Y12 inhibitor is recommended, in recommended to base the
addition to aspirin, for 12 months unless revascularization strategy (e.g. ad hoc
I A culprit-lesion PCI, multivessel PCI, CABG)
there are contraindications such as
excessive risk of bleeds. on the clinical status and comorbidities as I C
well as the disease severity (including
† Ticagrelor (180 mg loading dose, 90 mg distribution, angiographic lesion
twice daily) is recommended, in the characteristics, SYNTAX score) according
absence of contraindications,c for all to the local Heart Team protocol.
patients at moderate to high risk of
ischaemic events (e.g. elevated cardiac I B Secondary cardiovascular prevention
troponins), regardless of initial treatment 10 It is recommended to start high-intensity
strategy and including those pretreated statin therapy as early as possible, unless I A
with clopidogrel (which should be contraindicated, and maintain it long term.
discontinued when ticagrelor is started).
† Prasugrel (60 mg loading dose, 10 mg ACS ¼ acute coronary syndromes; CABG ¼ coronary artery bypass graft;
daily dose) is recommended in patients CAD ¼ coronary artery disease; eGFR ¼ estimated glomerular filtration rate;
I B
who are proceeding to PCI if there are GRACE ¼ Global Registry of Acute Coronary Events; LV ¼ left ventricular;
no contraindications.c LVEF ¼ left ventricular ejection fraction; MI ¼ myocardial infarction; PCI ¼
percutaneous coronary intervention; SYNTAX ¼ SYNergy between
† Clopidogrel (300–600 mg loading dose,
percutaneous coronary intervention with TAXus and cardiac surgery.
75 mg daily dose) is recommended for a
Class of recommendation.
patients who cannot receive ticagrelor I B b
Level of evidence.
or prasugrel or who require oral c
Contraindications for ticagrelor: previous intracranial haemorrhage or ongoing
anticoagulation. bleeds. Contraindications for prasugrel: previous intracranial haemorrhage, previous
ischaemic stroke or transient ischaemic attack or ongoing bleeds; prasugrel is
4 It is not recommended to administer generally not recommended for patients ≥75 years of age or with a bodyweight
prasugrel in patients in whom the III B ,60 kg.
coronary anatomy is not known.
ESC Guidelines 309

10. Web addenda and companion Cardiology, Lia Bang; Egypt: Egyptian Society of Cardiology, Adel El
Etriby; Estonia: Estonian Society of Cardiology, Toomas Marandi; Fin-
documents land: Finnish Cardiac Society, Mikko Pietilä; Former Yugoslav Re-
public of Macedonia: Macedonian Society of Cardiology, Sasko
All Web figures and Web tables are available in the online addenda
Kedev; France: French Society of Cardiology, René Koning; Georgia:
at: http://www.escardio.org/Guidelines-&-Education/Clinical- Georgian Society of Cardiology, Alexander Aladashvili; Germany:
Practice-Guidelines/Acute-Coronary-Syndromes-ACS-in-patients- German Cardiac Society, Franz-Josef Neumann; Greece: Hellenic Car-
presenting-without-persistent-ST-segm diological Society, Kostantinos Tsioufis; Hungary: Hungarian Society of
Questions and answers companion manuscripts of these guide- Cardiology, Dávid Becker; Iceland: Icelandic Society of Cardiology,
lines are available via this same link. Thorarinn Guðnason; Israel: Israel Heart Society, Shlomi Matetzky;
Italy: Italian Federation of Cardiology, Leonardo Bolognese; Kazakh-
11. Acknowledgements stan: Association of Cardiologists of Kazakhstan, Aisulu Mussagaliyeva;
Kyrgyzstan: Kyrgyz Society of Cardiology, Medet Beishenkulov; Lat-

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We are indebted to Veronica Dean, Nathalie Cameron, Catherine via: Latvian Society of Cardiology, Gustavs Latkovskis; Lithuania:
Despres and the entire ESC Practice Guidelines Staff for their invalu- Lithuanian Society of Cardiology, Pranas Serpytis; Luxembourg: Lux-
able support throughout the project. embourg Society of Cardiology, Bruno Pereira; Malta: Maltese Cardiac
Society, Caroline Jane Magri; Moldova: Moldavian Society of Cardi-
ology, Aurel Grosu; Morocco: Moroccan Society of Cardiology, Saadia
12. Appendix Abir-Khalil; Norway: Norwegian Society of Cardiology, Alf Inge Larsen;
ESC Committee for Practice Guidelines (CPG): Jose Luis Zamorano Poland: Polish Cardiac Society, Andrzej Budaj; Portugal: Portuguese
(Chairperson) (Spain), Victor Aboyans (France), Stephan Achenbach Society of Cardiology, Jorge M. Vieira Mimoso; Romania: Romanian
(Germany), Stefan Agewall (Norway), Lina Badimon (Spain), Gonzalo Society of Cardiology, Carmen Ginghina; Russia: Russian Society of
Barón-Esquivias (Spain), Helmut Baumgartner (Germany), Jeroen J. Bax Cardiology, Oleg Averkov; Serbia: Cardiology Society of Serbia, Milan
(The Netherlands), Héctor Bueno (Spain), Scipione Carerj (Italy), Veron- A. Nedeljkovic; Slovakia: Slovak Society of Cardiology, Martin Studen-
ica Dean (France), Çetin Erol (Turkey), Donna Fitzsimons (UK), Oliver čan; Spain: Spanish Society of Cardiology, José A. Barrabés; Sweden:
Gaemperli (Switzerland), Paulus Kirchhof (UK/Germany), Philippe Kolh Swedish Society of Cardiology, Claes Held; Switzerland: Swiss Society
(Belgium), Patrizio Lancellotti (Belgium), Gregory Y.H. Lip (UK), Petros of Cardiology, Hans Rickli; The Netherlands: Netherlands Society of
Nihoyannopoulos (UK), Massimo F. Piepoli (Italy), Piotr Ponikowski Cardiology, Ron J.G. Peters; Tunisia: Tunisian Society of Cardiology
(Poland), Marco Roffi (Switzerland), Adam Torbicki (Poland), Antonio and Cardio-Vascular Surgery, Mohamed Sami Mourali; Turkey: Turkish
Vaz Carneiro (Portugal), Stephan Windecker (Switzerland). Society of Cardiology, Enver Atalar; UK: British Cardiovascular Society,
ESC National Cardiac Societies actively involved in the review Neil Swanson; Ukraine: Ukrainian Association of Cardiology, Alexan-
process of the 2015 ESC Guidelines for the Management of Acute Cor- der Parkhomenko.

onary Syndromes in Patients Presenting Without Persistent ST-Segment Section Coordinators affiliations: Jean-Philippe Collet, ACTION
Elevation: study Group, Institut de Cardiologie, INSERM_UMRS 1166, Pitié-
Armenia: Armenian Cardiologists Association, Aram Chilingaryan; Salpêtrière Hospital (AP-HP), Sorbonne Universités UPMC (Paris 6),
Austria: Austrian Society of Cardiology, Franz Weidinger; Azerbai- F-75013 Paris, France, Tel: +33 1 42 16 30 13, Fax: +33 1 42 16 29
jan: Azerbaijan Society of Cardiology, Ruslan Najafov; Belgium: 31, Email: jean-philippe.collet@psl.aphp.fr
Belgian Society of Cardiology, Peter R. Sinnaeve; Bosnia & Herzegov- Christian Mueller, Department of Cardiology, University Hospital
ina: Association of Cardiologists of Bosnia & Herzegovina, Ibrahim Basel, Petersgraben 4, CH-4031 Basel, Switzerland, Tel: +41 61 265
Terzić; Bulgaria: Bulgarian Society of Cardiology, Arman Postadzhiyan; 25 25, Fax: +41 61 265 53 53, Email: christian.mueller@usb.ch
Croatia: Croatian Cardiac Society, Davor Miličić; Cyprus: Cyprus So- Marco Valgimigli: Thoraxcenter, Erasmus MC, s Gravendijkwal 230,
ciety of Cardiology, Christos Eftychiou; Czech Republic: Czech Soci- 3015 CE Rotterdam, The Netherlands, Tel: +31 10 7033938,
ety of Cardiology, Petr Widimsky; Denmark: Danish Society of Fax: +31 10 7035258, Email: m.valgimigli@erasmusmc.nl

The CME text ‘2015 ESC Guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation’ is accredited by the European
Board for Accreditation in Cardiology (EBAC). EBAC works according to the quality standards of the European Accreditation Council for Continuing Medical Education (EACCME),
which is an institution of the European Union of Medical Specialists (UEMS). In compliance with EBAC/EACCME Guidelines, all authors participating in this programme have disclosed
any potential conflicts of interest that might cause a bias in the article. The Organizing Committee is responsible for ensuring that all potential conflicts of interest relevant to the
programme are declared to the participants prior to the CME activities.
CME questions for this article are available at: European Heart Journal http://www.oxforde-learning.com/eurheartj and European Society of Cardiology http://www.escardio.org/
guidelines.

Atar D, Newby LK, Galvani M, Hamm CW, Uretsky BF, Steg PG, Wijns W,
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2. Thygesen K, Alpert JS, Jaffe AS, Simoons ML, Chaitman BR, White HD, Katus HA, Simoons ML, Akkerhuis M, Ohman EM, Kitt MM, Vahanian A, Ruzyllo W,
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European Heart Journal (2018) 39, 119–177 ESC GUIDELINES
doi:10.1093/eurheartj/ehx393

2017 ESC Guidelines for the management of


acute myocardial infarction in patients
presenting with ST-segment elevation

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The Task Force for the management of acute myocardial infarction
in patients presenting with ST-segment elevation of the European
Society of Cardiology (ESC)

Authors/Task Force Members: Borja Ibanez* (Chairperson) (Spain), Stefan James*


(Chairperson) (Sweden), Stefan Agewall (Norway), Manuel J. Antunes (Portugal),
Chiara Bucciarelli-Ducci (UK), Héctor Bueno (Spain), Alida L. P. Caforio (Italy),
Filippo Crea (Italy), John A. Goudevenos (Greece), Sigrun Halvorsen (Norway),
Gerhard Hindricks (Germany), Adnan Kastrati (Germany), Mattie J. Lenzen
(The Netherlands), Eva Prescott (Denmark), Marco Roffi (Switzerland),
Marco Valgimigli (Switzerland), Christoph Varenhorst (Sweden), Pascal Vranckx
(Belgium), Petr Widimsk y (Czech Republic)

Document Reviewers: Jean-Philippe Collet (CPG Review Coordinator) (France),


Steen Dalby Kristensen (CPG Review Coordinator) (Denmark), Victor Aboyans (France),

* Corresponding authors. The two chairmen contributed equally to the document: Borja Ibanez, Director Clinical Research, Centro Nacional de Investigaciones
Cardiovasculares Carlos III (CNIC), Melchor Fernandez Almagro 3, 28029 Madrid, Spain; Department of Cardiology, IIS-Fundacion Jiménez Dıaz University Hospital, Madrid,
Spain; and CIBERCV, Spain. Tel: þ34 91 453.12.00 (ext: 4302), Fax: þ34 91 453.12.45, E-mail: bibanez@cnic.es or bibanez@fjd.es. Stefan James, Professor of Cardiology,
Department of Medical Sciences, Scientific Director UCR, Uppsala University and Sr. Interventional Cardiologist, Department of Cardiology Uppsala University Hospital UCR
Uppsala Clinical Research Center Dag Hammarskjölds v€ag 14B SE-752 37 Uppsala, Sweden. Tel: þ46 705 944 404, Email: stefan.james@ucr.uu.se
ESC Committee for Practice Guidelines (CPG) and National Cardiac Societies document reviewers: listed in the Appendix.
ESC entities having participated in the development of this document:
Associations: Acute Cardiovascular Care Association (ACCA), European Association of Preventive Cardiology (EAPC), European Association of Cardiovascular Imaging
(EACVI), European Association of Percutaneous Cardiovascular Interventions (EAPCI), European Heart Rhythm Association (EHRA), Heart Failure Association (HFA).
Councils: Council on Cardiovascular Nursing and Allied Professions (CCNAP), Council for Cardiology Practice (CCP).
Working Groups: Cardiovascular Pharmacotherapy, Cardiovascular Surgery, Coronary Pathophysiology and Microcirculation, Myocardial and Pericardial Diseases, Thrombosis.
The content of these European Society of Cardiology (ESC) Guidelines has been published for personal and educational use only. No commercial use is authorized. No part of
the ESC Guidelines may be translated or reproduced in any form without written permission from the ESC. Permission can be obtained upon submission of a written request to
Oxford University Press, the publisher of the European Heart Journal and the party authorized to handle such permissions on behalf of the ESC
(journals.permissions@oxfordjournals.org).
Disclaimer. The ESC Guidelines represent the views of the ESC and were produced after careful consideration of the scientific and medical knowledge and the evidence avail-
able at the time of their publication. The ESC is not responsible in the event of any contradiction, discrepancy and/or ambiguity between the ESC Guidelines and any other offi-
cial recommendations or guidelines issued by the relevant public health authorities, in particular in relation to good use of healthcare or therapeutic strategies. Health
professionals are encouraged to take the ESC Guidelines fully into account when exercising their clinical judgment, as well as in the determination and the implementation of pre-
ventive, diagnostic or therapeutic medical strategies; however, the ESC Guidelines do not override, in any way whatsoever, the individual responsibility of health professionals to
make appropriate and accurate decisions in consideration of each patient’s health condition and in consultation with that patient and, where appropriate and/or necessary, the
patient’s caregiver. Nor do the ESC Guidelines exempt health professionals from taking into full and careful consideration the relevant official updated recommendations or
guidelines issued by the competent public health authorities, in order to manage each patient’s case in light of the scientifically accepted data pursuant to their respective ethical
and professional obligations. It is also the health professional’s responsibility to verify the applicable rules and regulations relating to drugs and medical devices at the time of
prescription.

C The European Society of Cardiology 2017. All rights reserved. For permissions please email: journals.permissions@oxfordjournals.org.
V
120 ESC Guidelines

Andreas Baumbach (UK), Raffaele Bugiardini (Italy), Ioan Mircea Coman (Romania), Victoria Delgado
(The Netherlands), Donna Fitzsimons (UK), Oliver Gaemperli (Switzerland), Anthony H. Gershlick (UK),
Stephan Gielen (Germany), Veli-Pekka Harjola (Finland), Hugo A. Katus (Germany), Juhani Knuuti
(Finland), Philippe Kolh (Belgium), Christophe Leclercq (France), Gregory Y. H. Lip (UK), Joao Morais
(Portugal), Aleksandar N. Neskovic (Serbia), Franz-Josef Neumann (Germany), Alexander Niessner
(Austria), Massimo Francesco Piepoli (Italy), Dimitrios J. Richter (France), Evgeny Shlyakhto (Russian
Federation), Iain A. Simpson (UK), Ph. Gabriel Steg (France), Christian Juhl Terkelsen (Denmark),
Kristian Thygesen (Denmark), Stephan Windecker (Switzerland), Jose Luis Zamorano (Spain),
Uwe Zeymer (Germany).

The disclosure forms of all experts involved in the development of these guidelines are available on the
ESC website www.escardio.org/guidelines

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Web addenda

Online publish-ahead-of-print 26 August 2017

...................................................................................................................................................................................................
Keywords Guidelines • Acute coronary syndromes • Acute myocardial infarction • Antithrombotic therapy •
Antithrombotics • Emergency medical system • Evidence • Fibrinolysis • Ischaemic heart disease • Primary
percutaneous coronary intervention • Quality indicators • MINOCA • Reperfusion therapy • Risk
assessment • Secondary prevention • ST-segment elevation.

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Table of Contents ..
..
5.4 Coronary artery bypass graft surgery. . . . . . . . . . . . . . . . . . . . . . . . . .142
6. Management during hospitalization and at discharge . . . . . . . . . . . . . . .142
..
Abbreviations and acronyms. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .121 .. 6.1 Coronary care unit/intensive cardiac care unit . . . . . . . . . . . . . . . . .142
1. Preamble . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .123 .. 6.2 Monitoring. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .142
..
2. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .124 .. 6.3 Ambulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .142
2.1 Definition of acute myocardial infarction . . . . . . . . . . . . . . . . . . . . . .124 .. 6.4 Length of stay . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .142
..
2.2 Epidemiology of ST-segment elevation myocardial infarction . . .124 .. 6.5 Special patient subsets. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .143
3. What is new in the 2017 version? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .125 .. 6.5.1 Patients taking oral anticoagulation. . . . . . . . . . . . . . . . . . . . . . . .143
..
4. Emergency care. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .126 .. 6.5.2 Elderly patients . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .143
4.1 Initial diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .126 .. 6.5.3 Renal dysfunction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .144
..
4.2 Relief of pain, breathlessness, and anxiety. . . . . . . . . . . . . . . . . . . . . .127 .. 6.5.4 Non-reperfused patients . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .144
4.3 Cardiac arrest. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .128 .. 6.5.5 Patients with diabetes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .146
..
4.4 Pre-hospital logistics of care . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .128 .. 6.6. Risk assessment. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .146
4.4.1 Delays. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .128
.. 6.6.1 Clinical risk assessment. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .146
..
4.4.2 Emergency medical system . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .130 .. 6.6.2 Non-invasive imaging in management and risk
4.4.3 Organization of ST-segment elevation myocardial
.. stratification . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .146
..
infarction treatment in networks . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .130 .. 7. Long-term therapies for ST-segment elevation myocardial
5. Reperfusion therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .131
.. infarction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .148
..
5.1 Selection of reperfusion strategies . . . . . . . . . . . . . . . . . . . . . . . . . . . .131 .. 7.1 Lifestyle interventions and risk factor control . . . . . . . . . . . . . . . . . .148
5.2 Primary percutaneous coronary intervention and
.. 7.1.1 Smoking cessation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .148
..
adjunctive therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .134 .. 7.1.2 Diet, alcohol, and weight control. . . . . . . . . . . . . . . . . . . . . . . . . .148
..
5.2.1 Procedural aspects of primary percutaneous .. 7.1.3 Exercise-based cardiac rehabilitation . . . . . . . . . . . . . . . . . . . . . .148
coronary intervention . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .134 .. 7.1.4 Resumption of activities . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .148
..
5.2.2 Periprocedural pharmacotherapy . . . . . . . . . . . . . . . . . . . . . . . . .136 .. 7.1.5 Blood pressure control. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .148
5.3 Fibrinolysis and pharmacoinvasive strategy . . . . . . . . . . . . . . . . . . . .138 .. 7.1.6 Adherence to treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .148
..
5.3.1 Benefit and indication of fibrinolysis . . . . . . . . . . . . . . . . . . . . . . .138 .. 7.2 Antithrombotic therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .149
5.3.2 Pre-hospital fibrinolysis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .139 .. 7.2.1 Aspirin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .149
..
5.3.3 Angiography and percutaneous coronary intervention .. 7.2.2 Duration of dual antiplatelet therapy and antithrombotic
after fibrinolysis (pharmacoinvasive strategy) . . . . . . . . . . . . . . . . . . .140 .. combination therapies. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .149
..
5.3.4 Comparison of fibrinolytic agents . . . . . . . . . . . . . . . . . . . . . . . . .141 .. 7.3 Beta-blockers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .150
5.3.5 Adjunctive antiplatelet and anticoagulant therapies . . . . . . . .141 .. 7.3.1 Early intravenous beta-blocker administration . . . . . . . . . . . . .150
..
5.3.6 Hazards of fibrinolysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .141 .. 7.3.2 Mid- and long-term beta-blocker treatment . . . . . . . . . . . . . . .151
5.3.7 Contraindications to fibrinolytic therapy . . . . . . . . . . . . . . . . . .141 .. 7.4 Lipid-lowering therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .151
ESC Guidelines 121

7.5 Nitrates . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .152 .. ATLAS ACS Anti-Xa Therapy to Lower cardiovascular


..
7.6 Calcium antagonists . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .152 .. 2–TIMI 51 events in Addition to Standard therapy
7.7 Angiotensin-converting enzyme inhibitors and angiotensin II .. in subjects with Acute Coronary
..
receptor blockers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .152 .. Syndrome–Thrombolysis In Myocardial
7.8 Mineralocorticoid/aldosterone receptor antagonists . . . . . . . . . . .152 ..
.. Infarction 51
8. Complications following ST-segment elevation myocardial .. ATOLL Acute myocardial infarction Treated with
infarction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .153 ..
.. primary angioplasty and inTravenous
8.1 Myocardial dysfunction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .156 .. enOxaparin or unfractionated heparin to
8.1.1 Left ventricular dysfunction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .156 ..
.. Lower ischaemic and bleeding events at short-
8.1.2 Right ventricular involvement. . . . . . . . . . . . . . . . . . . . . . . . . . . . .156 .. and Long-term follow-up
8.2 Heart failure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .156 ..
.. AV atrioventricular
8.2.1 Clinical presentations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .156 ..

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b.i.d. bis in die (twice a day)
8.2.2 Management. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .156
..
.. BMI body mass index
8.3 Management of arrhythmias and conduction disturbances .. BMS bare-metal stent
in the acute phase. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .158
..
.. BNP B-type natriuretic peptide
8.3.1 Supraventricular arrhythmias . . . . . . . . . . . . . . . . . . . . . . . . . . . . .158 .. CABG coronary artery bypass graft surgery
8.3.2 Ventricular arrhythmias . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .159
..
.. CAD coronary artery disease
8.3.3 Sinus bradycardia and atrioventricular block . . . . . . . . . . . . . . .160 .. CAPITAL AMI Combined Angioplasty and Pharmacological
8.4 Mechanical complications. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .161
..
.. Intervention versus Thrombolytics ALone in
8.4.1 Free wall rupture . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .161 .. Acute Myocardial Infarction
..
8.4.2 Ventricular septal rupture . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .161 .. CCNAP Council on Cardiovascular Nursing and Allied
8.4.3 Papillary muscle rupture. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .161 .. Professions
..
8.5 Pericarditis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .161 .. CCP Council for Cardiology Practice;
8.5.1 Early and late (Dressler syndrome) infarct-associated .. CCU coronary care unit
..
pericarditis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .161 .. CHA2DS2-VASc Cardiac failure, Hypertension, Age 75
8.5.2 Pericardial effusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .161 .. (Doubled), Diabetes, Stroke (Doubled) –
..
9. Myocardial infarction with non-obstructive coronary arteries . . . . . .161 .. VAScular disease, Age 65–74 and Sex category
10. Assessment of quality of care. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .161 ..
.. (Female)
11. Gaps in the evidence and areas for future research . . . . . . . . . . . . . . .163 .. CI confidence interval
12. Key messages. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .165 ..
.. CKD chronic kidney disease
13. Evidenced-based ‘to do and not to do’ messages .. CMR cardiac magnetic resonance
from the Guidelines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .166 ..
.. CPG Committee for Practice Guidelines
14. Web addenda . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .168 .. CRISP AMI Counterpulsation to Reduce Infarct Size Pre-
15. Appendix . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .168 ..
.. PCI-Acute Myocardial Infarction
16. References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .169 .. CT computed tomography
..
.. COMFORTABLE- Effect of biolimus-eluting stents with
.. AMI biodegradable polymer vs. bare-metal
..
.. stents on cardiovascular events among
..
Abbreviations and acronyms .. patients with acute myocardial infarction
.. trial;
ACE angiotensin-converting enzyme .. Compare-Acute Comparison Between FFR Guided
..
ACCA Acute Cardiovascular Care Association ... Revascularization Versus Conventional
ACS acute coronary syndrome .. Strategy in Acute STEMI Patients With
AF atrial fibrillation .. Multivessel disease trial
..
ALBATROSS Aldosterone Lethal effects Blockade in Acute .. CURRENT- The Clopidogrel and aspirin Optimal Dose
myocardial infarction Treated with or without .. OASIS 7 usage to reduce recurrent events–Seventh
..
Reperfusion to improve Outcome and Survival .. organization to assess strategies in ischaemic
at Six months follow-up .. syndromes
..
AMI acute myocardial infarction .. CvLPRIT Complete Versus Lesion-Only Primary PCI
ARB angiotensin II receptor blocker
..
.. Trial
ASSENT 3 ASsessment of the Safety and Efficacy of a New .. DANAMI DANish Study of Optimal Acute Treatment of
Thrombolytic 3
..
.. Patients with ST-segment Elevation Myocardial
ATLANTIC Administration of Ticagrelor in the Cath Lab or .. Infarction
in the Ambulance for New ST Elevation
..
.. DANAMI 3- DANAMI 3 – Deferred versus conventional
Myocardial Infarction to Open the Coronary .. DEFER stent implantation in patients with ST-segment
Artery
..
. elevation myocardial infarction
122 ESC Guidelines

DANAMI-3– DANAMI 3 – Complete revascularisation ... LV left ventricle/ventricular


PRIMULTI versus treatment of the culprit lesion only in
.. LVAD Left ventricular assist device
..
patients with ST-segment elevation myocardial .. LVEF left ventricular ejection fraction
infarction and multivessel disease
.. MACE major adverse cardiac event
..
DAPT dual antiplatelet therapy .. MATRIX Minimizing Adverse Haemorrhagic Events by
DES drug-eluting stent
.. TRansradial Access Site and Systemic
..
EACVI European Association of Cardiovascular .. Implementation of angioX
..
Imaging .. METOCARD- Effect of Metoprolol in Cardioprotection
EAPC European Association of Preventive Cardiology .. CNIC During an Acute Myocardial Infarction
..
EAPCI European Association of Percutaneous .. MI myocardial infarction
Cardiovascular Interventions .. MINOCA myocardial infarction with non-obstructive
..
..

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EARLY-BAMI Early Intravenous Beta-Blockers in Patients coronary arteries
With ST-Segment Elevation Myocardial .. MRA mineralocorticoid receptor antagonist
..
Infarction Before Primary Percutaneous .. MVO microvascular obstruction
Coronary Intervention .. NORSTENT Norwegian Coronary Stent
..
ECG electrocardiogram .. NSTEMI non-ST-segment elevation myocardial
ECLS extracorporeal life support .. infarction
..
ECMO extracorporeal membrane oxygenation .. NT-proBNP N-terminal pro B-type natriuretic peptide
eGFR estimated glomerular filtration rate .. OASIS-6 Organization for the Assessment of Strategies
..
EHRA European Heart Rhythm Association .. for Ischemic Syndromes
EMS emergency medical system .. o.d. omni die (once a day)
..
EPHESUS Eplerenone Post-AMI Heart failure Efficacy and .. PAMI-II Second Primary Angioplasty in Myocardial
SUrvival Study ... Infarction
ESC European Society of Cardiology
.. PaO2 partial pressure of oxygen
..
EXAMINATION Everolimus-Eluting Stents Versus Bare-Metal .. PCI percutaneous coronary intervention
Stents in ST-Segment Elevation Myocardial
.. PCSK9 proprotein convertase subtilisin/kexin type 9
..
Infarction .. PEGASUS- Prevention of Cardiovascular Events in Patients
ExTRACT– Enoxaparin and Thrombolysis Reperfusion for
.. TIMI 54 with Prior Heart Attack Using Ticagrelor
..
TIMI 25 Acute myocardial infarction .. Compared to Placebo on a Background of
..
Treatment–Thrombolysis In Myocardial .. Aspirin–Thrombolysis in Myocardial Infarction 54
Infarction .. PET positron emission tomography
..
FFR fractional flow reserve .. PIONEER Open-Label, Randomized, Controlled,
FMC first medical contact .. AF-PCI Multicenter Study Exploring Two Treatment
..
FOCUS Fixed-Dose Combination Drug for Secondary .. Strategies of Rivaroxaban and a Dose-Adjusted
Cardiovascular Prevention .. Oral Vitamin K Antagonist Treatment Strategy
..
FOURIER Further Cardiovascular Outcomes Research .. in Subjects with Atrial Fibrillation who
with PCSK9 Inhibition in Subjects with Elevated .. Undergo Percutaneous Coronary Intervention
..
Risk trial. .. p.o. per os (orally)
GP glycoprotein .. PPI proton pump inhibitor
..
GRACE Global Registry of Acute Coronary Events .. PRAMI Preventive Angioplasty in Acute Myocardial
GRACIA Grupo de Analisis de la Cardiopatıa Isquémica .. Infarction
..
Aguda .. PRODIGY PROlonging Dual Antiplatelet Treatment After
HDL-C high-density lipoprotein cholesterol .. Grading stent-induced Intimal hyperplasia
..
HFA Heart Failure Association .. studY
HR hazard ratio
.. RBBB right bundle branch block
..
IABP intra-aortic balloon pump .. REMINDER A Double-Blind, Randomized, Placebo-
ICCU intensive cardiac care unit
.. Controlled Trial Evaluating The Safety And
..
ICD implantable cardioverter defibrillator .. Efficacy Of Early Treatment With Eplerenone
IMPROVE-IT Improved Reduction of Outcomes: Vytorin
.. In Patients With Acute Myocardial Infarction
..
Efficacy International Trial .. RIFLE- Radial Versus Femoral Randomized
IRA infarct-related artery
.. STEACS Investigation in ST-Elevation Acute Coronary
..
IU international units .. Syndrome
..
i.v. intravenous .. RIVAL Radial Versus Femoral Access for Coronary
LBBB left bundle branch block .. intervention
..
LDL-C low-density lipoprotein cholesterol .. RV right ventricle/ventricular
LGE late gadolinium enhancement .. SaO2 arterial oxygen saturation
..
ESC Guidelines 123

..
SBP systolic blood pressure .. established in order to make all decisions transparent to the user.
s.c. subcutaneous
.. The recommendations for formulating and issuing ESC Guidelines
..
SGLT2 sodium-glucose co-transporter-2 .. can be found on the ESC website (https://www.escardio.org/
SPECT single-photon emission computed tomography
.. Guidelines/Clinical-Practice-Guidelines/Guidelines-development/
..
STEMI ST-segment elevation myocardial infarction .. Writing-ESC-Guidelines). ESC Guidelines represent the official posi-
STREAM STrategic Reperfusion Early After Myocardial
.. tion of the ESC on a given topic and are regularly updated.
..
infarction .. Members of this Task Force were selected by the ESC, including
TIMI Thrombolysis In Myocardial Infarction
.. representation from its relevant ESC sub-specialty groups, in order
..
TNK-tPA Tenecteplase tissue plasminogen activator .. to represent professionals involved with the medical care of patients
.. with this pathology. Selected experts in the field undertook a com-
TOTAL Trial of Routine Aspiration Thrombectomy ..
with PCI versus PCI Alone in Patients with .. prehensive review of the published evidence for management of a
.. given condition according to ESC Committee for Practice Guidelines

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STEMI ..
tPA tissue plasminogen activator .. (CPG) policy. A critical evaluation of diagnostic and therapeutic pro-
.. cedures was performed, including assessment of the risk–benefit
UFH unfractionated heparin ..
VALIANT VALsartan In Acute myocardial iNfarcTion .. ratio. The level of evidence and the strength of the recommendation
.. of particular management options were weighed and graded accord-
VF ventricular fibrillation ..
VT ventricular tachycardia .. ing to predefined scales, as outlined in Tables 1 and 2.
.. The experts of the writing and reviewing panels provided declara-
24/7 24 h a day, seven days a week ..
.. tion of interest forms for all relationships that might be perceived as
.. real or potential sources of conflicts of interest. These forms were
..
.. compiled into one file and can be found on the ESC website (http://
1. Preamble .. www.escardio.org/guidelines). Any changes in declarations of interest
..
Guidelines summarize and evaluate available evidence with the aim of .. that arise during the writing period were notified to the ESC and
..
assisting health professionals in selecting the best management strat- .. updated. The Task Force received its entire financial support from
egies for an individual patient with a given condition. Guidelines and .. the ESC without any involvement from the healthcare industry.
..
their recommendations should facilitate decision making of health .. The ESC CPG supervises and coordinates the preparation of new
professionals in their daily practice. However, the final decisions con- .. ESC Guidelines. The Committee is also responsible for the endorse-
..
cerning an individual patient must be made by the responsible health .. ment process of these Guidelines. The ESC Guidelines undergo
professional(s) in consultation with the patient and caregiver as .. extensive review by the CPG and external experts. After appropriate
..
appropriate. .. revisions the Guidelines are approved by all the experts involved in
A great number of guidelines have been issued in recent years by .. the Task Force. The finalized document is approved by the CPG for
..
the European Society of Cardiology (ESC), as well as by other soci- .. publication in the European Heart Journal. The Guidelines were
eties and organisations. Because of the impact on clinical practice,
.. developed after careful consideration of the scientific and medical
..
quality criteria for the development of guidelines have been . knowledge and the evidence available at the time of their dating.

Table 1 Classes of recommendations


124 ESC Guidelines

..
Table 2 Levels of evidence
.. strategy. The levels of evidence and the strengths of recommenda-
.. tion of particular treatment options were weighed and graded
..
.. according to pre-defined scales, as outlined in Tables 1 and 2. Despite
.. recommendations with a level of evidence being based on expert
..
.. opinion, this Task Force decided to add references to guide the
.. reader regarding data that were taken into consideration for these
..
.. decisions in some cases.
..
..
.. 2.1 Definition of acute myocardial
..
.. infarction
..
.. The term acute myocardial infarction (AMI) should be used when
..

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there is evidence of myocardial injury (defined as an elevation of car-
..
.. diac troponin values with at least one value above the 99th percentile
.. upper reference limit) with necrosis in a clinical setting consistent
..
The task of developing ESC Guidelines also includes the creation .. with myocardial ischaemia.8 For the sake of immediate treatment
of educational tools and implementation programmes for the recom- .. strategies such as reperfusion therapy, it is usual practice to designate
..
mendations including condensed pocket guideline versions, summary .. patients with persistent chest discomfort or other symptoms sugges-
slides, booklets with essential messages, summary cards for non- .. tive of ischaemia and ST-segment elevation in at least two contiguous
..
specialists and an electronic version for digital applications (smart- .. leads as STEMI. In contrast, patients without ST-segment elevation at
phones, etc.). These versions are abridged and thus, if needed, one .. presentation are usually designated as having a non-ST-segment ele-
..
should always refer to the full text version, which is freely available .. vation myocardial infarction (MI) (NSTEMI) and separate guidelines
via the ESC website and hosted on the EHJ website. The National .. have recently been developed for these.2 Some patients with MI
..
Societies of the ESC are encouraged to endorse, translate and imple- .. develop Q-waves (Q-wave MI), but many do not (non-Q-wave MI).
ment all ESC Guidelines. Implementation programmes are needed .. In addition to these categories, MI is classified into various types,
..
because it has been shown that the outcome of disease may be .. based on pathological, clinical, and prognostic differences, along with
favourably influenced by the thorough application of clinical
.. different treatment strategies (see the Third Universal Definition of
..
recommendations. .. MI document,8 which will be updated in 2018). Despite the fact that
Surveys and registries are needed to verify that real-life daily prac-
.. the majority of STEMI patients are classified as a type 1 MI (with evi-
..
tice is in keeping with what is recommended in the guidelines, thus .. dence of a coronary thrombus), some STEMIs fall into other MI
completing the loop between clinical research, writing of guidelines,
.. types.8 MI, even presenting as STEMI, also occurs in the absence of
..
disseminating them and implementing them into clinical practice. .. obstructive coronary artery disease (CAD) on angiography.9–12 This
Health professionals are encouraged to take the ESC Guidelines
..
.. type of MI is termed ‘myocardial infarction with non-obstructive cor-
fully into account when exercising their clinical judgment, as well as in .. onary arteries’ (MINOCA) and is discussed in Chapter 9 of this
..
the determination and the implementation of preventive, diagnostic .. document.
or therapeutic medical strategies. However, the ESC Guidelines do ..
..
not override in any way whatsoever the individual responsibility of .. 2.2 Epidemiology of ST-segment
health professionals to make appropriate and accurate decisions in ..
.. elevation myocardial infarction
consideration of each patient’s health condition and in consultation .. Worldwide, ischaemic heart disease is the single most common cause
with that patient or the patient’s caregiver where appropriate and/or ..
.. of death and its frequency is increasing. However, in Europe, there
necessary. It is also the health professional’s responsibility to verify ..
.. has been an overall trend for a reduction in ischaemic heart disease
the rules and regulations applicable to drugs and devices at the time .. mortality over the past three decades.13 Ischaemic heart disease now
of prescription. ..
.. accounts for almost 1.8 million annual deaths, or 20% of all deaths in
.. Europe, although with large variations between countries.14
..
2. Introduction .. The relative incidences of STEMI and NSTEMI are decreasing and
.. increasing, respectively.15,16 Probably the most comprehensive
..
Updates on the management of patients presenting with ST-segment .. European STEMI registry is found in Sweden, where the incidence
elevation myocardial infarction (STEMI) should be based on sound .. rate of STEMI was 58 per 100 000 per year in 2015.17 In other
..
evidence, derived from well-conducted clinical trials whenever possi- .. European countries, the incidence rate ranged from 43 to 144 per
ble, or motivated expert opinion when needed. It must be recognized .. 100 000 per year.18 Similarly, the reported adjusted incidence rates
..
that, even when excellent clinical trials have been undertaken, the .. from the USA decreased from 133 per 100 000 in 1999 to 50 per
results are open to interpretation and treatments may need to be .. 100 000 in 2008, whereas the incidence of NSTEMI remained con-
..
adapted to take account of clinical circumstances and resources. .. stant or increased slightly.19 There is a consistent pattern for STEMI
The present Task Force has made an important effort to be as .. to be relatively more common in younger than in older people, and
..
aligned as possible with the other ESC Guidelines1–6 and consensus .. more common in men than in women.17,20
documents, including the simultaneously published update on dual
.. The mortality in STEMI patients is influenced by many factors,
..
antiplatelet therapy (DAPT),7 for consistency in the ESC Guidelines . among them advanced age, Killip class, time delay to treatment,
ESC Guidelines 125

..
presence of emergency medical system (EMS)-based STEMI net- .. toms, up to 30% in some registries,27 and tend to present later than
works, treatment strategy, history of MI, diabetes mellitus, renal fail- .. men.28,29 It is therefore important to maintain a high degree of aware-
..
ure, number of diseased coronary arteries, and left ventricular .. ness for MI in women with potential symptoms of ischaemia. Women
ejection fraction (LVEF). Several recent studies have highlighted a fall
.. also have a higher risk of bleeding complications with PCI. There is an
..
in acute and long-term mortality following STEMI in parallel with .. ongoing debate regarding whether outcomes are poorer in women,
greater use of reperfusion therapy, primary percutaneous coronary
.. with several studies indicating that a poorer outcome is related to
..
intervention (PCI), modern antithrombotic therapy, and secondary .. older age and more comorbidities among women suffering MI.26,30,31
prevention.14,21,22 Nevertheless, mortality remains substantial; the in-
.. Some studies have indicated that women tend to undergo fewer inter-
..
hospital mortality of unselected patients with STEMI in the national .. ventions than men and receive reperfusion therapy less fre-
registries of the ESC countries varies between 4 and 12%,23 while
.. quently.26,32,33 These guidelines aim to highlight the fact that women
..
reported 1-year mortality among STEMI patients in angiography .. and men receive equal benefit from a reperfusion strategy and STEMI-
..
registries is approximately 10%.24,25 .. related therapy, and that both genders must be managed in a similar

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Although ischaemic heart disease develops on average 7–10 years .. fashion.
..
later in women compared with men, MI remains a leading cause of ..
death in women. Acute coronary syndrome (ACS) occurs three to ..
..
four times more often in men than in women below the age of .. 3. What is new in the 2017
60 years, but after the age of 75, women represent the majority of ..
.. version?
patients.26 Women tend to present more often with atypical symp- ..
..
.

patients

stenting

Figure 1 What is new in 2017 STEMI Guidelines. BMS = bare metal stent; DES = drug eluting stent; IRA = infarct related artery; i.v. = intravenous;
LDL = low-density lipoprotein; PCI = percutaneous coronary intervention; SaO2 = arterial oxygen saturation; STEMI = ST-elevation myocardial
infarction; TNK-tPA = Tenecteplase tissue plasminogen activator. For explanation of trial names, see list of.
a
Only for experienced radial operators.
b
Before hospital discharge (either immediate or staged).
c
Routine thrombus aspiration (bailout in certain cases may be considered).
d
In 2012 early discharge was considered after 72h, in 2017 early discharge is 48–72h.
e
If symptoms or haemodynamic instability IRA should be opened regardless time from symptoms onset.
In left and mid panels, below each recommendation, the most representative trial (acronym and reference) driving the indication is
mentioned.
126 ESC Guidelines

..
4. Emergency care ..
..
The presence of a Q-wave on the ECG should not necessarily change
the reperfusion strategy decision.
..
4.1 Initial diagnosis ..
Management—including diagnosis and treatment—of STEMI starts .. Recommendations for initial diagnosis
..
from the point of first medical contact (FMC, defined in Table 4). It is ..
recommended that a regional reperfusion strategy should be estab- .. Recommendations Classa Levelb
lished to maximize efficiency. ...
.. ECG monitoring
A working diagnosis of STEMI (called the ‘STEMI diagnosis’ ..
throughout this document) must first be made. This is usually based .. 12-lead ECG recording and interpretation is
..
on symptoms consistent with myocardial ischaemia (i.e. persistent .. indicated as soon as possible at the point of
chest pain) and signs [i.e. 12-lead electrocardiogram (ECG)].
.. FMC, with a maximum target delay of
I B
..
Important clues are a history of CAD and radiation of pain to the .. 10 min.36,38

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neck, lower jaw, or left arm. Some patients present with less-typical
..
.. ECG monitoring with defibrillator capacity
symptoms such as shortness of breath, nausea/vomiting, fatigue, pal- ..
pitations, or syncope.34 A reduction in chest pain after nitroglycerin
.. is indicated as soon as possible in all patients I B
.. with suspected STEMI.44,45
(glyceryl trinitrate) administration can be misleading and is not rec- ..
ommended as a diagnostic manoeuvre.35 In cases of symptom relief
..
.. The use of additional posterior chest wall
after nitroglycerin administration, another 12-lead ECG must be .. leads (V7 –V9) in patients with high suspicion
.. IIa B
obtained. A complete normalization of the ST-segment elevation .. of posterior MI (circumflex occlusion)
after nitroglycerin administration, along with complete relief of symp- .. should be considered.8,46–49
..
toms, is suggestive of coronary spasm, with or without associated MI. ..
In these cases, an early coronary angiography (within 24 h) is recom- .. The use of additional right precordial leads
.. (V3R and V4R) in patients with inferior MI
mended. In cases of recurrent episodes of ST-segment elevation or .. IIa B
chest pain, immediate angiography is required. .. should be considered to identify concomi-
.. tant RV infarction.8,43
It is recommended to initiate ECG monitoring as soon as possible ..
in all patients with suspected STEMI in order to detect life- .. Blood sampling
..
threatening arrhythmias and allow prompt defibrillation if indicated. ..
When a STEMI is suspected, a 12-lead ECG must be acquired and .. Routine blood sampling for serum markers

interpreted as soon as possible at the time of FMC to facilitate early ... is indicated as soon as possible in the acute
.. phase but should not delay reperfusion
I C
STEMI diagnosis and triage.36–40 ..
In patients with a clinical suspicion of myocardial ischaemia and ST- .. treatment.8
..
segment elevation, reperfusion therapy needs to be initiated as soon ..
as possible.41 If the ECG is equivocal or does not show evidence to
.. ECG = electrocardiogram; FMC = first medical contact; MI = myocardial infarc-
.. tion; RV = right ventricle; STEMI = ST-segment elevation myocardial infarction.
support the clinical suspicion of MI, ECGs should be repeated and, .. a
Class of recommendation.
when possible compared with previous recordings. If interpretation
.. b
.. Level of evidence.
of pre-hospital ECG is not possible on-site, field transmission of the ..
ECG is recommended.42
..
..
ECG criteria are based on changes of electrical currents of the .. The ECG diagnosis may be more difficult in some cases, which
heart (measured in millivolts). Standard calibration of the ECG is
..
.. nevertheless deserve prompt management and triage. Among these:
10mm/mV. Therefore 0.1 mV equals to 1 mm square on the vertical .. Bundle branch block. In the presence of LBBB, the ECG diagno-
..
axis. For simplicity, in this document ECG deviations are expressed in .. sis of AMI is difficult but often possible if marked ST-segment abnor-
mm following the standard calibration. .. malities are present. Somewhat complex algorithms have been offered
..
In the proper clinical context, ST-segment elevation (measured at .. to assist the diagnosis,50,51 but they do not provide diagnostic cer-
the J-point) is considered suggestive of ongoing coronary artery acute .. tainty.52 The presence of concordant ST-segment elevation (i.e. in
..
occlusion in the following cases: at least two contiguous leads with .. leads with positive QRS deflections) appears to be one of the best indi-
ST-segment elevation  2.5 mm in men < 40 years, 2 mm in men .. cators of ongoing MI with an occluded infarct artery.53 Patients with a
..
 40 years, or  1.5 mm in women in leads V2 –V3 and/or  1 mm in .. clinical suspicion of ongoing myocardial ischaemia and LBBB should be
the other leads [in the absence of left ventricular (LV) hypertrophy .. managed in a way similar to STEMI patients, regardless of whether the
..
or left bundle branch block LBBB)].8 In patients with inferior MI, it is .. LBBB is previously known. It is important to remark that the presence
recommended to record right precordial leads (V3R and V4R) seek- .. of a (presumed) new LBBB does not predict an MI per se.54
..
ing ST-segment elevation, to identify concomitant right ventricular .. Patients with MI and right bundle branch block (RBBB) have a
(RV) infarction.8,43 Likewise, ST-segment depression in leads V1 –V3 .. poor prognosis.55 It may be difficult to detect transmural ischaemia in
..
suggests myocardial ischaemia, especially when the terminal T-wave .. patients with chest pain and RBBB.55 Therefore, a primary PCI strat-
is positive (ST-segment elevation equivalent), and confirmation by
.. egy (emergent coronary angiography and PCI if indicated) should be
..
concomitant ST-segment elevation  0.5 mm recorded in leads .. considered when persistent ischaemic symptoms occur in the pres-
V7 –V9 should be considered as a means to identify posterior MI.8
.. ence of RBBB.
ESC Guidelines 127

..
Ventricular pacing. Pacemaker rhythm may also prevent .. (1 mm in men, 40 years old)] is recommended to detect ST-
interpretation of ST-segment changes and may require urgent angiog- .. segment elevation consistent with inferior and basal MI.
..
raphy to confirm diagnosis and initiate therapy. Reprogramming the .. Left main coronary obstruction. The presence of ST depres-
pacemaker—allowing an evaluation of ECG changes during intrinsic .. sion  1 mm in eight or more surface leads (inferolateral ST depres-
..
heart rhythm—may be considered in patients who are not depend- .. sion), coupled with ST-segment elevation in aVR and/or V1, suggests
ent on ventricular pacing, without delaying invasive investigation.56,57
.. multivessel ischemia or left main coronary artery obstruction, partic-
..
Non-diagnostic ECG. Some patients with an acute coronary .. ularly if the patient presents with haemodynamic compromise.60
occlusion may have an initial ECG without ST-segment elevation,
.. Blood sampling for serum markers is routinely carried out in the
..
sometimes because they are seen very early after symptom onset (in .. acute phase. This is indicated, but should not delay the reperfusion
which case, one should look for hyper-acute T-waves, which may pre-
.. strategy/treatment.
..
cede ST-segment elevation). It is important to repeat the ECG or .. If in doubt regarding the possibility of acute evolving MI, emergency
monitor for dynamic ST-segment changes. In addition, there is a con-
.. imaging aids the provision of timely reperfusion therapy to these
..

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cern that some patients with acute occlusion of a coronary artery and .. patients. Recommendations for the use of echocardiography for ini-
..
ongoing MI, such as those with an occluded circumflex coronary .. tial diagnosis are described in section 6.6.2. If echocardiography is not
artery,58,59 acute occlusion of a vein graft, or left main disease, may .. available or if doubts persist after echo, a primary PCI strategy is indi-
..
present without ST-segment elevation and be denied reperfusion ther- .. cated (including immediate transfer to a PCI centre if the patient is
apy, resulting in a larger infarction and worse outcomes. Extending the .. being treated in a non-PCI centre).
..
standard 12-lead ECG with V7–V9 leads may identify some of these .. In the STEMI emergency setting, there is no role for routine com-
patients. In any case, suspicion of ongoing myocardial ischaemia is an .. puted tomography (CT). Use of CT should be confined to selected
..
indication for a primary PCI strategy even in patients without diagnos- .. cases where acute aortic dissection or pulmonary embolism is sus-
tic ST-segment elevation.8,38,46–49 Table 3 lists the atypical ECG pre- .. pected, but CT is not recommended if STEMI diagnosis is likely.
..
sentations that should prompt a primary PCI strategy in patients with .. Some non-AMI conditions can present with symptoms and ECG
ongoing symptoms consistent with myocardial ischaemia. .. findings similar to STEMI. An emergency coronary angiography is
..
Isolated posterior MI. In AMI of the inferior and basal portion .. therefore indicated in these cases (Chapter 9 expands on this topic).
of the heart, often corresponding to the left circumflex territory, iso- ..
..
lated ST-segment depression  0.5 mm in leads V1 –V3 represents .. 4.2 Relief of pain, breathlessness, and
..
the dominant finding. These should be managed as a STEMI. The use .. anxiety
of additional posterior chest wall leads [elevation V7 –V9  0.5 mm .. Relief of pain is of paramount importance, not only for comfort rea-
..
.. sons but because the pain is associated with sympathetic activation,
.. which causes vasoconstriction and increases the workload of the
Table 3 Atypical electrocardiographic presentations ..
that should prompt a primary percutaneous coronary .. heart. Titrated intravenous (i.v.) opioids (e.g. morphine) are the anal-
intervention strategy in patients with ongoing symp- .. gesics most commonly used in this context. However, morphine use
toms consistent with myocardial ischaemia
..
.. is associated with a slower uptake, delayed onset of action, and
.. diminished effects of oral antiplatelet agents (i.e. clopidogrel, ticagre-
..
.. lor, and prasugrel), which may lead to early treatment failure in sus-
.. ceptible individuals.61–63

Relief of hypoxaemia and symptoms

Recommendations Classa Levelb

Hypoxia

Oxygen is indicated in patients with hypo-


I C
xaemia (SaO2 < 90% or PaO2 < 60 mmHg).

Routine oxygen is not recommended in


III B
patients with SaO2  90%.64–66

Symptoms

Titrated i.v. opioids should be considered to


IIa C
relieve pain.

A mild tranquillizer (usually a benzodiaze-


pine) should be considered in very anxious IIa C
patients.

ECG = electrocardiogram; LBBB = left bundle branch block; RBBB = right bundle
branch block; RV = right ventricular; STEMI = ST-segment elevation myocardial i.v. = intravenous; PaO2 = partial pressure of oxygen; SaO2 = arterial oxygen
infarction. saturation.
a
Class of recommendation.
b
Level of evidence.
128 ESC Guidelines

..
Oxygen is indicated in hypoxic patients with arterial oxygen satu- .. catheterization laboratory. Close attention to anticoagulation needs
ration (SaO2) < 90%. There is some evidence suggesting that hyper- .. to be paid in patients reaching low temperatures.84
..
oxia may be harmful in patients with uncomplicated MI, presumably .. Prevention and improved treatment of out-of-hospital cardiac
due to increased myocardial injury.64–67 Thus, routine oxygen is not .. arrest is crucial to reduce the mortality related to CAD. For a more
..
recommended when SaO2 is  90%. . detailed discussion of these issues, refer to the recent European
Anxiety is a natural response to the pain and the circumstances ... Resuscitation Council Guidelines for resuscitation.74
..
surrounding an MI. Reassurance of patients and those closely associ- ..
ated with them is of great importance. ..
.. Cardiac arrest
A mild tranquillizer (usually a benzodiazepine) should be consid- ..
ered in anxious patients. ..
.. Recommendations Classa Levelb
..
4.3 Cardiac arrest .. A primary PCI strategy is recommended in
..

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Many deaths occur very early after STEMI onset due to ventricular .. patients with resuscitated cardiac arrest and I B
fibrillation (VF).68 As this arrhythmia frequently occurs at an early
.. an ECG consistent with STEMI. 69–71,85
..
stage, these deaths usually happen out of hospital. It is indicated that ..
all medical and paramedical personnel caring for patients with sus-
.. Targeted temperature managementc is indi-
.. cated early after resuscitation of cardiac
pected MI have access to defibrillation equipment and are trained in .. I B
.. arrest patients who remain
cardiac life support, and that, at the point of FMC, ECG monitoring ..
.. unresponsive.77,78,80–82
must be implemented immediately for all patients with suspected MI.
..
Patients with chest pain suggestive of MI should be directed .. It is indicated that healthcare systems imple-
through public awareness programmes to contact the EMS and wait .. ment strategies to facilitate transfer of all
..
to be transferred to the hospital by the EMS. .. patients in whom a MI is suspected directly I C
In patients following cardiac arrest and ST-segment elevation on .. to the hospital offering 24/7 PCI-mediated
..
the ECG, primary PCI is the strategy of choice.69–74 .. reperfusion therapy via one specialized EMS.
Given the high prevalence of coronary occlusions and the potential ..
.. It is indicated that all medical and paramedi-
difficulties in interpreting the ECG in patients after cardiac arrest, ..
urgent angiography (within 2 h)2 should be considered in survivors of .. cal personnel caring for patients with sus-
.. pected MI have access to defibrillation I C
cardiac arrest, including unresponsive survivors, when there is a high ..
index of suspicion of ongoing infarction (such as the presence of .. equipment and are trained in basic cardiac
.. life support.
chest pain before arrest, a history of established CAD, and abnormal ..
or uncertain ECG results).73,74 However, in patients without ST- .. Urgent angiography (and PCI if indicated)
..
segment elevation, a quick evaluation at the emergency department .. should be considered in patients with resus-
or intensive cardiac care unit (ICCU) to exclude non-coronary
.. IIa C
.. citated cardiac arrest without diagnostic ST-
causes (cerebrovascular event, respiratory failure, non-cardiogenic .. segment elevation but with a high suspicion
..
shock, pulmonary embolism, and intoxication), and to perform .. of ongoing myocardial ischaemia.69–71,73
urgent echocardiography, is reasonable. The decision to perform ..
urgent coronary angiography and PCI if indicated should also take
.. Pre-hospital cooling using a rapid infusion of
.. large volumes of cold i.v. fluid immediately
into account factors associated with poor neurological outcome. .. III B
Unfavourable pre-hospital settings indicating a remote likelihood for
.. after return of spontaneous circulation is
.. not recommended. 86
neurological recovery [i.e. unwitnessed cardiac arrest, late arrival of a ..
..
pre-hospital team without lay basic life support (>10 min), presence ..
of an initial non-shockable rhythm, or more than 20 min of advanced .. 24/7 = 24 h a day, 7 days a week; ECG = electrocardiogram; EMS = emergency
.. medical system; i.v. = intravenous; MI = myocardial infarction; PCI = percutane-
life support without return to spontaneous circulation]75 should be .. ous coronary intervention; STEMI = ST-segment elevation myocardial infarction.
taken strongly into consideration to argue against an invasive coro- a .. Class of recommendation.
b ..
nary strategy.73 c .. Level of evidence.
.. ters, Targeted temperature management refers to active methods (i.e. cooling cathe-
Unconscious patients admitted to critical care units after out-of-
.. cooling blankets, and application of ice applied around the body) to achieve
hospital cardiac arrest are at high risk for death, and neurologic defi- .. and maintain a constant specific body temperature between 32 and 36  C in a
cits are common among those who survive.76 Targeted temperature .. person for a specific duration of time (most commonly used  24 h).
..
management (also called therapeutic hypothermia), aiming for a con- ..
stant temperature between 32 and 36  C for at least 24 h, is indicated ..
..
in patients who remain unconscious after resuscitation from cardiac ..
arrest (of presumed cardiac cause).73,77–82 However, hypothermia .. 4.4 Pre-hospital logistics of care
..
conditions are associated with slow uptake, delayed onset of action, .. 4.4.1 Delays
and diminished effects of oral antiplatelet agents (i.e. clopidogrel, tica- .. Treatment delays are the most easily audited index of quality of care
..
grelor, and prasugrel). Moreover, metabolic conversion of clopidog- .. in STEMI; they should be recorded in every system providing care to
rel in the liver may be reduced in hypothermia conditions.83 Cooling
.. STEMI patients and be reviewed regularly, to ensure that simple qual-
..
should not delay primary PCI and can be started in parallel in the . ity of care indicators are met and maintained over time (see Chapter
ESC Guidelines 129

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Figure 2 Modes of patient presentation, components of ischaemia time and flowchart for reperfusion strategy selection. EMS = Emergency
Medical System; FMC = First Medical Contact; PCI = Percutaneous Coronary Intervention; STEMI = ST-segment elevation myocardial infarction.
The recommended mode of patient presentation is by alerting the EMS (call national emergency number: 112 or similar number
according to region). When STEMI diagnosis is made in the out-of-hospital setting (via EMS) or in a non-PCI centre, the decision for
choosing reperfusion strategy is based on the estimated time from STEMI diagnosis to PCI-mediated reperfusion (wire crossing).
System delay for patients alerting the EMS starts at the time of phone alert, although FMC occurs when EMS arrives to the scene (see
Table 4).denotes minutes. aPatients with fibrinolysis should be transferred to a PCI centre immediately after administration of the lytic
bolus.

..
10). If projected target times are not met, then interventions are .. to <_ 10 min. STEMI diagnosis refers to the time when the ECG is
needed to improve performance of the system. Components of the .. interpreted as ST-segment elevation or equivalent and it is the time
..
ischaemic time, delays of initial management, and selection of reperfu- .. zero to guide appropriate therapy.
sion strategy are shown in Figure 2.
.. System delay is more readily modifiable by organizational meas-
..
To minimize patient delay, it is recommended to increase public .. ures than is patient delay, and it is a predictor of outcomes.87
awareness of how to recognize common symptoms of AMI and to
.. When STEMI diagnosis is made in the pre-hospital setting (EMS),
..
call the emergency services. All components of the system delay rep- .. immediate activation of the catheterization laboratory not only
resent the quality of care and it is recommended to measure them as
.. reduces treatment delays but may also reduce patient mortality.88–91
..
quality indicators (see Chapter 10). .. When a STEMI diagnosis is made by the EMS in the pre-hospital set-
In hospitals and EMS participating in the care of STEMI patients,
.. ting and the patient is triaged for a primary PCI strategy, it is indicated
..
the goal is to reduce the delay between FMC and STEMI diagnosis .. to bypass the emergency department and bring the patient straight
.
130 ESC Guidelines

to the catheterization laboratory. Bypassing the emergency depart-


.. 䊏 Pre-hospital triage of STEMI patients to the appropriate institution,
..
ment is associated with a 20 min saving in the time from FMC to wire .. bypassing non-PCI hospitals or hospitals without a 24 h a day, 7 days a
crossing.92 For patients presenting in a non-PCI centre, door-in to
.. week (24/7) primary PCI programme.
..
door-out time, defined as the duration between arrival of the patient .. 䊏 On arrival at the appropriate hospital, the patient should immediately
at the hospital to discharge of the patient in an ambulance en route
.. be taken to the catheterization laboratory, bypassing the emergency
..
to the PCI centre, is a new clinical performance measure, and .. department.
<_30 min is recommended to expedite reperfusion care.93
.. 䊏 Patients presenting to a non-PCI-capable hospital and awaiting trans-
..
.. portation for primary or rescue PCI must be attended in an appropri-
.. ately monitored and staffed area.
...
.. 䊏 If the diagnosis of STEMI has not been made by the ambulance crew
4.4.2 Emergency medical system
.. and the ambulance arrives at a non-PCI-capable hospital, the ambu-
..
.. lance should await the diagnosis and, if a STEMI diagnosis is made,

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An EMS with an easily recalled and well publicized unique medical dis-
patching number (112 for most medical emergencies across Europe)
.. should continue to a PCI-capable hospital.
..
is important to speed up activation. Parallel circuits for referral and .. To maximize staff experience, primary PCI centres should perform
..
transport of patients with a STEMI that bypass the EMS should be .. the procedure systematically on a 24/7 basis for all STEMI patients.
avoided. The ambulance system has a critical role in the early man- ..
.. Other models, although not ideal, may include weekly or daily rotation
agement of STEMI patients and it is not only a mode of transport but .. of primary PCI centres or multiple primary PCI centres in the same
also a system to enhance early initial diagnosis, triage, and ..
.. region. Hospitals that cannot offer a 24/7 service for primary PCI
treatment.87,94 .. should be allowed to perform primary PCI in patients already admit-
It is indicated that all ambulances in the EMS are equipped with ..
.. ted for another reason who develop STEMI during their hospital stay.
ECG recorders, defibrillators, and at least one person trained in .. However, these hospitals should be discouraged from initiating a serv-
advanced life support. The quality of the care provided depends ..
.. ice limited to daytime- or within-hours primary PCI, as this may gener-
on the training of the staff involved. It is indicated that all ambulance .. ate confusion with the EMS operators and may affect the STEMI
personnel are trained to recognize the symptoms of an AMI, adminis- ..
.. diagnosis-to-reperfusion time and the quality of intervention of
ter oxygen when appropriate, relieve pain, and provide basic life sup- .. focused 24/7 true primary PCI centres. Therefore, it is indicated that
port.95 Ambulance staff should be able to record an ECG for ..
.. the EMS transports STEMI patients to hospitals with an established
diagnostic purposes and either interpret or transmit it, so that it can .. interventional cardiology programme available 24/7, if necessary
be reviewed by experienced staff in a coronary care unit (CCU)/ ..
.. bypassing a non-PCI-capable hospital (if the transfer time is within the
ICCU or elsewhere and establish a STEMI diagnosis. Paramedics .. recommended time-windows for primary PCI; see Figure 3).
trained to administer fibrinolytics do so safely and effectively.96 As
..
.. Geographic areas where the expected transfer time to the primary
pre-hospital fibrinolysis is indicated in patients presenting early when .. PCI centre makes it impossible to achieve the maximal allowable
anticipated STEMI diagnosis to PCI-mediated reperfusion time
..
.. delays indicated in the recommendations (Figure 2) should develop
is > 120 min,97–99 ongoing training of paramedics to undertake .. systems for rapid fibrinolysis, at the place of STEMI diagnosis, with
these functions is recommended, even in the current setting of pri-
..
.. subsequent immediate transfer to primary PCI centres. Such net-
mary PCI. .. works increase the proportion of patients receiving reperfusion with
..
.. the shortest possible treatment delay.100–102 The quality of care,
.. time delays, and patient outcomes should be measured and com-
..
.. pared at regular intervals for improvement.
4.4.3 Organization of ST-segment elevation myocardial
..
..
infarction treatment in networks .. 4.4.3.1. General practitioners
Optimal treatment of STEMI should be based on the implementation
..
.. In some countries, general practitioners play a role in the early care
of networks between hospitals (‘hub’ and ‘spoke’) with various levels .. of patients with AMI and are often the first to be contacted by the
..
of technology, linked by a prioritized and efficient ambulance service. .. patients.
The goal of these networks is to provide optimal care while minimiz- .. If general practitioners respond quickly they can be very effective,
..
ing delays, thereby improving clinical outcomes. Cardiologists should .. as they usually know the patient and can perform and interpret the
actively collaborate with all stakeholders, particularly emergency .. ECG. Their first task after the STEMI diagnosis should be to alert the
..
physicians, in establishing such networks. The main features of such a .. EMS. In addition, they can administer opioids and antithrombotic
network are: .. drugs (including fibrinolytics, if that management strategy is indi-
..
.. cated), and can undertake defibrillation if needed. However, in most
䊏 Clear definition of geographic areas of responsibility.
.. settings, consultation with a general practitioner—instead of a direct
..
䊏 Shared written protocols, based on risk stratification and transportation .. call to the EMS—will increase pre-hospital delay. Therefore, in gen-
by a trained physician, nurse, or paramedic staff in appropriately
.. eral, the public should be educated to call the EMS rather than the
..
equipped ambulances or helicopters. . primary care physician for symptoms suggestive of MI.
ESC Guidelines 131

..
Logistics of pre-hospital care
.. 5. Reperfusion therapy
..
..
.. 5.1 Selection of reperfusion strategies
Recommendations Classa Levelb .
... Table 4 lists the definitions of terms relating to reperfusion therapy.
It is recommended that the pre-hospital ..
.. Table 4 Definitions of terms related to reperfusion
management of STEMI patients is based on .. therapy
regional networks designed to deliver ..
..
reperfusion therapy expeditiously and effec- I B ..
tively, with efforts made to make primary
..
..
PCI available to as many patients as ..
possible.100
..
..
..

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It is recommended that primary PCI-capable ..
centres deliver a 24/7 service and are able ..
I B ..
to perform primary PCI without ..
delay.18,103,104 ..
..
..
It is recommended that patients transferred ..
to a PCI-capable centre for primary PCI ..
..
bypass the emergency department and I B ..
CCU/ICCU and are transferred directly to ..
..
the catheterization laboratory.92,107–110 ..
..
It is recommended that ambulance teams ..
are trained and equipped to identify STEMI
..
..
(with use of ECG recorders and telemetry I C ..
..
as necessary) and administer initial therapy, ..
including fibrinolysis when applicable.95 ..
..
It is recommended that all hospitals and
..
..
EMS participating in the care of patients ..
with STEMI record and audit delay times I C
..
..
and work to achieve and maintain quality ..
targets.105–107
..
..
..
It is recommended that EMS transfer STEMI ..
patients to a PCI-capable centre, bypassing I C ..
..
non-PCI centres. ..
.. ECG = electrocardiogram; EMS = emergency medical system; FMC = first medi-
It is recommended that EMS, emergency .. cal contact; IRA = infarct-related artery; PCI = percutaneous coronary interven-
.. tion; STEMI = ST-segment elevation myocardial infarction.
departments, and CCU/ICCU have a writ- ..
ten updated STEMI management protocol, I C ..
..
preferably shared within geographic ..
networks. .. Primary PCI is the preferred reperfusion strategy in patients with
..
.. STEMI within 12 h of symptom onset, provided it can be performed
It is recommended that patients presenting .. expeditiously (i.e. 120 min from STEMI diagnosis, Figures 2 and 3) by
to a non-PCI-capable hospital and awaiting ..
.. an experienced team. An experienced team includes not only inter-
transportation for primary or rescue PCI .. ventional cardiologists but also skilled support staff. Lower mortality
are attended in an appropriately monitored
I C ..
.. rates among patients undergoing primary PCI are observed in centres
area (e.g. the emergency department, CCU/ .. with a high volume of PCI procedures.111 Real-life data confirm that
ICCU, or intermediate care unit). ..
.. primary PCI is performed faster and results in lower mortality if per-
.. formed in high-volume centres.112 Randomized clinical trials in high-
24/7 = 24 h a day, 7 days a week; CCU = coronary care unit; ECG = electrocar-
..
.. volume, experienced centres have repeatedly shown that, if delay to
diogram; EMS = emergency medical system; ICCU = intensive cardiac care unit; .. treatment is similar, primary PCI is superior to fibrinolysis in reducing
PCI = percutaneous coronary intervention; STEMI = ST-segment elevation myo- ..
cardial infarction. .. mortality, reinfarction, or stroke.113–116 However, in some circum-
a
Class of recommendation. .. stances, primary PCI is not an immediate option and fibrinolysis could
b
Level of evidence. ..
.. be initiated expeditiously. The extent to which the PCI-related time
.. delay diminishes the advantages of PCI over fibrinolysis has been
..
.. widely debated. Because no specifically designed study has addressed
132 ESC Guidelines

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Figure 3 Maximum target times according to reperfusion strategy selection in patients presenting via EMS or in a non-PCI centre. ECG = electro-
cardiogram; PCI = Percutaneous Coronary Intervention; STEMI = ST-segment elevation myocardial infarction. STEMI diagnosis is the time 0 for the
strategy clock. The decision for choosing reperfusion strategy in patients presenting via EMS (out-of-hospital setting) or in a non-PCI centre is based
on the estimated time from STEMI diagnosis to PCI-mediated reperfusion. Target times from STEMI diagnosis represent the maximum time to do
specific interventions.
a
if fibrinolysis is contra-indicated, direct for primary PCI strategy regardless of time to PCI.
b
10 min is the maximum target delay time from STEMI diagnosis to fibrinolytic bolus administration, however, it should be given as
soon as possible after STEMI diagnosis (after ruling out contra-indications).

..
this issue, caution is needed when interpreting available data from .. trial randomized early STEMI presenters without the possibility of
post hoc analyses. A PCI-related time delay potentially mitigating the .. immediate PCI to immediate fibrinolysis (followed by routine early
..
benefits of PCI has been calculated as 60 min117, 110 min,118 and .. angiography) or transfer to primary PCI.121 The median PCI-related
120 min119 in different studies. Registry data estimated this time limit .. delay in this trial was 78 min, and there were no differences in clinical
..
as 114 min for in-hospital patients107 and 120 min in patients present- .. outcomes. This Task Force recognizes the lack of contemporaneous
ing in a non-PCI centre.120 All these data are old and patients under- .. data to set the limit to choose PCI over fibrinolysis. For simplicity, an
..
going fibrinolysis did not undergo routine early angiography, which .. absolute time from STEMI diagnosis to PCI-mediated reperfusion [i.e.
improves outcomes in patients receiving fibrinolysis. The recent .. wire crossing of the infarct-related artery (IRA)] rather than a relative
..
STrategic Reperfusion Early After Myocardial infarction (STREAM) . PCI-related delay over fibrinolysis has been chosen. This limit is set to
ESC Guidelines 133

120 min. Given the maximum limit of 10 min from STEMI diagnosis to .. Recommendations for reperfusion therapy
bolus of fibrinolytics (see below), the 120 min absolute time would ..
..
correspond to a PCI-related delay in the range of 110–120 min, being ..
in the range of the times identified in old studies and registries as the .. Recommendation Classa Levelb
..
limit delay to choose PCI.107,117–120 .. Reperfusion therapy is indicated in all
If the reperfusion strategy is fibrinolysis, the goal is to inject the ..
.. patients with symptoms of ischaemia
I A
bolus of fibrinolytics within 10 min from STEMI diagnosis. This time is .. of <_ 12 h duration and persistent ST-seg-
selected based on the median time from randomization to bolus ..
.. ment elevation.119,138
recorded in the STREAM trial, which was 9 min.121 In previous ESC ..
STEMI guidelines,122 the target time was 30 min, but this was calcu- .. A primary PCI strategy is recommended
..
lated from FMC (as opposed to STEMI diagnosis). STEMI diagnosis .. over fibrinolysis within indicated I A
should occur within 10 min from FMC. .. timeframes.114,116,139,140
..

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Figure 3 summarizes target times for patients presenting in the pre- .. If timely primary PCI cannot be performed
hospital setting or in a non-PCI centre.
..
.. after STEMI diagnosis, fibrinolytic therapy is
To shorten time to treatment, fibrinolysis should be administered .. recommended within 12 h of symptom I A
in the pre-hospital setting if possible98,121,123 (Figures 2 and 3).
..
.. onset in patients without
Patients should be transferred to a PCI-capable facility as soon as pos- .. contraindications.107,120,122
sible after bolus of lytics administration. Rescue PCI is indicated in the
..
..
case of failed fibrinolysis (i.e. ST-segment resolution < 50% within .. In the absence of ST-segment elevation, a
60–90 min of fibrinolytic administration), or in the presence of hae-
.. primary PCI strategy is indicated in patients
..
modynamic or electrical instability, worsening ischaemia, or persis- .. with suspected ongoing ischaemic symp-
tent chest pain,121,124 while a routine early PCI strategy is indicated ... toms suggestive of MI and at least one of
.. the following criteria present:
after successful fibrinolysis (preferably 2–24 h after fibrinolysis) (see ..
section 5.3).125–130 .. - haemodynamic instability or cardiogenic
.. shock
Patients with a clinical presentation compatible with AMI and a ..
non-interpretable ST-segment on the ECG, such as those with bun- .. - recurrent or ongoing chest pain refrac-
.. I C
dle branch block or ventricular pacing,55,131,132 should undergo a pri- .. tory to medical treatment
mary PCI strategy. .. - life-threatening arrhythmias or cardiac
..
There is general agreement that a primary PCI strategy should also .. arrest
be followed for patients with symptoms lasting >12 h in the presence .. - mechanical complications of MI
..
of: (1) ECG evidence of ongoing ischaemia; (2) ongoing or recurrent .. - acute heart failure
pain and dynamic ECG changes; and (3) ongoing or recurrent pain, .. - recurrent dynamic ST-segment or T-
..
symptoms, and signs of heart failure, shock, or malignant arrhythmias. .. wave changes, particularly with intermit-
However, there is no consensus as to whether PCI is also beneficial .. tent ST-segment elevation.
..
in patients presenting >12 h from symptom onset in the absence of .. Early angiography (within 24 h) is recom-
clinical and/or electrocardiographic evidence of ongoing ischaemia. In
..
.. mended if symptoms are completely
asymptomatic patients without persistent symptoms 12–48 h after ..
symptom onset, a small (n = 347) randomized study showed
.. relieved and ST-segment elevation is com-
.. pletely normalized spontaneously or after I C
improved myocardial salvage and 4 year survival in patients treated ..
with primary PCI compared with conservative treatment alone.133,134
.. nitroglycerin administration (provided there
.. is no recurrence of symptoms or ST-seg-
However, in stable patients with persistent occlusion of the IRA ..
3–28 days after MI, the large (n = 2166) Occluded Artery Trial
.. ment elevation).
..
(OAT) revealed no clinical benefit from routine coronary interven- .. In patients with time from symptom onset
.. >12 h, a primary PCI strategy is indicated in
tion with medical management, beyond that from medical manage- ..
ment alone.135,136 A meta-analysis of trials testing whether late .. the presence of ongoing symptoms sugges- I C
.. tive of ischaemia, haemodynamic instability,
recanalization of an occluded IRA is beneficial showed no benefit of ..
reperfusion.137 Therefore, routine PCI of an occluded IRA in asymp- .. or life-threatening arrhythmias.141
..
tomatic patients >48 h after onset of symptoms is not indicated. .. A routine primary PCI strategy should be
These patients should be managed like all patients with chronic total ..
.. considered in patients presenting late IIa B
occlusion, in which revascularization should be considered in the .. (12–48 h) after symptom onset.133,134,142
presence of symptoms or objective evidence of viability/ischaemia in ..
..
the territory of the occluded artery.1 .. In asymptomatic patients, routine PCI of an
occluded IRA >48 h after onset of STEMI is III A
not indicated.135,137

IRA = infarct-related artery; MI, myocardial infarction; PCI = percutaneous coro-


nary intervention; STEMI = ST-segment elevation myocardial infarction.
a
Class of recommendation.
b
Level of evidence.
134 ESC Guidelines

..
Table 5 Summary of important time targets
.. stent (BMS) is associated with a lower risk of reinfarction and target
.. vessel revascularization but is not associated with a reduction in the
..
.. mortality rate.146,147 In primary PCI, drug-eluting stents (DES) reduce
.. the risk of repeated target vessel revascularization compared with
..
.. BMS.148
.. New-generation DES have shown superior safety and preserved
..
.. or even improved efficacy compared with first-generation DES, in
.. particular with respect to lower risks of stent thrombosis and recur-
..
.. rent MI. In two recent trials—the Effect of biolimus-eluting stents
.. with biodegradable polymer vs. bare-metal stents on cardiovascular
..
.. events among patients with AMI (COMFORTABLE AMI) trial149 and
.. the Everolimus-Eluting Stents Versus Bare-Metal Stents in ST-
..

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.. Segment Elevation Myocardial Infarction (EXAMINATION)
.. trial150—new-generation DES have been shown to be superior to
..
.. BMS in patients with AMI, mostly in terms of need for reintervention.
.. In the latter trial, the recently released 5 year follow-up results
..
.. showed a reduction in all-cause mortality by DES as compared to
.. BMS.151 In the Norwegian Coronary Stent (NORSTENT) trial,152
..
.. 9013 patients undergoing PCI (26% with STEMI) were randomized
.. to DES or BMS. There were no differences in the incidence of the pri-
..
.. mary endpoint (composite of death from any cause or non-fatal
..
.. spontaneous MI) after a median follow-up of 5 years. However, DES
.. were associated with lower rates of definite stent thrombosis (0.8%
..
ECG = electrocardiogram; FMC = first medical contact; PCI = percutaneous cor- .. vs. 1.2%; P = 0.0498) and of target lesion and any repeat revasculariza-
onary intervention; STEMI = ST-segment elevation myocardial infarction
.. tion (16.5% vs. 19.8%; P < 0.001).152
a ..
ECG should be interpreted immediately. .. Deferring stenting in primary PCI has been investigated as an
.. option to reduce microvascular obstruction (MVO) and preserve
..
.. microcirculatory function. Two small studies recently found opposite
Table 5 summarizes the important time targets in acute STEMI. .. results in the effect of deferred stenting on cardiac magnetic reso-
..
.. nance (CMR) imaging-measured MVO.153,154 In the larger DANish
5.2 Primary percutaneous coronary .. Study of Optimal Acute Treatment of Patients with ST-segment
..
intervention and adjunctive therapy .. Elevation Myocardial Infarction – Deferred versus conventional stent
5.2.1 Procedural aspects of primary percutaneous
.. implantation in patients with ST-segment elevation myocardial infarc-
..
coronary intervention .. tion (DANAMI 3-DEFER) trial,155 in 1215 STEMI patients, deferred
5.2.1.1 Access route
.. stenting (48 h after the index procedure) had no effect on the pri-
..
Over recent years, several studies have provided robust evidence in .. mary clinical outcome (composite of all-cause mortality, non-fatal MI,
favour of the radial approach as the default access site in ACS patients
.. or ischaemia-driven revascularization of non-IRA lesions). Routine
..
undergoing primary PCI by experienced radial operators. The .. deferred stenting was associated with a higher need for target vessel
Minimizing Adverse Haemorrhagic Events by TRansradial Access Site
.. revascularization. Based on these findings, routine use of deferred
..
and Systemic Implementation of angioX (MATRIX)143 trial recruited .. stenting is not recommended.
..
8404 ACS patients (48% STEMI) who were randomly allocated to ..
transradial or transfemoral access. Radial access was associated with .. 5.2.1.3 Thrombus aspiration
.. A number of small-scale or single-centre studies and one meta-analysis
lower risks of access site bleeding, vascular complications, and need ..
for transfusion. Importantly, there was a significant mortality benefit .. of 11 small trials156 suggested that there could be benefits from routine
..
in patients allocated to the transradial access site, which reinforced .. manual thrombus aspiration during primary PCI. Recently, two large
previous observations from the Radial Versus Femoral Access for .. (>10 000 and >7000 patients) randomized controlled trials, which
..
Coronary Intervention (RIVAL) access for coronary intervention .. were adequately powered to detect superiority of routine manual
trial,144 and the Radial Versus Femoral Randomized Investigation in .. thrombus aspiration versus conventional PCI, showed no benefit on
..
ST-Elevation Acute Coronary Syndrome (RIFLE-STEACS) trial.145 .. clinical outcomes of routine aspiration strategy overall.157–160 A safety
No significant interaction was observed in the MATRIX trial between .. concern emerged in the Trial of Routine Aspiration Thrombectomy
..
the type of ACS and treatment benefit, suggesting that the results of .. with PCI versus PCI Alone in Patients with STEMI (TOTAL) trial (n =
this investigation can be extended with confidence to the treatment .. 10 732), with an increase in the risk of stroke.161 In the subgroup with
..
of patients with STEMI. .. high thrombus burden [TIMI (Thrombolysis in Myocardial Infarction)
.. thrombus grade  3], thrombus aspiration was associated with fewer
..
5.2.1.2 Stenting in primary percutaneous intervention .. cardiovascular deaths [170 (2.5%) vs. 205 (3.1%); hazard ratio (HR)
Coronary stenting is the technique of choice during primary PCI.
.. 0.80, 95% confidence interval (CI) 0.65–0.98; P = 0.03] and with more
..
Compared with balloon angioplasty alone, stenting with a bare-metal . strokes or transient ischaemic attacks [55 (0.9%) vs. 34 (0.5%); odds
ESC Guidelines 135

..
ratio 1.56, 95% CI 1.02–2.42, P =0.04]. However, the interaction P val- .. DANAMI-3–PRIMULTI). Based on these data, revascularization of
ues were 0.32 and 0.34, respectively.162 .. non-IRA lesions should be considered in STEMI patients with multives-
..
In the Taste157 and TOTAL trials159, 1–5% of randomized patients .. sel disease before hospital discharge. As the optimal timing of revascu-
crossed over from PCI alone to thrombus aspiration. Based on these .. larization (immediate vs. staged) has not been adequately investigated,
..
data and the results of a recent meta-analysis,162 routine thrombus .. no recommendation in favour of immediate vs. staged multivessel PCI
aspiration is not recommended, but in cases of large residual throm- .. can be formulated.
..
bus burden after opening the vessel with a guide wire or a balloon, ..
thrombus aspiration may be considered.
.. 5.2.1.5 Intra-aortic balloon pump
..
.. The Counterpulsation to Reduce Infarct Size Pre-PCI-Acute Myocar-
5.2.1.4 Multivessel coronary revascularization
.. dial Infarction (CRISP AMI) trial showed no benefit from a routine
..
Multivessel disease is common (in approximately 50%) in patients .. intra-aortic balloon pump (IABP) in anterior MI without shock,175 but
with STEMI.163,164 While it is recommended to always treat the IRA,
.. there was increased bleeding, which is consistent with previous data
..

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evidence supporting immediate (preventive) revascularization of .. regarding the role of IABP in high-risk STEMI without cardiogenic
additional significant coronary stenoses is conflicting. It has been
.. shock.176 In addition, a recent randomized trial showed that IABP did
..
reported that patients with extensive CAD in vessels remote from .. not improve outcomes in MI with cardiogenic shock.177 Haemody-
..
the IRA have lower rates of ST-segment recovery and an adverse .. namic support in patients with cardiogenic shock is discussed in
prognosis following primary PCI.163 Data from the US National .. Chapter 8.
Cardiovascular Data Registry and New York State’s Percutaneous ...
Coronary Interventions Reporting System suggested an increase in
.. Procedural aspects of the primary percutaneous cor-
.. onary intervention strategy
adverse events, including mortality, in patients treated with immedi- ..
ate multivessel revascularization versus IRA PCI only, while patients
..
.. Recommendations Classa Levelb
in cardiogenic shock were excluded from the analysis.165,166 ..
..
Randomized clinical trials addressing this issue have been small (each .. IRA strategy
of them included from 69 to 885 patients). One study allocated 214 .. Primary PCI of the IRA is indicated.114,116,139,140
.. I A
STEMI patients with multivessel disease to three arms: IRA angioplasty- ..
only, simultaneous treatment of non-IRA lesions, and staged revascula- .. New coronary angiography with PCI if indicated is
.. recommended in patients with symptoms or signs
I C
rization of the non-IRA. At a mean follow-up of 2.5 years, patients allo- .. of recurrent or remaining ischaemia after primary
cated to IRA angioplasty-only had more major adverse cardiac events .. PCI.
..
(MACE) (i.e. death, reinfarction, rehospitalization for ACS, and repeat ..
coronary revascularization) than the patients treated with other strat- .. IRA technique
..
egies.167 After this study, four randomized clinical trials have compared .. Stenting is recommended (over balloon angio-
I A
PCI of the IRA only vs. complete revascularization: the Preventive .. plasty) for primary PCI.146,147
..
Angioplasty in Acute Myocardial Infarction (PRAMI) trial (n = 465, .. Stenting with new-generation DES is recom-
I A
23 months follow-up),168 the Complete Versus Lesion-Only Primary .. mended over BMS for primary PCI.148–151,178,179
..
PCI Trial (CvLPRIT) (n = 296, 12 months follow-up),169 the Complete .. Radial access is recommended over femoral
revascularisation versus treatment of the culprit lesion only in patients .. I A
.. access if performed by an experienced radial
with ST-segment elevation myocardial infarction and multivessel dis- .. operator.143–145,180
ease (DANAMI-3–PRIMULTI) trial (n = 627, 27 months follow-up),170
..
.. Routine use of thrombus aspiration is not
III A
and the Comparison Between FFR Guided Revascularization Versus .. recommended.157,159
Conventional Strategy in Acute STEMI Patients With Multivessel dis-
..
.. Routine use of deferred stenting is not
ease (Compare-Acute, n = 885, 12 months follow-up) trial.171 PCI of .. recommended.153–155
III B

non-IRA was done either during the index procedure (PRAMI and
..
..
Compare-Acute), staged during hospital admission (DANAMI- .. Non-IRA strategy
..
3–PRIMULTI), or any time before discharge (immediate or staged) .. Routine revascularization of non-IRA lesions
(CVLPRIT). Indication for PCI in non-IRA was angiography-guided in .. should be considered in STEMI patients with mul- IIa A
.. tivessel disease before hospital discharge.167–173
lesions with 50% stenosis (PRAMI), >70% stenosis (CVLPRIT), or ..
fractional flow reserve (FFR)-guided (DANAMI-3–PRIMULTI and .. Non-IRA PCI during the index procedure should
.. be considered in patients with cardiogenic shock.
IIa C
Compare-Acute). Primary outcome (composite of different end- ..
points) was significantly reduced in the complete revascularization ..
.. CABG should be considered in patients with
group in all four trials. Total mortality was not statistically different in .. ongoing ischaemia and large areas of jeopardized IIa C
any of the four trials. Repeat revascularization was significantly reduced .. myocardium if PCI of the IRA cannot be performed.
..
in the complete revascularization arm in the PRAMI, DANAMI- ..
3–PRIMULTI, and Compare-Acute trials. Non-fatal MI was reduced in .. CABG = coronary artery bypass graft surgery; DES = drug-eluting stent; IRA =
.. infarct-related artery; PCI = percutaneous coronary intervention; STEMI = ST-
the non-IRA PCI group only in PRAMI. The lack of significant treatment ..
effect of non-IRA lesion intervention on death or MI was confirmed by .. segment elevation myocardial infarction.
a
.. Class of recommendation.
three meta-analyses172–174 (none of these meta-analyses included .. b
Level of evidence.
the Compare-Acute trial, and one173 did not include the ..
136 ESC Guidelines

5.2.2 Periprocedural pharmacotherapy


.. lung abnormalities, and which rarely leads to permanent discontinua-
..
5.2.2.1 Platelet inhibition .. tion.189 Neither prasugrel nor ticagrelor should be used in patients
Patients undergoing primary PCI should receive DAPT, a combina-
.. with a previous haemorrhagic stroke, in patients on oral anticoagu-
..
tion of aspirin and a P2Y12 inhibitor, and a parenteral anticoagulant. .. lants, or in patients with moderate-to-severe liver disease.
Aspirin can be given orally including chewing, or i.v. to ensure com-
.. When neither of these agents is available (or if they are contraindi-
..
plete inhibition of thromboxane A2-dependent platelet aggregation. .. cated), clopidogrel 600 mg p.o. should be given instead.190
The oral dose of plain aspirin (non-enteric-coated formulation)
.. Clopidogrel has not been evaluated against placebo in any large out-
..
should preferably be 150–300 mg. There are few clinical data on the .. comes studies in the setting of primary PCI, but a higher regimen of a
.. 600 mg loading dose/150 mg maintenance dose in the first week was
optimal i.v. dosage. Given a 50% oral bioavailability of oral aspirin, a ..
corresponding dose is 75–150 mg. Pharmacological data suggest that .. superior to the 300/75 mg regimen in the subset of patients under-
this lower dose range avoids inhibition of cyclooxygenase-2- ... going PCI in the Clopidogrel and aspirin Optimal Dose usage to
..
dependent prostacyclin. A recent randomized study showed that a .. reduce recurrent events–Seventh organization to assess strategies in

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single dose of 250 or 500 mg acetylsalicylic acid i.v. compared to .. ischaemic syndromes (CURRENT-OASIS 7) trial,190 and use of high
..
300 mg orally was associated with a faster and more complete inhibi- .. clopidogrel loading doses has been demonstrated to achieve more
tion of thromboxane generation and platelet aggregation at 5 min, .. rapid inhibition of the adenosine diphosphate receptor. All P2Y12
..
with comparable rates of bleeding complications.181 .. inhibitors should be used with caution in patients at high risk of bleed-
There is limited evidence with respect to when the P2Y12 inhibitor .. ing or with significant anaemia.
..
should be initiated in STEMI patients. The Administration of .. Cangrelor is a potent i.v. reversible P2Y12 inhibitor with a rapid
Ticagrelor in the Cath Lab or in the Ambulance for New ST Elevation .. onset and offset of action. It has been assessed in three random-
..
Myocardial Infarction to Open the Coronary Artery (ATLANTIC) .. ized controlled trials enrolling patients with PCI for stable angina
trial182 is the only randomized study testing the safety and efficacy of .. or ACS against clopidogrel loading or placebo.191–193 A pooled
..
different timings of P2Y12 inhibitor initiation in STEMI. In this trial, .. analysis of these three trials showed that cangrelor reduced peri-
patients were randomized to receive ticagrelor either during transfer
.. procedural ischaemic complications at the expense of an increased
..
to a primary PCI centre or immediately before angiography.182 The .. risk of bleeding.194 The fact that no potent P2Y12 inhibitors (prasu-
median difference between the two tested loading treatment strat-
.. grel or ticagrelor) were used in patients with an ACS, and only
..
egies was only 31 min. This study failed to meet the pre-specified pri- .. about 18% of the enrolled patients presented with STEMI,193 limits
mary endpoint in terms of improved ST-segment elevation
.. the applicability of the results to current practice of management
..
resolution or TIMI flow before intervention. Rates of major and .. of STEMI patients. Nevertheless, cangrelor may be considered in
minor bleeding events were identical in both treatment arms. While
.. patients not pre-treated with oral P2Y12 receptor inhibitors at the
..
the evidence of a clinical benefit of P2Y12 inhibitor pre-treatment in .. time of PCI or in those who are considered unable to absorb oral
.. agents.
this setting is lacking, early initiation of a P2Y12 inhibitor while the ..
patient is being transported to a primary PCI centre is common prac- .. The pre-hospital routine upstream use of glycoprotein (GP) IIb/IIIa
..
tice in Europe and is consistent with the pharmacokinetic data. .. inhibitors before primary PCI has not been demonstrated to offer a
Furthermore, early treatment with high-dose clopidogrel was supe- .. benefit and increases bleeding risk compared with routine use in the
..
rior to in-catheterization laboratory treatment in observational stud- .. catheterization laboratory.195,196 Procedural use of abciximab plus
ies and one small randomized trial.183–185 In all, the data suggest that .. unfractionated heparin (UFH) showed no benefit compared to biva-
..
the earliest administration may be preferable to achieve early efficacy, .. lirudin.197 Using GP IIb/IIIa inhibitors as bailout therapy in the event of
particularly for long delays. However, in cases in which the STEMI .. angiographic evidence of a large thrombus, slow- or no-reflow, and
..
diagnosis is not clear, delaying P2Y12 inhibitor loading until the anat- .. other thrombotic complications is reasonable, although this strategy
omy is known should be considered. .. has not been tested in a randomized trial. Overall, there is no evi-
..
The preferred P2Y12 inhibitors are prasugrel [60 mg loading dose .. dence to recommend the routine use of GP IIb/IIIa inhibitors for pri-
and 10 mg maintenance dose once daily per os (p.o.)] or ticagrelor .. mary PCI. The intracoronary administration of GP IIb/IIIa inhibitors is
..
(180 mg p.o. loading dose and 90 mg maintenance dose twice daily). .. not superior to its i.v. use.198
These drugs have a more rapid onset of action, greater potency, and ..
..
are superior to clopidogrel in clinical outcomes.186,187 Prasugrel is .. 5.2.2.2 Anticoagulation
contraindicated in patients with previous stroke/transient ischaemic
.. Anticoagulant options for primary PCI include UFH, enoxaparin, and
..
attack, and its use is generally not recommended in patients aged .. bivalirudin. Use of fondaparinux in the context of primary PCI was
75 years or in patients with lower body weight (<60 kg) as it was
.. associated with potential harm in the Organization for the
..
not associated with net clinical benefit in these subsets. In case prasu- .. Assessment of Strategies for Ischemic Syndromes 6 (OASIS 6) trial
grel is used in these patients, a reduced dose (5 mg)188 is recom-
.. and is not recommended.199
..
mended. Ticagrelor may cause transient dyspnoea at the onset of .. There has been no placebo-controlled trial evaluating UFH in pri-
therapy, which is not associated with morphological or functional
.. mary PCI, but there is a large body of experience with this agent.
.
ESC Guidelines 137

Dosage should follow standard recommendations for PCI (i.e. initial


Periprocedural and post-procedural antithrombotic
bolus 70–100 U/kg). There are no robust data recommending the
therapya in patients undergoing primary percutaneous
use of activated clotting time to tailor dose or monitor UFH, and if coronary intervention
activated clotting time is used, it should not delay recanalization of
the IRA. An i.v. bolus of enoxaparin 0.5 mg/kg was compared with
Recommendations Classb Levelc
UFH in the randomized open-label Acute myocardial infarction
Treated with primary angioplasty and inTravenous enOxaparin or Antiplatelet therapy
unfractionated heparin to Lower ischaemic and bleeding events at
A potent P2Y12 inhibitor (prasugrel or tica-
short- and Long-term follow-up (ATOLL) trial, including 910 STEMI
grelor), or clopidogrel if these are not avail-
patients.200 The primary composite endpoint of 30 day death, MI,
able or are contraindicated, is
procedural failure, or major bleeding was not significantly reduced by
recommended before (or at latest at the
enoxaparin (17% relative risk reduction, P = 0.063), but there was a I A

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time of) PCI and maintained over
reduction in the composite main secondary endpoint of death, recur-
12 months, unless there are contraindica-
rent MI or ACS, or urgent revascularization. Importantly, there was
tions such as excessive risk of
no evidence of increased bleeding following the use of enoxaparin
bleeding.186,187
over UFH.200 In the per-protocol analysis of the ATOLL trial (87% of
the study population), i.v. enoxaparin was superior to UFH in reduc- Aspirin (oral or i.v. if unable to swallow) is
ing the primary endpoint, ischaemic endpoints, mortality, and major recommended as soon as possible for all I B
bleeding.201 In a meta-analysis of 23 PCI trials (30 966 patients, 33% patients without contraindications.213,214
primary PCI), enoxaparin was associated with a significant reduction
GP IIb/IIIa inhibitors should be considered
in death compared to UHF. This effect was particularly significant in
for bailout if there is evidence of no-reflow IIa C
the primary PCI context and was associated with a reduction in major
or a thrombotic complication.
bleeding.202 Based on these considerations, enoxaparin should be
considered in STEMI. Cangrelor may be considered in patients
Five dedicated randomized controlled trials have compared bivalir- who have not received P2Y12 receptor IIb A
udin with UFH with or without planned use of GP IIb/IIIa inhibitors in inhibitors.192–194
patients with STEMI.197,203–207 A meta-analysis of these trials showed
Anticoagulant therapy
no mortality advantage with bivalirudin and a reduction in the risk of
major bleeding, but at the cost of an increased risk of acute stent Anticoagulation is recommended for all
thrombosis.208 In the recent MATRIX trial including 7213 ACS patients in addition to antiplatelet therapy I C
patients (56% with STEMI), bivalirudin did not reduce the incidence during primary PCI.
of the primary endpoint (composite of death, MI, or stroke) com-
Routine use of UFH is recommended. I C
pared to UFH. Bivalirudin was associated with lower total and cardio-
vascular mortality, lower bleeding, and more definite stent In patients with heparin-induced thrombo-
thrombosis.209 The recently published STEMI subanalysis confirmed cytopenia, bivalirudin is recommended as I C
a lack of statistical interaction between the type of ACS and out- the anticoagulant agent during primary PCI.
comes within the study.210 The MATRIX trial showed that prolonging
Routine use of enoxaparin i.v. should be
bivalirudin infusion after PCI did not improve the outcomes com- IIa A
considered.200–202
pared with bivalirudin infusion confined to the duration of PCI.209
However, a post hoc analysis suggested that prolonging bivalirudin Routine use of bivalirudin should be
IIa A
with a full-PCI dose after PCI was associated with the lowest risk of considered.209,215
ischaemic and bleeding events, which is in accordance with the cur-
rent label of the drug.209 Based on these data, bivalirudin should be Fondaparinux is not recommended for pri-
III B
considered in STEMI, especially in patients at high bleeding mary PCI.199
risk.197,211,212 Bivalirudin is recommended for patients with heparin-
induced thrombocytopenia. GP = glycoprotein; i.v. = intravenous; PCI = percutaneous coronary intervention;
UFH = unfractionated heparin.
Routine post-procedural anticoagulant therapy is not indicated a
Dose regimens are specified in Table 6.
after primary PCI, except when there is a separate indication for b
Class of recommendation.
c
either full-dose anticoagulation [due, for instance, to atrial fibrillation Level of evidence.

(AF), mechanical valves, or LV thrombus)2 or prophylactic doses for


the prevention of venous thromboembolism in patients requiring
prolonged bed rest.
138 ESC Guidelines

.. 5.2.2.3 Therapies to reduce infarct size and microvascular obstruction


Table 6 Doses of antiplatelet and anticoagulant
..
.. Final infarct size and MVO are major independent predictors of
cotherapies in patients undergoing primary percutane- ..
ous coronary intervention or not reperfused .. long-term mortality and heart failure in survivors of STEMI.216,217
.. MVO is defined as inadequate myocardial perfusion after success-
..
.. ful mechanical opening of the IRA, and is caused by several fac-
.. tors.218 MVO is diagnosed immediately after PCI when post-
..
.. procedural angiographic TIMI flow is < 3, or in the case of a TIMI
.. flow of 3 when myocardial blush grade is 0 or 1, or when ST reso-
..
.. lution within 60–90 min of the procedure is < 70%. Other non-
.. invasive techniques to diagnose MVO are late gadolinium
..
.. enhancement (LGE) CMR (the current state of the art for MVO
.. identification and quantification), contrast echocardiography,
..

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.. single-photon emission computed tomography (SPECT), and posi-
.. tron emission tomography (PET).218 Different strategies, such as
..
.. coronary post-conditioning, remote ischaemic conditioning, early
.. i.v. metoprolol, GP IIb/IIIa inhibitors, drugs targeting mitochondrial
..
.. integrity or nitric oxide pathways, adenosine, glucose modulators,
.. hypothermia, and others, have been shown to be beneficial in pre-
..
.. clinical and small-scale clinical trials,217,219 but still there is no ther-
.. apy aimed at reducing ischaemia/reperfusion injury (MI size) that is
..
.. clearly associated with improved clinical outcomes. The reduction
.. of ischaemia/reperfusion injury in general, and MVO in particular,
..
.. remains an unmet need to further improve long-term ventricular
.. function in STEMI.
..
..
..
..
..
.. 5.3 Fibrinolysis and pharmacoinvasive
..
.. strategy
.. 5.3.1 Benefit and indication of fibrinolysis
..
.. Fibrinolytic therapy is an important reperfusion strategy in settings
..
.. where primary PCI cannot be offered in a timely manner, and pre-
.. vents 30 early deaths per 1000 patients treated within 6 h after
..
.. symptom onset.220 The largest absolute benefit is seen among
.. patients at highest risk, including the elderly, and when treatment
..
.. is offered <2 h after symptom onset.138,221 Fibrinolytic therapy is
.. recommended within 12 h of symptom onset if primary PCI can-
..
.. not be performed within 120 min from STEMI diagnosis (see Figure
.. 3) and there are no contraindications. The later the patient
..
.. presents (particularly after 3 h),98,120,121 the more consideration
.. should be given to transfer for primary PCI (as opposed to admin-
..
.. istering fibrinolytic therapy) because the efficacy and clinical bene-
.. fit of fibrinolysis decrease as the time from symptom onset
..
.. increases.120 In the presence of contraindications for fibrinolytic
.. treatment, it is important to weigh the potentially life-saving
..
... effect of fibrinolysis against potentially life-threatening side effects,
.. taking into account alternative treatment options such as delayed
.. primary PCI.

b.i.d. = twice a day; GP = glycoprotein; i.v. = intravenous; IU = international units;


PCI = percutaneous coronary intervention; UFH = unfractionated heparin.
ESC Guidelines 139

Fibrinolytic therapy

Recommendations Classa Levelb

When fibrinolysis is the reperfusion strategy, it is recommended to initiate this treatment as soon as possible after STEMI
I A
diagnosis, preferably in the pre-hospital setting.96,98,123,222

A fibrin-specific agent (i.e. tenecteplase, alteplase, or reteplase) is recommended.223,224 I B

A half-dose of tenecteplase should be considered in patients 75 years of age.121 IIa B

Antiplatelet co-therapy with fibrinolysis

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Oral or i.v. aspirin is indicated.213 I B

Clopidogrel is indicated in addition to aspirin.225,226 I A


c
DAPT (in the form of aspirin plus a P2Y12 inhibitor ) is indicated for up to 1 year in patients undergoing fibrinolysis and
I C
subsequent PCI.

Anticoagulation co-therapy with fibrinolysis

Anticoagulation is recommended in patients treated with lytics until revascularization (if performed) or for the duration of I A
hospital stay up to 8 days.199,224,227–233 The anticoagulant can be:
I A
• Enoxaparin i.v. followed by s.c. (preferred over UFH).227–232
UFH given as a weight-adjusted i.v. bolus followed by infusion.224 I B

• In patients treated with streptokinase: fondaparinux i.v. bolus followed by an s.c. dose 24 h later.199,233 IIa B

Transfer after fibrinolysis

Transfer to a PCI-capable centre following fibrinolysis is indicated in all patients immediately after fibrinolysis.121,124,126–130,234 I A

Interventions following fibrinolysis

Emergency angiography and PCI if indicated is recommended in patients with heart failure/shock.124, 235 I A

Rescue PCI is indicated immediately when fibrinolysis has failed (<50% ST-segment resolution at 60–90 min) or at any time in
I A
the presence of haemodynamic or electrical instability, or worsening ischaemia.121,124,236

Angiography and PCI of the IRA, if indicated, is recommended between 2 and 24 h after successful fibrinolysis.125–128,234 I A

Emergency angiography and PCI if needed is indicated in the case of recurrent ischaemia or evidence of reocclusion after initial
I B
successful fibrinolysis.124

DAPT = dual antiplatelet therapy; IRA = infarct-related artery; i.v. = intravenous; PCI = percutaneous coronary intervention; SBP = systolic blood pressure; s.c. = subcutaneous;
STEMI = ST-segment elevation myocardial infarction; UFH = unfractionated heparin.
a
Class of recommendation.
b
Level of evidence.
c
Clopidogrel is the P2Y12 inhibitor of choice as co-adjuvant and after fibrinolysis, but 48 h after fibrinolysis, switch to prasugrel/ticagrelor may be considered in patients who
underwent PCI.

..
Doses of fibrinolytic agents and antithrombotic co-therapies are .. initiation of fibrinolytic treatment when a reperfusion strategy is indi-
listed in Table 7. .. cated.97,99,100,237 The STREAM trial showed that pre-hospital fibrinol-
..
.. ysis followed by an early PCI strategy was associated with a similar
5.3.2 Pre-hospital fibrinolysis .. outcome as transfer for primary PCI in STEMI patients presenting
..
In a meta-analysis of six randomized trials (n = 6434), pre-hospital .. within 3 h after symptom onset who could not undergo primary PCI
fibrinolysis reduced early mortality by 17% compared with in-hospital
.. within 1 h after FMC.121,238
..
fibrinolysis,123 particularly when administered in the first 2 h of symp- .. If trained medical or paramedical staff are able to analyse the ECG on-
tom onset.138 These and more recent data support pre-hospital
.. site or to transmit the ECG to the hospital for interpretation, it is
140 ESC Guidelines

Table 7 Doses of fibrinolytic agents and antithrombotic co-therapies

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a
PTT = activated partial thromboplastin time; eGFR = estimated glomerular filtration rate; i.v. = intravenous; IU = international units; rPA = recombinant plasminogen activator;
s.c. = subcutaneous; tPA = tissue plasminogen activator; UFH = unfractionated heparin.

recommended to initiate fibrinolytic therapy in the pre-hospital .. compared with a ‘watchful waiting’ strategy, in which angiography
..
setting. The aim is to start fibrinolytic therapy within 10 min from STEMI .. and revascularization were indicated only in patients with spontane-
diagnosis.
.. ous or induced severe ischaemia or LV dysfunction, or in those with a
..
.. positive outpatient ischaemia test. The benefits of early routine PCI
.. after fibrinolysis were seen in the absence of an increased risk of
5.3.3 Angiography and percutaneous coronary ..
intervention after fibrinolysis (pharmacoinvasive .. adverse events (stroke or major bleeding), and across patient sub-
.. groups.241 Thus, early angiography with subsequent PCI if indicated is
strategy) ..
Following initiation of lytic therapy, it is recommended to transfer the .. also the recommended standard of care after successful fibrinolysis
..
patients to a PCI centre (Figure 3). In cases of failed fibrinolysis, or if .. (see Figure 3).
there is evidence of reocclusion or reinfarction with recurrence of .. A crucial issue is the optimal time delay between successful lysis and
..
ST-segment elevation, immediate angiography and rescue PCI is indi- .. PCI; there was a wide variation in delay in trials, from a median of 1.3 h
cated.124 In this setting, re-administration of fibrinolysis has not been .. in the Combined Angioplasty and Pharmacological Intervention versus
..
shown to be beneficial and should be discouraged.124 Even if it is .. Thrombolytics ALone in Acute Myocardial Infarction (CAPITAL AMI)
likely that fibrinolysis will be successful (ST-segment resolution .. trial240 to 17 h in the Grupo de Analisis de la Cardiopatıa Isquémica
..
> 50% at 60–90 min; typical reperfusion arrhythmia; and disappear- .. Aguda (GRACIA)-1234 and STREAM trials.121 In a pooled patient-level
ance of chest pain), a strategy of routine early angiography is recom- .. analysis of six randomized trials, very early angiography (<2 h) after
..
mended if there are no contraindications. Several randomized .. fibrinolysis was not associated with an increased risk of 30 day death/
trials126–128,234,239,240 and meta-analyses129,130 have shown that early
.. reinfarction or in-hospital major bleeding, and a shorter time from
..
routine angiography with subsequent PCI (if needed) after .. symptom onset to angiography (<4 h) was associated with reduced
fibrinolysis reduced the rates of reinfarction and recurrent ischaemia
.. 30 day and 1 year death/reinfarction and 30 day recurrent ischaemia.125
ESC Guidelines 141

..
Based on this analysis, as well as on trials having a median delay .. lower weight, female sex, previous cerebrovascular disease, and systolic
between start of lysis and angiography of 2–17 h,121,126–128 a time- .. and diastolic hypertension on admission are significant predictors of
..
window of 2–24 h after successful lysis is recommended. .. intracranial haemorrhage.245 In the latest trials, intracranial bleeding
.. occurred in 0.9–1.0% of the total population studied.121,223,246 In the
..
5.3.4 Comparison of fibrinolytic agents .. STREAM trial, the initial excess in intracranial haemorrhage in patients
A fibrin-specific agent should be preferred.224 Single-bolus weight- .. 75 years was reduced after the protocol amendment to reduce the
..
adjusted tenecteplase tissue plasminogen activator (TNK-tPA) is .. dose of tenecteplase by 50%. Data from a number of studies suggest
equivalent to accelerated tPA in reducing 30 day mortality, but is .. that major non-cerebral bleeds occurred in 4–13% of the patients
..
safer in preventing non-cerebral bleeds and blood transfusion, and is .. treated.121,223,224,246 Administration of streptokinase may be associated
easier to use in the pre-hospital setting.223 .. with hypotension, but severe allergic reactions are rare. Re-
..
.. administration of streptokinase should be avoided because of antibodies
.. that can impair its activity, and because of the risk of allergic reactions.
5.3.5 Adjunctive antiplatelet and anticoagulant therapies ..

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An early study showed that the benefits of aspirin and fibrinolytics ..
..
(i.e. streptokinase) were additive.213 The first dose of aspirin should ..
.. 5.3.7 Contraindications to fibrinolytic therapy
be chewed or given i.v. and a low dose (75–100 mg) given orally daily
.. Short successful resuscitation does not contraindicate fibrinolytic
thereafter. Clopidogrel added to aspirin reduces the risk of cardio- .. therapy. In patients in refractory cardiac arrest, lytic therapy is not
vascular events and overall mortality in patients treated with fibrinol- ..
.. effective, increases the risk of bleeding, and is therefore not recom-
ysis225,226 and should be added to aspirin as an adjunct to lytic
... mended. Prolonged, or traumatic but successful, resuscitation
therapy. Prasugrel and ticagrelor have not been studied as adjuncts to .. increases bleeding risk and is a relative contraindication to fibrinoly-
fibrinolysis. There is no evidence that administration of GP IIb/IIIa ..
.. sis.247 Table 8 lists the absolute and relative contraindications to fibri-
inhibitors improves myocardial perfusion or outcomes in patients .
treated with fibrinolysis, and bleeding may increase.242 ... nolytic therapy.
..
Parenteral anticoagulation should preferably be given until revascula- ..
rization (if performed). Otherwise, it should be given for at least 48 h .. Table 8 Contra-indications to fibrinolytic therapy
..
or for the duration of hospital stay, up to 8 days. In spite of an increased ..
risk of major bleeding, the net clinical benefit favoured enoxaparin over ..
..
UFH in the ASsessment of the Safety and Efficacy of a New ..
Thrombolytic 3 (ASSENT 3) trial (n = 6095).227 In the large ..
..
Enoxaparin and Thrombolysis Reperfusion for Acute myocardial ..
infarction Treatment–Thrombolysis In Myocardial Infarction
..
..
25 (ExTRACT–TIMI 25) trial (n = 20 506), a lower dose of enoxaparin ..
was given to patients 75 years of age and to those with impaired renal
..
..
function (estimated creatinine clearance <30 mL/min). Enoxaparin was ..
associated with a reduction in the risk of death and reinfarction at 30
..
..
days when compared with a weight-adjusted UFH dose, but at the cost ..
of a significant increase in non-cerebral bleeding complications. The net
..
..
clinical benefit (i.e. absence of death, non-fatal infarction, and intracra- ..
..
nial haemorrhage) favoured enoxaparin.229,230 Finally, fondaparinux ..
was shown in the large OASIS-6 trial to be superior in this setting to ..
..
placebo or UFH in preventing death and reinfarction,199,233 especially ..
in patients who received streptokinase. ..
..
In a large trial with streptokinase,243 significantly fewer reinfarc- ..
tions were seen with bivalirudin given for 48 h compared with UFH, ..
..
though at the cost of a modest and non-significant increase in non- ..
cerebral bleeding complications. Bivalirudin has not been studied ..
..
with fibrin-specific agents. Thus, there is no evidence in support of ..
direct thrombin inhibitors as an adjunct to fibrinolysis. ..
..
Weight-adjusted i.v. tenecteplase, aspirin, and clopidogrel given ..
orally, and enoxaparin i.v. followed by s.c. administration until the ..
..
time of PCI (revascularisation), comprise the antithrombotic cocktail ..
most extensively studied as part of a pharmacoinvasive ..
..
strategy.121,126,128,242,244 ..
..
..
5.3.6 Hazards of fibrinolysis ..
Fibrinolytic therapy is associated with a small but significant excess of
..
..
strokes, largely attributable to cerebral haemorrhage, with the excess .. DBP = diastolic blood pressure; SBP = systolic blood pressure.
hazard appearing on the first day after treatment.220 Advanced age,
..
142 ESC Guidelines

.. patients. Longer monitoring should be considered in patients at


5.4 Coronary artery bypass graft surgery ..
Emergent coronary artery bypass graft surgery (CABG) should be .. intermediate- to high-risk for cardiac arrhythmias (those
.. with more than one of the following criteria: haemodynamically
considered for patients with a patent IRA but with unsuitable anat- ..
omy for PCI, and either a large myocardial area at jeopardy or with .. unstable, presenting major arrhythmias, LVEF <40%, failed reper-
.. fusion, additional critical coronary stenoses of major vessels, or
cardiogenic shock.248 In patients with MI-related mechanical compli- ..
cations who require coronary revascularization, CABG is recom-
.. complications related to PCI). Further monitoring for arrhythmias
.. depends on estimated risk. When a patient leaves the CCU/ICCU
mended at the time of repair. In STEMI patients with failed PCI or ..
coronary occlusion not amenable to PCI, emergent CABG is infre-
.. or equivalent, monitoring may be continued by telemetry. It is
.. recommended that personnel adequately equipped and trained
quently performed because the benefits of surgical revascularization ..
in this setting are uncertain. As the delay to reperfusion is long, the
.. to manage life-threatening arrhythmias and cardiac arrest accom-
..
probabilities of myocardial salvage affecting prognosis are low and .. pany patients who are transferred between facilities during
.. the time-window in which they require continuous rhythm

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the surgical risks are elevated. ..
In the absence of randomized data, optimal timing for non- .. monitoring.
..
emergent CABG in stabilized post-MI patients should be determined ..
individually. A review of California discharge data compared patients ..
.. 6.3 Ambulation
who underwent early (<3 days, n = 4676) versus delayed (3 days, ..
n = 4800) post-MI CABG.249 Patients who underwent early CABG .. Early ambulation (day 1) is recommended in the majority of patients
.. and is facilitated by using the radial access for PCI. Patients with
had a higher mortality rate (unadjusted mortality 5.6% vs. 3.8%; ..
propensity-adjusted odds ratio 1.40, 95% CI 1.12–1.74; P < 0.001), .. extensive myocardial damage, heart failure, hypotension, or arrhyth-
.. mias may initially rest in bed before assessment of myocardial func-
with the highest mortality observed in patients on whom surgery was ..
performed on the day of the MI (8.2%). However, no differentiation .. tion and achievement of clinical stabilization. Prolongation of bed rest
.. and limitation of physical activity may occasionally be needed for
was made between NSTEMI and STEMI, and higher-risk patients were ..
more likely to be treated rapidly. Patients with haemodynamic deteri- .. patients with large infarcts or with severe complications depending
.. on symptoms and ability.
oration or who are at high risk of recurrent ischaemic events (i.e. ..
patients with a large area of myocardium at jeopardy due to critical ..
..
coronary stenoses or recurrent ischaemia) should be operated on as ..
soon as possible without waiting for the full recovery of platelet func- .. 6.4 Length of stay
.. The optimal length of stay in the CCU/ICCU and hospital should
tion following discontinuation of DAPT. For all other patients, a wait- ..
ing period of 3–7 days may be the best compromise (at least 3 days
.. be determined on an individual basis, according to the patient’s
.. cardiac risk, comorbidities, functional status, and social support.
following interruption of ticagrelor,187,250 5 days for clopidogrel, and 7 ..
days for prasugrel),7 while it is recommended that aspirin is contin-
.. Generalization of successful reperfusion and knowledge of coro-
.. nary anatomy has led to progressive reductions in length of stay
ued.251 The first aspirin administration post-CABG is recommended ..
6–24 h after surgery in the absence of ongoing bleeding events.252,253
.. after STEMI, with significant reductions in 30 day mortality, sug-
.. gesting that earlier discharge is not associated with late mortal-
..
.. ity.255,256 Several studies have shown that low-risk patients with
.. successful primary PCI and complete revascularization can safely
6. Management during ..
.. be discharged from hospital on day 2 or day 3 after PCI.256–262
hospitalization and at discharge .. Candidates for early discharge after STEMI can be identified using
..
.. simple criteria [e.g. the Second Primary Angioplasty in Myocardial
6.1 Coronary care unit/intensive cardiac ..
.. Infarction (PAMI-II) criteria, the Zwolle primary PCI Index, or
care unit .. other criteria].257,258 The PAMI-II criteria designate as low risk
Following reperfusion, it is recommended to admit STEMI patients to
..
.. patients aged <70 years, with an LVEF >45%, one- or two-vessel
a CCU/ICCU or equivalent unit where continuous monitoring and .. disease, successful PCI, and no persistent arrhythmias. A short
specialized care can be provided. The staff should be thoroughly famil-
..
.. hospital stay implies limited time for proper patient education and
iar with the management of ACS, arrhythmias, heart failure, mechani- .. up-titration of secondary prevention treatments. Consequently,
cal circulatory support, invasive and non-invasive haemodynamic
..
.. these patients should have early post-discharge consultations with
monitoring (arterial and pulmonary artery pressures), respiratory .. a cardiologist, primary care physician, or specialized nurse sched-
..
monitoring, mechanical ventilation, and targeted temperature man- .. uled and be rapidly enrolled in a formal rehabilitation programme,
agement. The unit should also be able to manage patients with serious .. either in-hospital or on an outpatient basis.
..
renal and pulmonary disease. The desirable organization, structure, .. Early (i.e. same day) transfer to a local hospital following successful
and criteria of the CCU/ICCU have been described in an ESC-Acute .. primary PCI is routine practice. This can be done safely under
..
Cardiovascular Care Association (ACCA) position paper.254 .. adequate monitoring and supervision in selected patients, i.e. those
.. without signs or symptoms consistent with ongoing myocardial
..
6.2 Monitoring .. ischaemia, without arrhythmia, who are haemodynamically stable,
ECG monitoring for arrhythmias and ST-segment deviations is
.. not requiring vasoactive or mechanical support, and are not sched-
..
recommended for at least 24 h after symptom onset in all STEMI . uled for further revascularization.263
ESC Guidelines 143

..
Logistical issues for hospital stay
.. should be avoided. Loading of aspirin should be done as in all STEMI
.. patients, and clopidogrel is the P2Y12 inhibitor of choice (600 mg
..
.. loading dose) before or at the latest at the time of PCI. Prasugrel and
Recommendations Classa Levelb .. ticagrelor are not recommended. Ideally, a chronic anticoagulation
..
It is indicated that all hospitals participating in the .. regimen should not be stopped during admission. Gastric protection
care of STEMI patients have a CCU/ICCU equipped .. with a proton pump inhibitor (PPI) is recommended.
I C
..
to provide all aspects of care for STEMI patients, .. Maintenance after STEMI: In general, continuation of oral anticoa-
including treatment of ischaemia, severe heart failure, .. gulation in patients with an indication for DAPT (e.g. after STEMI)
arrhythmias, and common comorbidities. ..
.. should be evaluated carefully and continued only if compelling evi-
Transfer back to a referring non-PCI hospital
.. dence exists. Ischaemic and bleeding risks should be taken into con-
..
Same day transfer should be considered appropri-
.. sideration. While there is a considerable overlap of risk factors
.. associated with ischaemic with bleeding outcomes, multiple bleeding
..

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ate in selected patients after successful primary
PCI, i.e. those without ongoing myocardial ischae- .. risk scores outperform CHA2DS2-VASc [Cardiac failure,
mia, arrhythmia, or haemodynamic instability, not
IIa C .. Hypertension, Age 75 (Doubled), Diabetes, Stroke (Doubled) –
..
requiring vasoactive or mechanical support, and .. VAScular disease, Age 65–74 and Sex category (Female)] in predict-
not needing further early revascularization.263 .. ing bleeding risk.270,271
..
Monitoring .. For most patients, triple therapy (in the form of oral anticoagula-
.. tion, aspirin, and clopidogrel) should be considered for 6 months.
It is indicated that all STEMI patients have ECG
..
I C .. Then, oral anticoagulation plus aspirin or clopidogrel should be con-
monitoring for a minimum of 24 h. .. sidered for an additional 6 months. After 1 year, it is indicated to
..
Length of stay in the CCU .. maintain only oral anticoagulation. In cases of very high bleeding risk,
..
It is indicated that patients with successful reperfu- .. triple therapy can be reduced to 1 month after STEMI, continuing on
sion therapy and an uncomplicated clinical course .. dual therapy (oral anticoagulation plus aspirin or clopidogrel) up to
..
are kept in the CCU/ICCU for a minimum of 24 h
I C .. 1 year, and thereafter only anticoagulation.5,7
whenever possible, after which they may be .. The dose intensity of oral anticoagulation should be carefully
moved to a step-down monitored bed for an addi- ..
.. monitored with a target international normalized ratio in the lower
tional 24–48 h. .. part of the recommended target range. When non-vitamin K antago-
..
Hospital discharge .. nist oral anticoagulants are used, the lowest effective tested dose for
.. stroke prevention should be applied. In general, dose reduction
Early discharge (within 48–72 h) should be consid- ..
ered appropriate in selected low-risk patientsc if .. below the approved dose is not recommended. Recently, the Open-
IIa A .. Label, Randomized, Controlled, Multicenter Study Exploring Two
early rehabilitation and adequate follow-up are ..
arranged.257,259–262,264,265 .. Treatment Strategies of Rivaroxaban and a Dose-Adjusted Oral
.. Vitamin K Antagonist Treatment Strategy in Subjects with Atrial
..
CCU = coronary care unit; ICCU = intensive cardiac care unit; LVEF = left ven- .. Fibrillation who Undergo Percutaneous Coronary Intervention
tricular ejection fraction; PAMI-II, Second Primary Angioplasty in Myocardial .. (PIONEER AF-PCI) study randomized 2124 patients with non-
Infarction; PCI = percutaneous coronary intervention; STEMI = ST-segment ele- ..
vation myocardial infarction.
.. valvular AF, who had undergone PCI with stenting (12% STEMI
a
.. patients), to receive low-dose rivaroxaban [15 mg o.d. (once a day)]
Class of recommendation. ..
b
Level of evidence. .. plus a P2Y12 inhibitor (93% clopidogrel) and no aspirin for 12 months,
c
For example, PAMI-II criteria: age <70 years, LVEF >45%, one- or two-vessel dis- .. very-low-dose rivaroxaban (2.5 mg b.i.d.) plus DAPT (95% clopidog-
ease, successful PCI and no persistent arrhythmias. ..
.. rel) for 1, 6, or 12 months, or standard therapy with a dose-adjusted
.. vitamin K antagonist plus DAPT (96% clopidogrel) for 1, 6, or
..
.. 12 months.272 The primary safety endpoint (TIMI clinically significant
6.5 Special patient subsets .. bleeding) was lower in the two groups receiving rivaroxaban. No dif-
Several specific patient subsets deserve particular consideration.
..
.. ference in major bleeding or transfusion was observed across groups.
..
.. However, this study was underpowered for assessing differences in
6.5.1 Patients taking oral anticoagulation .. ischaemic events such as stent thrombosis or stroke rates.
..
Many patients presenting with STEMI are previously on oral anticoa- .. Therefore, uncertainty remains regarding the comparative perform-
gulation or require long-term anticoagulation afterwards. The addi- .. ance of three tested antithrombotic regimens in patients at high
..
tion of DAPT to oral anticoagulation increases the risk of bleeding .. stroke and/or stent thrombosis risk.
complications two- to three-fold compared to anticoagulation ..
..
alone.266–269 ..
Management during STEMI: Given that oral anticoagulation is a rel- .. 6.5.2 Elderly patients
..
ative contraindication for fibrinolysis, when these patients present .. Owing to the ageing of the population, a higher proportion of elderly
with a STEMI, they should be triaged for primary PCI strategy regard- .. patients is expected to present with STEMI. As these patients may
..
less of the anticipated time to PCI-mediated reperfusion. Patients .. present with atypical symptoms, the diagnosis of MI may be delayed
should receive additional parenteral anticoagulation, regardless of the
.. or missed.27 In addition, the elderly have more comorbidities and are
..
timing of the last dose of oral anticoagulant. GP IIb/IIIa inhibitors . less likely to receive reperfusion therapy compared with younger
144 ESC Guidelines

Table 9 Recommended doses of antithrombotic agents in the acute care of patients with chronic kidney disease

30 mL/min/1.73 m2)
(eGFR 15 to <30

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70-100 IU/kg i.v. (50-70 IU/kg if concomitant with
GP IIb/IIIa inhibitors)

aPTT = activated partial thromboplastin time; CKD = chronic kidney disease; eGFR = estimated glomerular filtration rate; GP = glycoprotein; IU = international units; i.v. =
intravenous; PCI = percutaneous coronary intervention; s.c. = subcutaneous; UFH = unfractionated heparin.
a
Double bolus if administered during primary PCI.

patients.273,274 Elderly patients are also at particular risk of bleeding .. (less frequent presentation with chest pain and fewer typical ECG
..
and other complications from acute therapies because bleeding risk .. signs) diagnosis may be delayed.
increases with age, renal function tends to decrease, and the preva-
.. Although decisions on reperfusion in patients with STEMI have to
..
lence of comorbidities is high. Observational studies have shown fre- .. be made before any assessment of renal function is available, it is
quent excess dosing of antithrombotic therapies in elderly
.. important to estimate the GFR as soon as possible. The type and
..
patients.275 Furthermore, they have a higher risk of mechanical .. dose of antithrombotic agent (see Table 9) and the amount of con-
complications.
.. trast agent should be considered based on renal function.277 ACS
..
It is key to maintain a high index of suspicion for MI in elderly .. patients with chronic kidney disease (CKD) receive frequently excess
patients who present with atypical complaints, treating them as rec-
.. dosing with antithrombotics, contributing to the increased bleeding
..
ommended, and using specific strategies to reduce bleeding risk; .. risk.275 Consequently, in patients with known or anticipated reduc-
..
these include paying attention to proper dosing of antithrombotic .. tion of renal function, several antithrombotic agents should either be
therapies, particularly in relation to renal function, frailty, or comor- .. withheld or their doses reduced appropriately. Ensuring proper
..
bidities, and using radial access whenever possible. There is no upper .. hydration during and after primary PCI and limiting the dose of con-
age limit with respect to reperfusion, especially with primary PCI.276 .. trast agents, preferentially low-osmolality contrast agents, are impor-
..
.. tant steps in minimizing the risk of contrast-induced nephropathy.1
..
6.5.3 Renal dysfunction ..
..
Renal dysfunction [estimated glomerular filtration rate (eGFR) .. 6.5.4 Non-reperfused patients
<30 mL/min/1.73 m2] is present in approximately 30–40% of patients
.. Patients who, for specific reasons (e.g. long delay), fail to receive reper-
..
with ACS and is associated with a worse prognosis and increased risk .. fusion therapy within the recommended time (first 12 h) should imme-
of in-hospital complications.277 Owing to differences in presentation
.. diately be evaluated clinically to rule out the presence of clinical,
ESC Guidelines 145

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Figure 4 Reperfusion strategies in the infarct-related artery according to time from symptoms onset. PCI = percutaneous coronary intervention;
STEMI = ST-segment elevation myocardial infarction.
In early presenters (i.e. those with STEMI diagnosis within 3 hours from symptoms onset), a primary PCI strategy is the reperfusion
strategy of choice. If the anticipated time from STEMI diagnosis to PCI-mediated reperfusion is > 120 min, then immediate fibrinolysis is
indicated. After 3 hours (and up to 12 hours) of symptoms onset, the later the patient presents, the more consideration should be given
to a primary PCI strategy as opposed to administering fibrinolytic therapy. In evolved STEMI (12–48 hours after symptoms onset), a
routine primary PCI strategy (urgent angiography and subsequent PCI if indicated) should be considered in all patients. After 48 hours
(recent STEMI) angiography should be performed but routine PCI of a total occluded IRA is not recommended. Regardless of the time
from symptoms onset, the presence of ongoing symptoms suggestive of ischaemia, haemodynamic instability, or lifethreatening arrhyth-
mias is an indication for a primary PCI strategy.

..
haemodynamic, or electrical instability. A primary PCI strategy is indi- .. ischaemia/viability to decide a late invasive strategy or elective coronary
cated in the presence of signs or symptoms suggestive of ongoing myo- .. angiography should be considered. However, routine PCI is not indi-
..
cardial ischaemia, heart failure, haemodynamic instability, or life- .. cated in totally occluded IRA beyond the first 48 h from symptom onset
threatening arrhythmias,141 and should be considered in stable asympto- .. due to the increased risk of late complications (see Figure 4).135,137
..
matic patients between 12–48 h after symptom onset.133,142 After that .. Early echocardiography with LVEF assessment is indicated in all
time, either a non-invasive test for the presence of residual myocardial .. patients. Medical therapy should include DAPT, anticoagulation, and
146 ESC Guidelines

secondary prevention therapies. In patients in whom PCI is finally


..
.. 6.6. Risk assessment
performed, ticagrelor or prasugrel are preferred,186,187 while in .. 6.6.1 Clinical risk assessment
..
patients who do not undergo PCI, clopidogrel is indicated.225 .. All patients with STEMI should have an early assessment of short-
Anticoagulation, preferably with fondaparinux, is indicated until coro- .. term risk, including an evaluation of the extent of myocardial damage,
..
nary revascularisation is done or hospital discharge.199 These patients .. the occurrence of successful reperfusion, and the presence of clinical
are often undertreated. Therefore, it is important to emphasize that ..
.. markers of high risk of further events including older age, fast heart
they should receive all the same secondary prevention medical thera- .. rate, hypotension, Killip class >I, anterior MI, previous MI, elevated
pies as those who receive timely reperfusion. ..
.. initial serum creatinine, history of heart failure, or peripheral arterial
.. disease. Several risk scores have been developed, based on readily
..
6.5.5 Patients with diabetes .. identifiable parameters in the acute phase before reperfusion.264,283
Patients with diabetes are known to present with atypical chest .. The Global Registry of Acute Coronary Events (GRACE) risk score
..
.. is recommended for risk assessment and adjustment.283,284 All

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pain more frequently than patients without diabetes and conse-
quently may receive delayed initiation of treatment.278 In addition,
.. patients should also have an evaluation of long-term risk before
..
diabetic patients are characterized by a more diffuse atheroscler- .. discharge, including LVEF, severity of CAD and completeness of cor-
otic disease.279 Although patients with diabetes are at higher risk of
.. onary revascularization, residual ischaemia, occurrence of complica-
..
death and complications (including repeat revascularization after .. tions during hospitalization, and levels of metabolic risk markers,
PCI), selection of antithrombotic therapies and reperfusion ther-
.. including total cholesterol, low-density lipoprotein cholesterol (LDL-
..
apy is the same as in patients without diabetes. Regarding the use .. C), high-density lipoprotein cholesterol (HDL-C), fasting triglycer-
of antiplatelet drugs, the more potent oral P2Y12 receptor inhibi-
.. ides, and plasma glucose, as well as renal function. As LDL-C levels
..
tors (prasugrel or ticagrelor) have consistently shown increased .. tend to decrease during the first days after MI, they should be meas-
.. ured as soon as possible after admission.
relative benefits with higher absolute risk reductions in patients ..
with diabetes compared with clopidogrel.280 On admission, it is .. Patients who do not get successful reperfusion are at higher risk of
.. early complications and death. These patients should have an assess-
recommended to evaluate glycaemic status in all STEMI patients ..
with and without a known history of diabetes or hyperglycaemia, .. ment of the presence of residual ischaemia and, if appropriate, myo-
and to monitor it frequently in diabetic patients and patients with ... cardial viability. Because the risk of events decreases with time, early
.. risk assessment is indicated.
hyperglycaemia. In critically ill patients, there is a high risk of ..
hypoglycaemia-related events when using intensive insulin ther- ..
..
apy.281 In the absence of robust data to guide the optimal glucose .. 6.6.2 Non-invasive imaging in management and risk
management (e.g. treatment thresholds and glucose targets) in .. stratification
..
STEMI patients, a close but not too strict glucose control seems .. LV dysfunction is a key prognostic factor. Therefore, it is recom-
the best approach. In the acute phase, it is reasonable to manage .. mended that the LVEF is determined before hospital discharge in all
..
hyperglycaemia (i.e. maintain a blood glucose concentration .. STEMI patients. Emergency echocardiography at presentation is indi-
<_11.0 mmol/L or 200 mg/dL) but absolutely avoid hypoglycae- .. cated in patients with cardiac arrest, cardiogenic shock, haemody-
..
mia.282 To assess the risk of renal insufficiency, it is recommended .. namic instability or suspected mechanical complications, and if the
to measure eGFR in patients on metformin and/or sodium-glucose
.. diagnosis of STEMI is uncertain. Routine echocardiography after pri-
..
co-transporter-2 (SGLT2) inhibitors. . mary PCI is recommended to assess resting LV function, as well as

Management of hyperglycaemia

Recommendations Classa Levelb

It is recommended to measure glycaemic status at initial evaluation in all patients, and perform frequent monitoring in patients
I C
with known diabetes or hyperglycaemia (defined as glucose levels 11.1 mmol/L or  200 mg/dL)

In patients on metformin and/or SGLT2 inhibitors, renal function should be carefully monitored for at least 3 days after
I C
coronary angiography/PCI.c

Glucose-lowering therapy should be considered in ACS patients with glucose levels >10 mmol/L (>180 mg/dL), while
IIa C
episodes of hypoglycaemia (defined as glucose levels <_3.9 mmol/L or <_ 70 mg/dL) should be avoided.

Less stringent glucose control should be considered in the acute phase in patients with more advanced cardiovascular
IIa C
disease, older age, longer diabetes duration, and more comorbidities.

ACS = acute coronary syndrome; PCI = percutaneous coronary intervention; SGLT2 = sodium-glucose co-transporter-2.
a
Class of recommendation.
b
Level of evidence.
c
A short withdrawal of metformin may be considered after an invasive coronary procedure.
ESC Guidelines 147

RV and valve function, to exclude early post-infarction mechanical


Summary of indications for imaging and stress testing
complications and LV thrombus. This assessment is usually per-
in ST-elevation myocardial infarction patients
formed with echocardiography, but in the limited cases in which
echocardiography may be suboptimal or inconclusive, CMR may be a
Recommendations Classa Levelb
good alternative. Patients with multivessel disease in which only the
IRA lesion has been treated, or patients with late-presenting STEMI, At presentation
may benefit from additional assessment for residual ischaemia or via-
Emergency echocardiography is indicated in
bility. Treatment of non-IRA lesions in patients with multivessel dis-
patients with cardiogenic shock and/or haemody-
ease is discussed in section 5.2.1.4. In patients presenting days after I C
namic instability or suspected mechanical compli-
the acute event with a completed MI, the presence of recurrent
cations without delaying angiography.295
angina or documented ischaemia and proven viability in a large myo-
cardial territory may help define a strategy of planned revasculariza- Emergency echocardiography before coronary

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tion of an occluded IRA,135,285,286 although the evidence is angiography should be considered if the diagnosis IIa C

controversial. is uncertain.295

The timing of and best imaging technique (echocardiography, Routine echocardiography that delays emergency
SPECT, CMR, or PET) to detect residual ischaemia and myocardial III C
angiography is not recommended.295
viability remains to be determined, but will also depend on local avail-
Coronary CT angiography is not recommended III C
ability and expertise. The best validated and widely available tests are
stress echocardiography and SPECT (both used in combination with During hospital stay (after primary PCI)
exercise or pharmacological stress), but PET and CMR are equally
Routine echocardiography to assess resting LV
indicated. However, in post-MI patients, the detection of residual
and RV function, detect early post-MI mechanical
ischaemia by echocardiography is challenging due to existing wall I B
complications, and exclude LV thrombus is rec-
motion abnormalities.287 LGE-CMR imaging has a high diagnostic
ommended in all patients.296,297
accuracy for assessing the transmural extent of myocardial scar tis-
sue.288 However, the ability to detect viability and predict recovery Emergency echocardiography is indicated in hae-
I C
of wall motion is not significantly superior to other imaging techni- modynamically unstable patients.295
ques.289 The presence of dysfunctional viable myocardium by LGE-
When echocardiography is suboptimal/inconclu-
CMR is an independent predictor of mortality in patients with ischae-
sive, an alternative imaging method (CMR prefera- IIa C
mic LV dysfunction.290
bly) should be considered.
More recently, the presence of wall thinning with limited scar bur-
den was shown to be associated with improved contractility and res- Either stress echo, CMR, SPECT, or PET may be
olution of wall thinning after revascularization, emphasizing the used to assess myocardial ischaemia and viability, IIb C

importance of viability beyond wall thickness and myocardial revascu- including in multivessel CAD.1,298–300

larization to improve prognosis.291 PET is also a high-resolution tech- After discharge


nique but its use is limited by cost and availability. A randomized
clinical trial with PET imaging demonstrated that patients with a sub- In patients with pre-discharge LVEF <_40%, repeat
echocardiography 6–12 weeks after MI, and after
stantial amount of dysfunctional but viable myocardium are likely to
complete revascularization and optimal medical
benefit from myocardial revascularization and may show improve- I C
therapy, is recommended to assess the potential
ments in regional and global contractile function, symptoms, exercise
need for primary prevention ICD
capacity, and long-term prognosis.292 The association between viabil-
implantation.3,296
ity and improved survival after revascularisation was also demon-
strated by a meta-analysis.293 When echo is suboptimal or inconclusive, alterna-
In patients with a pre-discharge LVEF <_40%, re-evaluation of tive imaging methods (CMR preferably) should be IIa C
LVEF 6–12 weeks after complete revascularization and optimal considered to assess LV function.
medical therapy is recommended to assess the potential need for
primary prevention implantable cardioverter defibrillator (ICD) CAD = coronary artery disease; CMR = cardiac magnetic resonance; CT = com-
implantation.3 Additional parameters that are measured by imag- puted tomography; ICD = implantable cardioverter defibrillator; LV = left ven-
tricular; LVEF = left ventricular ejection fraction; MI = myocardial infarction; PCI
ing in these patients and that could be used as endpoints in clinical = percutaneous coronary intervention; PET = positron emission tomography; RV
trials are: (1) infarct size (CMR, SPECT, and PET); (2) myocar- = right ventricular; SPECT = single-photon emission computed tomography.
a
dium at risk (SPECT, CMR); (3) MVO (CMR); and (4) intra- Class of recommendation.
b
Level of evidence.
myocardial haemorrhage (CMR). Infarct size and MVO are pre-
dictors of long-term mortality and heart failure in STEMI
survivors.216,217,294
148 ESC Guidelines

..
7. Long-term therapies for ..
..
with STEMI. However, it has not been established that weight reduc-
tion per se reduces mortality.
ST-segment elevation myocardial ..
..
infarction .. 7.1.3 Exercise-based cardiac rehabilitation
..
.. All AMI patients should participate in an exercise-based cardiac reha-
7.1 Lifestyle interventions and risk factor ..
.. bilitation programme,309 taking into account their age, pre-infarction
control .. level of activity, and physical limitations. A cardiac rehabilitation pro-
Key lifestyle interventions include cessation of smoking, optimal
..
.. gramme preferably includes exercise training, risk factor modification,
blood pressure control, diet advice and weight control, and encour- .. education, stress management, and psychological support.309 In a large
aging physical activity. Detailed recommendations are available from
..
.. meta-analysis, exercise training as part of a cardiac rehabilitation pro-
the ESC Guidelines on prevention.4 During hospitalization, the time .. gramme was associated with a 22% reduction in cardiac mortality rate
..
for implementing secondary prevention is limited and a close collabo- .. in patients with CAD.309 The benefit of cardiac rehabilitation appears

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ration between the cardiologist and the general practitioner, special- .. to be through direct physiological effects of exercise training and
..
ist rehabilitation nurses, pharmacists, dieticians, and physiotherapists .. through cardiac rehabilitation effects on risk factor control, lifestyle
is critically important. Habits of a lifetime are not easily changed, and .. behaviours, and mood.310 An additional benefit in the context of a
..
the implementation and follow-up of these changes are a long-term .. short hospital stay is to ensure proper titration and monitoring of key,
undertaking. .. evidence-based therapies after STEMI. Nowadays, most rehabilitation
..
.. is offered as an outpatient programme of 8–24 weeks’ duration.311,312
..
..
7.1.1 Smoking cessation .. 7.1.4 Resumption of activities
Smoking has a strong pro-thrombotic effect, and smoking cessation is ..
.. Return to work after AMI represents an important indicator of
potentially the most (cost) effective of all secondary prevention .. recovery. Younger women in particular are at greater risk of not
measures.301 Smoking cessation interventions should start during ..
.. returning to work, given evidence of their worse recovery after MI
hospitalization, when smoking is not allowed, and continue during the .. than similarly aged men.313 Decisions should be individualized, based
post-discharge follow-up period.302,303 The beneficial effect of smok- ..
.. on LV function, completeness of revascularization and rhythm con-
ing cessation in patients with CAD, including a majority suffering an .. trol, and the job characteristics. Extended sick leave is usually not
MI, has been shown in a meta-analysis (20 observational studies, ..
.. beneficial and light-to-moderate physical activity after discharge
including 12 603 patients) reporting a 36% reduction of mortality in .. should be encouraged. Sexual activity can be resumed early if
quitters.304
..
.. adjusted to physical ability.
A significant number of CAD patients continue or restart smoking, .. Guidance on air travel including repatriation for patients suffering
illustrating the addictive nature of the smoking habit.305 There is a
..
.. an MI abroad is constrained by limited data. Factors related to the
strong evidence base for brief interventions, with a combination of ..
behavioural support and pharmacotherapies including nicotine
.. clinical circumstances as well as length of travel, whether accompa-
.. nied, and the degree of anxiety also play a role. For uncomplicated
replacement therapy, bupropion, and varenicline.305,306 Electronic ..
cigarettes may also be helpful in achieving smoking cessation, as there
.. completely revascularized MI with LVEF >40% the risk is low and
.. travelling is regarded as safe after hospital discharge (from day 3
is some evidence from two pooled randomized clinical trials (662 ..
patients) showing that electronic cigarettes with nicotine had higher
.. onwards). In complicated STEMI, including patients with heart failure,
.. LVEF <40%, residual ischaemia, and arrhythmia, travelling should be
quit or reduced smoking rates when compared with placebo.307 ..
.. deferred until the condition is stable.314
..
..
.. 7.1.5 Blood pressure control
7.1.2 Diet, alcohol, and weight control ..
Current guidelines on prevention recommend: (i) a diet similar to the .. Hypertension is a prevalent risk factor in patients admitted with
.. STEMI and, consequently, blood pressure should be well controlled.
Mediterranean diet, which includes a maximum of 10% of total ..
energy intake from saturated fat, by replacing it with polyunsaturated .. In addition to lifestyle changes, including reduced salt intake,
.. increased physical activity, and weight loss, pharmacotherapy with a
fatty acids and as little as possible of trans fatty acids; (ii) salt intake ..
of < 5 g per day; (iii) 30–45 g fibre per day; (iv) 200 g fruits and 200 g .. systolic blood pressure (SBP) target of < 140 mmHg should be initi-
.. ated. In elderly, frail patients, the target can be more lenient, whereas
vegetables per day; (v) fish 1–2 times per week (especially oily vari- ..
eties); (vi) 30 g unsalted nuts daily; (vii) limited alcohol intake [maxi- .. in patients at very high risk who tolerate multiple blood pressure-
.. lowering drugs, a target of < 120 mmHg may be considered.4,315,316
mum of 2 glasses (20 g of alcohol) daily for men and 1 for women]; ..
and (viii) discouraging sugar-sweetened drinks.4 Moderate alcohol .. Despite the proven efficacy of this treatment, non-adherence to life-
.. style interventions and medications may affect treatment effect.
consumption in abstainers is not recommended. ..
Overweight and obesity [body mass index (BMI) 25 kg/m2] is ..
..
associated with higher all-cause mortality compared with a healthy .. 7.1.6 Adherence to treatment
weight (BMI between 20 kg/m2 and <25 kg/m2). Abdominal fat is par- .. Low treatment adherence is an important barrier to achieving opti-
..
ticularly harmful and weight loss has beneficial effects on cardiovascu- .. mal treatment targets and is associated with worse outcomes.317
lar disease risk factors. Consequently, maintaining a healthy weight or
.. Delayed outpatient follow-up after AMI results in worse short- and
..
losing weight is recommended for all subjects,308 including patients . long-term medication adherence.318 In a meta-analysis of 376 162
ESC Guidelines 149

..
patients, adherence to cardiovascular medications was estimated to .. 7.2.2 Duration of dual antiplatelet therapy and
be about 57% after a median of 2 years.319 .. antithrombotic combination therapies
..
It is generally recognized that adherence is determined by the .. DAPT, combining aspirin and a P2Y12 inhibitor (i.e. prasugrel, ticagre-
interplay of socioeconomic, medication-related, condition-related, .. lor, or clopidogrel), is recommended in patients with STEMI who are
..
health system-related, and patient-related factors.320 A strategy to .. undergoing primary PCI (for up to 12 months).186,187 Clopidogrel is
reduce poor adherence is the use of a fixed-dose combination or pol- .. recommended for 1 month in patients treated with fibrinolysis with-
..
ypill, including key medications to reduce cardiovascular risk, as a .. out subsequent PCI.225,226 Expanding the duration of DAPT up to
once-daily dose pill.321,322 The only study dedicated to post-MI .. 12 months should be considered in these patients.
..
patients is the recent phase 2 Fixed-Dose Combination Drug for .. For patients undergoing fibrinolysis and subsequent PCI, DAPT is
Secondary Cardiovascular Prevention (FOCUS) trial,323 in which 695 .. recommended for 12 months. Clopidogrel is the P2Y12 inhibitor of
..
patients post-MI were randomized to usual care or to a polypill- .. choice as co-adjuvant and after fibrinolysis. Potent P2Y12 inhibitors
based strategy [polypill containing aspirin, an angiotensin-converting .. have not been properly tested in patients undergoing fibrinolysis, and
..

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enzyme (ACE) inhibitor, and a statin]. In this trial, after 9 months of .. safety (i.e. bleeding complications) is not well established. However,
follow-up, the polypill group showed improved adherence compared .. in patients who underwent PCI after fibrinolysis, after a safety period
..
with the group receiving separate medications. Larger trials are .. (arbitrarily considered 48 h), there are no biological grounds to con-
needed to confirm a clinical benefit in secondary prevention.
.. sider that potent P2Y12 inhibitors will add risk and not exert a benefit
..
Although low adherence has been qualified as an ubiquitous prob- .. over clopidogrel as in the primary PCI setting.
lem,324 healthcare professionals and patients should be aware of this
.. Whereas no dedicated study exists on optimal DAPT duration in
..
challenge and optimize communication by providing clear informa- .. patients at high bleeding risk, multiple studies have shown that short-
tion, simplify treatment regimens, aim at shared decision-making, and
.. ening DAPT to 6 months, compared with 12 months or longer,
..
implement repetitive monitoring and feedback. .. reduces the risk of major bleeding complications, with no apparent
..
.. trade-off in ischaemic events.331,332
.. Two major studies have shown the benefit towards reduction of
Behavioural aspects after ST-elevation myocardial ..
infarction .. non-fatal ischaemic events in patients receiving longer than
.. 12 months of DAPT.333,334 The DAPT Study included only roughly
..
Classa Levelb
.. 10% of STEMI patients and no information has so far been provided
Recommendations .. with respect to the benefit of prolonging clopidogrel or prasugrel
..
It is recommended to identify smokers and .. from 12 to 30 months in this patient subset. Hence, no formal recom-
provide repeated advice on stopping, with offers .. mendations are possible for the use of clopidogrel or prasugrel
..
to help with the use of follow-up support, nicotine I A .. beyond 1 year.334
replacement therapies, varenicline, and bupropion .. More recently, the Prevention of Cardiovascular Events in Patients
..
individually or in combination.4,302,303,325–327 .. with Prior Heart Attack Using Ticagrelor Compared to Placebo on a
.. Background of Aspirin–Thrombolysis in Myocardial Infarction 54
Participation in a cardiac rehabilitation programme ..
is recommended.4,309,328
I A .. (PEGASUS-TIMI 54) trial examined two doses of ticagrelor (60 mg
.. and 90 mg b.i.d.) vs. placebo in patients with a history of MI 1–3 years
..
A smoking cessation protocol is indicated for each
I C .. previously and with high-risk features; the study showed a reduction
hospital participating in the care of STEMI patients. .. in MACE with 90 mg ticagrelor.333 There was no reduction in total
..
The use of the polypill and combination therapy
.. mortality, but there was a borderline signal towards reduced cardio-
.. vascular mortality (when both doses were pooled) consistent with
to increase adherence to drug therapy may be IIb B ..
considered.4,322,323 .. the reduction in non-fatal outcomes.333 The 60 mg (but not the
.. 90 mg) ticagrelor (plus aspirin) regimen also significantly reduced the
..
.. stroke risk compared with aspirin monotherapy. The ticagrelor regi-
STEMI = ST-segment elevation myocardial infarction.
a
.. men was associated with a significantly increased bleeding risk.
Class of recommendation. ..
b
Level of evidence. .. Patients with previous STEMI comprised more than 50% of the over-
..
.. all PEGASUS-TIMI 54 population, and subgroup analysis has shown
.. consistent results in patients with previous STEMI vs. NSTEMI.333
7.2 Antithrombotic therapy ..
.. According to the available data, extension of DAPT beyond 1 year
Full text about long-term antithrombotic therapy can be found in the .. (up to 3 years) in the form of aspirin plus ticagrelor 60 mg b.i.d. may
online Web Addenda. In addition, this topic is covered in great detail ..
.. be considered in patients who have tolerated DAPT without a bleed-
in the ESC Focused Update on DAPT in CAD published simultane- .. ing complication and having one additional risk factor for ischaemic
ously with these guidelines.7 ..
.. events.
.. Gastric protection with a PPI is recommended for patients with a
..
7.2.1 Aspirin .. history of gastrointestinal bleeding and is appropriate for patients
Aspirin is recommended indefinitely in all patients with STEMI.329,330 .. with multiple risk factors for bleeding, such as advanced age, concur-
..
For long-term prevention, low aspirin doses (75–100 mg) are indi- .. rent use of anticoagulants, steroids or non-steroidal anti-inflamma-
cated due to similar anti-ischaemic and less adverse events than
.. tory drugs including high-dose aspirin, and Helicobacter pylori
..
higher doses, as demonstrated in the CURRENT-OASIS 7 trial.330 . infection.335–337
150 ESC Guidelines

..
In the Acute Coronary Syndrome–Thrombolysis In Myocardial .. (METOCARD-CNIC) trial (n = 270) showed that the very early
Infarction 51 (ATLAS ACS 2–TIMI 51) trial (n = 15 526, 50% STEMI), .. administration of i.v. metoprolol (15 mg) at the time of diagnosis
..
a low dose of rivaroxaban (2.5 mg twice daily), on top of aspirin plus .. in patients with anterior STEMI, no signs of heart failure, and
clopidogrel, reduced the composite primary endpoint of cardiovas- .. SBP >120 mmHg was associated with a reduction in infarct
..
cular death, MI, or stroke, but also all-cause mortality, over a mean .. size measured by CMR at 5–7 days (25.6 g vs. 32.0 g; P = 0.012),
follow-up of 13 months.338 Stent thrombosis was reduced by one- .. and higher LVEF at 6 months CMR (48.7% vs. 45.0%; P = 0.018)
..
third. However, this was associated with a three-fold increase in non- .. compared with control treatment.347,348 All patients without con-
CABG-related major bleeding and intracranial haemorrhage.338 .. traindications received oral metoprolol within 24 h. The
..
Based on the ATLAS ACS 2–TIMI 51 trial, in selected patients at low .. incidence of MACE (composite of death, admission as a result of
bleeding risk, the 2.5 mg dose of rivaroxaban may be considered in .. heart failure, reinfarction, or malignant ventricular arrhythmias) at
..
patients who receive aspirin and clopidogrel after STEMI. .. 2 years was 10.8% vs. 18.3% in the i.v. metoprolol and control
.

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Maintenance antithrombotic strategy after ST-elevation myocardial infarction

Recommendations Classa Levelb

Antiplatelet therapy with low-dose aspirin (75–100 mg) is indicated.329 I A

DAPT in the form of aspirin plus ticagrelor or prasugrel (or clopidogrel if ticagrelor or prasugrel are not available or are contraindicated), is
I A
recommended for 12 months after PCI, unless there are contraindications such as excessive risk of bleeding.186,187

A PPI in combination with DAPT is recommended in patients at high risk of gastrointestinal bleedingc.335–337 I B

In patients with an indication for oral anticoagulation, oral anticoagulants are indicated in addition to antiplatelet therapy.5 I C

In patients who are at high risk of severe bleeding complications, discontinuation of P2Y12 inhibitor therapy after 6 months should be
IIa B
considered.332,339,340

In STEMI patients with stent implantation and an indication for oral anticoagulation, triple therapyd should be considered for 1–6 months
IIa C
(according to a balance between the estimated risk of recurrent coronary events and bleeding).5

DAPT for 12 months in patients who did not undergo PCI should be considered unless there are contraindications such as excessive risk of
IIa C
bleeding.

In patients with LV thrombus, anticoagulation should be administered for up to 6 months guided by repeated imaging.341–343 IIa C

In high ischaemic-risk patientse who have tolerated DAPT without a bleeding complication, treatment with DAPT in the form of ticagrelor
IIb B
60 mg twice a day on top of aspirin for longer than 12 months may be considered for up to 3 years.333

In low bleeding-risk patients who receive aspirin and clopidogrel, low-dose rivaroxaban (2.5 mg twice daily) may be considered.338 IIb B

The use of ticagrelor or prasugrel is not recommended as part of triple antithrombotic therapy with aspirin and oral anticoagulation. III C

AMI = acute myocardial infarction; CAD = coronary artery disease; DAPT = dual antiplatelet therapy; eGFR = estimated glomerular filtration rate; LV = left ventricular; PCI =
percutaneous coronary intervention; PPI = proton pump inhibitor; STEMI = ST-segment elevation myocardial infarction.
a
Class of recommendation.
b
Level of evidence.
c
History of gastrointestinal bleeding, anticoagulant therapy, chronic non-steroidal anti-inflammatory drug/corticosteroid user, and 2 or more of the following: age 65 years,
dyspepsia, gastro-oesophageal reflux disease, H. pylori infection, and chronic alcohol use.
d
Oral anticoagulant, aspirin, and clopidogrel.
e
Defined as age 50 years, and at least one of the following additional high-risk features: age 65 years, diabetes mellitus on medication, a prior spontaneous AMI, multivessel
CAD, or chronic renal dysfunction (eGFR <60 ml/min/1.73 m2).

..
..
7.3 Beta-blockers .. arms (P = 0.065).348 Metoprolol treatment was associated with a
..
7.3.1 Early intravenous beta-blocker administration .. significant reduction in the incidence and extent of MVO.349 The
In patients undergoing fibrinolysis, early i.v. beta-blocker treatment .. Early Intravenous Beta-Blockers in Patients With ST-Segment
..
reduces the incidence of acute malignant ventricular arrhythmias, .. Elevation Myocardial Infarction Before Primary Percutaneous
although there is no clear evidence of long-term clinical .. Coronary Intervention (EARLY-BAMI) trial randomized
..
benefit.344–346 .. 683 patients with STEMI within 12 h of onset to i.v. metoprolol
In patients undergoing primary PCI, the Effect of Metoprolol in .. (5 mg at recruitment and an additional 5 mg immediately before
..
Cardioprotection During an Acute Myocardial Infarction . PCI) or placebo.350 All patients without contraindications
ESC Guidelines 151

..
received oral metoprolol within 12 h. Early i.v. metoprolol admin- .. of early and intensive statin therapy in ACS.364,365 A meta-analysis
istration did not show any benefit in reducing CMR-based .. of trials comparing more- vs. less-intensive LDL-C lowering with
..
infarct size, the trial primary endpoint, available only in 342 .. statins indicated that more-intensive statin therapy produced
patients (55%), or the level of cardiac biomarker release. Early i.v. .. greater reductions in the risks of cardiovascular death, non-fatal
..
metoprolol was associated with a borderline reduction of malig- .. MI, ischaemic stroke, and coronary revascularization.366 For every
nant ventricular arrhythmias (3.6% vs. 6.9%; P = 0.050). Patients .. 1.0 mmol/L reduction in LDL-C, these further reductions in risk
..
treated with i.v. metoprolol showed no increased risk of haemo- .. were similar to the proportional reductions in the trials of statins
dynamic instability, atrioventricular (AV) block, or MACE at .. vs. control. Therefore, statins are recommended in all patients
..
30 days. Post hoc analyses from primary PCI trials testing .. with AMI, irrespective of cholesterol concentration at presenta-
other hypotheses have suggested that early i.v. beta-blocker .. tion. Lipid-lowering treatment should be started as early as possi-
..
administration might be associated with a clinical benefit, but a .. ble, as this increases patient adherence after discharge, and given
selection bias cannot be excluded even after correction for imbal- .. as high-intensity treatment, as this is associated with early and sus-
..

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ances in baseline characteristics.351,352 Based on the current avail- .. tained clinical benefits.4 The intensity of statin therapy should be
able evidence, early administration of i.v. beta-blockers at the .. increased in those receiving a low- or moderate-intensity statin
..
time of presentation followed by oral beta-blockers should .. treatment at presentation, unless they have a history of intoler-
be considered in haemodynamically stable patients undergoing
.. ance to high-intensity statin therapy or other characteristics that
..
primary PCI. .. may influence safety.366–368 The treatment goal is an LDL-C con-
.. centration of < 1.8 mmol/L (<70 mg/dL) or at least 50% reduction
..
7.3.2 Mid- and long-term beta-blocker treatment .. in LDL-C if the baseline LDL-C level is 1.8–3.5 mmol/L.4,367,369
The benefit of long-term treatment with oral beta-blockers after
.. The use of lower-intensity statin therapy should be considered in
..
STEMI is well established, although most of the supporting data .. patients at increased risk of side effects from statins (e.g. elderly,
come from trials performed in the pre-reperfusion era.353 A
..
.. hepatic or renal impairment, previous side effects, or a potential
recent multicentre registry enrolling 7057 consecutive patients .. for interaction with essential concomitant therapy). Following MI,
..
with AMI showed a benefit in terms of mortality reduction at a .. the lipid profile goes through phasic changes, with small reduc-
median follow-up of 2.1 years associated with beta-blocker pre- .. tions in total cholesterol, LDL-C, and HDL-C, and increases in tri-
..
scription at discharge, although no relationship between dose and .. glycerides within the first 24 h.370,371 A lipid profile should be
outcomes could be identified.354 Using registry data, the impact of .. obtained as early as possible after admission for STEMI and can be
..
newly introduced beta-blocker treatment on cardiovascular .. non-fasting, as total and HDL-C show little diurnal variation and
events in 19 843 patients with either ACS or undergoing PCI was .. LDL-C variation is within 10%.372 Lipids should be re-evaluated
..
studied.355 At an average of 3.7 years of follow-up, the use of beta- .. 4–6 weeks after the ACS to determine whether the target levels
blockers was associated with a significant mortality reduction .. have been reached and regarding safety issues; the lipid lowering
..
(adjusted HR 0.90, 95% CI 0.84–0.96). The association between .. therapy can then be adjusted accordingly. Trial results with high
beta-blockers and outcomes differed significantly between .. doses of atorvastatin and simvastatin366,373–375 favour a high-
..
patients with and without a recent MI (HR for death 0.85 vs. 1.02; .. intensity statin.
Pint = 0.007). Opposing these results, in a longitudinal observatio- .. In patients known to be intolerant of any dose of statin, treat-
..
nal propensity-matched study including 6758 patients with pre- .. ment with ezetimibe should be considered. In the Improved
vious MI, beta-blocker use was not associated with a lower risk of .. Reduction of Outcomes: Vytorin Efficacy International Trial
..
cardiovascular events or mortality.356 Based on the current evi- .. (IMPROVE-IT), 18 144 patients with a recent ACS (29% with
dence, routine administration of beta-blockers in all post-STEMI
.. STEMI) were randomized to either ezetimibe 10 mg/simvastatin
..
patients should be considered as discussed in detail in the heart .. 40 mg or simvastatin 40 mg alone (simvastatin was up-titrated to
failure guidelines;6 beta-blockers are recommended in patients
.. 80 mg if LDL-C was >79 mg/dL or 2.04 mmol/L).376 Over a period
..
with reduced systolic LV function (LVEF <_40%), in the absence of .. of 7 years, the composite primary endpoint of cardiovascular
contraindications such as acute heart failure, haemodynamic insta-
.. death, MI, hospital admission for unstable angina, coronary revas-
..
bility, or higher degree AV block. Agents and doses of proven effi- .. cularization, or stroke was significantly lower in the combined
cacy should be administered.357–361 As no study has properly
..
.. treatment arm compared with the statin-only arm (32.7% vs.
addressed beta-blocker duration to date, no recommendation in .. 34.7%; HR 0.94, 95% CI 0.89–0.99).
..
this respect can be made. Regarding the timing of initiation of oral .. Recent data from phase I–III trials show that proprotein con-
beta-blocker treatment in patients not receiving early i.v. beta- .. vertase subtilisin/kexin type 9 (PCSK9) inhibitors decrease LDL-
..
blockade, a retrospective registry analysis on 5259 patients sug- .. C up to 60%, either as monotherapy or in addition to a statin
gested that early (i.e. <24 h) beta-blocker administration con- .. dose, and also have beneficial effects on triglycerides and HDL-
..
veyed a survival benefit compared with a delayed one.362 .. C.377–380 Meta-analyses of existing trials with more than 10 000
Therefore, in haemodynamically stable patients, oral beta-blocker .. patients indicate a significant mortality benefit (HR 0.45, 95% CI
..
initiation should be considered within the first 24 h. .. 0.23–0.86) but are based on relatively few endpoints.378,381 In
.. the Further Cardiovascular Outcomes Research with PCSK9
..
7.4 Lipid-lowering therapy .. Inhibition in Subjects with Elevated Risk (FOURIER) trial consist-
The benefits of statins in secondary prevention have been
.. ing of 27 564 patients with atherosclerotic cardiovascular disease,
..
unequivocally demonstrated,363 and trials have shown the benefits . additional risk factors, and LDL 70 mg/dL (1.8 mmol/L), who
152 ESC Guidelines

were already receiving moderate or high intensity statin therapy


.. week.383,393 Treatment with ACE inhibitors is recommended in
..
as compared to placebo, evolocumab injections reduced the pri- .. patients with systolic LV dysfunction or heart failure, hyperten-
mary composite endpoint of cardiovascular death, MI, stroke,
.. sion, or diabetes, and should be considered in all STEMI
..
hospitalization for unstable angina, or coronary revascularization .. patients.394,395 Patients who do not tolerate an ACE inhibitor
by 15% in relative rate and by 1.5% in absolute rate. There were
.. should be given an angiotensin II receptor blocker (ARB). In the
..
no differences in all-cause mortality or cardiovascular mortality .. context of STEMI, valsartan was found to be non-inferior to cap-
..
and no significant differences in adverse events.382 Given the .. topril in the VALsartan In Acute myocardial iNfarcTion
moderate effect over 2 years and the absence of mortality reduc- .. (VALIANT) trial.396
..
tion, its use should still be restricted to selected high-risk ..
patients. ..
..
Based on this relatively limited body of evidence, clinicians should .. 7.8 Mineralocorticoid/aldosterone
consider adding a non-statin treatment to patients at high risk who .. receptor antagonists

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..
do not reach treatment targets after STEMI despite the maximum .. Mineralocorticoid receptor antagonist (MRA) therapy is recom-
tolerated dose of statin. ..
.. mended in patients with LV dysfunction (LVEF <_40%) and heart
.. failure after STEMI.397–400 Eplerenone, a selective aldosterone
..
7.5 Nitrates .. receptor antagonist, has been shown to reduce morbidity and
The routine use of nitrates in STEMI was of no benefit in a .. mortality in these patients. The Eplerenone Post-AMI Heart fail-
..
randomized controlled trial against placebo and is therefore not .. ure Efficacy and SUrvival Study (EPHESUS) randomized 6642
recommended.383 Intravenous nitrates may be useful during the .. post-MI patients with LV dysfunction (LVEF <_40%) and symptoms
..
acute phase in patients with hypertension or heart failure, pro- .. of heart failure/diabetes to eplerenone or placebo within 3–14
vided there is no hypotension, RV infarction, or use of phospho- .. days after their infarction.397 After a mean follow-up of 16 months,
..
diesterase type 5 inhibitors in the previous 48 h. Following the .. there was a 15% relative reduction in total mortality and a 13%
acute phase, nitrates remain valuable agents to control residual
.. reduction in the composite of death and hospitalization for cardi-
..
angina symptoms. .. ovascular events.
.. Two recent studies have indicated a beneficial effect of early
..
7.6 Calcium antagonists .. treatment with MRA in the setting of STEMI without heart failure.
.. The Double-Blind, Randomized, Placebo-Controlled Trial
A meta-analysis of 17 trials involving calcium antagonists early in ..
the course of STEMI showed no beneficial effect on death or rein-
.. Evaluating The Safety And Efficacy Of Early Treatment With
.. Eplerenone In Patients With Acute Myocardial Infarction
farction, with a trend of higher mortality for patients treated with ..
nifedipine. Therefore, routine use of calcium antagonists in the
.. (REMINDER) trial randomized 1012 patients with acute STEMI
.. without heart failure to eplerenone or placebo within 24 h of
acute phase is not indicated.384,385 In the chronic phase, a random- ..
ized controlled trial allocating 1775 patients with MI not on beta-
.. symptom onset.401 After 10.5 months, the primary combined end-
.. point [CV mortality, re-hospitalization, or extended initial hospital
blockers to verapamil or placebo found that the risk of mortality ..
.. stay due to diagnosis of heart failure, sustained ventricular tachy-
and reinfarction was reduced with verapamil.386 Thus, in patients .. cardia or fibrillation, ejection fraction <_40%, or elevated B-type
with contraindications to beta-blockers, particularly in the pres- ..
.. natriuretic peptide (BNP)/N-terminal pro B-type natriuretic pep-
ence of obstructive airway disease, calcium antagonists are a rea- ..
sonable option for patients without heart failure or impaired LV .. tide (NT-proBNP)] occurred in 18.2% of the active group vs.
.. 29.4% in the placebo group (P < 0.0001), with the difference pri-
function. Routine use of dihydropyridines, on the other hand, has ..
failed to show benefit after STEMI,387 and they should therefore .. marily driven by BNP levels.401 The Aldosterone Lethal effects
.. Blockade in Acute myocardial infarction Treated with or without
only be prescribed for clear additional indications such as hyper- ..
tension or residual angina.388 .. Reperfusion to improve Outcome and Survival at Six months
.. follow-up (ALBATROSS) trial randomized 1603 patients with
..
.. acute STEMI or high-risk NSTEMI to a single i.v. bolus of potassium
7.7 Angiotensin-converting enzyme .. canrenoate (200 mg) followed by spironolactone (25 mg daily) vs.
inhibitors and angiotensin II receptor ..
.. placebo. Overall, the study found no effect on the composite out-
blockers .. come (death, resuscitated cardiac arrest, significant ventricular
..
ACE inhibitors are recommended in patients with an impaired .. arrhythmia, indication for implantable defibrillator, or new or
LVEF (<_40%) or who have experienced heart failure in the early .. worsening heart failure) at 6 months. In an exploratory analysis of
..
phase.383,389–392 A systematic overview of trials of ACE inhibition .. the STEMI subgroup (n = 1229), the outcome was significantly
early in STEMI indicated that this therapy is safe, well tolerated,
.. reduced in the active treatment group (HR 0.20, 95% CI
..
and associated with a small but significant reduction in 30-day .. 0.06–0.70).402 Future studies will clarify the role of MRA treat-
mortality, with most of the benefit observed in the first
.. ment in this setting.
ESC Guidelines 153

Routine therapies in the acute, subacute, and long-term phases: beta-blockers, angiotensin-converting enzyme
inhibitors, angiotensin II receptor blockers, mineralocorticoid receptor antagonists, and lipid-lowering treatments
after ST-elevation myocardial infarction

Recommendations Classa Levelb

Beta-blockers

Oral treatment with beta-blockers is indicated in patients with heart failure and/or LVEF <_40% unless contraindicated.357–361 I A

Intravenous beta-blockers should be considered at the time of presentation in patients undergoing primary PCI without con-
IIa A
traindications, with no signs of acute heart failure, and with an SBP >120 mmHg.346–348,350,403

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Routine oral treatment with beta-blockers should be considered during hospital stay and continued thereafter in all patients
IIa B
without contraindications.344,354–356,404,405

Intravenous beta-blockers must be avoided in patients with hypotension, acute heart failure or AV block, or severe
III B
bradycardia.344

Lipid lowering therapies

It is recommended to start high-intensity statin therapyc as early as possible, unless contraindicated, and maintain it long-
I A
term.364,366,368

An LDL-C goal of < 1.8 mmol/L (70 mg/dL) or a reduction of at least 50% if the baseline LDL-C is between 1.8–3.5 mmol/L
I B
(70–135 mg/dL) is recommended.367,369,376,382

It is recommended to obtain a lipid profile in all STEMI patients as soon as possible after presentation.369,406 I C

In patients with LDL-C 1.8 mmol/L (70 mg/dL) despite a maximally tolerated statin dose who remain at high risk, further
IIa A
therapy to reduce LDL-C should be considered.376,382

ACE inhibitors/ARBs

ACE inhibitors are recommended, starting within the first 24 h of STEMI in patients with evidence of heart failure, LV systolic
I A
dysfunction, diabetes, or an anterior infarct.383

An ARB, preferably valsartan, is an alternative to ACE inhibitors in patients with heart failure and/or LV systolic dysfunction,
I B
particularly those who are intolerant of ACE inhibitors.396,407

ACE inhibitors should be considered in all patients in the absence of contraindications.394,395 IIa A

MRAs

MRAs are recommended in patients with an LVEF <_40% and heart failure or diabetes, who are already receiving an ACE inhib-
I B
itor and a beta-blocker, provided there is no renal failure or hyperkalaemia.397

AV = atrioventricular; ACE = angiotensin-converting enzyme; ARB = angiotensin II receptor blocker; LDL-C = low-density lipoprotein cholesterol; LV = left ventricular; LVEF
= left ventricular ejection fraction; MRA = mineralocorticoid receptor antagonist; PCI = percutaneous coronary intervention; SBP = systolic blood pressure; STEMI = ST-seg-
ment elevation myocardial infarction.
a
Class of recommendation.
b
Level of evidence.
c
High-intensity statin defined as atorvastatin 40–80 mg and rosuvastatin 20–40 mg.

..
When using MRA, care should be taken with reduced renal func- .. 8. Complications following ST-
tion [creatinine concentration >221 mmol/L (2.5 mg/dL) in men and ..
.. segment elevation myocardial
>177 mmol/L (2.0 mg/dL) in women] and routine monitoring of ..
serum potassium is warranted. .. infarction
..
Figures 5 and 6 present the mostly prescribed interventions ..
(class I and IIa) in patients undergoing primary PCI or fibrinolysis
.. Expanded information about complications following STEMI is pre-
.. sented in the Web Addenda.
strategies. .
154 ESC Guidelines

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Figure 5 “Do not forget” interventions in STEMI patients undergoing a primary PCI strategy. ACE = angiotensin-converting enzyme; DAPT = dual
antiplatelet therapy; DES = drug eluting stent; ECG = electrocardiogram; echo = echocardiogram; ED = emergency department; HF = heart failure;
i.v. = intravenous; IRA = infarct related artery; LVEF = left ventricular ejection fraction; MRA = mineralcorticoid receptor antagonist; PCI = percuta-
neous coronary intervention; STEMI = ST-segment elevation myocardial infarction; UFH = Unfractionated heparin.
Mostly prescribed interventions (class I, green, and IIa, yellow) are presented along with the expected timing of delivery. Solid lines represent recur-
rent (daily) intervention. Double-arrowed dashed lines represent a time-window in which the intervention can be delivered.
1
Aspirin loading dose: 150–300 mg chewed or 75–250 mg intravenous (in patients not already on an aspirin maintenance dose).
2
Prasugrel loading dose: 60 mg. Ticagrelor loading dose: 180 mg. If there are contra-indications for prasugrel/ticagrelor or these are not
available, a loading dose of clopidogrel (600 mg) is indicated.
3
If the interventional cardiologist is not expert in radial access, the femoral route is then preferred.
4
Enoxaparin or bivalirudin are alternatives to unfractionated heparin (Class IIa A).
5
Aspirin maintenance dose: 75–100 mg oral.
6
Prasugrel maintenance dose: 10 mg once daily. Ticagrelor maintenance dose: 90 mg twice daily. If there are contra-indications for pra-
sugrel/ticagrelor or these are not available, clopidogrel maintenance (75 mg daily) is indicated.
a
90 min represents the maximum target time to PCI-mediated reperfusion. For patients presenting in a PCI-centre, this target time is
60 min.
b
Prolongation of ticagrelor (60 mg twice daily) in addition to aspirin may be considered for up to 36 months in patients at high ischaemic
risk who have tolerated DAPT without a bleeding complication.
ESC Guidelines 155

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Figure 6 “Do not forget” interventions in STEMI patients undergoing a successful fibrinolysis strategy. ACE = angiotensin-converting enzyme;
DAPT = dual antiplatelet therapy; DES = drug eluting stent; ECG = electrocardiogram; echo = echocardiogram; HF = heart failure; i.v. = intravenous;
IRA = infarct related artery; LVEF = left ventricular ejection fraction; MRA = mineralcorticoid receptor antagonist; PCI = percutaneous coronary
intervention; STEMI = ST-segment elevation myocardial infarction; UFH = Unfractionated heparin.
Mostly prescribed interventions (class I, green, and IIa, light yellow) are presented along with the expected timing of delivery. Solid lines represent
recurrent (daily) intervention. Double-arrowed dashed lines represent a time-window in which the intervention can be delivered.
1
Enoxaparin dose: 30 mg i.v. bolus followed by 1 mg/kg subcutaneous every 12 hours (dose adjustment for 75 years and renal insuffi-
ciency is presented in Table 9). Unfractionated heparin is an alternative to enoxaparin.
2
Aspirin loading dose: 150–300 mg chewed or 75–250 mg intravenous.
3
Clopidogrel loading dose: 300 mg oral (75 mg in  75 years).
4
Aspirin maintenance dose: 75–100 mg oral
5
Clopidogrel maintenance therapy: 75 mg daily.
6
48 hours after fibrinolysis, switch to prasugrel/ticagrelor may be considered in PCI-treated patients.
156 ESC Guidelines

.. Patients with pulmonary congestion and SaO2 <90% or partial


8.1 Myocardial dysfunction ..
8.1.1 Left ventricular dysfunction .. pressure of oxygen (PaO2) <60 mmHg (8.0 kPa) require oxygen
.. therapy and SaO2 monitoring to correct hypoxaemia, with a tar-
See Web Addenda. ..
.. get of 95%, and may require periodic blood-gas assessment. Initial
.. pharmacological treatment includes i.v. loop diuretics (e.g. furose-
8.1.2 Right ventricular involvement ..
.. mide 20–40 mg i.v. with repeated doses at intervals as needed
See Web Addenda. .. according to clinical evolution and diuresis) and, if blood pressure
..
.. allows it, i.v. nitrates, avoiding hypotension or excessive falls in
8.2 Heart failure ..
.. blood pressure. The early use of beta-blockers, ACE inhibitors/
8.2.1 Clinical presentations .. ARBs, and MRA is recommended in the absence of hypotension,
See Web Addenda. ..
.. hypovolaemia, or renal dysfunction. Causal treatment is essential.
.. Coronary revascularization should be performed early when sig-

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..
8.2.2 Management .. nificant CAD is still present. Rhythm disturbances, valvular dys-
Patients with heart failure should be under continuous monitoring .. function, and hypertension should be corrected as soon as
..
of heart rhythm, blood pressure, and urinary output. The mecha- .. possible. Hypertension should be treated promptly with oral ACE
nism of heart failure should be assessed early by physical examina- .. inhibitors/ARBs and i.v. nitrates. In very severe cases, sodium
..
tion, ECG, echocardiography, and (when not rapidly controlled) .. nitroprusside infusion may be necessary. Persistent myocardial
with invasive haemodynamic monitoring, and corrected as soon as
.. ischaemia should be treated with early coronary revascularization.
..
possible. . Atrial and ventricular dysrhythmias, and valvular dysfunction or

Recommendations for the management of left ventricular dysfunction and acute heart failure in ST-elevation myocar-
dial infarction

Recommendations Classa Levelb

ACE inhibitor (or if not tolerated, ARB) therapy is indicated as soon as haemodynamically stable for all patients with
I A
evidence of LVEF <_40% and/or heart failure to reduce the risk of hospitalization and death.390,396,412,413

Beta-blocker therapy is recommended in patients with LVEF <_40% and/or heart failure after stabilization, to reduce the risk
I A
of death, recurrent MI, and hospitalization for heart failure.358–361,414–416

An MRA is recommended in patients with heart failure and LVEF <_40% with no severe renal failure or hyperkalaemia to reduce
I B
the risk of cardiovascular hospitalization and death.397

Loop diuretics are recommended in patients with acute heart failure with symptoms/signs of fluid overload to improve
I C
symptoms.

Nitrates are recommended in patients with symptomatic heart failure with SBP >90 mmHg to improve symptoms and
I C
reduce congestion.

Oxygen is indicated in patients with pulmonary oedema with SaO2 <90% to maintain a saturation >95%. I C

Patient intubation is indicated in patients with respiratory failure or exhaustion, leading to hypoxaemia, hypercapnia, or acidosis,
I C
and if non-invasive ventilation is not tolerated.

Non-invasive positive pressure ventilation (continuous positive airway pressure, biphasic positive airway pressure) should
be considered in patients with respiratory distress (respiratory rate >25 breaths/min, SaO2 <90%) without IIa B
hypotension.410,411,417–419

Intravenous nitrates or sodium nitroprusside should be considered in patients with heart failure and elevated SBP to control
IIa C
blood pressure and improve symptoms.

Opiates may be considered to relieve dyspnoea and anxiety in patients with pulmonary oedema and severe dyspnoea.
IIb B
Respiration should be monitored.6,408

Inotropic agents may be considered in patients with severe heart failure with hypotension refractory to standard medical
IIb C
treatment.

ACE = angiotensin-converting enzyme; ARB = angiotensin II receptor blocker; LV = left ventricular; LVEF = left ventricular ejection fraction; MRA = mineralocorticoid receptor
antagonist; SaO2 = arterial oxygen saturation; SBP = systolic blood pressure; STEMI = ST-segment elevation myocardial infarction.
a
Class of recommendation.
b
Level of evidence.
ESC Guidelines 157

..
mechanical complications, should be treated as appropriate (see .. The first step in patients with cardiogenic shock is to identify
specific sections in this document). .. the mechanism and to correct any reversible cause such as hypo-
..
Severely symptomatic patients with pulmonary congestion may .. volaemia, drug-induced hypotension, or arrhythmias; alternatively,
also need i.v. morphine to reduce dyspnoea and anxiety, but rou- .. initiate the treatment of potential specific causes, such as mechani-
..
tine use is not recommended due to concerns about its safety, as .. cal complications or tamponade.
it may induce nausea and hypopnea.408,409 Non-invasive positive .. Treatments include immediate reperfusion, with primary PCI
..
pressure ventilation (continuous positive airway pressure, bipha- .. whenever possible,248,427 and complete revascularisation if multives-
sic positive airway pressure) or high-flow nasal cannula is effective
.. sel disease is present. In addition, patients at the highest risk for devel-
..
in treating pulmonary oedema and should be considered in .. opment of shock might benefit from an early transfer to tertiary
patients with respiratory distress (respiratory rate >25 breaths/
.. centres before the onset of haemodynamic instability.
..
min, SaO2 <90%) and started soon.410,411 Endotracheal intubation .. Antithrombotic therapy does not differ from that in any STEMI
and ventilatory support may be required in patients unable to
.. patient. The specificities of the management of low-output cardio-
..

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achieve adequate oxygenation, or in those with excess respiratory .. genic shock associated with RV infarction are mentioned in the Web
work or evidence of hypercapnia due to respiratory exhaustion.
.. Addenda.
..
Ultrafiltration to reduce fluid overload may be considered in .. Invasive monitoring with an arterial line is recommended.6 A
..
patients who are refractory to diuretics, especially in patients with .. pulmonary artery catheter may be considered, in order to per-
hyponatraemia. .. form a careful adjustment of filling pressures and assessment of
..
In patients with heart failure and adequate blood pressure .. cardiac output or in cases of shock of unexplained cause.
(SBP >90 mmHg), but a severe reduction in cardiac output resulting .. Hypovolaemia should be ruled out first and corrected with fluid
..
in compromised vital organ perfusion not responding to standard .. loading. Pharmacological therapy aims to improve organ perfusion
therapy, treatment with dobutamine or levosimendan may .. by increasing cardiac output and blood pressure. Diuretic therapy
..
be considered. However, the clinical evidence of levosimendan in .. is recommended when adequate perfusion is attained.
cardiogenic shock is limited. Further details on the management .. Intravenous inotropic agents or vasopressors are usually required
..
of acute heart failure can be found in the 2016 ESC Guidelines .. to maintain an SBP >90 mmHg, and to increase cardiac output and
for the diagnosis and treatment of acute and chronic heart failure.6 .. improve vital organ perfusion. Dobutamine is the initial therapy
..
.. for patients with predominant low cardiac output, whereas nore-
8.2.2.1 Management of hypotension .. pinephrine may be safer and more effective than dopamine in
..
In patients with hypotension and normal perfusion without evidence .. patients with cardiogenic shock and severe hypotension.428
of congestion or volume overload (i.e. collapsible inferior vena cava), .. Levosimendan may be considered as an alternative, especially
..
gentle volume loading should be attempted after ruling out complica- .. for patients on chronic beta-blocker therapy, because its
tions such as mechanical or severe mitral regurgitation, with central
.. inotropic effect is independent of beta-adrenergic stimulation.
..
pressure monitoring. Bradycardia or tachyarrhythmias should be cor- .. Phosphodiesterase III inhibitors are not recommended in STEMI
rected or controlled. In patients with RV infarction, volume overload-
.. patients.
..
ing should be avoided because it might worsen haemodynamics.420 .. IABP counterpulsation does not improve outcomes in patients
If hypotension persists, inotropic therapy, preferably with dobut-
.. with STEMI and cardiogenic shock without mechanical complica-
..
amine, may be considered.420 .. tions,177 nor does it significantly limit infarct size in those with
.. potentially large anterior MIs.175 Therefore, routine IABP coun-
..
8.2.2.2 Management of cardiogenic shock .. terpulsation cannot be recommended, but may be considered for
..
Cardiogenic shock is defined as persistent hypotension (SBP .. haemodynamic support in selected patients (i.e. severe mitral
<90 mmHg) despite adequate filling status with signs of hypoperfu- .. insufficiency or ventricular septal defect). A small exploratory trial
..
sion. It complicates 6–10% of all STEMI cases and remains a leading .. studying the Impella CP percutaneous circulatory support device
cause of death, with in-hospital mortality rates 50%.421 Shock is also .. did not find any benefit compared with IABP in AMI complicated
..
considered to be present if i.v. inotropes and/or mechanical support .. by cardiogenic shock.429
are needed to maintain an SBP >90 mmHg. In STEMI patients present- .. Mechanical LV assist devices (LVADs), including percutaneous
..
ing with cardiogenic shock in which PCI-mediated reperfusion is esti- .. short-term mechanical circulatory support devices (i.e. intra-cardiac
mated to occur >120 min, immediate fibrinolysis and transfer to a PCI .. axial flow pumps and arterial-venous extracorporeal membrane oxy-
..
centre should be considered. In these cases, upon arrival at the PCI .. genation), have been used in patients not responding to standard
centre, emergent angiography is indicated, regardless of the .. therapy, including inotropes, fluids, and IABP, but evidence regarding
..
ST resolution and the time from fibrinolysis administration. It is usually .. their benefits is limited.430 Therefore, short-term mechanical
associated with extensive LV damage, but may occur in RV infarction. .. circulatory support may be considered as a rescue therapy in order
..
Cardiogenic shock characterization and management do not necessa- .. to stabilize the patients and preserve organ perfusion (oxygenation)
rily need invasive haemodynamic monitoring, but ventricular and valve
.. as a bridge to recovery of myocardial function, cardiac transplanta-
..
function should be urgently evaluated by transthoracic echocardiogra- .. tion, or even LV assist device destination therapy on an individual
phy and associated mechanical complications ruled out.422–426
.. basis.431,432
158 ESC Guidelines

..
Recommendations for the management of cardio-
.. 8.3 Management of arrhythmias and
..
genic shock in ST-elevation myocardial infarction .. conduction disturbances in the acute
.. phase
..
Recommendations Classa Levelb .. Arrhythmias and conduction disturbances are common during the
..
Immediate PCI is indicated for patients with
.. early hours of STEMI and are also important prognostic factors.438
.. Despite increased awareness and improved basic and advanced life
cardiogenic shock if coronary anatomy is ..
I B
.. support, the incidence of sudden cardiac death, mainly due to fast
suitable. If coronary anatomy is not suitable .. ventricular tachycardia (VT) and VF in the pre-hospital phase,
for PCI, or PCI has failed, emergency CABG ..
.. remains high.438,439 Early reperfusion therapy reduces the risk of ven-
is recommended.248 .. tricular arrhythmias and cardiovascular death.440,441 The presence of
..
Invasive blood pressure monitoring with an .. life-threatening arrhythmias requires an urgent need for a fast and
I C .. complete revascularization in STEMI.438,442 The evidence for benefits

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arterial line is recommended. ..
.. of antiarrhythmic drugs in STEMI patients is limited and negative
Immediate Doppler echocardiography is .. effects of antiarrhythmic drugs on early mortality have been demon-
indicated to assess ventricular and valvular ..
I C .. strated.439 Careful use of antiarrhythmic drugs is generally recom-
functions, loading conditions, and to detect .. mended and alternative treatment options such as electrical
mechanical complications. ..
.. cardioversion, a ‘wait and see’ strategy for arrhythmias with no or
.. moderate haemodynamic relevance, or in selected cases cardiac pac-
It is indicated that mechanical complications ..
are treated as early as possible after discus- I C ... ing and catheter ablation, should be considered. Correction of elec-
sion by the Heart Team. .. trolyte imbalances and early treatment with beta-blockers, ACE
.. inhibitors/ARBs, and statins is recommended.438,443
Oxygen/mechanical respiratory support is
..
I C ..
indicated according to blood gases. ..
..
Fibrinolysis should be considered in patients ..
.. 8.3.1 Supraventricular arrhythmias
presenting with cardiogenic shock if a pri- .. The most frequent supraventricular arrhythmia is AF, with up to
mary PCI strategy is not available within IIa C ..
.. 21% of STEMI patients affected.444 AF may be pre-existing, first-
120 min from STEMI diagnosis and mechani- .. time detected, or of new onset. Patients with AF have more
cal complications have been ruled out.
..
.. comorbidities and are at higher risk for complications.445 In many
.. cases, the arrhythmia is well tolerated and no specific treatment is
Complete revascularization during the index ..
procedure should be considered in patients IIa C .. required, other than anticoagulation.5 Prompt treatment is
.. required in acute haemodynamic instability. There is scarce infor-
presenting with cardiogenic shock. ..
.. mation indicating preferences for rate control over rhythm control
Intra-aortic balloon pumping should be con- .. in this situation.446 Electrical cardioversion should be considered
..
sidered in patients with haemodynamic
IIa C .. but early recurrence of AF is frequent after successful cardiover-
instability/cardiogenic shock due to mechan- .. sion. Acute rhythm control with antiarrhythmic drugs is limited to
..
ical complications. .. the use of amiodarone.5,444 Adequate rate control can be accom-
.. plished by administration of beta-blockers.438,446 In patients with
Haemodynamic assessment with pulmonary ..
artery catheter may be considered for con- IIb B
.. extensive myocardial damage or severe LV dysfunction, rate con-
..
firming diagnosis or guiding therapy.433 .. trol is more safely achieved with i.v. digoxin with or without con-
.. comitant administration of i.v. amiodarone. When co-
Ultrafiltration may be considered for ..
.. administering i.v. digoxin and amiodarone, close monitoring for
patients with refractory congestion, who .. digoxin toxicity is necessary as digoxin serum concentrations may
failed to respond to diuretic-based
IIb B ..
.. be increased. Several, but not all, studies have suggested that new-
strategies.434–436 .. onset AF may be reduced by beta-blockers, ACE inhibitors/ARBs,
..
Inotropic/vasopressor agents may be con- .. and also early-onset statin therapy.444 Patients with AF and risk fac-
IIb C .. tors for thromboembolism should be adequately treated with
sidered for haemodynamic stabilization. ..
.. chronic oral anticoagulation.5 STEMI patients with documented AF
Short-term mechanical supportc may be .. have worse short- and long-term prognoses when compared with
IIb C ..
considered in patients in refractory shock. .. patients in sinus rhythm.445,447 Presence of AF is associated with a
.. higher reinfarction rate, higher stroke rate, higher risk for heart fail-
Routine intra-aortic balloon pumping is not ..
indicated.177,437
III B .. ure, and may also increase the risk for sudden cardiac
.. death.444,445,448 Of note, also transient, self-terminating AF during
..
.. STEMI relates to a significantly higher stroke rate during long-term
CABG = coronary artery bypass graft surgery; ECLS = extracorporeal life sup- .. follow-up.445,448
port; ECMO = extracorporeal membrane oxygenation; PCI = percutaneous cor-
onary intervention; STEMI = ST-segment elevation myocardial infarction.
a
Class of recommendation.
b
Level of evidence.
c
Percutaneous cardiac support devices, ECLS, and ECMO.
ESC Guidelines 159

.. 8.3.2 Ventricular arrhythmias


Management of atrial fibrillation ..
.. The incidence of VT and VF has declined over recent decades,
..
.. most probably due to the uptake of reperfusion strategies and the
Recommendations Classa Levelb
... early use of beta-blockers.3 However, 6–8% of patients still
.. develop haemodynamically significant VT or VF during this
Acute rate control of AF ..
.. phase.439 The typical arrhythmia presentation is unstable, fre-
Intravenous beta-blockers are indicated for .. quently polymorphic, and relatively fast VT, often degenerating
rate control if necessary and there are no
..
I C .. into VF. Urgent reperfusion is most important as ischaemia often
clinical signs of acute heart failure or .. triggers these arrhythmias.72 Beta-blockers are recommended if no
hypotension.449
..
.. contraindications exist.346,347,350,454 Repetitive electrical cardiover-
.. sion or defibrillation may be necessary.455 If there is no sufficient
Intravenous amiodarone is indicated for rate ..
.. control, i.v. administration of amiodarone is recommended.439,456

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control if necessary in the presence of con-
I C .. In case of contraindications to amiodarone, i.v. lidocaine may be
comitant acute heart failure and no ..
hypotension.450
.. considered, although no studies comparing superiority of
.. either drug in STEMI patients are available. The prognostic role of
..
Intravenous digitalis should be considered .. early VT/VF within the first 48 h of STEMI is still controversial.
for rate control if necessary in the presence .. Available data suggest that patients with early VT/VF have
IIa B ..
of concomitant acute heart failure and .. increased 30-day mortality but no increased long-term arrhythmic
hypotension.451 .. risks.442,457,458
..
.. VT or VF may occur at the time of restoration of coronary blood
Cardioversion .. flow (reperfusion arrhythmias). No specific antiarrhythmic drug
..
Immediate electrical cardioversion is indi- .. therapy is necessary due to the benign long-term course.
cated when adequate rate control cannot
.. Ventricular premature beats are very frequent on the first day of
..
be achieved promptly with pharmacological .. the acute phase and complex arrhythmias (multiform complexes,
agents in patients with AF and ongoing
I C ..
.. short runs, or the R-on-T phenomenon) are common. Their value
ischaemia, severe haemodynamic compro- .. as predictors of VF is questionable and no specific therapy is
mise, or heart failure.
..
.. required. Sustained VT or VF outside the early phase (usually 48 h
.. after STEMI onset) not triggered by recurrent ischaemia has a poor
Intravenous amiodarone is indicated to pro- ..
mote electrical cardioversion and/or .. prognostic implication, and evaluation for ICD implantation for sec-
.. ondary prevention of sudden cardiac death is recommended
decrease risk for early recurrence of AF I C ..
.. according to current guidelines.3 Primary prevention of sudden car-
after electrical cardioversion in unstable ..
.. diac death with the ICD within 40 days after MI in the absence of
patients with recent onset AF.
.. VT/VF is generally not indicated.3 Patients should be re-evaluated
In patients with documented de novo AF .. for ICD implantation 6–12 weeks after revascularization, although
..
during the acute phase of STEMI, long-term .. those with pre-existing impaired LVEF may be considered for ICD
oral anticoagulation should be considered .. implantation for primary prevention even within the early post-
IIa C ..
depending on CHA2DS2-VASc score and .. infarction period.3,438
taking concomitant antithrombotic therapy .. Some patients may develop electrical storm and/or incessant VT
..
into account.5,444 .. despite complete revascularization and treatment with antiarrhyth-
.. mic drugs. Overdrive stimulation may help to control this situation;
Digoxin is ineffective in converting recent ..
.. however, recurrence of VT/VF upon cessation of stimulation is fre-
onset AF to sinus rhythm and is not indi- III A .. quent and catheter ablation of such triggers appears to be the only
cated for rhythm control.452,453 ..
.. treatment option. Successful radiofrequency ablation has been
Calcium channel blockers and beta-blockers
.. shown to abolish recurrent VT/VF.459–461
..
including sotalol are ineffective in converting III B ..
recent onset AF to sinus rhythm.453
.

Prophylactic treatment with antiarrhythmic


III B
drugs to prevent AF is not indicated.438,444

AF = atrial fibrillation; CHA2DS2-VASc = Cardiac failure, Hypertension, Age 75


(Doubled), Diabetes, Stroke (Doubled) – VAScular disease, Age 65–74 and Sex
category (Female); STEMI = ST-segment elevation myocardial infarction.
a
Class of recommendation.
b
Level of evidence.
160 ESC Guidelines

Management of ventricular arrhythmias and conduc- Long-term management of ventricular arrhythmias


tion disturbances in the acute phase and risk evaluation for sudden death

Recommendations Classa Levelb Recommendations Classa Levelb

Intravenous beta-blocker treatment is indicated ICD therapy is recommended to reduce sudden


for patients with polymorphic VT and/or VF unless I B cardiac death in patients with symptomatic heart
contraindicated.462,463 failure (NYHA class II–III) and LVEF <_35% despite
optimal medical therapy for >3 months and I A
Prompt and complete revascularization is recom-
6 weeks after MI, who are expected to survive
mended to treat myocardial ischaemia that may
I C for at least 1 year with good functional
be present in patients with recurrent VT and/or
71,72
status.3,466,467
VF

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ICD implantation or temporary use of a wearable
Intravenous amiodarone is recommended for
I C cardioverter defibrillator may be considered <40
treatment of recurrent polymorphic VT.3
days after MI in selected patients (incomplete
IIb C
Correction of electrolyte imbalances (especially revascularization, pre-existing LVEF dysfunction,
hypokalaemia and hypomagnesemia) is recom- I C occurrence of arrhythmias >48 h after STEMI
mended in patients with VT and/or VF.3 onset, polymorphic VT or VF).

In cases of sinus bradycardia with haemodynamic


ICD = implantable cardioverter defibrillator; LVEF = left ventricular ejection frac-
intolerance or high degree AV block without
tion; MI = myocardial infarction; NYHA = New York Heart Association; STEMI =
stable escape rhythm: ST-segment elevation myocardial infarction; VF = ventricular fibrillation; VT =
 i.v. positive chronotropic medication (epinephrine, ventricular tachycardia.
I C a
Class of recommendation.
vasopressin, and/or atropine) is indicated b
Level of evidence.
 temporary pacing is indicated in cases of failure to
I C
respond to positive chronotropic medication
 urgent angiography with a view to revasculariza-
tion is indicated if the patient has not received pre- I C
vious reperfusion therapy.
Intravenous amiodarone should be considered for .. 8.3.3 Sinus bradycardia and atrioventricular block
recurrent VT with haemodynamic intolerance IIa C ..
.. Sinus bradycardia is common in the first hours of STEMI, especially in
despite repetitive electrical cardioversion.438 .. inferior MI. In some cases, opioids are responsible.468 It often
..
Transvenous catheter pace termination and/or .. requires no treatment. If accompanied by severe hypotension, sinus
overdrive pacing should be considered if VT can- .. bradycardia should be treated with i.v. atropine. Second-degree type
IIa C ..
not be controlled by repetitive electrical .. I (Mobitz I or Wenckebach) AV block is usually associated with infe-
cardioversion. .. rior wall MI and seldom causes adverse haemodynamic effects. If so,
..
Radiofrequency catheter ablation at a specialized .. atropine should be used first; if it fails, pacing should be instituted.
ablation centre followed by ICD implantation ..
.. Agents that slow AV conduction (such as beta-blockers, digitalis,
should be considered in patients with recurrent IIa C .. verapamil, or amiodarone) should be used with caution. Second-
VT, VF, or electrical storm despite complete ..
revascularization and optimal medical therapy. .. degree type II (Mobitz II) AV block and complete AV block may be
... indications for pacing. AV sequential pacing should be considered in
Recurrent VT with haemodynamic repercussion .. patients with complete AV block, RV infarction, and haemodynamic
despite repetitive electrical cardioversion may be ..
.. compromise. Revascularization should be considered in patients with
treated with lidocaine if beta-blockers, amiodar- IIb C .. AV block who have not yet received reperfusion therapy (e.g. late
one, and overdrive stimulation are not effective/ ..
applicable.438 .. arrival).
.. AV block associated with inferior wall infarction is usually supra-
Prophylactic treatment with antiarrhythmic drugs
..
III B .. Hisian and usually resolves spontaneously or after reperfusion. AV
is not indicated and may be harmful.464,465 .. block associated with anterior wall MI is usually infra-Hisian and has a
..
Asymptomatic and haemodynamically irrelevant .. high mortality rate due to the extensive myocardial necrosis. The
ventricular arrhythmias should not be treated III C
.. development of a new bundle branch block or hemiblock usually indi-
..
with antiarrhythmic drugs. .. cates extensive anterior MI. A transvenous pacing electrode should
.. be inserted in the presence of advanced AV block with a low escape
..
AV = atrioventricular; i.v. = intravenous; ICD = implantable cardioverter defibril- .. rhythm, as described above, and considered if bifascicular or trifascic-
lator; VF = ventricular fibrillation; VT = ventricular tachycardia. .. ular block develops. Indications for pacing are outlined in detail in the
a
Class of recommendation. ..
b
Level of evidence. .. ESC Guidelines for cardiac pacing and cardiac resynchronization
.. therapy.469
..
..
ESC Guidelines 161

8.4 Mechanical complications Table 10 Diagnostic criteria for myocardial infarction


Mechanical complications may occur in the first days following with non-obstructive coronary arteries (adapted from
STEMI, although incidence has fallen significantly in the era of primary Agewall et al12)
PCI. Mechanical complications are life-threatening and need prompt
detection and management. Sudden hypotension, recurrence of
chest pain, new cardiac murmurs suggestive of mitral regurgitation or
ventricular septal defect, pulmonary congestion, or jugular vein dis-
tension should raise suspicion. Immediate echocardiographic assess-
ment is needed when mechanical complications are suspected. A full
section describing mechanical complications can be found in the
Web Addenda.

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8.4.1 Free wall rupture
See Web Addenda.
AMI = acute myocardial infarction; IRA = infarct-related artery; MINOCA = myo-
8.4.2 Ventricular septal rupture cardial infarction with non-obstructive coronary arteries.
See Web Addenda.
.. secondary to epicardial coronary artery disorders (e.g. atheroscler-
8.4.3 Papillary muscle rupture ..
See Web Addenda.
.. otic plaque rupture, ulceration, fissuring, erosion, or coronary dissec-
.. tion with non-obstructive or no CAD) (MI type 1); (2) imbalance
..
.. between oxygen supply and demand (e.g. coronary artery spasm and
8.5 Pericarditis ..
.. coronary embolism) (MI type 2); (3) coronary endothelial dysfunc-
Three major pericardial complications may occur: early infarct-
.. tion (e.g. microvascular spasm) (MI type 2); and (4) secondary to
associated pericarditis, late pericarditis or post-cardiac injury ..
.. myocardial disorders without involvement of the coronary arteries
(Dressler syndrome), and pericardial effusion. These are expanded .. (e.g. myocarditis470 or Takotsubo syndrome). The last two entities
upon in the Web Addenda. ..
.. may mimic MI but are better classified as myocardial injury condi-
.. tions. The identification of the underlying cause of MINOCA should
8.5.1 Early and late (Dressler syndrome) ..
infarct-associated pericarditis
.. lead to specific treatment strategies. Although the outcome of
.. MINOCA strongly depends on the underlying cause, its overall prog-
See Web Addenda. ..
.. nosis is serious, with a 1 year mortality of about 3.5%.10
.. To determine the cause of MINOCA, the use of additional diag-
8.5.2 Pericardial effusion ..
.. nostic tests beyond coronary angiography is recommended. In gen-
See Web Addenda. .. eral, after ruling out obstructive CAD in a patient presenting with
..
.. STEMI, an LV angiogram or echocardiography should be considered
.. in the acute setting to assess wall motion or pericardial effusion. In
9. Myocardial infarction with ..
.. addition, if any of the possible aetiologies described above is sus-
non-obstructive coronary arteries .. pected, additional diagnostic tests may be considered.
..
.. CMR is a very helpful imaging technique due to its unique non-
A sizeable proportion of MIs, ranging between 1–14%, occur in the .. invasive tissue characterization, allowing the identification of wall
..
absence of obstructive (>50% stenosis) CAD.10,11 The demonstra- .. motion abnormalities, presence of oedema, and myocardial scar/fib-
tion of non-obstructive (<50%) CAD in a patient presenting with .. rosis presence and pattern. Performance of CMR within 2 weeks
..
symptoms suggestive of ischaemia and ST-segment elevation or .. after onset of symptoms should be considered to increase the diag-
equivalent does not preclude an atherothrombosis aetiology, as .. nostic accuracy of the test for identifying the aetiological cause of
..
thrombosis is a very dynamic phenomenon and the underlying athe- .. MINOCA.471–473
rosclerotic plaque can be non-obstructive. ..
..
The diagnostic criteria of MINOCA are presented in Table 10. ..
..
MINOCA is a working diagnosis and should lead the treating physician
.. 10. Assessment of quality of care
to investigate underlying causes. Failure to identify the underlying cause ..
may result in inadequate and inappropriate therapy in these patients. .. There is a wide practice gap between optimal and actual care
..
The description of the pathophysiology of the different aetiological .. for patients with STEMI in hospitals around the world.474,475 To
entities leading to MINOCA is beyond the scope of the present .. reduce this gap and improve quality of care, it is recommended that
..
document, and has been extensively described and defined in posi- .. STEMI networks and their individual components establish measura-
tion papers from the ESC12 and in dedicated review papers.10,11 .. ble quality indicators, systems to measure and compare these indica-
..
MINOCA patients can fulfil the criteria for both MI type 1 and type 2 .. tors, perform routine audits, and implement strategies to ensure that
according to the universal definition of MI.8 There are disparate aeti-
.. every patient with STEMI receives the best possible care according
..
ologies causing MINOCA and they can be grouped into: (1) . to accepted standards and has the best possible outcomes
162 ESC Guidelines

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Figure 7 Diagnostic test flow chart in MINOCA. CMR = Cardiac Magnetic Resonance; IVUS = IntraVascular UltraSound; LV = Left Ventricle;
MINOCA = Myocardial Infarction with Non-Obstructed Coronary Arteries; OCT = Optical Coherence Tomography; STEMI = ST segment
Elevation Myocardial Infarction; TOE = Trans-Oesofageal Echocardiography; TTE = Trans-Thoracic Echocardiography. Takotsubo syndrome cannot
be diagnosed with certainty in the acute phase as the definition requires follow up imaging to document recovery of left ventricular function. IVUS
and OCT frequently show more atherosclerotic plaque than may be appreciated on angiography. They also increase sensitivity for dissection. If intra-
coronary imaging is to be performed, it is appropriate to carry out this imaging at the time of the acute cardiac catheterization, after diagnostic angiog-
raphy. Patients should be made aware of the additional information the test can provide and the small increase in risk associated with intracoronary
imaging.
1 • Provocative testing for coronary artery spasm might be considered in selected patients with a recent AMI with suspected vasospas-
tic angina. Provocative manoeuvres have to be always performed by operators with experience and not necessarily in the acute phase
of STEMI.
2 • Clinically suspected myocarditis by ESC Task Force criteria = No angiographic stenosis 50% plus non ischemic pattern on CMR.
Definite myocarditis by ESC Task Force criteria = No angiographic stenosis 50% plus endomyocardial biopsy confirmation (histology,
immunohistology, polymerase-chain reaction based techniques to search for genome of infectious agents, mainly viruses).
ESC Guidelines 163

Table 11 Quality indicators

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ACE = angiotensin-converting enzyme; ARB = angiotensin II receptor blocker; DAPT = dual antiplatelet therapy; ECG = electrocardiogram; GRACE = Global Registry of
Acute Coronary Events; IRA = Infarct-related artery; LVEF = left ventricular ejection fraction; PCI = percutaneous coronary intervention; STEMI = ST-segment elevation myo-
cardial infarction.

..
(see Web Addenda). Quality indicators are intended to measure and ..
..
11. Gaps in the evidence and areas
compare the quality of health service provision and serve as a founda- ..
..
for future research
tion for quality improvement initiatives.476 Proposed quality indica-
..
tors to assess the quality of the care for patients are presented in .. Despite the great advances in STEMI management over recent deca-
Table 11. .. des, important areas of uncertainty persist that should be explored in
..
Expanded text about quality indicators can be found in the Web .. the future. Here, we identify some, but not all, specific areas that
Addenda. .. should be addressed within the next few years.
164 ESC Guidelines

..
Public awareness and emergency care .. STEMI has not been prospectively tested in dedicated clinical trials of
.. reperfused patients. Similar limitations apply to the use of mainte-
The very early stages of STEMI are the most vulnerable time, when ..
most sudden cardiac deaths occur. Public campaigns aiming to .. nance ACE inhibitors.
..
increase early alerting of patients with ischaemic symptoms should ..
clearly state that the safest way to alert is to call the EMS. While ..
.. Post-STEMI risk stratification
selected centres and geographic areas have made great progress in .. The optimal therapeutic strategy to minimize the risk of sudden
ensuring high-quality rapid care for STEMI patients with routine pre- ..
.. death in patients who develop VT or VF during or early after STEMI
alert of the interventional team, there remains a need for streamlining ..
.. is not entirely clear. Despite the clinical benefit of ICDs in patients
of (pre-)hospital management in a homogeneous fashion worldwide, .. with low LVEF and reduced functional class weeks after STEMI being
including rural areas. Educational programmes and cross-country ..
exchange of experiences should help in this matter. .. well established, there is a need for better sudden death risk stratifi-
.. cation algorithms.
..

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The selection of a 120 min from STEMI diagnosis to PCI-mediated
reperfusion as the cut-off to choose PCI or fibrinolysis is based on .. The best management of non-IRA lesions should be addressed.
.. Unresolved issues are the best criteria to guide PCI (angiography,
relatively old registries and trials with different treatment strategies ..
from those presented in this document. The identification of the best
.. FFR, or assessment of plaque vulnerability) and the best timing for
.. complete revascularization if indicated (during index PCI or staged,
cut-off timing to choose a strategy is of extreme importance. ..
.. including staged during hospitalization vs. after discharge).
..
Reduction of ischaemia/reperfusion ...
.. Shock and left ventricular assist devices
injury ..
Final infarct size is one of the best predictors of long-term adverse .. Severe heart failure and shock are among the most important nega-
..
events in STEMI survivors. The introduction of a specific infarct- .. tive prognostic predictors in patients with STEMI. In addition to
limiting therapy in clinical practice might have a massive clinical and .. urgent revascularization of IRA and standard medical therapies for
..
socioeconomic impact. Several strategies, including pharmacological .. pre- and afterload reduction, there is limited evidence for the system-
and mechanical therapies, have shown a reduction of infarct size by .. atic use of inotropic and vasopressor agents as well as mechanical
..
reducing ischaemia/reperfusion injury (including MVO) in experimen- .. support. Similarly, the benefit of routine complete revascularization
tal and small-scale clinical trials, but to date no large trial has demon- .. during the index PCI procedure has not been formally demonstrated.
..
strated a clinical benefit. One potential reason for this poor .. The use of IABP has not met prior expectations of benefit, while LV
translation is the difficulty of securing funds to conduct proper large- .. assist devices and ECMO are increasingly popular but have not been
..
scale clinical trials in this context. .. sufficiently evaluated in clinical trials. Systematic evaluation of phar-
.. macological and interventional strategies and LV assist devices for
..
Refinement of (acute and long-term) .. patients with shock are urgently needed.
..
antithrombotic regimes ..
..
Antithrombotic therapy is the cornerstone of the pharmacological .. Myocardial repair/rescue
approach in STEMI. Despite major recent advances, important ques- ..
.. The effectiveness and safety of novel therapies able to replace dead
tions remain unaddressed. What is the best acute and maintenance .. myocardium or prevent poor remodelling (e.g. cell therapy or gene
antithrombotic regimen in patients who have an indication for oral ..
.. therapy) is an unfulfilled promise. There is a strong need for basic
anticoagulants? What is the best timing for the loading dose of oral .. research studies to better understand the biological processes
P2Y12 inhibitors and what are the best strategies for i.v. antithrom- ..
.. involved in cardiac development and repair, in order for these to be
botic therapies? What is the role of potent P2Y12 inhibitors in .. strong grounds to translate studies into clinically relevant animal
patients undergoing fibrinolysis? What is the real role of aspirin in this ..
.. models and finally into humans.
new era of potent antiplatelet agents and low dose anticoagulation? ..
What is the best duration of maintenance therapy with P2Y12 inhibi- ..
..
tors as single or multiple antithrombotic regimens? .. Need for observational data and real-
..
.. world evidence
Beta-blockers and ACE inhibitors .. In order to understand shortcomings and challenges in clinical prac-
..
Although research regarding these classes of drugs was intense sev- .. tice, for quality assessment and for benchmarking, unselected and
eral decades ago, more recently, there has been a lack of properly .. validated registries and clinical databases are needed. In this docu-
..
powered clinical trials. The best timing for initiation (and route of .. ment, we have specified quality indicators intended to measure and
administration) of beta-blockers is still not well established. The role
.. compare the quality of health service provision and serve as a founda-
..
of maintenance beta-blocker therapy is well established for patients .. tion for quality improvement initiatives. Their effects on procedural
with heart failure and/or low LVEF, but its clinical value for the rest of
.. and clinical outcomes need to be evaluated.
ESC Guidelines 165

.. (6) Cardiac arrest and reperfusion strategy: Patients with ST-elevation


Need for pragmatic real-life clinical trials ..
One major limitation of highly selective controlled clinical trials is
.. on post-resuscitation ECG should undergo a primary PCI strategy.
..
their applicability in the real world. Strict inclusion criteria, tailored .. In cases without ST-segment elevation on post-resuscitation ECG
management, and very close follow-up results in a bias that precludes
.. but with a high suspicion of ongoing myocardial ischaemia, urgent
..
universal implementation. An opportunity is the implementation of .. angiography should be done within 2 h after a quick evaluation to
.. exclude non-coronary causes. In all cases, the decision to perform
pragmatic clinical trials including registry-based randomized clinical ..
trials.477 These trials are less selective and less expensive alternatives .. urgent coronary angiography should take into account factors
.. associated with poor neurological outcome.
to classical ones, especially for therapies used in clinical practice. ..
.. (7) Technical aspects during primary PCI: Routine radial access and
.. routine DES implant is the standard of care during primary PCI.
..
12. Key messages .. Routine thrombus aspiration or deferred stenting are
.. contraindicated.
..

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(1) Epidemiology of STEMI: Although the rate of mortality associated .. (8) Management of non-IRA lesions: Treatment of severe stenosis
.. (evaluated either by angiography or FFR) should be considered
with ischaemic heart disease have reduced in Europe over the last ..
few decades, this is still the single most common cause of death .. before hospital discharge (either immediately during the index PCI
.. or staged at a later time). In cardiogenic shock, non-IRA PCI should
worldwide. The relative incidences of STEMI and NSTEMI are ..
decreasing and increasing, respectively. Despite the decline in .. be considered during the index procedure.
.. (9) Antithrombotic therapy: Anticoagulants and DAPT are the cor-
acute and long-term death associated with STEMI, in parallel with ..
the widespread use of reperfusion, mortality remains substantial. .. nerstone of the pharmacological approach in the acute phase of
.. STEMI. Primary PCI: unfractionated heparin (enoxaparin or bivalir-
The in-hospital mortality rates of unselected patients with STEMI ..
in national European registries vary between 4–12%. .. udin may be alternatives), and loading dose of aspirin and prasu-
.. grel/ticagrelor. Fibrinolysis: enoxaparin (unfractionated heparin
(2) Gender aspects: Women tend to receive reperfusion therapy and ..
other evidence-based treatments less frequently and/or in a .. may be alternative), and loading dose of aspirin and clopidogrel.
..
delayed way than men. It is important to highlight that women and .. Maintenance therapy in the majority of patients is based on one
men receive equal benefit from a reperfusion and other STEMI-
.. year DAPT in the form of aspirin plus prasugrel/ticagrelor.
..
related therapies, and so both genders must be managed equally. .. (10) Early care: After reperfusion therapy, patients should be moni-
(3) ECG and STEMI diagnosis: In some cases, patients may have coro-
.. tored for at least 24 h. Early ambulation and early discharge are the
..
nary artery occlusion/global ischaemia in the absence of character- .. best option in uncomplicated patients. Consequently, time for
istic ST elevation (e.g. bundle branch block, ventricular pacing,
.. implementing secondary prevention is limited highlighting the
..
hyperacute T-waves, isolated ST-depression in anterior leads, and/ .. importance of close collaboration between all stakeholders.
or universal ST depression with ST-elevation in aVR). In patients
.. (11) Special patient subsets: Patients taking oral anticoagulants with
..
with the mentioned ECG changes and clinical presentation com- .. renal insufficiency and/or the elderly represent a challenge in terms
.. of optimal antithrombotic therapy. Special attention should be
patible with ongoing myocardial ischaemia, a primary PCI strategy ..
(i.e. urgent angiography and PCI if indicated) should be followed. .. paid to dose adjustment of some pharmacological strategies in
.. these subsets. Patients with diabetes and those not undergoing
(4) Reperfusion strategy selection: STEMI diagnosis (defined as the ..
time at which the ECG of a patient with ischaemic symptoms is .. reperfusion represent another subset of patients that require addi-
.. tional attention.
interpreted as presenting ST-segment elevation or equivalent) is ..
the time zero in the reperfusion strategy clock. STEMI patients .. (12) Imaging in STEMI: Non-invasive imaging is very important for the
.. acute and long-term management of STEMI patients.
should undergo a primary PCI strategy unless the anticipated abso- ..
lute time from STEMI diagnosis to PCI-mediated reperfusion .. (13) MINOCA: A sizeable proportion of STEMI patients do not present
.. significant coronary artery stenosis on urgent angiography. It is
is > 120 min, when fibrinolysis should be initiated immediately (i.e. ..
within 10 min of STEMI diagnosis). .. important to perform additional diagnostic tests in these patients
.. to identify the aetiology and tailor appropriate therapy, which may
(5) STEMI management networks: Coordination between EMS and ..
hospitals with common written protocols is at the centre of .. be different from typical STEMI.
.. (14) Quality indicators: In some cases, there is a gap between optimal
STEMI management. EMS should transfer patients to 24/7 high- ..
volume PCI centres irrespective of whether the primary treatment ... guideline-based treatment and actual care of STEMI patients. In
strategy is PCI or pre-hospital fibrinolysis. EMS should always alert
.. order to reduce this gap, it is important to measure established
..
the PCI centre immediately after selection of the reperfusion strat- .. quality indicators to audit practice and improve outcomes in real-
egy. Patient transfer to the PCI centre should bypass the emer-
.. life. The use of well-defined and validated quality indicators to
..
gency department. . measure and improve STEMI care is recommended.
166 ESC Guidelines

13. Evidenced-based ‘to do and not to do’ messages from the Guidelines

Recommendations

Recommendations for initial diagnosis Classa Levelb

Twelve-lead ECG recording and interpretation is indicated as soon as possible at the point of FMC, with a maximum target
I B
delay of 10 min.

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ECG monitoring with defibrillator capacity is indicated as soon as possible in all patients with suspected STEMI. I B

Recommendations for relief of hypoxaemia and symptoms

Routine oxygen is not recommended in patients with SaO2 90%. III B

Recommendations for cardiac arrest

A primary PCI strategy is recommended in patients with resuscitated cardiac arrest and an ECG consistent with STEMI. I B

Targeted temperature management is indicated early after resuscitation of cardiac arrest patients who remain unresponsive. I B

Pre-hospital cooling using a rapid infusion of large volumes of cold i.v. fluid immediately after return of spontaneous circulation
III B
is not recommended.

Recommendations for logistics of pre-hospital care

It is recommended that the pre-hospital management of STEMI patients is based on regional networks designed to deliver
reperfusion therapy expeditiously and effectively, with efforts made to make primary PCI available to as many patients as I B
possible.

It is recommended that primary PCI-capable centres deliver a 24/7 service and are able to perform primary PCI without delay. I B

It is recommended that patients transferred to a PCI-capable centre for primary PCI bypass the emergency department and
I B
CCU/ICCU and are transferred directly to the catheterization laboratory.

Recommendations for reperfusion therapy

Reperfusion therapy is indicated in all patients with symptoms of ischaemia of <_ 12 h duration and persistent ST-segment
I A
elevation.

If primary PCI cannot be performed in a timely way after STEMI diagnosis, fibrinolytic therapy is recommended within 12 h of
I A
symptom onset in patients without contraindications.

In asymptomatic patients, routine PCI of an occluded IRA >48 h after onset of STEMI is not indicated. III A

Recommendations for procedural aspects of the primary PCI strategy

Primary PCI of the IRA is indicated. I A

Stenting is recommended (over balloon angioplasty) for primary PCI. I A

Stenting with new-generation DES is recommended over BMS for primary PCI. I A

Radial access is recommended over femoral access if performed by an experienced radial operator. I A

Routine use of thrombus aspiration is not recommended. III A

Routine use of deferred stenting is not recommended. III B

Recommendations for periprocedural and post-procedural antithrombotic therapy in patients undergoing primary PCI

A potent P2Y12 inhibitor (prasugrel or ticagrelor), or clopidogrel if these are not available or are contraindicated, is recom-
mended before (or at latest at the time of) PCI and maintained over 12 months unless there are contraindications such as I A
excessive risk of bleeding.
Continued
ESC Guidelines 167

Aspirin oral or i.v. (if unable to swallow) is recommended as soon as possible for all patients without contraindications. I B

Fondaparinux is not recommended for primary PCI. III B

Recommendations for Fibrinolytic therapy

When fibrinolysis is the reperfusion strategy, it is recommended to initiate this treatment as soon as possible after STEMI diag-
I A
nosis, preferably in the pre-hospital setting.

A fibrin-specific agent (i.e. tenecteplase, alteplase, or reteplase) is recommended. I B

Oral or i.v. aspirin is indicated. I B

Clopidogrel is indicated in addition to aspirin. I A

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Anticoagulation is recommended in patients treated with lytics until revascularization (if performed) or for the duration of hos-
I A
pital stay up to 8 days. The anticoagulant can be:

 Enoxaparin i.v. followed by s.c. (preferred over UFH). I A

 UFH given as a weight-adjusted i.v. bolus followed by infusion. I B

Transfer to a PCI-capable centre following fibrinolysis is indicated in all patients immediately after fibrinolysis. I A

Emergency angiography and PCI if indicated is recommended in patients with heart failure/shock. I A

Rescue PCI is indicated immediately when fibrinolysis has failed (<50% ST-segment resolution at 60–90 min) or at any time in
I A
the presence of haemodynamic or electrical instability, or worsening ischaemia.

Angiography and PCI of the IRA, if indicated, is recommended between 2–24 h after successful fibrinolysis. I A

Emergency angiography and PCI if needed is indicated in the case of recurrent ischaemia or evidence of reocclusion after initial
I B
successful fibrinolysis.

Recommendations for imaging and stress testing in STEMI patients

Routine echocardiography during hospital stay to assess resting LV and RV function, detect early post-MI mechanical complica-
I B
tions, and exclude LV thrombus is recommended in all patients.

Recommendations for behavioural aspects after STEMI

It is recommended to identify smokers and provide repeated advice on stopping, with offers to help with the use of follow-up
I A
support, nicotine replacement therapies, varenicline, and bupropion individually or in combination.

Participation in a cardiac rehabilitation programme is recommended. I A

Recommendations for maintenance antithrombotic strategy after STEMI

Antiplatelet therapy with low-dose aspirin (75–100 mg) is indicated. I A

DAPT in the form of aspirin plus ticagrelor or prasugrel (or clopidogrel if ticagrelor or prasugrel are not available or are contra-
I A
indicated) is recommended for 12 months after PCI, unless there are contraindications such as excessive risk of bleeding.

A PPI in combination with DAPT is recommended in patients at high risk of gastrointestinal bleeding. I B

Recommendations for routine therapies in the acute, subacute, and long-term phases

Oral treatment with beta-blockers is indicated in patients with heart failure and/or LVEF <_40% unless contraindicated. I A

Intravenous beta-blockers must be avoided in patients with hypotension, acute heart failure, or AV block or severe bradycardia. III B

It is recommended to start high-intensity statin therapy as early as possible, unless contraindicated, and maintain it long-term. I A

An LDL-C goal of < 1.8 mmol/L (70 mg/dL) or a reduction of at least 50% if the baseline LDL-C is between 1.8–3.5 mmol/L
I B
(70–135 mg/dL) is recommended.

ACE inhibitors are recommended, starting within the first 24 h of STEMI in patients with evidence of heart failure, LV systolic
I A
dysfunction, diabetes, or an anterior infarct.
Continued
168 ESC Guidelines

An ARB, preferably valsartan, is an alternative to ACE inhibitors in patients with heart failure and/or LV systolic dysfunction,
I B
particularly those who are intolerant of ACE inhibitors.

MRAs are recommended in patients with an ejection fraction <_40% and heart failure or diabetes, who are already receiving an
I B
ACE inhibitor and a beta-blocker, provided there is no renal failure or hyperkalaemia.

Recommendations for the management of LV dysfunction and acute heart failure in STEMI

ACE inhibitor (or if not tolerated, ARB) therapy is indicated as soon as haemodynamically stable for all patients with evidence
I A
of LVEF <_40% and/or heart failure to reduce the risk of hospitalization and death.

Beta-blocker therapy is recommended in patients with LVEF <_40% and/or heart failure after stabilization, to reduce the risk of
I A
death, recurrent MI, and hospitalization for heart failure.

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An MRA is recommended in patients with heart failure and LVEF <_40% with no severe renal failure or hyperkalaemia to reduce
I B
the risk of cardiovascular hospitalization and death.

Recommendations for the management of cardiogenic shock in STEMI

Immediate PCI is indicated for patients with cardiogenic shock if coronary anatomy is suitable. If coronary anatomy is not suit-
I B
able for PCI, or PCI has failed, emergency CABG is recommended.

Routine intra-aortic balloon pumping is not indicated. III B

Recommendations for management of atrial fibrillation

Digoxin is ineffective in converting recent onset AF to sinus rhythm and is not indicated for rhythm control. III A

Calcium channel blockers and beta-blockers including sotalol are ineffective in converting recent onset AF to sinus rhythm. III B

Prophylactic treatment with antiarrhythmic drugs to prevent AF is not indicated. III B

Recommendations for management of ventricular arrhythmias and conduction disturbances in the acute phase

Intravenous beta-blocker treatment is indicated for patients with polymorphic VT and/or VF unless contraindicated. I B

Prophylactic treatment with antiarrhythmic drugs is not indicated and may be harmful. III B

Recommendations for long-term management of ventricular arrhythmias and risk evaluation for sudden death

ICD therapy is recommended to reduce sudden cardiac death in patients with symptomatic heart failure (New York Heart
Association class II–III) and LVEF <_35%, despite optimal medical therapy for >3 months and at least 6 weeks after MI, who are I A
expected to survive for at least 1 year with good functional status.

Recommendations with a class I or III and a level of evidence A or B. See ‘Abbreviations and acronyms’ list for explanation of abbreviations.
a
Class of recommendation.
b
Level of evidence.

..
14. Web addenda ..
..
Netherlands), Donna Fitzsimons (UK), Oliver Gaemperli (Switzerland),
Gerhard Hindricks (Germany), Bernard Iung (France), Peter Jüni
All Web figures and Web tables are available in the online Web
..
.. (Canada), Hugo A. Katus (Germany), Juhani Knuuti (Finland), Patrizio
Addenda at: European Heart Journal online and also via the ESC .. Lancellotti (Belgium), Christophe Leclercq (France), Theresa McDonagh
Website at: https://www.escardio.org/Guidelines/Clinical-Practice-
..
.. (UK), Massimo Francesco Piepoli (Italy), Piotr Ponikowski (Poland),
Guidelines/Acute-Myocardial-Infarction-in-patients-presenting-with- .. Dimitrios J. Richter (Greece), Marco Roffi (Switzerland), Evgeny
..
ST-segment-elevation-Ma .. Shlyakhto (Russia), Iain A. Simpson (UK), Jose Luis Zamorano (Spain).
.. ESC National Cardiac Societies actively involved in the
..
15. Appendix .. review process of the 2017 ESC Guidelines for the manage-
.. ment of acute myocardial infarction in patients presenting
..
ESC Committee for Practice Guidelines (CPG): Stephan .. with ST-segment elevation:
Windecker (Chairperson) (Switzerland), Victor Aboyans (France), .. Algeria: Algerian Society of Cardiology, Mohamed Chettibi;
..
Stefan Agewall (Norway), Emanuele Barbato (Italy), Héctor Bueno .. Armenia: Armenian Cardiologists Association, Hamlet G.
(Spain), Antonio Coca (Spain), Jean-Philippe Collet (France), Ioan Mircea
.. Hayrapetyan; Austria: Austrian Society of Cardiology, Bernhard
..
Coman (Romania), Veronica Dean (France), Victoria Delgado (The . Metzler; Azerbaijan: Azerbaijan Society of Cardiology, Firdovsi
ESC Guidelines 169

.. Halle M, Hamm C, Hildick-Smith D, Huber K, Iliodromitis E, James S, Lewis BS,


Ibrahimov; Belarus: Belorussian Scientific Society of Cardiologists, ..
Volha Sujayeva; Belgium: Belgian Society of Cardiology, Christophe .. Lip GY, Piepoli MF, Richter D, Rosemann T, Sechtem U, Steg PG, Vrints C, Luis
.. Zamorano J. 2015 ESC Guidelines for the management of acute coronary syn-
Beauloye; Bosnia and Herzegovina: Association of Cardiologists .. dromes in patients presenting without persistent ST-segment elevation: Task
of Bosnia and Herzegovina, Larisa Dizdarevic-Hudic; Bulgaria: .. Force for the Management of Acute Coronary Syndromes in Patients
.. Presenting without Persistent ST-Segment Elevation of the European Society of
Bulgarian Society of Cardiology, Kiril Karamfiloff; Croatia: Croatian .. Cardiology (ESC). Eur Heart J 2016;37(3):267–315.
Cardiac Society, Bosko Skoric; Cyprus: Cyprus Society of .. 3. Priori SG, Blomstrom-Lundqvist C, Mazzanti A, Blom N, Borggrefe M, Camm J,
..
Cardiology, Loizos Antoniades; Czech Republic: Czech Society of .. Elliott PM, Fitzsimons D, Hatala R, Hindricks G, Kirchhof P, Kjeldsen K, Kuck
Cardiology, Petr Tousek; Denmark: Danish Society of Cardiology, .. KH, Hernandez-Madrid A, Nikolaou N, Norekval TM, Spaulding C, Van
.. Veldhuisen DJ. 2015 ESC Guidelines for the management of patients with ven-
Christian Juhl Terkelsen; Egypt: Egyptian Society of Cardiology, .. tricular arrhythmias and the prevention of sudden cardiac death: The Task
Sameh Mohamad Shaheen; Estonia: Estonian Society of Cardiology, .. Force for the Management of Patients with Ventricular Arrhythmias and the
.. Prevention of Sudden Cardiac Death of the European Society of Cardiology
Toomas Marandi; Finland: Finnish Cardiac Society, Matti Niemel€a; .. (ESC). Endorsed by: Association for European Paediatric and Congenital
The Former Yugoslav Republic of Macedonia: Macedonian ..
..

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Cardiology (AEPC). Eur Heart J 2015;36(41):2793–2867.
Society of Cardiology, Sasko Kedev; France: French Society of .. 4. Piepoli MF, Hoes AW, Agewall S, Albus C, Brotons C, Catapano AL, Cooney
Cardiology, Martine Gilard; Georgia: Georgian Society of .. MT, Corra U, Cosyns B, Deaton C, Graham I, Hall MS, Hobbs FD, Lochen ML,
.. Lollgen H, Marques-Vidal P, Perk J, Prescott E, Redon J, Richter DJ, Sattar N,
Cardiology, Alexander Aladashvili; Germany: German Cardiac .. Smulders Y, Tiberi M, van der Worp HB, van Dis I, Verschuren WM. 2016
Society, Albrecht Elsaesser; Greece: Hellenic Society of Cardiology,
.. European Guidelines on cardiovascular disease prevention in clinical practice:
.. The Sixth Joint Task Force of the European Society of Cardiology and Other
Ioannis Georgios Kanakakis; Hungary: Hungarian Society of ..
Cardiology, Béla Merkely; Iceland: Icelandic Society of Cardiology,
.. Societies on Cardiovascular Disease Prevention in Clinical Practice (constituted
.. by representatives of 10 societies and by invited experts). Developed with the
Thorarinn Gudnason; Israel: Israel Heart Society, Zaza Iakobishvili; .. special contribution of the European Association for Cardiovascular Prevention

Italy: Italian Federation of Cardiology, Leonardo Bolognese;


.. & Rehabilitation (EACPR). Eur Heart J 2016;37(29):2315–2381.
.. 5. Kirchhof P, Benussi S, Kotecha D, Ahlsson A, Atar D, Casadei B, Castella M,
Kazakhstan: Association of Cardiologists of Kazakhstan, Salim .. Diener HC, Heidbuchel H, Hendriks J, Hindricks G, Manolis AS, Oldgren J,
.. Popescu BA, Schotten U, Van Putte B, Vardas P, Agewall S, Camm J, Baron
Berkinbayev; Kosovo: Kosovo Society of Cardiology, Gani Bajraktari; ..
Kyrgyzstan: Kyrgyz Society of Cardiology, Medet Beishenkulov; .. Esquivias G, Budts W, Carerj S, Casselman F, Coca A, De Caterina R,
.. Deftereos S, Dobrev D, Ferro JM, Filippatos G, Fitzsimons D, Gorenek B,
Latvia: Latvian Society of Cardiology, Ilja Zake; Libya: Libyan .. Guenoun M, Hohnloser SH, Kolh P, Lip GY, Manolis A, McMurray J, Ponikowski
Cardiac Society, Hisham Ben Lamin; Lithuania: Lithuanian Society .. P, Rosenhek R, Ruschitzka F, Savelieva I, Sharma S, Suwalski P, Tamargo JL,
.. Taylor CJ, Van Gelder IC, Voors AA, Windecker S, Zamorano JL, Zeppenfeld
of Cardiology, Olivija Gustiene; Luxembourg: Luxembourg Society .. K. 2016 ESC Guidelines for the management of atrial fibrillation developed in
of Cardiology, Bruno Pereira; Malta: Maltese Cardiac Society, .. collaboration with EACTS. Eur Heart J 2016;37(38):2893–2962.
.. 6. Ponikowski P, Voors AA, Anker SD, Bueno H, Cleland JG, Coats AJ, Falk V,
Robert G. Xuereb; Morocco: Moroccan Society of Cardiology, ..
Samir Ztot; Norway: Norwegian Society of Cardiology, Vibeke .. Gonzalez-Juanatey JR, Harjola VP, Jankowska EA, Jessup M, Linde C,
.. Nihoyannopoulos P, Parissis JT, Pieske B, Riley JP, Rosano GM, Ruilope LM,
Juliebø; Poland: Polish Cardiac Society, Jacek Legutko; Portugal: .. Ruschitzka F, Rutten FH, van der Meer P. 2016 ESC Guidelines for the diagno-
Portuguese Society of Cardiology, Ana Teresa Tim oteo; Romania: .. sis and treatment of acute and chronic heart failure: The Task Force for the
.. diagnosis and treatment of acute and chronic heart failure of the European
Romanian Society of Cardiology, Gabriel Tatu-Chiţoiu; Russian .. Society of Cardiology (ESC). Developed with the special contribution of the
Federation: Russian Society of Cardiology, Alexey Yakovlev; San .. Heart Failure Association (HFA) of the ESC. Eur Heart J 2016;37(27):
..
Marino: San Marino Society of Cardiology, Luca Bertelli; Serbia: .. 2129–2200.

Cardiology Society of Serbia, Milan Nedeljkovic; Slovakia: Slovak .. 7. Valgimigli M, OTHER AUTHORS TO BE INSERTED HERE. 2017 ESC Focused
.. Update on Dual Antiplatelet Therapy in Coronary Artery Disease in collabora-
Society of Cardiology, Martin Studencan; Slovenia: Slovenian .. tion with the European Association for Cardio-Thoracic Surgery (EACTS). The
Society of Cardiology, Matjaz Bunc; Spain: Spanish Society of
.. Task Force for the Management of Dual Antiplatelet Therapy in Coronary
.. Artery Disease of the European Society of Cardiology (ESC). Eur Heart J 2017.
Cardiology, Ana Maria Garcıa de Castro; Sweden: Swedish Society .. 8. Thygesen K, Alpert JS, Jaffe AS, Simoons ML, Chaitman BR, White HD, Writing
of Cardiology, Petur Petursson; Switzerland: Swiss Society of
..
.. Group on the Joint ESC/ACCF/AHA/WHF Task Force for the Universal
Cardiology, Raban Jeger; Tunisia: Tunisian Society of Cardiology and .. Definition of Myocardial Infarction, Thygesen K, Alpert JS, White HD, Jaffe AS,

Cardio-Vascular Surgery, Mohamed Sami Mourali; Turkey: Turkish


.. Katus HA, Apple FS, Lindahl B, Morrow DA, Chaitman BA, Clemmensen PM,
.. Johanson P, Hod H, Underwood R, Bax JJ, Bonow RO, Pinto F, Gibbons RJ, Fox
Society of Cardiology, Aylin Yildirir; Ukraine: Ukrainian Association .. KA, Atar D, Newby LK, Galvani M, Hamm CW, Uretsky BF, Steg PG, Wijns W,
of Cardiology, Alexander Parkhomenko; United Kingdom: British
.. Bassand JP, Menasche P, Ravkilde J, Ohman EM, Antman EM, Wallentin LC,
.. Armstrong PW, Simoons ML, Januzzi JL, Nieminen MS, Gheorghiade M,
Cardiovascular Society, Chris P. Gale. ..
.. Filippatos G, Luepker RV, Fortmann SP, Rosamond WD, Levy D, Wood D,
.. Smith SC, Hu D, Lopez-Sendon JL, Robertson RM, Weaver D, Tendera M,
.. Bove AA, Parkhomenko AN, Vasilieva EJ, Mendis S, ESC Committee for
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Baumgartner H, Gaemperli O, Achenbach S, Agewall S, Badimon L, Baigent C, .. coronary atherosclerosis: mechanisms and management. Eur Heart J
Bueno H, Bugiardini R, Carerj S, Casselman F, Cuisset T, Erol C, Fitzsimons D, . 2015;36(8):475–481.
European Heart Journal (2019) 40, 87–165 ESC/EACTS GUIDELINES
doi:10.1093/eurheartj/ehy394

2018 ESC/EACTS Guidelines on myocardial


revascularization
The Task Force on myocardial revascularization of the European
Society of Cardiology (ESC) and European Association for

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Cardio-Thoracic Surgery (EACTS)

Developed with the special contribution of the European


Association for Percutaneous Cardiovascular Interventions (EAPCI)

Authors/Task Force Members: Franz-Josef Neumann* (ESC Chairperson)


(Germany), Miguel Sousa-Uva*1 (EACTS Chairperson) (Portugal), Anders Ahlsson1
(Sweden), Fernando Alfonso (Spain), Adrian P. Banning (UK), Umberto Benedetto1
(UK), Robert A. Byrne (Germany), Jean-Philippe Collet (France), Volkmar Falk1
(Germany), Stuart J. Head1 (The Netherlands), Peter Jüni (Canada),
Adnan Kastrati (Germany), Akos Koller (Hungary), Steen D. Kristensen (Denmark),
Josef Niebauer (Austria), Dimitrios J. Richter (Greece), Petar M. Seferovic (Serbia),
Dirk Sibbing (Germany), Giulio G. Stefanini (Italy), Stephan Windecker
(Switzerland), Rashmi Yadav1 (UK), Michael O. Zembala1 (Poland)
Document Reviewers: William Wijns (ESC Review Co-ordinator) (Ireland), David Glineur1 (EACTS Review
Co-ordinator) (Canada), Victor Aboyans (France), Stephan Achenbach (Germany), Stefan Agewall
(Norway), Felicita Andreotti (Italy), Emanuele Barbato (Italy), Andreas Baumbach (UK), James Brophy
(Canada), Héctor Bueno (Spain), Patrick A. Calvert (UK), Davide Capodanno (Italy), Piroze M. Davierwala1

* Corresponding authors. Franz-Josef Neumann, Department of Cardiology and Angiology II, University Heart Centre Freiburg-Bad Krozingen, Suedring 15, 79189 Bad Krozingen,
Germany. Tel: þ49 7633 402 2000, Fax: þ49 7633 402 2009, Email: franz-josef.neumann@universitaets-herzzentrum.de. Miguel Sousa-Uva, Cardiac Surgery Department, Hospital
Santa Cruz, Avenue Prof Reynaldo dos Santos, 2790-134 Carnaxide, Portugal. Tel: þ 351 210 433 163, Fax: þ 351 21 424 13 88, Cardiovascular Research Centre, Department of
Surgery and Physiology, Faculty of Medicine-University of Porto, Alameda Prof Hernani Monteiro, 4200-319 Porto, Portugal Email: migueluva@gmail.com.
ESC Committee for Practice Guidelines (CPG), EACTS Clinical Guidelines Committee, and National Cardiac Societies document reviewers: listed in the Appendix.
1
Representing the European Association for Cardio-Thoracic Surgery (EACTS).
ESC entities having participated in the development of this document:
Associations: Acute Cardiovascular Care Association (ACCA), European Association of Preventive Cardiology (EAPC), European Association of Cardiovascular Imaging
(EACVI), European Association of Percutaneous Cardiovascular Interventions (EAPCI), European Heart Rhythm Association (EHRA), Heart Failure Association (HFA).
Councils: Council on Cardiovascular Nursing and Allied Professions, Council for Cardiology Practice, Council on Cardiovascular Primary Care, Council on Stroke, Council on
Valvular Heart Disease
Working Groups: Aorta and Peripheral Vascular Diseases, Cardiovascular Pharmacotherapy, Coronary Pathophysiology and Microcirculation, Thrombosis.
Disclaimer. The ESC Guidelines represent the views of the ESC and were produced after careful consideration of the scientific and medical knowledge and the evidence avail-
able at the time of their dating. The ESC is not responsible in the event of any contradiction, discrepancy and/or ambiguity between the ESC Guidelines and any other official rec-
ommendations or guidelines issued by the relevant public health authorities, in particular in relation to good use of health care or therapeutic strategies. Health professionals are
encouraged to take the ESC Guidelines fully into account when exercising their clinical judgment as well as in the determination and the implementation of preventive, diagnostic
or therapeutic medical strategies. However, the ESC Guidelines do not override in any way whatsoever the individual responsibility of health professionals to make appropriate
and accurate decisions in consideration of each patient’s health condition and in consultation with that patient and the patient’s caregiver where appropriate and/or necessary.
Nor do the ESC Guidelines exempt health professionals from taking careful and full consideration of the relevant official updated recommendations or guidelines issued by the
competent public health authorities in order to manage each patient’s case in light of the scientifically accepted data pursuant to their respective ethical and professional obliga-
tions. It is also the health professional’s responsibility to verify the applicable rules and regulations relating to drugs and medical devices at the time of prescription.
This article has been co-published with permission in the European Heart Journal and European Journal of Cardio-Thoracic Surgery. All rights reserved. V C 2018 European Society of

Cardiology. The articles are identical except for minor stylistic and spelling differences in keeping with each journal’s style. Either citation can be used when citing this article.
88 ESC/EACTS Guidelines

(Germany), Victoria Delgado (The Netherlands), Dariusz Dudek (Poland), Nick Freemantle1 (UK),
Christian Funck-Brentano (France), Oliver Gaemperli (Switzerland), Stephan Gielen (Germany), Martine
Gilard (France), Bulent Gorenek (Turkey), Joerg Haasenritter (Germany), Michael Haude (Germany),
Borja Ibanez (Spain), Bernard Iung (France), Anders Jeppsson1 (Sweden), Demosthenes Katritsis (Greece),
Juhani Knuuti (Finland), Philippe Kolh1 (Belgium), Adelino Leite-Moreira1 (Portugal), Lars H. Lund
(Sweden), Francesco Maisano (Switzerland), Julinda Mehilli (Germany), Bernhard Metzler (Austria), Gilles
Montalescot (France), Domenico Pagano1 (UK), Anna Sonia Petronio (Italy), Massimo Francesco Piepoli
(Italy), Bogdan A. Popescu (Romania), Rafael Sa daba1 (Spain), Evgeny Shlyakhto (Russia), Sigmund Silber
(Germany), Iain A. Simpson (UK), David Sparv (Sweden), Giuseppe Tavilla1 (The Netherlands), Holger
Thiele (Germany), Petr Tousek (Czech Republic), Eric Van Belle (France), Pascal Vranckx (Belgium), Adam
Witkowski (Poland), Jose Luis Zamorano (Spain), Marco Roffi (ESC CPG Supervisor) (Switzerland)

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The disclosure forms of all experts involved in the development of these Guidelines are available on the
ESC website www.escardio.org/guidelines

Online publish-ahead-of-print 25 August 2018

...................................................................................................................................................................................................
Keywords Acute coronary syndromes • Antithrombotic therapy • Bare-metal stents • Coronary artery bypass
grafting • Coronary artery disease • Drug-eluting stents • Guidelines • Heart Team • Myocardial
infarction • Myocardial ischaemia • Myocardial revascularization • Medical therapy • Percutaneous coronary
intervention • Recommendation • Revascularization • Risk stratification • Stents • Stable angina • Stable
coronary artery disease • ST-segment elevation myocardial infarction • SYNTAX score

..
Table of contents ..
..
4.1 Patient information and informed consent . . . . . . . . . . . . . . . . . . . . . 98
4.2 Multidisciplinary decision-making (Heart Team) . . . . . . . . . . . . . . . . 99
..
Abbreviations and acronyms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 90 .. 4.3 Timing of revascularization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 99
1 Preamble . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 93 .. 5 Revascularization for stable coronary artery disease . . . . . . . . . . . . . . .101
..
2 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 94 .. 5.1 Rationale for revascularization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .101
2.1 What is new in the 2018 Guidelines? . . . . . . . . . . . . . . . . . . . . . . . . . . . 95 .. 5.2 Evidence basis for revascularization . . . . . . . . . . . . . . . . . . . . . . . . . . .101
..
3 Diagnostic tools to guide myocardial revascularization . . . . . . . . . . . . . . 96 .. 5.2.1 Revascularization with the use of percutaneous coronary
3.1 Non-invasive diagnostic tools . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 96 .. intervention . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .102
..
3.1.1 Assessment of myocardial ischaemia . . . . . . . . . . . . . . . . . . . . . . . 96 .. 5.2.2 Revascularization with the use of coronary artery bypass
3.1.2 Assessment of myocardial viability in patients with heart .. grafting . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .102
..
failure and coronary artery disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 96 .. 5.3 Percutaneous coronary intervention vs. coronary artery
3.2 Invasive diagnostic tools . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 96 .. bypass grafting . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .102
..
3.2.1 Pressure-derived fractional flow reserve . . . . . . . . . . . . . . . . . . . 96 .. 5.3.1 Criteria for decision making . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .102
3.2.1.1 Use of fractional flow reserve in patients with .. 5.3.1.1 Predicted surgical mortality . . . . . . . . . . . . . . . . . . . . . . . . . .104
..
intermediate-grade coronary stenosis including left main .. 5.3.1.2 Anatomical complexity of coronary artery disease . . . . . .104
stenosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 96
.. 5.3.1.3 Completeness of revascularization . . . . . . . . . . . . . . . . . . . .106
..
3.2.1.2 Use of fractional flow reserve to identify lesions .. 5.3.2 Isolated proximal left anterior descending coronary
requiring revascularization in patients with multivessel
.. artery disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .109
..
coronary artery disease undergoing percutaneous coronary .. 5.3.3 Left main coronary artery disease . . . . . . . . . . . . . . . . . . . . . . . .109
intervention . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 97
.. 5.3.4 Multivessel coronary artery disease . . . . . . . . . . . . . . . . . . . . . . .109
..
3.2.1.3 Fractional flow reserve-guided management vs. medical .. 5.4 Gaps in the evidence . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .110
therapy in patients with coronary artery disease . . . . . . . . . . . . . . . . 97
.. 6 Revascularization in non-ST-elevation acute coronary syndrome . . .110
..
3.2.2 Other pressure-derived indices . . . . . . . . . . . . . . . . . . . . . . . . . . . 97 .. 6.1 Early invasive vs. conservative strategy . . . . . . . . . . . . . . . . . . . . . . . .110
..
3.2.3 Use of fractional flow reserve and pressure-derived .. 6.2 Timing of angiography and intervention . . . . . . . . . . . . . . . . . . . . . . .110
indices in patients with severe aortic stenosis . . . . . . . . . . . . . . . . . . . 98 .. 6.3 Type of revascularization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .110
..
3.2.4 Use of intravascular imaging for diagnostic assessment .. 6.3.1 Percutaneous coronary intervention . . . . . . . . . . . . . . . . . . . . .110
of stenosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 98 .. 6.3.1.1 Technical aspects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .110
..
3.3 Gaps in the evidence . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 98 .. 6.3.1.2 Revascularization strategies and outcomes . . . . . . . . . . . .111
4 Process for decision-making and patient information . . . . . . . . . . . . . . . . 98 .. 6.3.2 Coronary artery bypass grafting . . . . . . . . . . . . . . . . . . . . . . . . . .111
.
ESC/EACTS Guidelines 89

6.3.3 Percutaneous coronary intervention vs. coronary artery


.. 13.4.1 Restenosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .125
..
bypass grafting . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .111 .. 13.4.2 Disease progression . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .126
..
6.4 Gaps in the evidence . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .112 .. 13.4.3 Stent thrombosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .126
7 Revascularization in ST-segment elevation myocardial infarction . . .112 .. 14 Arrhythmias . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .127
..
7.1 Time delays . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .112 .. 14.1 Ventricular arrhythmias . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .127
7.2 Selection of reperfusion strategy . . . . . . . . . . . . . . . . . . . . . . . . . . . . .112 .. 14.1.1 Revascularization for the prevention of sudden cardiac
..
7.3 Primary percutaneous coronary intervention . . . . . . . . . . . . . . . . .113 .. death in patients with stable coronary artery disease and
7.4 Percutaneous coronary intervention after thrombolysis .. reduced left ventricular function . . . . . . . . . . . . . . . . . . . . . . . . . . . .127
..
and in patients with late diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .114 .. 14.1.2 Revascularization for the treatment of electrical storm 128
7.5 Gaps in the evidence . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .114 .. 14.1.3 Revascularization after out-of-hospital cardiac arrest . .128
..
8 Myocardial revascularization in patients with heart failure . . . . . . . . . .116 .. 14.2 Atrial arrhythmias . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .128
8.1 Chronic heart failure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .116 .. 14.2.1 Atrial fibrillation complicating percutaneous coronary
..

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8.1.1 Recommendations for myocardial revascularization in .. intervention . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .128
patients with chronic heart failure . . . . . . . . . . . . . . . . . . . . . . . . . . . . .116 .. 14.2.2 Atrial fibrillation complicating coronary artery bypass
..
8.1.2 Ventricular reconstruction and aneurysm resection . . . . . . .116 .. grafting . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .128
8.2 Acute heart failure and cardiogenic shock . . . . . . . . . . . . . . . . . . . . .117
.. 14.2.3 Postoperative atrial fibrillation and stroke risk . . . . . . . . .128
..
8.2.1 Revascularization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .117 .. 14.3 Gaps in the evidence . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .129
8.2.2 Mechanical circulatory support . . . . . . . . . . . . . . . . . . . . . . . . . . .117
.. 15 Procedural aspects of coronary artery bypass grafting . . . . . . . . . . . .129
..
8.2.2.1 Intra-aortic balloon pump . . . . . . . . . . . . . . . . . . . . . . . . . . .117 .. 15.1 Surgical techniques . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .129
8.2.2.2 Extracorporeal membrane oxygenation . . . . . . . . . . . . . . .117
.. 15.1.1 Completeness of revascularization . . . . . . . . . . . . . . . . . . . .129
..
8.2.2.3 Percutaneous left ventricular assist devices . . . . . . . . . . . .118 .. 15.1.2 Conduit selection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .130
8.2.2.4 Surgically implanted left ventricular assist devices . . . . . . .118
.. 15.1.3 Mammary artery harvesting . . . . . . . . . . . . . . . . . . . . . . . . . .130
..
8.3 Gaps in the evidence . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .119 .. 15.1.4 Radial artery harvesting . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .130
..
9 Revascularization in patients with diabetes . . . . . . . . . . . . . . . . . . . . . . . .119 .. 15.1.5 Saphenous vein harvesting . . . . . . . . . . . . . . . . . . . . . . . . . . .130
9.1 Evidence for myocardial revascularization . . . . . . . . . . . . . . . . . . . . .119 .. 15.1.6 Construction of central anastomosis . . . . . . . . . . . . . . . . . .131
..
9.2 Type of myocardial revascularization . . . . . . . . . . . . . . . . . . . . . . . . .119 .. 15.1.7 Intraoperative quality control . . . . . . . . . . . . . . . . . . . . . . . . .131
9.2.1. Randomized clinical trials . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .119 .. 15.1.8 On-pump and off-pump procedures . . . . . . . . . . . . . . . . . .131
..
9.2.2 Meta-analysis of coronary artery bypass grafting vs. .. 15.1.9 Minimally invasive and hybrid procedures . . . . . . . . . . . . .131
percutaneous coronary intervention in patients with diabetes . . .120 .. 15.2 Reporting perioperative outcomes . . . . . . . . . . . . . . . . . . . . . . . . . .131
..
9.3 Revascularization with the use of percutaneous coronary .. 15.3 Gaps in the evidence . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .131
intervention . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .120 .. 16 Procedural aspects of percutaneous coronary intervention . . . . . . .133
..
9.4 Antithrombotic pharmacotherapy . . . . . . . . . . . . . . . . . . . . . . . . . . . .120 .. 16.1 Percutaneous coronary intervention devices . . . . . . . . . . . . . . . . .133
9.5 Metformin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .120 .. 16.1.1 Balloon angioplasty . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .133
..
9.6 Gaps in the evidence . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .121 .. 16.1.2 Choice of coronary stents . . . . . . . . . . . . . . . . . . . . . . . . . . . .133
10 Revascularization in patients with chronic kidney disease . . . . . . . . .121 .. 16.1.3 Bioresorbable scaffolds . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .134
..
10.1 Evidence base for revascularization and recommendations . . .121 .. 16.1.4 Drug-coated balloons . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .134
10.2 Prevention of contrast-induced nephropathy . . . . . . . . . . . . . . . .121 .. 16.1.5 Devices for lesion preparation . . . . . . . . . . . . . . . . . . . . . . . .134
..
10.3 Gaps in the evidence . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .121 .. 16.2 Invasive imaging tools for procedural guidance . . . . . . . . . . . . . . .134
11 Revascularization in patients requiring valve interventions . . . . . . . .122
.. 16.2.1 Intravascular ultrasound . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .134
..
11.1 Primary indication for valve interventions . . . . . . . . . . . . . . . . . . . .122 .. 16.2.2 Optical coherence tomography . . . . . . . . . . . . . . . . . . . . . .135
11.2 Primary indication for myocardial revascularization . . . . . . . . . . .122
.. 16.3 Specific lesion subsets . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .135
..
11.2.1 Aortic valve disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .122 .. 16.3.1 Bifurcation stenosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .135
11.2.2 Mitral valve disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .122
.. 16.3.2 Chronic total coronary occlusion . . . . . . . . . . . . . . . . . . . . .135
..
11.3 Gaps in the evidence . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .122 .. 16.3.3 Ostial lesions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .136
12 Associated peripheral artery diseases . . . . . . . . . . . . . . . . . . . . . . . . . . . .123
.. 16.4 Vascular access . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .136
..
12.1 Prevention of stroke associated with carotid artery .. 17 Antithrombotic treatments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .137
..
disease and myocardial revascularization . . . . . . . . . . . . . . . . . . . . . . . . .123 .. 17.1 Percutaneous coronary intervention in stable coronary
12.2 Associated coronary and peripheral artery diseases . . . . . . . . . .123 .. artery disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .138
..
13 Repeat revascularization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .124 .. 17.1.1 Choice of treatment and pre-treatment . . . . . . . . . . . . . . .138
13.1 Early graft failure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .124 .. 17.1.2 Peri-interventional treatment . . . . . . . . . . . . . . . . . . . . . . . . .138
..
13.2 Acute percutaneous coronary intervention failure . . . . . . . . . . .125 .. 17.1.3 Post-interventional and maintenance treatment . . . . . . .139
13.3 Disease progression and late graft failure . . . . . . . . . . . . . . . . . . . .125 .. 17.2 Non-ST-segment elevation acute coronary syndrome . . . . . . . .141
..
13.3.1 Redo coronary artery bypass grafting or percutaneous .. 17.2.1 Choice of treatment and pre-treatment . . . . . . . . . . . . . . .141
coronary intervention . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .125 .. 17.2.2 Peri-interventional treatment . . . . . . . . . . . . . . . . . . . . . . . . .141
..
13.3.2 Percutaneous coronary intervention for saphenous vein .. 17.2.3 Post-interventional and maintenance treatment . . . . . . .141
graft lesions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .125 .. 17.3 ST-segment elevation myocardial infarction . . . . . . . . . . . . . . . . . .144
..
13.4 Repeat percutaneous coronary intervention . . . . . . . . . . . . . . . . .125 . 17.3.1 Choice of treatment and pre-treatment . . . . . . . . . . . . . . .144
90 ESC/EACTS Guidelines

17.3.2 Peri-interventional treatment . . . . . . . . . . . . . . . . . . . . . . . . .144 ..


.. ARCTIC Assessment by a Double Randomization of a
17.3.3 Post-interventional and maintenance treatment . . . . . . .144 .. Conventional Antiplatelet Strategy versus a
17.4 Coronary artery bypass grafting . . . . . . . . . . . . . . . . . . . . . . . . . . . . .145 ..
.. Monitoring-guided Strategy for Drug-Eluting
17.5 Special conditions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .145 .. Stent Implantation and of Treatment
17.5.1 Antithrombotic therapy after percutaneous ..
.. Interruption versus Continuation One Year
coronary intervention in patients requiring oral .. after Stenting
anticoagulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .145 ..
.. ART Arterial Revascularization Trial
17.5.2 Revascularization in patients with renal failure . . . . . . . . .148 .. AS Aortic stenosis
17.5.3 Monitoring of antiplatelet drugs (platelet function
..
.. ASE American Society of Echocardiography
testing and genotyping) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .148 .. ATLANTIC Administration of Ticagrelor in the Cath Lab
17.5.4 Surgery in patients on dual antiplatelet therapy . . . . . . . .148
..
.. or in the Ambulance for New ST-Elevation
17.6 Gaps in the evidence . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .148 .. Myocardial Infarction to Open the Coronary

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18 Volume–outcome relationship for revascularization
..
.. Artery
procedures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .149 .. ATLAS-ACS Anti-Xa Therapy to Lower cardiovascular
18.1 Coronary artery bypass grafting . . . . . . . . . . . . . . . . . . . . . . . . . . . . .149
..
.. 2–TIMI 51 events in Addition to Standard therapy in
18.2 Percutaneous coronary intervention . . . . . . . . . . . . . . . . . . . . . . . .149 .. subjects with Acute Coronary
..
18.3 Training in cardiac surgery and interventional cardiology .. Syndrome–Thrombolysis In Myocardial
for myocardial revascularization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .149 .. Infarction 51
..
19 Medical therapy, secondary prevention, and strategies for .. ATOLL Acute STEMI Treated with primary PCI and
follow-up . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .151 .. intravenous enoxaparin Or UFH to Lower
..
19.1 Gaps in the evidence . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .152 .. ischaemic and bleeding events at short- and
20 Key messages . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .152 .. Long-term follow-up
..
21 Evidence-based 0 to do0 and 0 not to do0 messages from the .. AWESOME Angina With Extremely Serious Operative
Guidelines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .152 ..
.. Mortality Evaluation
22 Appendix . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .156 .. BARC Bleeding Academic Research Consortium
23 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .157 ..
.. BARI-2D Bypass Angioplasty Revascularization
.. Investigation 2 Diabetes
..
.. BES Biolimus-eluting stent
Abbreviations and acronyms .. BEST Randomised Comparison of Coronary
..
.. Artery Bypass Surgery and Everolimus-Eluting
ABC Age, Biomarkers, Clinical History .. Stent Implantation in the Treatment of
ABSORB II A Bioresorbable Everolimus-Eluting Scaffold
..
.. Patients with Multivessel Coronary Artery
Versus a Metallic Everolimus-Eluting Stent II .. Disease
AIDA Amsterdam Investigator-Initiated Absorb
..
.. b.i.d. Bis in die (twice daily)
Strategy All-Comers .. BIMA Bilateral internal mammary artery
..
ACCOAST Comparison of Prasugrel at the Time of .. BMS Bare-metal stent
Percutaneous Coronary Intervention or as .. BRAVE Bavarian Reperfusion Alternatives Evaluation
..
Pretreatment at the Time of Diagnosis in
... BRS Bioresorbable scaffolds
Patients with Non-ST Elevation Myocardial .. BVS Bioresorbable vascular scaffold
Infarction .. CABG Coronary artery bypass grafting
..
ACS Acute coronary syndrome .. CAD Coronary artery disease
ACUITY Acute Catheterization and Urgent .. CARDia Coronary Artery Revascularization in
..
Intervention Triage strategy .. Diabetes
ADAPT-DES Assessment of Dual Antiplatelet Therapy .. CCS Canadian Cardiovascular Society
..
With Drug-Eluting Stents .. CEA Carotid endarterectomy
AF Atrial fibrillation ..
.. CHA2DS2-VASc Cardiac Congestive heart failure,
ALPHEUS Assessment of Loading With the P2Y12- .. Hypertension, Age >_75 [Doubled], Diabetes
Inhibitor Ticagrelor or Clopidogrel to Halt ..
.. mellitus, prior Stroke or transient ischaemic
Ischemic Events in Patients Undergoing .. attack or thromboembolism [Doubled] –
Elective Coronary Stenting
..
.. Vascular disease, Age 65–74 and Sex
AMI Acute myocardial infarction .. category [Female]
AMACING A Maastricht Contrast-Induced
..
.. CHAMPION Cangrelor versus Standard Therapy to
Nephropathy Guideline .. Achieve Optimal Management of Platelet
ANTARCTIC Platelet function monitoring to adjust
..
.. Inhibition
antiplatelet therapy in elderly patients .. CI Confidence interval
stented for an acute coronary syndrome
..
. CIN Contrast-induced nephropathy
ESC/EACTS Guidelines 91

CKD Chronic kidney disease .. EUROMAX European Ambulance Acute Coronary


..
CMR Cardiac magnetic resonance .. Syndrome Angiography
COMPASS Rivaroxaban for the Prevention of Major .. EXCEL Evaluation of XIENCE Versus Coronary
..
Cardiovascular Events in Coronary or .. Artery Bypass Surgery for Effectiveness of
Peripheral Artery Disease
.. Left Main Revascularization
..
COURAGE Clinical Outcomes Utilizing Revascularization .. FAME Fractional Flow Reserve versus Angiography
and Aggressive Drug Evaluation
.. for Multivessel Evaluation
..
CPG ESC Committee for Practice Guidelines .. FDG-PET Fluorodeoxyglucose positron emission
CT Computed tomography
.. tomography
..
CT-FFR CT-derived fractional flow reserve .. FFR Fractional flow reserve
CTO Chronic total occlusion
.. FITT-STEMI Feedback Intervention and Treatment
..
CTSN Cardiothoracic Surgical Trial Network .. Times in ST-Elevation Myocardial

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..
CULPRIT-SHOCK Culprit Lesion Only PCI versus Multivessel .. Infarction
PCI in Cardiogenic Shock .. FMC First medical contact
..
CVA Cerebrovascular accident .. FREEDOM Future Revascularization Evaluation in
CvLPRIT Complete Versus Lesion-Only Primary PCI Trial .. Patients with Diabetes Mellitus
..
DANAMI 3-DEFER The Third DANish Study of Optimal Acute .. GLOBAL Long-term ticagrelor monotherapy versus
Treatment of Patients with ST-segment .. LEADERS standard dual antiplatelet therapy followed by
..
Elevation Myocardial Infarction: DEFERred .. aspirin monotherapy in patients undergoing
stent implantation in connection with .. biolimus-eluting stent implantation
..
primary PCI .. GP IIb/IIIa Glycoprotein IIb/IIIa
DANAMI-3- The Third DANish Study of Optimal Acute .. GRAVITAS Gauging Responsiveness with A
..
PRIMULTI Treatment of Patients with ST-segment .. VerifyNow assay-Impact on Thrombosis
Elevation Myocardial Infarction: PRImary PCI .. And Safety
..
in MULTIvessel Disease .. HAS-BLED Hypertension, Abnormal renal/liver function,
DAPT Dual antiplatelet therapy
.. Stroke, Bleeding history or predisposition,
..
DCB Drug-coated balloon .. Labile INR, Elderly, Drugs/alcohol
DEFINE-FLAIR Define Functional Lesion Assessment of
.. HEAT-PPCI How Effective are Antithrombotic Therapies
..
Intermediate Stenosis to Guide .. in primary PCI
Revascularization
.. HF Heart failure
..
DES Drug-eluting stents .. HFrEF Heart failure with reduced ejection fraction
DUS Duplex ultrasound
.. HORIZONS Harmonizing Outcomes with
..
EACTS European Association for Cardio-Thoracic .. Revascularization and Stents in Acute
..
Surgery .. Myocardial Infarction
EAPCI European Association for Percutaneous .. HPR High platelet reactivity
..
Cardiovascular Interventions .. HR Hazard ratio
EBC TWO European Bifurcation Coronary TWO .. i.v. Intravenous
..
ECG Electrocardiogram .. IABP Intra-aortic balloon pump
ECLS Extracorporeal life support .. IABP-SHOCK II Intraaortic Balloon Pump in Cardiogenic
..
ECMO Extracorporeal membrane oxygenation .. Shock II Trial
EES Everolimus-eluting stent .. ICD Implantable cardioverter defibrillator
..
EF Ejection fraction .. iwFR Instantaneous wave-free ratio
EMS Emergency medical service .. IMA Internal mammary artery
..
EROA Effective regurgitant orifice area .. IMR Ischaemic mitral regurgitation
ENTRUST-AF-PCI Evaluation of the safety and efficacy of an .. INR International normalized ratio
..
edoxaban-based antithrombotic regimen in .. IRA Infarct-related artery
patients with atrial fibrillation following .. ISAR-CABG Is Drug-Eluting-Stenting Associated with
..
successful percutaneous coronary intervention .. Improved Results in Coronary Artery Bypass
ESC European Society of Cardiology ... Grafts
EUROCTO Randomized Multicentre Trial to Compare
.. ISAR-REACT Intracoronary Stenting and Antithrombotic
..
Revascularization With Optimal Medical .. Regimen Rapid Early Action for Coronary
Therapy for the Treatment of Chronic Total
.. Treatment
..
Occlusions .. ISCHEMIA International Study of Comparative Health
EuroSCORE European System for Cardiac Operative Risk
.. Effectiveness With Medical and Invasive
..
Evaluation .. Approaches
92 ESC/EACTS Guidelines

..
IVUS Intravascular ultrasound imaging .. PIONEER Prevention of bleeding in patients with AF
LAA Left atrial appendage .. undergoing PCI
..
LAD Left anterior descending .. PLATFORM Prospective LongitudinAl Trial of FFRct:
LEAD Lower extremity artery disease .. Outcome and Resource Impacts,
..
LGE-CMR Late gadolinium enhancement cardiac .. PLATO Study of Platelet Inhibition and Patient
magnetic resonance .. Outcomes
..
LIMA Left internal mammary artery .. pLVAD Percutaneous left ventricular assist device
LM/LMS Left main/left main stem .. p.o. Per os (orally)
..
LMWH Low-molecular-weight heparin .. POSEIDON Prevention of Contrast Renal Injury with
LPR Low platelet reactivity .. Different Hydration Strategies
..
LV Left ventricle/left ventricular .. PPI Proton pump inhibitor
LVAD Left ventricular assist device,
.. PRAGUE-18 Comparison of Prasugrel and Ticagrelor in
..

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LVEF Left ventricular ejection fraction .. the Treatment of Acute Myocardial Infarction
MACCE Major adverse cardiac and cerebrovascular
.. PRAMI Preventive Angioplasty in Acute Myocardial
..
events .. Infarction
MACE Major adverse cardiac events
.. PRECISE-DAPT PREdicting bleeding Complications In
..
MADIT II Multicenter Automatic Defibrillator .. patients undergoing Stent implantation and
Implantation Trial II
.. subsEquent Dual Anti Platelet Therapy
..
MATRIX Minimizing Adverse Haemorrhagic Events by .. PRECOMBAT Premier of Randomised Comparison of
..
Transradial Access Site and Systemic .. Bypass Surgery versus Angioplasty Using
Implementation of AngioX .. Sirolimus-Eluting Stent in Patients with Left
..
MCS Mechanical circulatory support .. Main Coronary Artery Disease
MI Myocardial infarction .. PRESERVE Prevention of Serious Adverse Events
..
MINOCA Myocardial infarction with non-obstructive .. Following Angiography
coronary arteries .. q.d. Quaque die (once daily)
..
MLA Minimal luminal area .. RCT Randomized controlled trial
MR Mitral regurgitation .. RE-DUAL Randomised Evaluation of Dual
..
MSCT Multi-slice computed tomography .. Antithrombotic Therapy with Dabigatran
MT Medical therapy .. versus Triple Therapy with Warfarin in
..
MVD Multivessel coronary artery disease .. Patients with Nonvalvular Atrial Fibrillation
MVO Microvascular obstruction .. Undergoing Percutaneous Coronary
..
NAC N-acetylcysteine .. Intervention
NNT Number needed to treat
.. REMEDIAL II Renal Insufficiency After Contrast Media
..
NOAC Non-vitamin K antagonist oral anticoagulant .. Administration II
NOBLE Nordic-Baltic-British Left Main
.. REPLACE-2 The Randomised Evaluation in PCI Linking
..
Revascularization Study .. Angiomax to Reduced Clinical Events 2
NSTE-ACS Non-ST-segment elevation acute coronary
.. RIVAL Radial versus femoral access for coronary
..
syndrome .. angiography and intervention in patients
NSTEMI Non-ST-segment elevation myocardial
.. with acute coronary syndromes
..
infarction .. ROMA Randomization of Single vs. Multiple Arterial
NYHA New York Heart Association
.. Grafts
..
OAC Oral anticoagulation .. RR Relative risk
..
OASIS-5 Optimal Antiplatelet Strategy for .. SASSICAIA Comparison of Loading Strategies With
Interventions-5 .. Antiplatelet Drugs in Patients Undergoing
..
OCT Optical coherence tomography .. Elective Coronary Intervention
OR Odds ratio .. SAVR Surgical aortic valve replacement
..
ORBITA Objective Randomised Blinded Investigation .. s.c. Subcutaneous
with optimal medical Therapy of Angioplasty .. SCAD Stable coronary artery disease
..
in stable angina .. SCD-HEFT Sudden Cardiac Death in Heart Failure Trial
PARR-2 PET and Recovery following .. SES Sirolimus-eluting stent
..
Revascularization .. SHOCK Should We Emergently Revascularize
PCI Percutaneous coronary intervention .. Occluded Coronaries for Cardiogenic Shock
..
Pd/Pa Distal coronary to aortic pressure .. SIMA Single internal mammary artery
PES Paclitaxel-eluting stent .. SMART-DATE Smart Angioplasty Research Team-safety of
..
PET Positron emission tomography .. 6-month duration of Dual Antiplatelet
PF Platelet function
.. Therapy after percutaneous coronary
ESC/EACTS Guidelines 93

..
intervention in patients with acute coronary .. for an individual patient with a given condition, taking into account
syndromes
.. the impact on outcome as well as the risk–benefit ratio of particular
..
SPECT Single-photon emission computed tomography .. diagnostic or therapeutic means. Clinical practice guidelines are no
SR Sinus rhythm
.. substitutes for textbooks, but complement them, and cover the
..
STEEPLE Safety and Efficacy of Intravenous .. European Society of Cardiology (ESC) Core Curriculum topics. As
Enoxaparin in Elective Percutaneous
.. such they should help physicians to make decisions in their daily prac-
..
Coronary Intervention Randomised .. tice. However, final decisions should be individualized by responsible
.. physicians and the patient.
Evaluation ..
STEMI ST-segment elevation myocardial infarction .. A great number of clinical practice guidelines have been issued in
.. recent years both by the ESC as well as by other societies and organi-
STICH Surgical Treatment for Ischemic Heart Failure ..
STICHES STICH Extension Study .. zations. Because of the impact on clinical practice, quality criteria for
.. the development of guidelines have been established in order to
STS Society of Thoracic Surgeons ..

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SVG Saphenous vein graft .. make all decisions transparent to the user. The recommendations for
.. formulating and issuing ESC and joint society guidelines can be found
SVR Surgical ventricular reconstruction ..
SWEDEHEART Swedish Web-system for Enhancement and .. on the ESC website (https://www.escardio.org/Guidelines/Clinical-
.. Practice-Guidelines/Guidelines-development/Writing-ESC-Guidelines).
Development of Evidence-based care in ..
Heart disease Evaluated According to .. These Guidelines represent the official position of the ESC and the
.. European Association for Cardio-Thoracic Surgery (EACTS) on this
Recommended Therapies ..
SYNTAX Synergy between Percutaneous Coronary .. given topic and will be regularly updated.
.. Members of this Task Force were selected by the ESC and EACTS
Intervention with TAXUS and Cardiac Surgery ..
TAP T and protrusion .. to represent professionals involved with the medical care of patients
..
TAVI Transcatheter aortic valve implantation .. with this pathology. Selected experts in the field undertook a com-
TIA Transient ischaemic attack
.. prehensive review of the published evidence for diagnosis, manage-
..
TIMI Thrombolysis in Myocardial Infarction .. ment (including treatment) and/or prevention of a given condition
TLR Target lesion revascularization
.. according to the ESC Committee for Practice Guidelines (CPG) and
..
TOTAL Trial of Routine Aspiration Thrombectomy with .. EACTS policy. A critical evaluation of diagnostic and therapeutic pro-
PCI versus PCI Alone in Patients with STEMI
.. cedures was performed including assessment of the risk–benefit
..
TRIGGER-PCI Testing platelet Reactivity In patients .. ratio. Estimates of expected health outcomes for larger populations
underGoing elective stent placement on
.. were included, where data exist. The level of evidence and the
..
clopidogrel to Guide alternative thErapy .. strength of recommendation of particular treatment options were
.. weighed and graded according to predefined scales, as outlined in
with pRasugrel ..
TRITON-TIMI 38 TRial to Assess Improvement in Therapeutic .. Tables 1 and 2.
.. The experts of the writing and reviewing panels completed decla-
Outcomes by Optimizing Platelet InhibitioN ..
with Prasugrel–Thrombolysis In Myocardial .. rations of interest forms on what might be perceived as real or
.. potential sources of conflicts of interest. These forms were compiled
Infarction ..
TROPICAL-ACS Testing responsiveness to platelet inhibition .. into one file and can be found on the ESC and EACTS websites
.. http://www.escardio.org/guidelines and http://www.eacts.org). Any
on chronic antiplatelet treatment for acute ..
coronary syndromes .. changes in declarations of interest that arise during the writing period
.. must be notified to the ESC and EACTS and updated. The Task
TVR Target vessel revascularization ..
TWILIGHT Ticagrelor With Aspirin or Alone in High- .. Force received its entire financial support from the ESC and EACTS
.. without any involvement from the healthcare industry.
Risk Patients After Coronary Intervention ..
UFH Unfractionated heparin .. The CPG-ESC and EACTS supervised and coordinated the prepa-
.. ration of these new Guidelines produced by the joint Task Force.
VA Veno-arterial ..
VACARDS Veterans Affairs Coronary Artery
.. These entities are also responsible for the endorsement process of
..
Revascularization in Diabetes Study .. these Guidelines. The ESC/EACTS Guidelines underwent extensive
VALIDATE Bivalirudin versus Heparin in ST-Segment
.. review by a wide panel of relevant external experts. After appropri-
..
and Non–ST-Segment Elevation Myocardial .. ate revisions it was approved by all the experts involved in the Task
Infarction in Patients on Modern Antiplatelet
.. Force. The finalized document was approved by the ESC CPG and
..
Therapy .. EACTS for joint publication in the European Heart Journal and the
VKA Vitamin K antagonist
.. European Journal of Cardio-Thoracic Surgery.
..
.. The task of developing clinical practice guidelines covers not only
.. the integration of the most recent research, but also the creation of
..
1 Preamble .. educational tools and implementation programmes for the recom-
.. mendations. To implement the guidelines, condensed pocket guide-
..
Clinical practice guidelines summarize and evaluate all available evi- .. lines, summary slides, booklets with essential messages, and an
dence at the time of the writing process on a particular issue with the
.. electronic version for digital applications (smartphones, etc.) are pro-
..
aim of assisting physicians in selecting the best management strategies . duced. These versions are abridged and, thus, if needed, one should
94 ESC/EACTS Guidelines

Table 1 Classes of recommendations

Classes of Definition Suggested wording to use


recommendations

Class I Evidence and/or general agreement Is recommended/is


that a given treatment or procedure is indicated
beneficial, useful, effective.

Class II Conflicting evidence and/or a


divergence of opinion about the
usefulness/efficacy of the given

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treatment or procedure.

Class IIa Weight of evidence/opinion is in favour Should be considered


of usefulness/efficacy.

Class IIb Usefulness/efficacy is less well May be considered


established by evidence/opinion.

Class III Evidence or general agreement that Is not recommended


the given treatment or procedure is

©ESC 2018
not useful/effective, and in some cases
may be harmful.

.. circumstances of the individual patients, in consultation with that


..
Table 2 Levels of evidence .. patient, and where appropriate and necessary the patient’s guardian
.. or carer. It is also the health professional’s responsibility to verify the
..
.. rules and regulations applicable to drugs and devices at the time of
.. prescription.
..
..
..
..
.. 2 Introduction
..
..
.. These Guidelines represent the third time that the ESC and EACTS
.. have brought together cardiologists and cardiac surgeons in a joint
..
.. Task Force to review the ever-increasing body of evidence, with the
..
.. mission of drafting balanced, patient-centred practice Guidelines on
.. myocardial revascularization. Summaries of the key changes in com-
..
.. parison with the previous Guidelines are provided in Figures 1 and 2.
.. There is considerable overlap of the current document with other
..
always refer to the full text version, which is freely available on the .. Guidelines, specifically those on stable coronary artery disease, non-
ESC and EACTS websites. The National Societies of the ESC are .. ST-elevation myocardial infarction, ST-elevation myocardial infarc-
..
encouraged to endorse, translate, and implement the ESC .. tion, heart failure, valvular heart disease and the Focused Update on
Guidelines. Implementation programmes are needed because it has .. Dual Antiplatelet Therapy. Unless supported by new evidence, we
..
been shown that the outcome of disease may be favourably influ- .. followed the recommendations of these Guidelines where pertinent
enced by the thorough application of clinical recommendations. .. to our Guidelines, and refer the reader to the respective sections in
..
Surveys and registries are needed to verify that real-life daily prac- .. those documents for detailed discussion. We reserve more in-depth
tice is in keeping with what is recommended in the guidelines, thus .. discussion for topics that are specific to issues pertaining to myocar-
..
completing the loop between clinical research, writing of guidelines, .. dial revascularization that are not covered in other Guidelines. To
and implementing them in clinical practice. .. keep the current document concise and reader-friendly, we also
..
The guidelines do not, however, override the individual responsi- .. moved some of the detailed descriptions of study results to the
bility of healthcare professionals to make appropriate decisions in the
.. online Supplementary Data.
ESC/EACTS Guidelines 95

2.1 What is new in the 2018 Guidelines?

Calculation of the Syntax Score, if left Completeness of revascularization Routine non-invasive imaging
main or multivessel revascularization prioritized, when considering CABG surveillance in high-risk patients
is considered vs PCI 6 months after revascularization
Radial access as standard approach NOAC preferred over VKA in patients Double-kissing crush technique
for coronary angiography and PCI with non-valvular AF requiring preferred over provisional T-stenting
anticoagulation and antiplatelet in true left main bifurcations.
DES for any PCI
treatment Cangrelor in P2Y12 -inhibitor naïve
Systematic re-evaluation of patients
after myocardial revascularization patients undergoing PCI
No-touch vein technique, if open vein

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Stabilised NSTE-ACS patients: harvesting for CABG GP IIb/IIIa inhibitors for PCI in P2Y12 -
revascularization strategy according inhibitor naïve patients with ACS
Annual operator volume for left main undergoing PCI
to principles for SCAD
PCI of at least 25 cases per year
Use of the radial artery grafts over Dabigatran 150-mg dose preferred
saphenous vein grafts in patients with Pre- and post-hydration with isotonic over 110-mg dose when combined with
saline in patients with moderate or
high-degree stenosis single antiplatelet therapy after PCI
severe CKD if the expected contrast
Myocardial revascularization in volume is >100 mL De-escalation of P2Y12 inhibitor guided
patients with CAD, heart failure, and by platelet function testing in ACS
LVEF ≤35% Class I Class IIa patients
CABG preferred
Class IIb Class III
Routine revascularization of non-IRA
PCI as alternative to CABG
lesions in myocardial infarction with
cardiogenic shock

The figure does not show changes Current generation BRS for clinical use
compared with the 2014 version of outside clinical studies
the Myocardial Revascularization
Guidelines that were due to updates for
consistency with other ESC Guidelines

©ESC 2018
published since 2014.

ACS = acute coronary syndromes; AF = atrial fibrillation; BRS = bioresorbable scaffolds; CABG = coronary artery bypass grafting; CAD = coronary artery disease;
CKD = chronic kidney disease; DES = drug-eluting stents; FFR = fractional flow reserve; GP = glycoprotein; IRA = infarct-related artery; LVEF = left ventricular
ejection fraction; NOAC = non-vitamin K oral anticoagulants; NSTEMI = non-ST-elevation; PCI = percutaneous coronary intervention; SCAD = stable coronary
artery disease; VKA = vitamin K antagonists.

Figure 1 New recommendations.

UPGRADES DOWNGRADES
For PCI of bifurcation lesions, stent implantation in Distal protection devices for PCI of SVG lesions
the main vessel only, followed by provisional balloon
Bivalirudin for PCI in NSTE-ACS
angioplasty with or without stenting of the side branch
Bivalirudin for PCI in STEMI
Immediate coronary angiography and revascularization,
if appropriate, in survivors of out-of-hospital cardiac arrest PCI for MVD with diabetes and SYNTAX score <23
and an ECG consistent with STEMI
Platelet function testing to guide antiplatelet therapy
Assess all patients for the risk of interruption in patients undergoing cardiac surgery
contrast-induced nephropathy
EuroSCORE II to assess in-hospital mortality after CABG
OCT for stent optimization
Class I Class IIa
Class IIb Class III
The figure does not show changes compared with the 2014
version of the Myocardial Revascularization Guidelines
©ESC 2018

that were due to updates for consistency with other ESC


Guidelines published since 2014.

CABG = coronary artery bypass grafting; MVD = multivessel coronary artery disease; NSTE-ACS = non-ST-elevation acute coronary syndromes; OCT = optical
coherence tomography; PCI = percutaneous coronary interventions; STEMI = ST-elevation myocardial infarction,
SVG = saphenous vein grafts;

Figure 2 Changes in class of recommendation.


96 ESC/EACTS Guidelines

..
3 Diagnostic tools to guide .. contractile reserve.1,5 Assessment of ischaemia provides incremental
.. benefit over viability in mild to moderate CAD, but with extensive
myocardial revascularization ..
.. CAD viability assessment may be sufficient.6 Patients with advanced
.. HF and viable myocardium should first undergo revascularization
The use of diagnostic imaging and functional testing modalities to ..
detect patients with coronary artery disease (CAD) is discussed in .. with coronary artery bypass grafting (CABG) or percutaneous coro-
.. nary intervention (PCI) before being considered for mechanical circu-
detail in the clinical practice Guidelines for patients with SCAD.1 ..
Further diagnostic assessment of patients with obstructive CAD is .. latory support (MCS) or heart transplantation.7,8
.. The PARR-2 (PET and Recovery following Revascularization) trial
critical in order to identify patients and select specific lesions that are ..
likely to benefit from myocardial revascularization, in addition to opti-
.. included patients with severe left ventricular (LV) dysfunction being
.. considered for revascularization or HF/transplantation workups, and
mal medical therapy. ..
.. randomized them to management assisted by fluorodeoxyglucose
.. PET (FDG-PET) or standard care.6 The primary outcome of cardiac
..

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3.1 Non-invasive diagnostic tools .. death, myocardial infarction (MI), or recurrent hospital stay for car-
3.1.1 Assessment of myocardial ischaemia .. diac cause at 1 year was not improved in the group managed by
Non-invasive diagnostic assessment of patients with CAD being con-
..
.. FDG-PET [relative risk (RR) 0.82, 95% confidence interval (CI)
sidered for myocardial revascularization comprises the assessment of ..
.. 0.59–1.14, P = 0.16], though the rate of compliance with the treat-
ischaemia and the evaluation of viability in patients with regional wall .. ment recommended by FDG-PET was variable.
motion abnormalities or reduced ejection fraction (EF). ..
.. The viability substudy of the STICH (Surgical Treatment for
Functional testing to assess ischaemia is critical for the assessment .. Ischemic Heart Failure) trial found viable myocardium in 487/601
of stable patients with CAD. Documentation of ischaemia using func- ..
.. patients (81%) and none in 114 (19%).9 There was a significant associ-
tional testing before elective invasive procedures for CAD is the pre- .. ation between myocardial viability and outcome by univariate analy-
ferred approach. It may also have a role in the assessment of some ..
.. sis, but not on multivariable analysis. The lack of correlation between
patients presenting with acute coronary syndrome (ACS). Because of .. myocardial viability and benefit from revascularization indicates that
the low sensitivity of exercise electrocardiogram (ECG) testing in the ..
.. this strategy should not be the only test when selecting the optimal
assessment of patients with symptoms of angina, non-invasive imaging .. therapy.
is recommended as the first-line test.1 Detection of a large area of .
myocardial ischaemia by functional imaging is associated with
impaired prognosis of patients and identifies patients who should Recommendations for non-invasive imaging in patients
undergo revascularization (see section 5). with coronary artery disease and heart failure with
reduced ejection fraction
In patients undergoing coronary computed tomography (CT),
both CT-derived fractional flow reserve (CT-FFR) and CT perfusion
represent possible approaches to evaluate lesion-specific ischaemia. Recommendations Classa Levelb
Although the evidence for both is limited at present, there are con- Non-invasive stress imaging (CMR, stress
siderably more data from clinical investigations of CT-FFR. A number echocardiography, SPECT, or PET) may be
of trials have shown that correlation between CT-derived FFR considered for the assessment of myocar-
and invasive FFR is high.2,3 The non-randomized PLATFORM dial ischaemia and viability in patients with IIb B
(Prospective LongitudinAl Trial of FFRct: Outcome and Resource HF and CAD (considered suitable for coro-
Impacts) study showed that in patients referred for invasive angiogra- nary revascularization) before the decision
phy due to chest pain (predominantly atypical angina) and intermedi- on revascularization.9–11
ate pre-test probability of CAD, assessment with CT and CT-FFR
reduced the number of patients with subsequently normal invasive
CAD = coronary artery disease; CMR = cardiac magnetic resonance; HF = heart
coronary angiograms compared with standard care.4 Currently, clini- failure; PET = positron emission tomography; SPECT = single-photon emission
cal trial data with CT-FFR are insufficient to make a recommendation computed tomography.
a
Class of recommendation.
for its use in clinical practice. b
Level of evidence.

3.1.2 Assessment of myocardial viability in patients with


heart failure and coronary artery disease
In patients with regional wall motion abnormalities or ventricular dys-
function, heart failure (HF) can be caused by stunned or hibernating 3.2 Invasive diagnostic tools
myocardium and may be reversed by revascularization. Assessment 3.2.1 Pressure-derived fractional flow reserve
of myocardial viability may be done in order to select patients that 3.2.1.1 Use of fractional flow reserve in patients with intermediate-grade
are more likely to benefit from myocardial revascularization and can coronary stenosis including left main stenosis
be achieved with several imaging modalities: myocardial contrast Coronary pressure-derived FFR is the current standard of care for
echocardiography, single-photon emission CT (SPECT), and late the functional assessment of lesion severity in patients with
gadolinium enhancement cardiac magnetic resonance (LGE-CMR) all intermediate-grade stenosis (typically around 40 – 90% stenosis)
assess cellular integrity; positron emission tomography (PET) without evidence of ischaemia in non-invasive testing, or in those
assesses cellular metabolism; and dobutamine techniques assess with multivessel disease.
ESC/EACTS Guidelines 97

..
Multiple studies have shown that PCI can be safely deferred if FFR .. been shown in an observational study.28 Of the 627 patients with
is >0.75.12–15 The DEFER trial enrolled 325 patients scheduled for .. intermediate stenosis that were evaluated, 429 had bypass without
..
PCI of an intermediate stenosis.15 If FFR was >_0.75, patients were .. FFR and 198 had bypass with FFR; in the latter group, the proportion
randomly assigned to deferral (defer group; n = 91) or performance .. of patients with three-vessel disease was reclassified from 94 to 86%.
..
(perform group; n = 90) of PCI. The composite rate of cardiac death .. Outcomes were similar in both groups at 3 years [hazard ratio (HR)
and acute MI (AMI) in the defer and perform groups was 3.3 vs. 7.9% .. for death/MI/target vessel revascularization (TVR) = 1.03, 95% CI
..
(P = 0.21). .. 0.67–1.69], though the group with FFR guidance was associated with
However, most contemporary studies use an FFR cut-off of 0.80. .. a lower number of graft anastomoses and a lower rate of on-pump
..
A recent large-scale observational study supports the use of FFR .. surgery compared with angiography-guided CABG surgery.
>0.80 rather than 0.75 as a cut-off.16 Indeed, the two largest studies ..
..
in this field, DEFINE-FLAIR (Define Functional Lesion Assessment of .. 3.2.1.2 Use of fractional flow reserve to identify lesions requiring revascu-
Intermediate Stenosis to Guide Revascularization DES drug-eluting .. larization in patients with multivessel coronary artery disease undergoing
..

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stent)17 and iFR-SWEDEHEART (Swedish Web-system for .. percutaneous coronary intervention
Enhancement and Development of Evidence-based care in Heart dis- .. FFR may also be useful for the selection of lesions requiring revascula-
..
ease Evaluated According to Recommended Therapies),18 used the .. rization in patients with multivessel CAD. The FAME trial showed that
0.80 cut-off for lesion selection by FFR, with favourable event rates at
.. in patients with multivessel disease randomized to an FFR-guided PCI
..
1 year. Thus, 0.80 is the accepted FFR threshold for defining haemo- .. strategy (using a cut-off <_0.80 to indicate requirement for PCI), out-
dynamically relevant lesions.
.. comes at 12 months in terms of death, non-fatal MI, and repeat revas-
..
Haemodynamic relevance, as defined by FFR <_0.80, correlates .. cularization were superior compared with angiography-guided PCI
poorly with diameter stenosis by visual assessment. In the FAME
.. and utilized fewer resources.29 In addition, the 2 year composite risk
..
(Fractional Flow Reserve versus Angiography for Multivessel .. of death or MI was significantly lower with the FFR-guided PCI strat-
..
Evaluation) trial, only 35% of the 50–70% stenoses were haemody- .. egy.30 Long-term follow-up at 5 years showed broadly consistent find-
namically relevant and, of the 71–90% stenoses, 20% were not. Only .. ings, although differences between groups in relation to the primary
..
an estimated diameter stenosis >90% predicted haemodynamic rele- .. endpoint were no longer significant.31 This suggests that FFR-guided
vance with high accuracy (96% correct classification). A number of .. PCI should be the preferred management strategy in these patients.
..
studies have shown that utilization of an FFR-based assessment strat- ..
egy at the time of angiography results in reclassification of the revas- .. 3.2.1.3 Fractional flow reserve-guided management vs. medical therapy
..
cularization strategy (PCI, bypass surgery, or medical therapy) in a .. in patients with coronary artery disease
high proportion of patients with intermediate-grade lesions (>40% of .. In patients with SCAD and at least one stenosis with FFR <_0.80, the
..
patients are reclassified).19–22 In addition, separate and pooled analy- .. FAME 2 trial showed that PCI using drug-eluting stent (DES) implan-
ses of the patients included in those studies have shown that the end .. tation improved the primary endpoint of death, non-fatal MI, or
..
results of ‘FFR-based reclassification’ in patients investigated at the .. urgent revascularization within 2 years compared with medical treat-
time of diagnostic angiography is neutral overall for the number of .. ment alone, which was driven by a lower need for urgent revasculari-
..
patients indicated for revascularization.23 .. zation.32 The advantage of FFR-guided PCI over medical therapy
A patient-level and study-level meta-analysis of 9173 lesions dem- .. alone was maintained at 3 years.33
..
onstrated that with lesions with FFR <0.75, revascularization reduced ..
the 1 year risk of major adverse cardiac events (MACE), including a
.. 3.2.2 Other pressure-derived indices
..
reduction in the composite risk of death and MI.24 Thus, the FFR .. FFR evaluation requires maximal and stable hyperaemia, which is usu-
threshold of 0.75 is used to define more severe ischaemia that is of
.. ally obtained by the administration of intravenous (i.v.) adenosine.
..
prognostic relevance. .. Recently, there has been renewed interest in resting indices derived
The presence of intermediate grade left main stem (LMS) disease is
..
.. from resting gradients alone [distal coronary to aortic pressure (Pd/
not infrequent and angiographic evaluation may be challenging. .. Pa) or instantaneous wave-free ratio (iwFR)]. Two recent large-scale
Assessment using pressure-derived FFR is more challenging in compar-
..
.. randomized trials showed broadly comparable results between FFR-
ison with non-LMS stenosis due to the requirement for disengagement .. guided and iwFR-guided revascularization strategies in patients with
..
of the guiding catheter and an inability to administer intracoronary .. intermediate-grade stenosis.17,18 Revascularization was indicated in
adenosine. Some observational data exist to support the use of FFR in .. both trials if FFR was <_0.80 or if iwFR was <_0.89. In the DEFINE-
..
order to decide if revascularization should be deferred or performed.25 .. FLAIR trial, the primary endpoint of MACE at 1 year occurred in
In the largest study, which included 230 patients with intermediate- .. 6.8% in patients randomized to iwFR-guided revascularization vs.
..
grade LMS stenosis, only 23% showed an FFR <0.80. Treatment was .. 7.0% in patients randomized to FFR-guided revascularization (P
deferred in patients with an FFR >_0.80 and bypass surgery was done in .. <0.001 for non-inferiority; HR 0.95, 95% CI 0.68–1.33, P = 0.78).17 In
..
patients with an FFR <0.80.26 Clinical outcomes at 5 years were similar .. the iFR-SWEDEHEART trial, the primary endpoint of death from any
in both groups. However, it is important to consider the potential influ- .. cause, non-fatal MI, or unplanned revascularization was 6.7% in the
..
ence of any untreated downstream disease in the left anterior .. iwFR group and 6.1% in the FFR group (P = 0.007 for non-inferiority;
descending (LAD) or left circumflex arteries, which may be associated .. HR 1.12, 95% CI 0.79–1.58, P = 0.53).18 In this trial, 17.5% of patients
..
with an increased risk of a false negative FFR.27 .. had ACS at the time of presentation. There was no interaction with
The value of FFR to evaluate intermediate stenosis and guide selec- .. outcomes. Both trials are limited by having a follow-up duration of
..
tion of lesions for revascularization at the time of bypass surgery has . only 1 year.
98 ESC/EACTS Guidelines

The SYNTAX II study (Synergy between Percutaneous Coronary


.. IVUS evaluation of intermediate-grade LMS disease in patients being
..
Intervention with TAXUS and Cardiac Surgery), a single-arm, pro- .. considered for bypass surgery or PCI is supported by data from a
spective study in patients with multivessel disease incorporating a
.. number of observational studies.35–38 In a multicentre, prospective
..
management strategy including combined iwFR/FFR assessment of .. study, revascularization was mainly deferred if the minimal luminal
stenosis severity in addition to intravascular ultrasound (IVUS)-
.. area (MLA) was >_6 mm2 and performed in cases of an MLA <6
..
guided stent implantation and guideline-directed medical therapy, .. mm2.37 After a 2 year follow-up, cardiac death-free survival was simi-
..
showed encouraging outcomes compared with a historical cohort .. lar in both groups (98 and 95%, respectively). Another study sug-
enrolled in the SYNTAX trial.34 .. gested that deferral of intervention in 131 patients with an MLA >_7.5
..
Randomized trials comparing iwFR-guided revascularization with .. mm2 showed favourable clinical outcomes.36 In Asian patients with
angiography-guided revascularization or medical therapy are not .. generally smaller heart sizes, studies have suggested that an IVUS
..
available. iwFR has not been extensively validated for patients with .. MLA of 4.5–4.8 mm2 may be the most appropriate.38
LMS stenosis. ..

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There is no adequate randomized controlled trial (RCT) data to
support the use of whole-cardiac cycle Pd/Pa for the guidance of Recommendations on functional testing and intravascu-
lar imaging for lesion assessment
revascularization decisions.

3.2.3 Use of fractional flow reserve and pressure-derived Recommendations Classa Levelb
indices in patients with severe aortic stenosis
When evidence of ischaemia is not avail-
In patients with intermediate coronary stenosis and concomitant
able, FFR or iwFR are recommended to
severe aortic stenosis, although some observational studies exist (see I A
assess the haemodynamic relevance of
section 11), there are no adequate RCT data to support the use of
intermediate-grade stenosis.15,17,18,39
FFR or iwFR for the guidance of revascularization decisions.
FFR-guided PCI should be considered in
3.2.4 Use of intravascular imaging for the diagnostic patients with multivessel disease under- IIa B
assessment of stenosis going PCI.29,31
IVUS is an ultrasound-based modality of intravascular imaging with an IVUS should be considered to assess the
axial resolution of about 150 mm. IVUS imaging allows real-time severity of unprotected left main IIa B
tomographic assessment of vessel size, lumen area, and plaque com- lesions.35–37
position and volume. In comparison with optical coherence tomogra-
phy (OCT), it has more limited spatial resolution, but better
FFR = fractional flow reserve; iwFR = instantaneous wave-free ratio; IVUS =
penetration depth and potential advantages in terms of vessel sizing. intravascular ultrasound; PCI = percutaneous coronary intervention.
a
OCT is a light-based modality of intravascular imaging with higher Class of recommendation.
b
axial resolution compared with IVUS (15 vs. 150 mm). The disadvan- Level of evidence.

tages of OCT imaging are that it requires complete blood clearance


from the lumen for imaging and that it has more limited penetration,
which can limit the assessment of complete plaque burden and may
3.3 Gaps in the evidence
impair accurate vessel sizing.
Further studies investigating the role of novel, combined, non-inva-
Potential clinical uses of intravascular imaging for diagnostic assess-
sive anatomical and functional imaging are needed, such as random-
ment in patients being considered for myocardial revascularization
ized clinical trials with CT-FFR in patients with suspected and known
are the evaluation of stenosis severity in lesions with intermediate-
CAD, as well as further clinical investigation of perfusion CT.
grade stenosis, evaluation of lesion morphology in lesions ambiguous
Randomized trials comparing iwFR-based management of patients
with angiographic assessment, and the characterization of plaque
with intermediate-grade stenosis compared with medical therapy are
composition. The majority of the existing data from clinical trials
missing. Further study of whole-cardiac cycle Pd/Pa for the guidance of
relate to the use of intravascular imaging guidance during PCI and are
revascularization in the setting of randomized clinical trials is also
discussed in section 16. The use of intravascular imaging to evaluate
required.
patients with stent failure is discussed in section 13.
Further studies including randomized trials are needed to assess
Regarding the assessment of intermediate-grade stenosis, a num-
the value of functional vs. anatomical guidance for CABG.
ber of studies have evaluated the optimal cut-off of minimal lumen
area for the identification of haemodynamically relevant lesions. One
prospective registry showed overall moderate correlation of minimal
lumen area with FFR values, with cut-off values for detecting haemo-
4 Process for decision-making and
dynamically relevant stenosis (<2.4, <2.7, and <3.6 mm2) dependent patient information
on vessel size (reference vessel diameters <3.0, 3.0–3.5, and >3.5
mm, respectively).34a Generally, haemodynamic assessment with FFR 4.1 Patient information and informed
should be preferred for this indication. consent
The presence of intermediate-grade LMS disease is not infrequent Informed consent requires transparency, especially if there is debate
and angiographic assessment may be challenging. Assessment using over various treatment options. Active patient participation in the
ESC/EACTS Guidelines 99

..
decision-making process should be encouraged. Patient information .. patients with CAD44 and (ii) inappropriate use of revascularization
needs to be unbiased, evidence-based, up-to-date, reliable, accessible, .. strategies with a lack of case discussions.45 The marked variability in
..
relevant, and consistent with legal requirements. Use of terminology .. PCI-to-CABG ratios between European countries (ranging from
that the patient understands is essential. Short-term procedure- .. 2.4–7.6 in 2013, for example) has raised concerns regarding the
..
related and long-term risks and benefits—such as survival, relief of .. appropriate selection of revascularization strategies.46 Rates for the
angina, quality of life, the potential need for late reintervention, the .. inappropriate use of PCI (10–15%)43,47,48 and CABG (1–2%) are
..
need for prevention measures, and uncertainties associated with dif- .. reported. Multidisciplinary decision-making in a Heart Team can mini-
ferent treatment strategies—should be thoroughly discussed.
.. mize specialty bias and prevent self-referral from interfering with
..
Although current recommendations are mostly based on the ability .. optimal patient care.49
of treatments to reduce adverse events including mortality, there is
.. Several reports from different centres have established that the
..
growing interest in patient-reported outcome measures.40,41 Patients .. treatment recommendations made in multidisciplinary Heart Team
are not only interested to know how recommended treatment
.. discussions are reproducible and implemented in the vast majority of
..

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impacts on prognosis but also on their quality of life in the way they .. cases (93–95%).50,51
perceive it. A written evidence-based patient information document
.. Interdisciplinary institutional protocols should be developed
..
should be provided, potentially with decision aids. .. for common case scenarios to avoid the need for systematic case-
..
Patients must have the time to reflect on the trade-offs imposed .. by-case review of all diagnostic angiograms. However, complex
by the outcome estimates. In order to seek a second opinion or to .. cases—defined by the protocols—should be discussed individu-
..
discuss the findings and consequences with referring physicians, .. ally. In these cases, revascularization should not be performed at
enough time should be allowed—up to several days, as required— .. the time of diagnostic angiography, to allow sufficient time to
..
between diagnostic catheterization and intervention. These recom- .. assess all available information and clearly explain and discuss the
mendations pertain to patients in a stable condition, for whom vari- .. findings with the patient. The rationale for a decision and consen-
..
ous treatment options exist and who can make a decision without .. sus on the optimal revascularization treatment should be docu-
the constraints of an urgent or emergent situation (Table 3). The .. mented on the patient’s chart. In institutions without an on-site
..
patient’s right to decline the treatment option recommended by the .. cardiac surgery unit, collaboration with an external cardiac sur-
Heart Team has to be respected. Patient refusal of a recommended .. gery unit is required to design protocols that define when Heart
..
treatment should be acknowledged in a written document after the .. Team discussion is needed.
patient has received the necessary information by the Heart Team ..
..
members. In this case, the patient may be offered an alternative treat- ..
ment option by the Heart Team. .. 4.3 Timing of revascularization
..
The patient has the right to obtain information on the level of .. Patients requiring myocardial revascularization may be at increased
expertise of the operator, the workload of the centre, whether all
.. risk of adverse events during the waiting period.52 A recent meta-
..
treatment options—including surgery—are available on-site, and .. analysis of observational studies calculated that a waiting period of 3
local results in the performance of percutaneous and surgical myo-
.. months for surgical myocardial revascularization may be associated
..
cardial revascularization procedures. Patients considered for revascu- .. with the risk of 1 death among 80 patients.53 Table 3 shows the pre-
larization should also be clearly informed of the continuing need for
.. ferred timing of revascularization depending on the clinical presenta-
..
medical therapy, as well as lifestyle modification and other secondary .. tion and the extent and localization of CAD.54 Sections 7 and 8 show
prevention strategies (see section 19).42
.. additional and more specific information in this regard for patients
..
.. with ACS.
..
.. Ad hoc PCI is defined as a therapeutic intervention performed
4.2 Multidisciplinary decision-making .. within the same procedure as the diagnostic coronary angiography.
..
(Heart Team) .. Ad hoc PCI is convenient, often cost-effective and safe, and is associ-
The Heart Team—comprising clinical or non-invasive cardiologists, .. ated with fewer access site complications and lower radiation expo-
..
cardiac surgeons, and interventional cardiologists, as well as anaes- .. sure.55,56 However, in the USA, up to 30% of patients undergoing ad
thetists and other specialists if deemed necessary—should provide a .. hoc PCI are potential candidates for CABG.56 This number may be
..
balanced, multidisciplinary decision-making process.43 Additional .. lower in Europe.45 Although it is not advisable for ad hoc PCI to rep-
input may be needed from other specialties involved in the care of .. resent the default approach for complex SCAD, it may be justified if a
..
the patient. The Heart Team should meet on a regular basis to ana- .. full diagnostic work-up, including functional testing, is available and
lyse and interpret the available diagnostic evidence, determine the .. the patient is adequately informed on both percutaneous and surgical
..
need for myocardial revascularization, and assess the relative short- .. myocardial revascularization options (see section 4.1). Institutional
and long-term safety and effectiveness of the percutaneous and surgi- .. protocols developed by the Heart Team in accordance with current
..
cal options. Ad hoc meetings of the Heart Team should facilitate and .. Guidelines should define specific anatomical criteria and clinical sub-
support efficient clinical workflows.
.. sets that may be—or should not be—treated ad hoc. Stable patients
..
The need for an interdisciplinary approach is underlined by reports .. with complex CAD, as reflected by a high SYNTAX score, should in
on (i) the underuse of revascularization procedures in 18–40% of
.. general be discussed by the Heart Team and not be treated ad hoc.
100

Table 3 Multidisciplinary decision pathways, patient informed consent, and timing of revascularization

ACS

Shock STEMI NSTE-ACS SCAD without ad hoc PCI SCAD with ad hoc PCI
indication according to Heart indication according to
Team protocol Heart Team protocol

Multidisciplinary Not mandatory during the acute Not mandatory during the acute Not mandatory during the acute Required Not required
decision-making phase; mechanical circulatory sup- phase phase; after stabilization, recom-
port according to Heart Team mended as in SCAD
protocol

Informed consent Witnessed verbal informed con- Witnessed verbal informed con- Written informed consenta; in Written informed consenta Written informed consenta
sent or family consent if possible sent may be sufficient unless writ- emergency cases witnessed verbal
without delay ten consent is legally required informed consent may be sufficient

Time to Emergency: no delay Emergency: no delay Urgency: within 2 h to within 72 h Within 2 weeks for high-risk Ad hoc
revascularization depending on the risk criteria patientsb and within 6 weeks for all
other patients

Procedure Proceed with intervention based Proceed with intervention based Proceed with intervention based Allow for enough time from diag- Proceed with intervention
on best evidence/availability. Ad hoc on best evidence/availability. Non- on best evidence/availability. Non- nostic catheterization to decide on according to institutional
treatment of culprit lesion, staged culprit lesions treated according to culprit lesions treated according to the appropriate intervention. protocol defined by Heart
treatment of non-culprit lesions institutional protocol or Heart institutional protocol or Heart Team.
according to institutional protocol Team decision. Team decision.
or Heart Team decision.

ACS = acute coronary syndromes; CCS = Canadian Cardiovascular Society; ESC = European Society of Cardiology; EACTS = European Association for Cardio-Thoracic Surgery; NSTE-ACS = non-ST-segment elevation acute coronary
syndrome; PCI = percutaneous coronary intervention; SCAD = stable coronary artery disease; STEMI = ST-segment elevation myocardial infarction.
a
This may not apply to countries that are not legally required to ask for written informed consent. The ESC and EACTS advocate the documentation of patient consent for all revascularization procedures.
b
Severe symptoms (CCS class 3), anatomy (left main disease or equivalent, three-vessel disease or proximal left anterior descending artery), or depressed ventricular function.
ESC/EACTS Guidelines

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ESC/EACTS Guidelines 101

Recommendations for decision-making and patient information in the elective setting

Recommendations Classa Levelb

It is recommended that patients undergoing coronary angiography are informed about benefits and risks, as well as potential
I C
therapeutic consequences, ahead of the procedure.

It is recommended that patients are adequately informed about short- and long-term benefits and risks of the revascularization
I C
procedure with information about local experience, and allowed enough time for informed decision-making.

It is recommended that institutional protocols are developed by the Heart Team to implement the appropriate revasculariza-
I C
tion strategy in accordance with current Guidelines.

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In PCI centres without on-site surgery, it is recommended that institutional protocols are established with partner institutions
I C
providing cardiac surgery.

PCI = percutaneous coronary intervention.


a
Class of recommendation.
b
Level of evidence.

.. (-0.09, 95% CI -0.15 to -0.04, P = 0.001). ORBITA raises the issue of


5 Revascularization for stable ..
.. whether the symptom relief of PCI in the specific setting of stable
coronary artery disease .. single-vessel CAD may be related at least in part to a placebo effect.
..
.. Limitations of the study, as acknowledged by the investigators and
5.1 Rationale for revascularization .. outlined elsewhere, include the short observation period (6 weeks),
The indications for revascularization in patients with SCAD who ..
.. the inclusion of patients with mild symptoms pre-randomization
receive guideline-recommended medical treatment are the persis- .. (CCS class 0-I in 25% of patients), the group imbalance in ostial and
tence of symptoms despite medical treatment and/or the improve- ..
.. proximal lesions (37 vs. 57%, P = 0.005), loss to follow-up after ran-
ment of prognosis.1 .. domization, and the insufficient power to detect a true difference.64
Several studies have shown that myocardial revascularization by
..
.. This precludes definite conclusions at this stage. Nevertheless, the
PCI or CABG more effectively relieves angina, reduces the use of ..
anti-anginal drugs, and improves exercise capacity and quality of life
.. ORBITA study underlines the value of optimal medical therapy in the
.. management of SCAD.
compared with a strategy of medical therapy alone during short- and ..
long-term follow-up (Supplementary Table 1).32,33,57–62 Recently, the
.. Three year follow-up of the FAME 2 study indicated yearly and
.. sustained improvement of angina (10.2 vs. 28.5% at 1 month and 5.2
ORBITA (Objective Randomised Blinded Investigation with optimal ..
.. vs. 9.7% at 3 years) in favour of FFR-guided PCI, despite considerable
medical Therapy of Angioplasty in stable angina) trial randomly com- .. crossover in the medical therapy arm.33 Among patients with multi-
pared PCI with placebo (sham procedure) in patients with SCAD ..
.. vessel disease, the assessment of frequency of angina and quality of
due to single-vessel CAD (diameter stenosis >70%) and preserved .. life measures in the SYNTAX, FREEDOM (Future Revascularization
LV function in the presence of moderate symptoms of angina ..
.. Evaluation in Patients with Diabetes Mellitus), and EXCEL (Evaluation
[Canadian Cardiovascular Society (CCS) class II in 59% of patients, .. of XIENCE Versus Coronary Artery Bypass Surgery for Effectiveness
duration 9 months] for the first time.63 After 6 weeks of medication ..
.. of Left Main Revascularization) trials consistently showed early and
optimization (mean number of anti-anginal drugs: 3) and baseline car- .. sustained improvement for both PCI and CABG during long-term fol-
diopulmonary exercise testing, 200 patients were randomized (105 ... low-up.65–67
PCI and 95 placebo). Following a 6-week post-randomization period, ..
..
the primary endpoint of increment in exercise time was not signifi- ..
cantly different, but estimates were imprecise (PCI minus placebo .. 5.2 Evidence basis for revascularization
..
16.6 sec, 95% CI –8.9 to 42.0, P = 0.20). The dobutamine stress echo- .. The indications for revascularization in patients with stable angina or
cardiography peak stress wall motion score index improved with PCI .. silent ischaemia are summarized in the recommendation table.
102 ESC/EACTS Guidelines

Indications for revascularization in patients with stable angina or silent ischaemia

Extent of CAD (anatomical and/or functional) Classa Levelb

For Left main disease with stenosis >50%.c 68–71 I A


prognosis
Proximal LAD stenosis >50%.c 62,68,70,72 I A
c 61,62,68,70,73–83
Two- or three-vessel disease with stenosis >50% with impaired LV function (LVEF <_35%). I A

Large area of ischaemia detected by functional testing (>10% LV) or abnormal invasive FFR.d 24,59,84–90 I B

Single remaining patent coronary artery with stenosis >50%.c I C

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For symptoms Haemodynamically significant coronary stenosisc in the presence of limiting angina or angina equivalent,
I A
with insufficient response to optimized medical therapy.e 24,63,91–97

CAD = coronary artery disease; FFR = fractional flow reserve; iwFR = instantaneous wave-free ratio; LAD = left anterior descending coronary artery; LV = left ventricular;
LVEF = left ventricular ejection fraction.
a
Class of recommendation.
b
Level of evidence.
c
With documented ischaemia or a haemodynamically relevant lesion defined by FFR <_0.80 or iwFR <_0.89 (see section 3.2.1.1), or >90% stenosis in a major coronary vessel.
d
Based on FFR <0.75 indicating a prognostically relevant lesion (see section 3.2.1.1).
e
In consideration of patient compliance and wishes in relation to the intensity of anti-anginal therapy.

.. with SCAD and left main (LM) or three-vessel disease, particularly


5.2.1 Revascularization with the use of percutaneous ..
coronary intervention .. when the proximal LAD coronary artery was involved, and has been
..
Several meta-analyses comparing a strategy of PCI with initial medical .. corroborated in more recent studies.100,101 A network meta-analysis
therapy among patients with SCAD found no or only modest bene- .. of 100 trials with 93 553 patients comparing a strategy of initial medi-
..
fits in terms of survival or MI for an invasive strategy, taking into .. cal therapy with revascularization reported improved survival (RR
account the fact that up to 40% of patients crossed over after to .. 0.80, 95% CI 0.63–0.99) and a reduced risk of MI (RR 0.79, 95% CI
..
revascularization during longer-term follow-up.91,98,99 A network .. 0.83–0.99) among patients undergoing CABG compared with initial
meta-analysis of 100 trials with 93 553 patients and 262 090 patient- .. medical treatment.100
..
years of follow-up comparing a strategy of initial medical therapy .. In the STICH trial, 1212 patients with CAD and an LV ejection
with revascularization reported improved survival using PCI with .. fraction (LVEF) <_35% were randomized to initial medical therapy or
..
new-generation DES (everolimus: rate ratio 0.75, 95% CI 0.59–0.96; .. CABG. The extended 10 year follow-up of the STICH trial reported
zotarolimus: rate ratio 0.65, 95% CI 0.42–1.00) compared with initial .. a significant reduction in all-cause (59 vs. 66%; HR 0.84, 95% CI
..
medical treatment.100 .. 0.73–0.97; P ¼ 0.02) and cardiovascular mortality (41 vs. 49%; HR
In the FAME 2 trial,32 patients with SCAD and at least one func- .. 0.79, 95% CI 0.66–0.93; P ¼ 0.006).81 For an overview of studies, see
..
tionally significant stenosis (invasive FFR <_0.80) were randomly .. Supplementary Table 2.
assigned to medical therapy or medical therapy plus FFR-guided PCI
..
..
using new-generation DES. The 3 year report of the FAME 2 trial .. 5.3 Percutaneous coronary intervention
reported a lower incidence of the primary composite endpoints of
..
.. vs. coronary artery bypass grafting
death, MI, and urgent revascularization (10.1 vs. 22.0%; P <0.001), ..
driven by a lower incidence of urgent revascularization in the PCI
.. The recommendations for the type of revascularization (CABG or
.. PCI) in patients with SCAD with suitable coronary anatomy for both
group (4.3 vs. 17.2%; P <0.001) and without significant differences in ..
.. procedures and low predicted surgical mortality are summarized
the rates of death and MI.33 At 2 years of follow-up, the rate of death
... below. The Heart Team should take into consideration the individual
or MI was lower in the PCI than the medical therapy group (4.6 vs. .. cardiac and extracardiac characteristics, in addition to patient prefer-
8.0%; HR 0.56, 95% CI 0.32–0.97, P = 0.04) in a landmark analysis ..
.. ence, in the overall decision-making process (Figure 3). A summary of
between 8 days and 2 years of follow-up, whereas event rates were .. trials comparing the outcomes of patients treated with angioplasty vs.
higher during days 0 - 7 due to periprocedural MI (for overview of ..
.. CABG and bare-metal stent (BMS) vs. CABG is shown in
studies see Supplementary Table 2).97 .. Supplementary Table 3, and of studies comparing DES and CABG in
..
.. Table 4.
..
5.2.2 Revascularization with the use of coronary artery ..
..
bypass grafting .. 5.3.1 Criteria for decision-making
The superiority of CABG over a strategy of initial medical therapy
.. Predicted surgical mortality, the anatomical complexity of CAD, and
..
was established in a meta-analysis of seven RCTs68 more than two .. the anticipated completeness of revascularization are important cri-
decades ago, demonstrating a survival benefit of CABG in patients
.. teria for decision-making with respect to the type of revascularization
ESC/EACTS Guidelines

Table 4 Randomized clinical trials comparing percutaneous coronary intervention with drug-eluting stents vs. surgical revascularization

Stent type Study N Baseline characteristics Primary endpointa Secondary endpointsa


and year of
Age Women Diabetes MV disease EF (%) Definition Y Results Y Death MI Revasc Stroke
publication
(y) (%) (%) (%)

DES

PES 2009 SYNTAX102 1800 65 22 25 MV 61 LM 39 - Death, MI, stroke, 1 17.8 vs. 12.4% 5 13.9 vs. 11.4% 9.7 vs. 3.8%* 25.9 vs. 2.4 vs. 3.7%
or repeat revasc 13.7%*

SES 2011 Boudriot103 201 68 25 36 LM 100 65 Death, MI, or 1 13.9 vs. 19% 1 2 vs. 5% 3 vs. 3% 14 vs. 5.9% -
repeat revasc

SES 2011 PRECOMBAT104 600 62 24 32 LM 100 61 Death, MI, stroke, 1 8.7 vs. 6.7%b 2 2.4 vs. 3.4% 1.7 vs. 1.0% 9.0 vs. 4.2%* 0.4 vs. 0.7%
or TVR

EES 2015 BEST105 880 64 29 41 MV 100 60 Death, MI, or TVR 2 11.0 vs. 7.9% 5 6.6 vs. 5.0% 4.8 vs 2.7% 13.4 vs. 6.6% 2.9 vs. 3.3%

BES 2016 NOBLE106 1201 66 22 15 LM 100 60 Death, MI, or TVR 5 15.4 vs. 7.2% 5 11.6 vs. 9.5% 6.9 vs. 1.9%*c 16.2 vs. 10.4%* 4.9 vs. 1.7%

EES 2016 EXCEL107 1905 66 24 30 LM 100 57 Death, MI, or stroke 3 15.4 vs. 14.7%b 3 8.2 vs. 5.9% 8.0 vs. 8.3% 13.4 vs. 6.6%* 2.3 vs. 2.9%

Age and EF are reported as means.


*P <0.05.
BES = biolimus-eluting stents; BEST = Randomised Comparison of Coronary Artery Bypass Surgery and Everolimus-Eluting Stent Implantation in the Treatment of Patients with Multivessel Coronary Artery Disease; DES = drug-eluting stents;
EES = everolimus-eluting stent; EF = ejection fraction; EXCEL = Evaluation of XIENCE Versus Coronary Artery Bypass Surgery for Effectiveness of Left Main Revascularization; LM = left main coronary artery disease; MI = myocardial infarc-
tion; MV = multivessel coronary artery disease; NOBLE = Nordic-Baltic-British Left Main Revascularization Study; PES = paclitaxel-eluting stents; PRECOMBAT = Premier of Randomised Comparison of Bypass Surgery versus Angioplasty
Using Sirolimus-Eluting Stent in Patients with Left Main Coronary Artery Disease; Revasc = revascularization; SES = sirolimus-eluting stents; SYNTAX = Synergy between Percutaneous Coronary Intervention with TAXUS and Cardiac
Surgery; TVR = target vessel revascularization; Y = years.
a
Results are reported as percutaneous coronary intervention vs. coronary artery bypass grafting.
b
Non-inferiority met.
c
Non-procedural MI (exclusion of periprocedural MI).
103

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104 ESC/EACTS Guidelines

(CABG or PCI). Whether conservative therapy, PCI, or CABG is


Table 5 Logistic EuroSCOREs in major randomized
preferred should depend on the risk-benefit ratios of these treatment
trials comparing percutaneous coronary intervention
strategies, weighing up the risks of periprocedural complications (e.g. with coronary artery bypass grafting
cerebrovascular events, blood transfusions, renal failure, new onset
arrhythmias, or wound infections) against improvements in health-
Trial EuroSCORE PCI EuroSCORE CABG
related quality of life, as well as long-term freedom from death, MI, or
repeat revascularization. SYNTAX 3.8 ± 2.6 3.8 ± 2.7

BEST 2.9 ± 2.0 3.0 ± 2.1


5.3.1.1 Predicted surgical mortality
To assess the predicted surgical mortality, the European System for FREEDOM 2.7 ± 2.4 2.8 ± 2.5
Cardiac Operative Risk Evaluation (EuroSCORE II) (www.euroscore.
PRECOMBAT 2.7 ± 1.8 2.8 ± 1.9
org/calc.html) and the Society of Thoracic Surgeons (STS) score

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(http://riskcalc.sts.org) were both developed based on clinical varia- EXCEL Not reported Not reported
bles to estimate the operative in-hospital or 30 day mortality
risk108–110 (Supplementary Table 4). Both scores have demonstrated NOBLE 2 (2–4) 2 (2–4)
their value in specific cohorts of patients undergoing CABG.111
Calibration of the STS score is updated on a regular basis. It has been Numbers are presented as mean ± SD or median (interquartile range).
BEST = Randomised Comparison of Coronary Artery Bypass Surgery and
suggested that the STS score outperforms the EuroSCORE II when Everolimus-Eluting Stent Implantation in the Treatment of Patients with
compared directly in a cohort of CABG patients,112 although other Multivessel Coronary Artery Disease; CABG = coronary artery bypass grafting;
studies have found comparable performance of both models.113,114 EuroSCORE = European System for Cardiac Operative Risk Evaluation; EXCEL
= Evaluation of XIENCE Versus Coronary Artery Bypass Surgery for
There are no established cut-offs for low predicted surgical mor- Effectiveness of Left Main Revascularization; NOBLE = Nordic-Baltic-British Left
tality based on the EuroSCORE II or STS score. Thus, individualized Main Revascularization Study; PCI = percutaneous coronary intervention;
treatment decisions are needed. These decisions should respect the PRECOMBAT = Premier of Randomised Comparison of Bypass Surgery versus
Angioplasty Using Sirolimus-Eluting Stent in Patients with Left Main Coronary
range of predicted surgical risks in the major RCTs that inform the Artery Disease; SYNTAX = Synergy between Percutaneous Coronary
choice of revascularization modality (Table 5). In these studies, Intervention with TAXUS and Cardiac Surgery.
the predicted surgical risk was assessed by the logistic EuroSCORE.
Compared with the more recent EuroSCORE II, the logistic
EuroSCORE has similar discrimination but poorer calibration and,
thus, overestimates surgical mortality by roughly two-fold.115 .. complexity of coronary lesions in patients with LM or three-vessel
..
Despite the usefulness of these scores, there is not a single risk .. disease (Table 6 and Supplementary Table 4).116 In the cohort of
model that provides perfect risk assessment because the scores are .. the SYNTAX trial, and subsequently in external validation cohorts,
..
limited by (i) the specific definitions used or the methodology applied, .. the SYNTAX score was found to be an independent predictor of
(ii) the absence of important variables such as frailty, (iii) the practic- .. long-term major adverse cardiac and cerebrovascular events
..
ability of calculation, (iv) a failure to reflect all relevant mortality and .. (MACCE) and of death in patients treated with PCI but not
morbidity endpoints, and (v) limited external validation. Decision- .. CABG.117–120
..
making should not be solely dependent on risk scores. These scores .. In the SYNTAX trial, tertiles of SYNTAX score with low, inter-
should be used as a guide within the multidisciplinary Heart Team
..
.. mediate, and high anatomical complexity stratified patients into those
discussion. .. who had similar outcomes with both PCI and CABG and those who
..
To combine clinical and anatomical risk estimation, the SYNTAX II .. derived significant benefit from CABG.121–123 In subsequent RCTs,
score was retrospectively derived from the SYNTAX cohort127 and .. the interaction of the strata of SYNTAX score with the effect of the
subsequently externally validated.120,128,129 Nevertheless, compared
..
.. randomized treatment was less pronounced and did not reach statis-
with the SYNTAX score, its value in assigning patients to PCI or .. tical significance.105–107 However, in a recent collaborative individual
CABG is less well investigated. The fact that the SYNTAX II score
..
.. patient pooled analysis of randomized trials including 11 518
failed to predict the outcome of the EXCEL trial raises additional .. patients,124 the test for trend across the ordered tertiles of the
..
concern.130
... SYNTAX score of the SYNTAX study was positive at P = 0.0011
.. (unpublished analysis), confirming the strata of the SYNTAX score as
5.3.1.2 Anatomical complexity of coronary artery disease .. an effect modifier to be considered. There is concern about bias and
..
The SYNTAX score (http://www.syntaxscore.com) was prospec- .. inter-individual variability in calculating the SYNTAX score.125 This
tively developed for the SYNTAX trial to grade the anatomical .. should be minimized by adequate training.
ESC/EACTS Guidelines 105

Table 6 Guide for calculating the SYNTAX score

Steps Variable assessed Description

Step 1 Dominance The weight of individual coronary segments varies according to coronary artery dominance (right or left). Co-
dominance does not exist as an option in the SYNTAX score.

Step 2 Coronary segment The diseased coronary segment directly affects the score as each coronary segment is assigned a weight depend-
ing on its location, ranging from 0.5 (i.e. the posterolateral branch) to 6 (i.e. left main in case of left dominance).

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Step 3 Diameter stenosis The score of each diseased coronary segment is multiplied by two in case of a stenosis 50–99% and by five in
case of total occlusion.
In case of total occlusion, additional points will be added as follows:
• Age >3 months or unknown þ1
• Blunt stump þ1
• Bridging þ1
• First segment visible distally þ1 per non-visible segment
• Side branch at the occlusion þ1 if <1.5 mm diameter
þ1 if both <1.5 mm and >_1.5 mm diameter
þ0 if >_1.5 mm diameter (i.e. bifurcation lesion)

Step 4 Trifurcation lesion The presence of a trifurcation lesion adds additional points based on the number of diseased segments:
 1 segment þ3
 2 segments þ4
 3 segments þ5
 4 segments þ6
Continued
106 ESC/EACTS Guidelines

Step 5 Bifurcation lesion The presence of a bifurcation lesion adds additional points based on the type of bifurcation according to the
Medina classification:126
• Medina 1,0,0–0,1,0–1,1,0 þ1
• Medina 1,1,1–0,0,1–1,0,1–0,1,1 þ2
Moreover, the presence of a bifurcation angle <70 adds one additional point

Step 6 Aorto-ostial lesion The presence of aorto-ostial lesion segments adds one additional point

Step 7 Severe tortuosity The presence of severe tortuosity proximal of the diseased segment adds two additional points

Step 8 Lesion length Lesion length >20 mm adds one additional point

Step 9 Calcification The presence of heavy calcification adds two additional points

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Step 10 Thrombus The presence of thrombus adds one additional point

Step 11 Diffuse disease/ The presence of diffusely diseased and narrowed segments distal to the lesion (i.e. when at least 75% of the
small vessels length of the segment distal to the lesion has a vessel diameter <2 mm) adds one point per segment number

SYNTAX = Synergy between Percutaneous Coronary Intervention with TAXUS and Cardiac Surgery.

5.3.1.3 Completeness of revascularization


.. BEST (Randomised Comparison of Coronary Artery Bypass Surgery
..
The aim of myocardial revascularization is to minimize residual .. and Everolimus-Eluting Stent Implantation in the Treatment of
ischaemia. In support of this concept, the nuclear substudy of the
.. Patients with Multivessel Coronary Artery Disease), and
..
COURAGE (Clinical Outcomes Utilizing Revascularization and .. PRECOMBAT (Premier of Randomised Comparison of Bypass
Aggressive Drug Evaluation) trial demonstrated an incremental bene-
.. Surgery versus Angioplasty Using Sirolimus-Eluting Stent in Patients
..
fit in reducing the risk of death and MI by reducing residual stress- .. with Left Main Coronary Artery Disease) trials.136 A mean SYNTAX
induced ischaemia from >10% of the myocardium to <_5%.86
..
.. score of 27 and an LVEF of 59% were obtained. In a propensity-
In the SYNTAX trial, anatomical complete revascularization was .. matched analysis, mortality and the composite risk of death, MI, and
..
defined as PCI or bypass of all epicardial vessels with a diameter .. stroke were significantly lower after PCI with complete vs. incom-
exceeding >_1.5 mm and a luminal reduction of >_50% in at least one .. plete revascularization. After PCI with complete revascularization,
..
angiographic view.131 A meta-analysis of 89 883 patients enrolled in .. the risk of death or of the composite of death, MI, or stroke was not
RCTs and observational studies revealed a lower long-term mortality .. significantly different from that after CABG with complete revascula-
..
(RR 0.71, 95% CI 0.65–0.77, P <0.001), MI (RR 0.78, 95% CI .. rization (adjusted HR 1.16, 95% CI 0.83–1.63, P = 0.39, and 1.14, 95%
0.68–0.90; P = 0.001), and repeat myocardial revascularization (RR .. CI 0.87–1.48, P = 0.35, respectively), whereas these risks were signifi-
..
0.74, 95% CI 0.65–0.83; P <0.001) by complete revascularization .. cantly elevated after PCI with incomplete revascularization.
(based on anatomical definition in 87% of the patients) as compared .. Functional complete revascularization is achieved when all lesions
..
with incomplete revascularization.132 The benefit of complete revas- .. causing resting or stress-induced ischaemia are bypassed or treated
cularization was independent of the treatment modality. A more .. by PCI. Given the limitations of non-invasive imaging techniques (see
..
recent meta-analysis suggested enhanced benefit when complete .. section 3), these lesions are identified by FFR or iwFR during diagnos-
revascularization is performed with state-of-the-art techniques in .. tic angiography. For PCI, the FAME study demonstrated that the
..
high-risk patients.133 Likewise, in a post hoc analysis of the SYNTAX .. more restrictive selection of target lesions by functional guidance
trial, anatomical incomplete revascularization was associated with .. conferred superior long-term outcomes compared with anatomically
..
inferior long-term outcomes after both CABG and PCI.131 A residual .. guided lesion selection (see section 3).31 In contrast, leaving function-
SYNTAX score >8 after PCI was associated with significant increases
.. ally relevant lesions untreated resulted in a high rate of reinterven-
..
in the 5-year risk of death and of the composite of death, MI, and .. tions in the FAME 2 study.33 Based on the data of the FAME and
stroke, and any residual SYNTAX score >0 was associated with the
.. FAME 2 studies, complete revascularization based on the functional
..
risk of repeat intervention.134 In an observational study from the .. definition is the preferred strategy for PCI.
New York State registry that compared CABG with PCI using new-
.. The role of functional guidance for CABG is less clear.28,137 One
..
generation DES [everolimus-eluting stent (EES)] in 9223 pairs of ... of the potential benefits of CABG is protection against disease pro-
propensity-matched patients with multivessel CAD, the significantly .. gression in proximal segments, which may be diminished by restrict-
..
higher risk of MI associated with PCI as compared with CABG was .. ing the bypass targets to functionally relevant lesions. This has to be
not seen among matched pairs of patients in which the PCI group had .. weighed against the risk of bypass closure when native vessel flow is
..
complete revascularization (Pinteraction = 0.02).135 Consistent findings .. high. Thus, for ambiguous lesions, functional testing may also help
were obtained in a pooled analysis of 3212 patients of the SYNTAX, .. guide the surgical revascularization strategy.
.
Recommendations on criteria for the choice between coronary artery bypass grafting and percutaneous coronary
intervention

Recommendations Classa Levelb

Assessment of surgical riskc

It is recommended that the STS score is calculated to assess in-hospital or 30 day mortality, and in-hospital morbidity
I B
after CABG.112,114,138

Calculation of the EuroSCORE II score may be considered to assess in-hospital mortality after CABG.112 IIb B

Assessment of CAD complexity

In patients with LM or multivessel disease, it is recommended that the SYNTAX score is calculated to assess the ana-
I B
tomical complexity of CAD and the long-term risk of mortality and morbidity after PCI.117–124

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When considering the decision between CABG and PCI, completeness of revascularization should be prioritized.131,132,134–136 IIa B

EuroSCORE = European System for Cardiac Operative Risk Evaluation; CABG = coronary artery bypass grafting; CAD = coronary artery disease; LM = left main; PCI = percu-
taneous coronary intervention; STS = Society of Thoracic Surgeons; SYNTAX = Synergy between Percutaneous Coronary Intervention with TAXUS and Cardiac Surgery.
a
Class of recommendation.
b
Level of evidence.
c
Level of evidence refers to prediction of outcomes.

Recommendation for the type of revascularization in patients with stable coronary artery disease with suitable coro-
nary anatomy for both procedures and low predicted surgical mortalityd

Recommendations according to extent of CAD CABG PCI

Classa Levelb Classa Levelb

One-vessel CAD

Without proximal LAD stenosis. IIb C I C

With proximal LAD stenosis.68,101,139–144 I A I A

Two-vessel CAD

Without proximal LAD stenosis. IIb C I C

With proximal LAD stenosis.68,70,73 I B I C

Left main CAD

Left main disease with low SYNTAX score (0 - 22).69,121,122,124,145–148 I A I A

Left main disease with intermediate SYNTAX score (23 - 32).69,121,122,124,145–148 I A IIa A

Left main disease with high SYNTAX score (>_33).c 69,121,122,124,146–148 I A III B

Three-vessel CAD without diabetes mellitus

Three-vessel disease with low SYNTAX score (0 - 22).102,105,121,123,124,135,149 I A I A

Three-vessel disease with intermediate or high SYNTAX score (>22).c 102,105,121,123,124,135,149 I A III A

Three-vessel CAD with diabetes mellitus

Three-vessel disease with low SYNTAX score 0–22.102,105,121,123,124,135,150–157 I A IIb A

Three-vessel disease with intermediate or high SYNTAX score (>22).c 102,105,121,123,124,135,150–157 I A III A

SYNTAX score calculation information is available at http://www.syntaxscore.com.


CABG = coronary artery bypass grafting; CAD = coronary artery disease; LAD = left anterior descending coronary artery; PCI = percutaneous coronary intervention;
SYNTAX = Synergy between Percutaneous Coronary Intervention with TAXUS and Cardiac Surgery.
a
Class of recommendation.
b
Level of evidence.
c
PCI should be considered if the Heart Team is concerned about the surgical risk or if the patient refuses CABG after adequate counselling by the Heart Team.
d
For example, absence of previous cardiac surgery, severe morbidities, frailty, or immobility precluding CABG (also see Table 5).
108 ESC/EACTS Guidelines

PCI CABG

Left internal thoracic


artery to left anterior
descending

Left coronary artery Right internal thoracic


artery or radial artery

Right coronary Circumflex


artery coronary artery

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Sequential anastomosis
Left anterior
to obtuse marginal
descending
1 and 3
coronary
artery
Distal right
coronary
artery

FAVOURS PCI FAVOURS CABG


Clinical characteristics Clinical characteristics
Presence of severe co-morbidity (not adequately reflected Diabetes
by scores) Reduced LV function (EF ≤35%)
Advanced age/frailty/reduced life expectancy Contraindication to DAPT
Restricted mobility and conditions that affect the Recurrent diffuse in-stent restenosis
rehabilitation process
Anatomical and technical aspects
Anatomical and technical aspects
MVD with SYNTAX score ≥23
MVD with SYNTAX score 0–22
Anatomy likely resulting in incomplete revascularization
Anatomy likely resulting in incomplete revascularization with PCI
with CABG due to poor quality or missing conduits
Severely calcified coronary artery lesions limiting lesion
Severe chest deformation or scoliosis expansion
Sequelae of chest radiation
Need for concomitant interventions
Porcelain aortaa

©ESC 2018
Ascending aortic pathology with indication for surgery
Concomitant cardiac surgery

CABG = coronary artery bypass grafting; Cx = circumflex; DAPT = dual antiplatelet therapy; EF = ejection fraction; LAD = left anterior descending
coronary artery; LIMA = left internal mammary artery; LV= left ventricular; MVD = multivessel coronary artery disease; PCI = percutaneous
coronary intervention; PDA = posterior descending artery; RA = radial artery; RIMA = right internal mammary artery; SYNTAX = Synergy between
Percutaneous Coronary Intervention with TAXUS and Cardiac Surgery.
a
Consider no-touch off-pump CABG in case of porcelain aorta.

Figure 3 Aspects to be considered by the Heart Team for decision-making between percutaneous coronary intervention and coronary artery
bypass grafting among patients with stable multivessel and/or left main coronary artery disease.
ESC/EACTS Guidelines 109

..
5.3.2 Isolated proximal left anterior descending coronary .. anatomical complexity, the number of patients studied in RCTs is
artery disease .. low due to exclusion criteria; the risk estimates and CIs are impre-
..
Comparing CABG and PCI among patients with isolated proximal .. cise, but suggest a trend towards better survival with CABG.
LAD disease, the available evidence suggests similar outcomes in .. Therefore, PCI in this setting cannot be endorsed as reflected by a
..
terms of death, MI, and stroke, but a higher risk of repeat revasculari- .. class III recommendation. For PCI in LM with intermediate anatomical
zation with PCI.68,70,73,101,139–144 .. complexity, the previous class IIa recommendation was maintained in
..
.. view of the incomplete 5 year follow-up of the two largest RCTs in
5.3.3 Left main coronary artery disease .. this setting.
..
The available evidence from RCTs and meta-analyses comparing ..
CABG with PCI using DES among patients with LM disease suggests .. 5.3.4 Multivessel coronary artery disease
..
equivalent results for the safety composite of death, MI, and stroke .. The observation of a survival advantage of CABG over PCI has been
up to 5 years of follow-up.148 A significant interaction with time is
.. consistent among patients with severe three-vessel CAD (intermedi-
..

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notable, providing early benefit for PCI in terms of MI and peri- .. ate to high SYNTAX score), and has been attributed at least in part
interventional stroke, which is subsequently offset by a higher risk of
.. to the placement of bypass grafts to the mid coronary vessels provid-
..
spontaneous MI during long-term follow-up. The need for repeat .. ing prophylaxis against the development of new proximal disease.
revascularization is higher with PCI than with CABG.
.. The BEST trial, comparing CABG with PCI using new-generation
..
The EXCEL trial compared CABG with PCI using new-generation .. DES (EES) among patients with multivessel CAD (77% three-vessel
..
DES (EES) among 1905 patients with significant LM disease.107 At 3 .. CAD and 23% two-vessel disease, mean SYNTAX score 24), prema-
years of follow-up, the primary endpoint of death, stroke, or MI .. turely stopped enrolment after the inclusion of 880 patients due to
..
occurred with similar frequency in the CABG and PCI group (14.7 vs. .. slow recruitment.105 At a median follow-up of 4.6 years, PCI was
15.4%; HR 1.00, 95% CI 0.79–1.26, P = 0.98). The pre-planned land- .. associated with a higher incidence of the primary endpoint (death,
..
mark analysis from 30 days to 3 years showed a significant difference .. MI, and TVR) (15.3 vs. 10.6%; HR 1.47, 95% CI 1.01–2.13, P = 0.04)
for the primary endpoint in favour of CABG (7.9 vs. 11.5%, P = 0.02). .. than CABG. The risk of death, MI, and stroke was not statistically dif-
..
The NOBLE (Nordic-Baltic-British Left Main Revascularization .. ferent between the two treatment groups (11.9 vs. 9.5%; HR 1.26,
Study) trial compared CABG with PCI using new-generation DES .. 95% CI 0.84–1.89, P = 0.26), whereas repeat revascularization of any
..
[biolimus-eluting stents (BES)] among 1201 patients with significant .. vessel (11.0 vs. 5.4%; HR 2.1, 95% CI 1.28–3.41, P = 0.003) but not
LM disease (mean SYNTAX score of 23).106 At a median follow-up .. target lesion revascularization (5.7 vs. 3.8%; HR 1.51, 95% CI
..
of 3.1 years, the primary endpoint of death, non-procedural MI, .. 0.82–2.80, P = 0.19) was more frequent in the PCI group. CABG
stroke, and repeat revascularization occurred more frequently in the .. resulted in more complete revascularization (71.5 vs. 50.9%;
..
PCI than the CABG group (29 vs. 19%; HR 1.48, 95% CI 1.11–1.96, .. P <0.001) and a lower incidence of revascularization for new lesions
P = 0.007). .. (5.5 vs. 2.3%; HR 2.47, 95% CI 1.18–5.17, P = 0.01).
..
A recent collaborative individual patient pooled analysis of .. Consistent with findings in the overall cohort (see section 5.3.3),
randomized trials including 11 518 patients reviewed the currently
.. the collaborative individual patient pooled analysis found that in 7040
..
available evidence from randomized trials comparing CABG with PCI .. patients with multivessel disease, those assigned to CABG had signifi-
for LM or multivessel disease.124 The primary outcome was all-cause
.. cantly lower 5 year all-cause mortality than those assigned to PCI
..
mortality. In the overall cohort, CABG was associated with a signifi- .. (PCI 11.5 vs. CABG 8.9%; HR 1.28, 95% CI 1.09–1.49, P = 0.0019).124
cant survival benefit during a mean follow-up of 3.8 ± 1.4 years (5
.. Outcomes for the endpoint all-cause mortality were modified by two
..
year all-cause mortality 11.2% after PCI vs. 9.2% after CABG; HR .. variables, diabetes and disease complexity, as assessed by the
1.20, 95% CI 1.06–1.37, P = 0.0038). There was a linear trend for
.. SYNTAX score. Compared with patients without diabetes (8.7 vs.
..
HRs of death increasing with increasing SYNTAX tertiles [P = 0.0011 .. 8.0%; HR 1.08, 95% CI 0.86–1.36, P = 0.49), mortality was higher after
..
for trend (unpublished analysis)]. However, among 4478 patients .. PCI than CABG in patients with diabetes (15.5 vs. 10.0%; HR 1.48,
with LM disease, those randomly assigned to CABG or PCI with a .. 95% CI 1.19–1.84, P = 0.0004, Pinteraction = 0.045). There was a gra-
..
mean follow-up of 3.4 ± 1.4 years reported similar risks for the pri- .. dient of risk with a stepwise increase in mortality for PCI according
mary outcome all-cause mortality (PCI 10.7 vs. CABG 10.5%; HR .. to SYNTAX score tertile (SYNTAX score 0 - 22: 10.5 vs. 8.4%; HR
..
1.07, 95% CI 0.87–1.33, P = 0.52) at 5 years. There were no signifi- .. 1.11, 95% CI 0.77–1.62, P = 0.57; SYNTAX score 23 - 32: 14.0 vs.
cant differences in mortality between PCI and CABG in subgroup .. 9.5%; HR 1.50, 95% CI 1.09–2.08, P =0.0129; SYNTAX score >32:
..
analyses according to SYNTAX scores. Nevertheless, in patients .. 19.2 vs. 11.2%; HR 1.70, 95% CI 1.13–2.55, P = 0.0094).
with a high SYNTAX score, a trend towards better survival was .. An individual patient data pooled analysis of SYNTAX and BEST,
..
noted with CABG. The proportion of patients with a high SYNTAX .. comparing CABG with PCI using DES among 1275 patients with mul-
score was limited in view of the inclusion criteria of the respective .. tivessel disease in the absence of diabetes (89% three-vessel CAD,
..
studies. .. mean SYNTAX score 26), reported a lower risk of death (6.0 vs.
Current evidence indicates that PCI is an appropriate alternative .. 9.3%; HR 0.65, 95% CI 0.43–0.98, P = 0.04) and MI (3.3 vs. 8.3%; HR
..
to CABG in LM disease and low-to-intermediate anatomical com- .. 0.40, 95% CI 0.24–0.65, P <0.001) in the CABG group at a median
plexity. Among patients with LM disease and low anatomical com- .. follow-up of 61 months.149 The risk of death was not significantly dif-
..
plexity, there is evidence that the outcomes with respect to major .. ferent among patients with a low (0 - 22) SYNTAX score (6.0 vs.
clinical endpoints are similar for PCI and CABG, resulting in a class I
.. 7.5%, P = 0.66), whereas the benefit of CABG over PCI was greater
..
recommendation. Among patients with LM disease and high . in patients with an intermediate-to-high (>22) SYNTAX score (7.1
110 ESC/EACTS Guidelines

..
vs. 11.6%, P = 0.02). Another individual patient data pooled analysis .. 6.1 Early invasive vs. conservative
of SYNTAX and BEST, comparing CABG with PCI using DES among ..
.. strategy
1166 patients with multivessel disease involving the proximal LAD .. An invasive strategy has become the standard of care for high-risk
(88% three-vessel CAD, mean SYNTAX score 28), reported a higher ..
.. patients.158 This approach allows prompt diagnosis of the underlying
risk of the composite of death, MI, and stroke (16.3 vs. 11.5%; HR .. CAD, identification of the culprit lesion, guidance for antithrombotic
1.43, 95% CI 1.05–1.96, P = 0.02), cardiac death, MI, and repeat revas- ..
.. management, and the assessment of the suitability of coronary anat-
cularization in the PCI group at 5 years of follow-up.147 Of note, out- ..
.. omy for PCI or CABG. Numerous factors interplay in the decision-
comes were not significantly different for CABG and PCI for any .. making process, including clinical presentation, comorbidities, risk
endpoint except for MI among the subgroup of patients with low .. stratification (Figure 4), and high-risk features specific for a revasculari-
SYNTAX score (0 - 22). ..
.. zation modality such as frailty, cognitive status, estimated life expect-
The available evidence suggests that in multivessel CAD without .. ancy, and the functional and anatomical severity of CAD.
diabetes and low anatomical complexity, PCI and CABG achieve sim- ..
..

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Up to 40% of NSTE-ACS patients with obstructive CAD present
ilar long-term outcomes with respect to survival and the composite .. with multiple complex plaques159–162 and 25% with an acute
of death, MI, and stroke, justifying a class I recommendation for PCI. ..
.. occluded coronary artery,163 so that identification of the culprit
In patients with multivessel CAD and intermediate-to-high anatomi- ..
.. lesion may be challenging. Correlation with ECG or echo changes
cal complexity, the two large trials using DES, SYNTAX and BEST, .. and the use of OCT in the 25% of NSTE-ACS patients with angio-
found a significantly higher mortality and a higher incidence of death, ..
.. graphically normal epicardial coronary arteries164–166 may be helpful
MI, and stroke with PCI in the absence of diabetes. Consistent results .. for identifying the culprit lesion, or rule out other mechanisms such
were also obtained for patients with multivessel CAD in the recent ..
individual patient-level meta-analysis.124 Thus, the previous class III
.. as dissection or haematomas [MI with non-obstructive coronary
.. arteries (MINOCA)].167–169
recommendation for PCI in multivessel CAD and intermediate-to- ..
.. A routine invasive strategy in NSTE-ACS has been shown to
high complexity was maintained. .. improve clinical outcomes,170 and benefit was mainly confined to
..
.. biomarker-positive patients171 and patients with other high-risk fea-
5.4 Gaps in the evidence .. tures as defined in Figure 4. Of importance, the use of a radial
..
It remains to be determined whether revascularization by PCI .. approach, new-generation DES, and more effective P2Y12-inhibitors
improves prognosis in patients with SCAD. The ISCHEMIA .. were not available or broadly implemented in these trials, and led to
..
(International Study of Comparative Health Effectiveness With .. a magnified benefit in frail ACS populations.172,173
Medical and Invasive Approaches) study (NCT01471522) is currently ..
..
recruiting 5000 patients with SCAD and evidence of moderate-to- .. 6.2 Timing of angiography and
severe ischaemia detected by non-invasive imaging, who are random- ..
.. intervention
ized before coronary angiography to medical therapy or an invasive .. The current recommendations on the timing of angiography and inter-
strategy to detect differences in the primary endpoint of death or MI. ..
.. vention, as defined in Figure 4, are based on evidence discussed in detail
Current techniques rely on coronary angiography and the detection ..
.. by the prior Guidelines on NSTE-ACS.158 Specifically, a reduction in
of ischaemia-producing lesions. However, future adverse events are .. recurrent or refractory ischaemia and length of hospital stay was
related at least in part to non-flow limiting, vulnerable plaques. Better ..
.. found with early intervention.174,175 More recently, an updated collab-
identification of vulnerable plaques and the development of appropri- .. orative meta-analysis on individual published and unpublished data
ate treatment strategies is needed. Along the same lines, the com- ..
pleteness and timing of revascularization are not well defined, and
.. (n = 5324 patients with a median follow-up of 180 days) suggested
.. that early intervention might also be associated with decreased mor-
neither are the roles of residual ischaemia and lesions. Moreover, we ..
.. tality.176 This meta-analysis showed a statistical trend towards
need more research on the use of the SYNTAX and other scores for .. decreased mortality with an early invasive strategy compared with a
informing treatment allocation, as well as dedicated trials in specific ..
subsets. Very long-term, extended follow-up (10 years) of trials com-
.. delayed invasive strategy in unselected patients with NSTE-ACS (HR
.. 0.81, 95% CI 0.64–1.03, P = 0.088). The survival benefit of the early
paring PCI and CABG, particularly in the setting of LM disease, will ..
provide further insights into the relative merits of both revasculariza-
.. invasive strategy appeared more pronounced in high-risk subsets,
.. including elevated cardiac biomarkers at baseline (HR 0.76, 95% CI
tion techniques. ..
.. 0.58–0.996), diabetes (HR 0.67, 95% CI 0.45–0.99), a Global Registry
.. of Acute Coronary Events risk score >140 (HR 0.70, 95% CI
..
.. 0.52–0.95), and age 75 years or older (HR 0.65, 95% CI 0.46–0.93),
6 Revascularization in ..
.. although tests for interaction were inconclusive.
non-ST-elevation acute coronary ..
..
syndrome .. 6.3 Type of revascularization
.. 6.3.1 Percutaneous coronary intervention
..
Myocardial revascularization in patients with non-ST-segment eleva- .. 6.3.1.1 Technical aspects
tion ACS (NSTE-ACS) is addressed by prior Guidelines that are .. Implantation of new-generation DES is the standard treatment strat-
..
endorsed by the current Task Force.158 In the present Guidelines, we .. egy even when dual antiplatelet therapy (DAPT) cannot be sustained
discuss new evidence where previous recommendations require an
.. beyond 1 month post-intervention173,177–179 (see section 17),
..
update. . and the radial approach has also become the standard of care.172
ESC/EACTS Guidelines 111

DAPT is recommended for 12 months irrespective of stent type, .. incidence of the primary outcome—the composite of death, MI, or
..
while in patients at high ischaemic risk not experiencing bleeding .. stroke—was significantly lower with CABG than with PCI (13.4 vs.
events, DAPT may be extended (see section 17). There is no evi-
.. 18%, P = 0.036). The findings of this meta-analysis were consistent
..
dence for any additional benefit of thrombectomy in patients under- .. with the main findings of the studies included, thus supporting the
going PCI in the setting of NSTE-ACS.180 While FFR is considered
.. concept that the principles of SCAD should apply to stabilized
..
the invasive gold standard for the functional assessment of lesion .. patients with NSTE-ACS as well.
severity in SCAD, it has been shown to be feasible, reliable, safe, and
.. For complex cases, Heart Team discussion and use of the
..
effective in NSTE-ACS patients with multivessel disease, although its .. SYNTAX score are recommended,195 given its ability to predict
prognostic value is unclear.22,137,181
.. death, MI, and revascularization in patients with NSTE-ACS and mul-
..
.. tivessel disease undergoing PCI. In patients with multivessel disease
..
6.3.1.2 Revascularization strategies and outcomes .. and diabetes in particular, recent evidence suggests a greater benefit
Complete revascularization of significant lesions should be attempted .. of CABG vs. PCI.196
..

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in multivessel disease NSTE-ACS patients, given that it was mandated ..
in trials testing early vs. late intervention171,182,183 and that the prog- ..
.
nosis of patients with incomplete revascularization is known to be
worse.131,184 In addition, it seems that complete one-stage revascula- Recommendations for invasive evaluation and
rization is associated with better clinical outcome than multistage revascularization in non-ST-elevation acute coronary
PCI.185 The risk of periprocedural complications of PCI defined as MI syndrome
or myocardial injury, as well as that of long-term ischaemia, remains
higher in NSTE-ACS than in stable patients.186,187 For ACS patients Recommendations Classa Levelb
who have undergone PCI, revascularization procedures represent
Urgent coronary angiography (<2 h) is rec-
the most frequent, most costly, and earliest causes for rehospitaliza-
ommended in patients at very high ischae- I C
tion.188,189 As in ST-elevation myocardial infarction (STEMI), routine
mic risk (Figure 4).197
treatment of non-culprit lesions during the primary intervention by
PCI is harmful in NSTE-ACS patients with cardiogenic shock, as An early invasive strategy (<24 h) is recom-
shown by the recently published CULPRIT-SHOCK (Culprit Lesion mended in patients with at least one high- I A
Only PCI versus Multivessel PCI in Cardiogenic Shock) trial (see sec- risk criterion (Figure 4).164,174,176
tion 7.3).190
An invasive strategy (<72 h after first
presentation) is indicated in patients
6.3.2 Coronary artery bypass grafting I A
with at least one intermediate-risk crite-
Approximately 5–10% of NSTE-ACS patients require CABG,191 and
rion (Figure 4) or recurrent
they represent a challenging subgroup given their high-risk character-
symptoms.170,171
istics compared with patients undergoing elective CABG.192 In the
absence of randomized data, optimal timing for non-emergent CABG It is recommended to base the revasculari-
in NSTE-ACS patients should be determined individually. The risk of zation strategy (ad hoc culprit lesion PCI/
ischaemic events possibly related to suboptimal antiplatelet therapy multivessel PCI/CABG) on the clinical status
while awaiting surgery is <0.1%, while that of perioperative bleeding and comorbidities, as well as the disease
I B
complications associated with platelet inhibitors is >10%.193 In severity [i.e. the distribution and angio-
patients with ongoing ischaemia or haemodynamic instability with an graphic lesion characteristics (e.g. SYNTAX
indication for CABG, emergency surgery should be performed and score)], according to the principles for
not postponed as a consequence of antiplatelet treatment exposure. SCAD.c 194

In cardiogenic shock, routine revasculariza-


6.3.3 Percutaneous coronary intervention vs. coronary tion of non-IRA lesions is not recommended III B
artery bypass grafting during primary PCI.190
There is no randomized comparison of PCI vs. CABG in the specific
setting of NSTE-ACS. The currently available evidence indirectly sug-
CABG = coronary artery bypass grafting; IRA = infarct-related artery; NSTE-ACS
gests that the criteria applied to patients with SCAD to guide the = non-ST-elevation acute coronary syndrome; PCI = percutaneous coronary
choice of revascularization modality should be applied to stabilized intervention; SCAD = stable coronary artery disease; SYNTAX = Synergy
Between Percutaneous Coronary Intervention with TAXUS and Cardiac Surgery.
patients with NSTE-ACS.100,121,150,194 Recent individual-patients data a
Class of recommendation.
analysis from the BEST, PRECOMBAT, and SYNTAX studies com- b
Level of evidence.
c
pared the outcome of CABG with that of PCI in 1246 patients with May apply to stabilized NSTE-ACS patients.
stabilized NSTE-ACS and multivessel or LM disease.194 The 5 year
112 ESC/EACTS Guidelines

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Figure 4 Selection of non-ST-elevation acute coronary syndrome treatment strategy and timing according to initial risk stratification.

..
6.4 Gaps in the evidence .. shock or out-of-hospital cardiac arrest.199 In shock without out-of-
.. hospital cardiac arrest, every 10 min treatment delay between
In the setting of NSTE-ACS, there are no dedicated prospective stud- ..
ies on the revascularization strategy with multivessel disease. Thus, .. 60–180 min from the first medical contact resulted in 3.3 additional
.. deaths per 100 PCI-treated patients, and in 1.3 additional deaths after
current recommendations on the choice of lesions to be treated and ..
treatment modality (PCI or CABG) are based on an analogy to find- .. out-of-hospital cardiac arrest without cardiogenic shock. In stable
.. STEMI patients, time delays were substantially less relevant (0.3 addi-
ings obtained in SCAD or STEMI. Likewise, the prognostic role of ..
FFR and iwFR in guiding myocardial revascularization needs additional .. tional deaths per 100 PCI-treated patients for every 10 min delay
.. between 60–180 min from the first medical contact). Thus, high-risk
clarification. ..
.. STEMI patients with cardiogenic shock or out-of-hospital cardiac
.. arrest are those who benefit most from expediting all steps of the
..
.. care pathway.
7 Revascularization in ST-segment ..
..
elevation myocardial infarction .. 7.2 Selection of reperfusion strategy
..
Myocardial revascularization in patients with STEMI is addressed by
.. Primary PCI, defined as percutaneous catheter intervention in the
.. setting of STEMI without previous fibrinolysis, is the preferred reper-
the 2017 ESC Guidelines on STEMI. After reviewing the subsequent ..
literature, the current Task Force endorses most recommendations
.. fusion strategy. It has replaced fibrinolysis in patients with STEMI, pro-
.. vided it can be performed in a timely manner in high-volume PCI
of these Guidelines.198 ..
.. centres with experienced operators and 24 h/7 days a week catheter-
.. ization laboratory activation.198,200,201 In settings where primary
..
7.1 Time delays .. PCI cannot be performed in a timely fashion, fibrinolysis should be
Delays in the timely implementation of reperfusion therapy are key .. administered as soon as possible. If first medical contact (FMC) is
..
issues in the management of STEMI. Detailed recommendations on .. out-of-hospital, lysis should be implemented pre-hospital (e.g. in the
timelines, logistics, and pre-hospital management have been provided .. ambulance) (Figure 5).202–206 It should be followed by transfer to
..
in the recent ESC STEMI Guidelines (Figure 5).198 .. PCI-capable centres for routine coronary angiography in all patients,
A recent analysis of 12 675 STEMI patients in the FITT-STEMI .. and should be performed without delay for rescue PCI in the case of
..
(Feedback Intervention and Treatment Times in ST-Elevation .. unsuccessful fibrinolysis or within 2–24 h after bolus administra-
Myocardial Infarction) trial emphasizes the strong impact of time
.. tion.198 Emergency CABG may be indicated in selected STEMI
..
delays on mortality, particularly in STEMI patients with cardiogenic . patients unsuitable for PCI.
ESC/EACTS Guidelines 113

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Figure 5 Modes of patient’s medical contact, components of ischaemia time, and flowchart for reperfusion strategy selection.

7.3 Primary percutaneous coronary .. Four major randomized trials-PRAMI (Preventive Angioplasty in
..
intervention .. Acute Myocardial Infarction),211 CvLPRIT (Complete Versus Lesion-
Key points for optimizing and guiding primary PCI are summarized
.. Only Primary PCI trial),212 DANAMI-3-PRIMULTI (The Third
..
below. .. DANish Study of Optimal Acute Treatment of Patients with ST-
The infarct-related artery (IRA) should be systematically treated
.. segment Elevation Myocardial Infarction: PRImary PCI in
..
during the initial intervention. Patients with extensive CAD in vessels .. MULTIvessel Disease),213 and Compare-Acute214-have consistently
remote from the IRA have an adverse prognosis following primary
.. shown a benefit of complete revascularization (performed immedi-
..
PCI.207 Staged PCI in patients with multivessel disease and no haemo- .. ately or staged) as compared with IRA-only PCI in patients with
..
dynamic compromise is an independent predictor of survival, and .. STEMI and multivessel disease (for details see the Supplementary
more frequent ischaemic events have been reported in direct vs. .. Data). A recent meta-analysis of 10 trials has shown that complete
..
staged revascularization of STEMI patients with multivessel .. revascularization was associated with a lower risk of MACE (RR 0.57,
disease.208–210 .. 95% CI 0.42–0.77), due to a lower risk of urgent revascularization
114 ESC/EACTS Guidelines

..
(RR 0.44, 95% CI 0.30–0.66), with no significant difference in mortal- .. median follow-up of 42 months.221 Routine deferred stenting was
ity (RR 0.76, 95% CI 0.52–1.12) or MI (RR 0.54, 95% CI .. associated with a higher risk of TVR.
..
0.23–1.27).215 This meta-analysis did not include Compare-Acute. .. Thrombus aspiration has been proposed as an adjunct during pri-
Yet, similar to earlier studies, the benefit of complete revasculariza- .. mary PCI to further improve epicardial and myocardial reperfusion
..
tion over culprit-only revascularization seen in Compare-Acute was .. by the prevention of distal embolization of thrombotic material and
driven by a lower need for unplanned reintervention, whereas the .. plaque debris.222 Two landmark RCTs, which were adequately pow-
..
incidences of death and recurrent MI were similar between the two .. ered to detect the superiority of routine manual thrombus aspiration
strategies.214 .. vs. conventional PCI, showed no benefit on clinical outcomes of the
..
Most of the studies support the concept of full revascularization .. routine aspiration strategy overall or in any subgroup of patients indi-
either during the initial hospital stay for STEMI or a staged admis- .. cating high thrombotic risk.223–226 A safety concern emerged in
..
sion,215 but it remains to be determined how clinicians can identify .. TOTAL (Trial of Routine Aspiration Thrombectomy with PCI versus
lesions that should be revascularized beyond the culprit lesion and .. PCI Alone in Patients with STEMI) trial with an increase in the risk of
..

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whether complete revascularization should be performed in single- .. stroke.225,227 Taken together, these results suggest that the routine
or multi-stage procedures. Moreover, there is a lack of evidence on
.. use of thrombus aspiration is not indicated. In the high-thrombus bur-
..
the optimal timing of staged procedures. In most of the studies, .. den subgroup, the trend towards reduced cardiovascular death and
staged procedures were performed during the initial hospital stay. At
.. increased stroke/transient ischaemic attack (TIA) provides a rationale
..
present, one-stage multivessel PCI during STEMI without cardiogenic .. for future trials of improved thrombus aspiration technologies in this
shock should be considered in patients in the presence of multiple,
.. high-risk subgroup (although statistical tests did not support signifi-
..
critical stenoses or highly unstable lesions (angiographic signs of pos- .. cant subgroup interaction).228
sible thrombus or lesion disruption), and if there is persistent ischae-
..
..
mia after PCI on the supposed culprit lesion. .. 7.4 Percutaneous coronary intervention
..
In patients with multivessel disease and AMI with cardiogenic
... after thrombolysis and in patients with
shock, the recently published CULPRIT-SHOCK trial showed that a ..
strategy with PCI of the culprit lesion only with possible staged revas- .. late diagnosis
.. The benefits of early, routine PCI after thrombolysis were seen in the
cularization determined a lower 30 day risk of the composite of all- ..
cause mortality or severe renal failure compared with immediate .. absence of an increased risk of adverse events (stroke or major
.. bleeding). Based on data from the four most recent trials, all of which
multivessel PCI.190 This was driven by a significant risk reduction in ..
30 day all-cause mortality by the culprit lesion-only strategy com- .. had a median delay between the start of thrombolysis and angiogra-
.. phy of 2–6 h, a time frame of 2–24 h after successful lysis is recom-
pared with immediate multivessel PCI (43.3 vs. 51.6%; HR 0.84, 95% ..
CI 0.72–0.98, P = 0.03). These findings need to be interpreted in light .. mended.206,229–231 In cases of failed fibrinolysis, or if there is evidence
.. of re-occlusion or reinfarction with recurrence of ST-segment eleva-
of a low 12.5% (43 out of 344 patients) crossover rate from culprit ..
lesion-only to immediate multivessel PCI based on physicians’ judg- .. tion, the patient should undergo immediate coronary angiography
.. and rescue PCI.232 Patients presenting between 12 and 48 h after the
ment. Based on these findings, culprit lesion-only PCI is recom- ..
mended as the default strategy in patients with AMI with cardiogenic .. onset of symptoms, even if pain free and with stable haemodynamics,
.. may still benefit from early coronary angiography and possibly
shock. A more detailed discussion of the revascularization strategy in ..
MI patients with cardiogenic shock is found in the Supplementary
.. PCI.233,234 In patients presenting days after the acute event with a
.. completed MI, only those with recurrent angina or documented
Data. ..
In patients with STEMI, DES (in particular new-generation DES)
.. residual ischaemia—and proven viability on non-invasive imaging in a
.. large myocardial territory—may be considered for revascularization
have demonstrated better efficacy as compared with BMS and should ..
be used as the default strategy in STEMI patients, even when DAPT
.. when the infarct artery is occluded. Routine late PCI of an occluded
..
cannot be sustained beyond 1 month.177,178,216–218 (see section .. IRA after MI in stable patients has no incremental benefit over medi-
16.1.2). As discussed in section 16.4, radial access is preferred over
.. cal therapy.235
..
femoral access. ..
..
Delaying stenting in primary PCI has been investigated as an option .. 7.5 Gaps in the evidence
to reduce microvascular obstruction (MVO) and preserve microcir- .. Patients undergoing primary PCI benefit from full revascularization,
..
culatory function in two small trials with conflicting results.219,220 .. but the optimal timing of treatment of the non-culprit lesion is not
More recently, in the larger deferred vs. conventional stent implanta- .. known. More studies evaluating the assessment of non-culprit lesions
..
tion in patients with STEMI [The Third DANish Study of Optimal .. by FFR or iwFR at the time of acute PCI, and studies investigating
Acute Treatment of Patients with ST-segment Elevation Myocardial .. whether intravascular imaging guidance of primary PCI can improve
..
Infarction: DEFERred stent implantation in connection with primary .. the outcomes of STEMI patients, are needed. Future trials of
PCI (DANAMI 3-DEFER)] trial in 1215 STEMI patients, there was no .. improved thrombus aspiration technologies may address the role of
..
effect on the primary clinical outcome (composite of death, non-fatal .. this strategy in patients with high-risk features, such as large thrombus
MI, or ischaemia-driven revascularization of non-IRA lesions) over a .. burden.228
ESC/EACTS Guidelines 115

Primary percutaneous coronary intervention for myocardial reperfusion in ST-elevation myocardial infarction: indica-
tions and logistics

Recommendations Classa Levelb

Indication

Reperfusion therapy is indicated in all patients with time from symptom onset <12 h duration and persistent ST-seg-
I A
ment elevation.200,201,236

In the absence of ST-segment elevation, a primary PCI strategy is indicated in patients with suspected ongoing
ischaemic symptoms suggestive of MI and at least one of the following criteria present:
• haemodynamic instability or cardiogenic shock

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• recurrent or ongoing chest pain refractory to medical treatment
I C
• life-threatening arrhythmias or cardiac arrest
• mechanical complications of MI
• acute heart failure
• recurrent dynamic ST-segment or T-wave changes, particularly with intermittent ST-segment elevation.

A primary PCI strategy is recommended over fibrinolysis within the indicated time frames.200,201,237,238 I A

In patients with time from symptom onset >12 h, a primary PCI strategy is indicated in the presence of ongoing
I C
symptoms or signs suggestive of ischaemia, haemodynamic instability, or life-threatening arrhythmias.

A routine primary PCI strategy should be considered in patients presenting late (12–48 h) after symptom
IIa B
onset.233,234,239

Logistics

It is recommended that the pre-hospital management of STEMI patients should be based on regional networks that
are designed to deliver reperfusion therapy effectively in a timely fashion, and to offer primary PCI to as many I B
patients as possible.240,241

It is recommended that all EMS, emergency departments, coronary care units, and catheterization laboratories have
I C
a written updated STEMI management protocol, preferably shared within geographical networks.

It is recommended that primary PCI-capable centres deliver a 24 h/7 day service and ensure that primary PCI is per-
I B
formed as fast as possible.242–244

It is recommended that patients transferred to a PCI-capable centre for primary PCI bypass the emergency depart-
I B
ment and CCU/ICCU, and are transferred directly to the catheterization laboratory.245–247

CCU = coronary care unit; EMS = emergency medical services; ICCU = intensive coronary care unit; MI = myocardial infarction; PCI = percutaneous coronary intervention;
STEMI = ST-segment elevation myocardial infarction.
a
Class of recommendation.
b
Level of evidence.
116 ESC/EACTS Guidelines

Primary percutaneous coronary intervention for myocardial reperfusion in ST-elevation myocardial infarction: proce-
dural aspects (strategy and technique)

Recommendations Classa Levelb

Strategy

Routine revascularization of non-IRA lesions should be considered in patients with multivessel disease before hospital
IIa A
discharge.211–214

CABG should be considered in patients with ongoing ischaemia and large areas of jeopardized myocardium if PCI of the
IIa C
IRA cannot be performed.

In cardiogenic shock, routine revascularization of non-IRA lesions is not recommended during primary PCI.190

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III B

Technique

Routine use of thrombus aspiration is not recommended.223–226,228 III A

CABG = coronary artery bypass grafting; IRA = infarct-related artery; PCI = percutaneous coronary intervention; STEMI = ST-segment elevation myocardial infarction.
a
Class of recommendation.
b
Level of evidence.

..
8 Myocardial revascularization in ..
..
revascularization with medical therapy in patients with an EF <_40%
showed that there was a significant mortality reduction with CABG
patients with heart failure ... (HR 0.66, 95% CI 0.61–0.72, P <0.001) and PCI (HR 0.73, 95% CI
..
.. 0.62–0.85, P <0.001) vs. medical therapy, though these finding are
8.1 Chronic heart failure .. limited by the predominantly observational nature of the included
8.1.1 Recommendations for myocardial revascularization ..
.. studies and missing information on the completeness of
in patients with chronic heart failure .. revascularization.248
When compared with medical therapy alone, coronary revasculariza- ..
.. A recent observational study investigated outcomes with PCI or
tion is superior in improving survival in patients with HF of ischaemic .. CABG for multivessel CAD and LV dysfunction in 1738 propensity-
origin and is recommended in clinical practice.81,248 However, the ..
.. matched patients with diabetes mellitus.251 Similar to the findings in
optimal revascularization strategy is not defined. The choice between .. the absence of LV dysfunction, when CABG was compared with PCI
CABG and PCI should be made by the Heart Team after careful eval- ..
.. it was associated with a significantly lower risk of MACE, which
uation of the patient’s clinical status and coronary anatomy, expected .. included a significant reduction in mortality. Event curves separated
completeness of revascularization (see section 5.3.1.3), myocardial ..
.. early during the first year and continued to separate out to 12 years.
viability, coexisting valvular disease, and comorbidities. .. PCI should be considered in older patients without diabetes in
Considerations relating to the need for viability testing prior to revas-
..
.. whom complete revascularization can be achieved, whereas CABG is
cularization are discussed in section 3. ..
.. preferred in younger patients with more extensive CAD or those
Randomized clinical trial data comparing revascularization with .. with diabetes. In patients with diabetes and LV moderate or severe
medical therapy exists only for CABG in the setting of the STICH ..
trial.81 One analysis from this trial showed that CABG can be per-
.. dysfunction (EF <50%), CABG is associated with better long-term
.. survival and reduced incidence of MACCE.250,251
formed with acceptable 30 day mortality rates (5.1%) in patients with ..
LV dysfunction (LVEF <_35%).249 Extended follow-up in the STICH
..
..
Extension Study (STICHES) supports a significant survival benefit of .. 8.1.2 Ventricular reconstruction and aneurysm resection
..
CABG combined with medical therapy vs. medical therapy alone in a .. The aim of surgical ventricular reconstruction (SVR) is to restore
10 year observation period.81 .. physiological volume, and achieve an elliptical shape of the LV, by scar
..
There are currently no dedicated randomized clinical trials com- .. resection and LV wall reconstruction on a mannequin of predefined
paring PCI vs. medical therapy in patients with HF with reduced EF .. size. The aim of ventricular aneurysmectomy is to remove fibrous
..
(HFrEF). In addition, CABG vs. PCI randomized trials have excluded .. scars in cases of severe dilatation, thrombus formation, or as a source
patients with severe HF. In one prospective registry including 4616 .. of life-threatening ventricular arrhythmias.
..
patients with multivessel disease and severe HFrEF, propensity .. The STICH trial revealed no difference in the primary outcome
score-matched comparison revealed similar survival (mean follow-up .. (total mortality or cardiac hospitalization) between patients ran-
..
2.9 years) with PCI (using EES) vs. CABG.250 PCI was associated with .. domly allocated to CABG vs. combined CABG and SVR.252
a higher risk of MI, particularly in patients with incomplete revascula- .. Subgroup analyses of patients with a less dilated LV and better LVEF
..
rization, and repeat revascularization. CABG was associated with a .. showed benefit from SVR.253 In the STICH trial, a post-operative LV
higher risk of stroke. The conclusion of the study was that multivessel .. end-systolic volume index <_70 mL/m2, after CABG plus SVR,
..
PCI can be a valuable option in HF patients if complete revasculariza- .. resulted in improved survival compared with CABG alone.252,254 In
tion is possible. A systematic review of studies comparing .. experienced centres, SVR may be done at the time of CABG if HF
ESC/EACTS Guidelines 117

..
symptoms are more predominant than angina, and if myocardial scar .. patients with cardiogenic shock complicating AMI, emergency revas-
and moderate LV remodelling are present. .. cularization with PCI or CABG improved long-term survival when
..
.. compared with initial intensive medical therapy. All-cause mortality
Recommendations on revascularizations in patients .. at 6 months was lower in the group assigned to revascularization
with chronic heart failure and systolic left ventricular ..
dysfunction (ejection fraction 35%)
.. than in the medically treated patients (50.3 vs. 63.1%, respectively;
.. RR 0.80, 95% CI 0.65–0.98, P = 0.03).258
..
.. The revascularization strategy for patients with cardiogenic shock
Recommendations Classa Levelb .. and multivessel disease is addressed in section 7.
..
In patients with severe LV systolic dysfunc- .. A subanalysis of the SHOCK trial comparing patients treated with
.. CABG or PCI showed similar survival rates between the two sub-
tion and coronary artery disease suitable for ..
intervention, myocardial revascularization is
I B .. groups.259 There were more patients with diabetes (48.9 vs. 26.9%;
.. P = 0.02), three-vessel disease (80.4 vs. 60.3%; P = 0.03), and LM cor-
recommended.81,250 ..

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.. onary disease (41.3 vs. 13.0%; P = 0.001) in the CABG group. The
CABG is recommended as the first revas- .. findings of this non-randomized comparison suggest that CABG
..
cularization strategy choice in patients
I B
.. should be considered in patients with cardiogenic shock who have
with multivessel disease and acceptable .. suitable anatomy, particularly if successful PCI is not feasible.
..
surgical risk.68,81,248,255 ..
..
In patients with one- or two-vessel dis- ..
.. 8.2.2 Mechanical circulatory support
ease, PCI should be considered as an
IIa C
..
alternative to CABG when complete .. Short-term MCS devices that are currently available are the intra-
.. aortic balloon pump (IABP), veno-arterial extracorporeal membrane
revascularization can be achieved. ..
.. oxygenation (ECMO), and percutaneous left ventricular assist devi-
In patients with three-vessel disease, PCI .. ces (pLVADs). Short-term MCS may be considered in refractory car-
..
should be considered based on the evalu- .. diogenic shock depending on patient age, comorbidities, neurological
ation by the Heart Team of the patient’s .. function, and the prospects for long-term survival and quality of life.
IIa C ..
coronary anatomy, the expected com- ..
pleteness of revascularization, diabetes .. 8.2.2.1 Intra-aortic balloon pump
..
status, and comorbidities. .. IABPs are low-cost devices that are easy to insert and remove. They
.. moderately increase cardiac output and coronary and cerebral perfu-
LV aneurysmectomy during CABG should ..
be considered in patients with NYHA class
.. sion, while decreasing ventricular workload. In patients with cardio-
.. genic shock complicating acute MI, the IABP-SHOCK II (Intraaortic
III/IV, large LV aneurysm, large thrombus IIa C ..
.. Balloon Pump in Cardiogenic Shock II) randomized trial (600 patients)
formation, or if the aneurysm is the origin of .. showed that the use of IABPs did not reduce 30 day mortality and that
arrhythmias. ..
.. there was no evidence of long-term benefit.260,261 A recent Cochrane
Surgical ventricular restoration during
.. review of seven trials (790 patients) showed that IABPs may have a
..
CABG may be considered in selected .. beneficial effect on some haemodynamic parameters but did not result
patients treated in centres with
IIb B .. in survival benefits.262 Thus, the routine use of IABPs in patients with
..
expertise.252–254,256,257 .. cardiogenic shock complicating acute MI is not recommended.
..
..
CABG = coronary artery bypass grafting; LV = left ventricular; NYHA = New .. 8.2.2.2 Extracorporeal membrane oxygenation
York Heart Association; PCI = percutaneous coronary intervention.
..
a .. Veno-arterial ECMO (VA-ECMO), also known as extracorporeal life
Class of recommendation. .. support (ECLS), in its current form is a modified form of cardiopul-
b
Level of evidence. ..
.. monary bypass. It decompresses the venous system; increases coro-
.. nary, cerebral, and peripheral perfusion; and also provides
..
8.2 Acute heart failure and cardiogenic .. supplementary blood oxygenation. When performed percutane-
shock .. ously, it does not allow for LV decompression and leads to increasing
..
Acute myocardial ischaemia in the setting of AMI is the antecedent .. LV afterload.
.. In patients with cardiac arrest, evidence from observational trials
event for the majority of patients with cardiogenic shock undergoing ..
percutaneous revascularization. Mechanical complications—such as .. supports better survival in patients treated with VA-ECMO com-
.. pared with those without.263 When compared with IABP, VA-
papillary muscle rupture with severe mitral valve regurgitation, ven- ..
tricular septal defect, or free wall rupture—are additional precipitat- .. ECMO provides superior circulatory support.264,265 Moreover, a
.. meta-analysis of observational studies suggested that in patients with
ing causes. ..
.. cardiogenic shock post-ACS, VA-ECMO showed a 33% higher 30
.. day survival compared with IABP [95% CI 14–52%, P <0.001; number
..
8.2.1 Revascularization .. needed to treat (NNT) 13].263 However, the low number of patients
The SHOCK (Should We Emergently Revascularize Occluded
.. included in the analysed studies and the non-random treatment allo-
..
Coronaries for Cardiogenic Shock) trial demonstrated that in . cation are important limitations.
118 ESC/EACTS Guidelines

8.2.2.3 Percutaneous left ventricular assist devices


.. were noted in an RCT of high-risk PCI in patients with impaired LV
..
The majority of clinical experience with currently available pLVADs .. function. The 30 day incidence of major adverse events was not dif-
..
is limited to two types of device: (i) a transaortic microaxial pump .. ferent for patients with pLVAD vs. IABP.267
(Impella) that directly unloads the LV providing 2.5 - 5 L/min blood .. In summary, the evidence for pLVAD is insufficient to provide a
..
flow and (ii) a transseptal centrifugal assist device (TandemHeart) .. recommendation on its clinical use in cardiogenic shock.
that unloads the LV via a cannula introduced into the left atrium ..
..
through a transseptal puncture. .. 8.2.2.4 Surgically implanted left ventricular assist devices
A recent meta-analysis on MCS in cardiogenic shock included four .. There are limited data on surgically-implanted LV assist device
..
randomized trials investigating the efficacy and safety of pLVADs vs. .. (LVAD) therapy in patients with AMI and cardiogenic shock. One
IABP, and demonstrated similar short-term mortality despite initial .. multicentre registry showed that despite being more critically ill prior
..
beneficial effects on arterial blood pressure and peripheral perfusion, .. to implantation, patients with acute MI managed with LVAD had out-
measured by serum lactate levels.266 In all trials, a higher rate of .. comes similar to other LVAD populations.268
..

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bleeding from vascular access sites and a significantly higher incidence .. A suggested algorithm for the management of patients with cardio-
of limb ischaemia following pLVAD was noted. Similar outcomes .. genic shock is shown in Figure 6.
..

Figure 6 Algorithm for the management of patients with cardiogenic shock.


ESC/EACTS Guidelines 119

..
8.3 Gaps in the evidence .. The anatomical pattern of CAD in patients with diabetes clearly
There is no RCT comparing revascularization with PCI vs. CABG in
.. influences their prognosis and response to revascularization.
..
patients with HF. .. Angiographic studies have demonstrated that patients with diabetes
.. are more likely to have LM disease and multivessel CAD, with more
There is limited evidence on the role of active MCS in patients ..
with cardiogenic shock compared with standard therapy. .. diffuse disease involving smaller vessels.273 In addition, patients with
.. diabetes have a greater atherosclerotic burden and an increased
..
.. number of lipid-rich plaques, which are prone to rupture,274,275 and
Recommendations for the management of patients with .. those with unstable angina have more fissured plaques and intracoro-
cardiogenic shock ..
.. nary thrombi.276 Patients with diabetes undergoing revascularization,
.. either with CABG or PCI, are at greater risk of kidney injury than
Recommendations Classa Levelb ..
.. patients without diabetes.
..
Emergency coronary angiography is indi- ..

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cated in patients with acute heart failure or I B .. 9.1 Evidence for myocardial
..
cardiogenic shock complicating ACS.258,269 .. revascularization
..
Emergency PCI of the culprit lesion is indi- .. In patients with diabetes, the indications for myocardial revasculariza-
.. tion are the same as those in patients without diabetes (see sections
cated for patients with cardiogenic shock ..
due to STEMI or NSTE-ACS, independent I B .. 5, 6, and 7). A meta-analysis of nine RCTs with 9904 ACS patients did
.. not show an interaction between diabetic status and the benefit from
of time delay of symptom onset, if coronary ..
anatomy is amenable to PCI.258 .. invasive management and revascularization.277 Yet, absolute risk
.. reductions were larger in the diabetic subsets compared with non-
Emergency CABG is recommended for
..
.. diabetic subsets. Consistent with the findings in the absence of diabe-
patients with cardiogenic shock if the coro- I B .. tes, the adverse impact of incomplete revascularization in patients
nary anatomy is not amenable to PCI.258
..
.. with diabetes was also demonstrated in the BARI-2D (Bypass
.. Angioplasty Revascularization Investigation 2 Diabetes) trial.278
In cases of haemodynamic instability, emer- ..
gency surgical or catheter-based repair of
.. Data from randomized trials on revascularization in patients with
I C .. diabetes are summarized in Supplementary Table 5.
mechanical complications of ACS is indi- ..
cated, as decided by the Heart Team.
..
..
.. 9.2 Type of myocardial revascularization
In selected patients with ACS and cardio- .. The selection of the optimal myocardial revascularization strategy for
genic shock, short-term mechanical circula- ..
.. patients with diabetes and multivessel CAD requires particular con-
tory support may be considered, depending
IIb C
.. sideration. The recommendations are provided in section 5.
on patient age, comorbidities, neurological ..
..
function, and the prospects for long-term ..
survival and predicted quality of life.
.. 9.2.1. Randomized clinical trials
.. The FREEDOM trial compared elective revascularization with CABG
..
Routine use of IABPs in patients with car- .. or PCI with first-generation DES (94%) in 1900 patients with diabetes
diogenic shock due to ACS is not III B .. (6% of the screened population) with multivessel disease but without
..
recommended.260–262 .. LM stenosis.150 The primary endpoint of any-cause death, non-fatal
.. MI, or stroke at 5 years occurred in 26.6% in the PCI group, com-
..
ACS = acute coronary syndrome; CABG = coronary artery bypass grafting; IABP .. pared with 18.7% in the CABG group (absolute difference 7.9%, 95%
= intra-aortic balloon pump; NSTE-ACS = non-ST-elevation acute coronary syn- ..
drome; PCI = percutaneous coronary intervention; STEMI = ST-elevation myo-
.. CI 3.3–12.5%, P = 0.005). The incidences of death (16.3% in the PCI
cardial infarction.
.. group vs. 10.9% in the CABG group; absolute difference 5.4%, 95%
a
..
Class of recommendation. .. CI 1.5–9.2%, P = 0.049) and MI (13.9% in the PCI group vs. 6.0% in
b
Level of evidence .. the CABG group, P <0.001) were higher in the PCI group, but the
..
.. incidence of stroke was lower (2.4 vs. 5.2%; P =0.03). Within the
.. FREEDOM trial at 5 years, patients with diabetes treated with insulin
9 Revascularization in patients ..
.. had higher event rates, but there was no significant interaction of
with diabetes .. treatment and insulin requirement for the primary endpoint
..
.. (Pinteraction = 0.40), even after adjusting for SYNTAX score: the NNT
Patients with diabetes mellitus have a higher prevalence of CAD, .. with CABG vs. PCI to prevent one event was 12.7 for insulin-treated
..
which often manifests earlier in life and confers a substantially worse .. patients and 13.2 in those not requiring insulin.279
prognosis than for patients without diabetes.270 Patients with diabe- .. VACARDS (Veterans Affairs Coronary Artery Revascularization
..
tes who have suffered an MI have a worse prognosis, particularly .. in Diabetes Study) compared CABG with PCI in patients with diabe-
those requiring treatment with insulin, and the presence of diabetes .. tes and extensive CAD in the USA.154 Only 198 patients with diabe-
..
amplifies the risk of any cardiovascular event.271 Diabetes mellitus is .. tes were randomized due to early termination of the study. The
present in 25–30% of patients admitted with ACS and in up to 40% .. combined risk of death or non-fatal MI was 18.4% for the CABG arm
..
of patients undergoing CABG.272 . and 25.3% for the PCI arm (HR 0.89, 95% CI 0.47–1.71, P <0.05).154
120 ESC/EACTS Guidelines

In the CARDia (Coronary Artery Revascularization in Diabetes)


.. high SYNTAX score. A network meta-analysis had suggested that the
..
trial, 510 patients with diabetes and multivessel or complex single- .. survival benefit of CABG over PCI in patients with diabetes might be
vessel CAD were randomly assigned to either CABG or PCI, with
.. lost when using EES,151 though this was not confirmed in a subse-
..
the use of either BMS or DES and routine use of abciximab.156 There .. quent meta-analysis that also included the direct comparison
..
were no differences between CABG and PCI for the primary end- between EES and CABG in the subset of BEST.153
...
point of 1 year composite of death, MI, or stroke, but the trial was .. In a collaborative, individual patient data pooled analysis of 11 518
underpowered to detect these differences. However, repeat revas- .. patients with multivessel or LM disease randomized to CABG or PCI
..
cularization was more likely to occur in patients treated with PCI .. with stents, all-cause death was significantly different after CABG
(P <0.001).156 .. (9.2%) and PCI (11.2%) (P = 0.0038), which was evident in patients
..
In the subset of 452 patients with diabetes and multivessel CAD .. with diabetes (10.7 vs. 15.7%, respectively; P = 0.0001) but not in
who were enrolled in the SYNTAX trial, there were no differences .. patients without diabetes (8.4 vs. 8.7%, respectively; P = 0.81)
..
in the composite safety endpoint of all-cause death, stroke, and MI at .. (Pinteraction = 0.0077).124 Similar results were found in the subgroup of

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5 year follow-up.155 However, the need for repeat revascularization .. 7040 patients with multivessel disease (Pinteraction = 0.0453), while the
..
(HR 2.01, 95% CI 1.04–3.88, P <0.001) was significantly more fre- .. interaction with diabetes was not significant in the 4478 patients with
quent in patients with diabetes treated with PCI than in those who .. LM disease (Pinteraction = 0.13).
..
underwent CABG.155,275 Patients with diabetes had a higher rate of .. A recent population-based analysis has confirmed the benefit of
repeat revascularization after PCI when compared with CABG in the .. CABG compared with PCI in patients with diabetes when patients
..
low (<_22) (38.5 vs. 18.5%, respectively, P = 0.014) and intermediate .. present with an ACS.196 Consequently, overall current evidence con-
(23 - 33) (27 vs. 13.4%, respectively, P = 0.049) SYNTAX score ter-
.. tinues to favour CABG as the revascularization modality of choice
..
tiles. Further analyses according to treatment with either oral hypo- .. for patients with diabetes and multivessel disease. When patients
glycaemic agents or insulin showed that the MACCE rate was
.. present with a comorbidity that increases surgical risk, the choice of
..
significantly greater after PCI in both the oral hypoglycaemic agent .. revascularization method is best decided by multidisciplinary individu-
group (PCI 40.4 vs. CABG 26.4%, P = 0.022) and the insulin-
.. alized risk assessment.
..
dependent group (PCI 56.2 vs. CABG 32.6%, P = 0.002). A higher ..
incidence of cardiac death was noted in the insulin-dependent
..
.. 9.3 Revascularization with the use of
patients treated with PCI (PCI 18.8 vs. CABG 7.1%, P = 0.023). ..
.. percutaneous coronary intervention
In the SYNTAX trial, diabetes was not an independent predictor ..
of outcomes once the SYNTAX score was entered into the multi- .. For the reasons discussed above, PCI in patients with diabetes is
.. often more complex than PCI in the absence of diabetes.
variable model.127 Consequently, the SYNTAX 2 score does not ..
include diabetes as one of the eight variables that impacts on the pref- .. Nevertheless, irrespective of diabetic status, the same principles
.. apply as discussed in section 16. Placement of a new-generation DES
erential selection of revascularization modality.127 Conflicting data ..
were seen in a patient-level pooled analysis of 6081 patients treated .. is the default strategy.
..
with stents (75% newer generation DES), stratified according to dia- ..
betes status and SYNTAX score.157 After Cox regression adjust- .. 9.4 Antithrombotic pharmacotherapy
..
ment, SYNTAX score and diabetes were both associated with .. In the current context of the use of oral P2Y12-inhibitors, there is no
MACE (P <0.001 and P = 0.0028, respectively). At 2 years, patients ..
.. indication that antithrombotic pharmacotherapy should differ
with diabetes had higher MACE (HR 1.25, 95% CI 1.03–1.53, P = .. between diabetics and patients without diabetes who are undergoing
0.026) and TVR, and similar death and MI rates.157 ..
.. revascularization. For detailed discussion refer to section 17.
In the BEST trial, patients with diabetes treated with PCI had a ..
higher rate of the primary endpoint of death, MI, or TVR compared ..
.. 9.5 Metformin
with CABG (EES: n=177; CABG: n=186) (19.2 vs. 9.1%, P = 0.007) ..
(see section 5).105
.. There is a theoretical risk of lactic acidosis and deteriorating renal
..
.. function in patients treated with metformin who are exposed to iodi-
.. nated contrast media.280 Consequently, it is generally recommended
..
9.2.2 Meta-analysis of coronary artery bypass grafting vs. .. that in elective cases, metformin should be withheld before angiogra-
percutaneous coronary intervention in patients with .. phy or PCI for 48 h, as the plasma half-life of metformin is 6.2 h,280
..
diabetes .. and reintroduced 48 h later. However, clinical experience suggests
A meta-analysis—restricted to four RCTs covering 3052 patients- .. that the actual risk of lactate acidosis is very small, and that checking
..
compared PCI with the use of early-generation DES vs. CABG in .. renal function after angiography in patients on metformin and with-
patients with diabetes and multivessel CAD. It suggested a higher risk .. holding the drug when renal function deteriorates appears to be an
..
of death and MI with revascularization by early-generation DES (RR .. acceptable alternative.280 In patients with renal failure, metformin
1.51, 95% CI 1.09–2.10; P <0.01), but a lower risk of stroke (2.3 vs. .. should be stopped before the procedure. Accurate recognition of
..
3.8%; RR 0.59, 95% CI 0.39– 0.90; P <0.01).152 A sensitivity analysis .. metformin-associated lactic acidosis based on arterial pH <7.35,
revealed that this superiority of CABG over early-generation DES for
.. blood lactate >5 mmol/L (45 mg/dL), and detectable plasma metfor-
..
the endpoint MACCE was most pronounced among patients with a . min concentration should prompt the initiation of haemodialysis.
ESC/EACTS Guidelines 121

..
Recommendation for patients on metformin
.. 10.3 Gaps in the evidence
.. Thus far, patients with CKD have been excluded from randomized
... trials on myocardial revascularization, hence current data are based
Recommendation Classa Levelb ..
.. on observational studies only. A randomized trial on optimal long-
.. term revascularization strategies in patients with moderate-to-severe
It is recommended to check renal function if ..
patients have taken metformin immediately .. stress-induced ischaemia and severe CKD is currently ongoing
I C ..
before angiography and withhold metformin .. (ISCHEMIA-CKD, https://clinicaltrials.gov/ct2/show/NCT01985360).
if renal function deteriorates. .. Moreover, additional randomized evidence on optimal strategies for
..
. CIN prevention is needed.
a
Class of recommendation.
b
Level of evidence. Recommendations for the prevention of contrast-
induced nephropathy

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Recommendations Dose Classa Levelb

Patients undergoing coronary angiography or MSCT


9.6 Gaps in the evidence
Following successful revascularization, the rate of events during It is recommended that all
follow-up remains high in patients with diabetes, independent of the patients are assessed for
I C
mode of revascularization. Future research should be focused on the risk of contrast-
identifying new disease-modifying therapies to influence the progres- induced nephropathy.
sion of vascular disease in this high-risk cohort.
Adequate hydration is
I C
recommended.

10 Revascularization in patients Patients with moderate or severe CKD (National


Kidney Foundation stages 3b and 4)
with chronic kidney disease
Use of low-osmolar or
10.1 Evidence base for revascularization iso-osmolar contrast
I A
and recommendations media is
Myocardial revascularization in patients with chronic kidney disease recommended.284–286
(CKD), specifically National Kidney Foundation stage 3 or higher, is
It is recommended that Total contrast
addressed by the 2014 ESC/EACTS Guidelines on myocardial revas-
the volume of contrast volume/GFR
cularization. After reviewing the subsequent literature, the current I B
media be <3.7.c
Task Force has not found any evidence to support a major update. A
minimized.287,288
recent post hoc analysis of the SYNTAX trial on patients with CKD
confirms the principles for allocating patients to PCI or CABG,281 as In statin-naı̈ve patients, Rosuvastatin
discussed in section 5 of this document. pre-treatment with high- 40/20 mg or
IIa A
dose statins should be atorvastatin 80
10.2 Prevention of contrast-induced considered.293 mg.

nephropathy Pre- and post-hydration 1 mL/kg/h 12 h


The risk of contrast-induced nephropathy (CIN) depends on patient- with isotonic saline should before and con-
related factors, such as CKD, diabetes mellitus, congestive HF, hae- be considered if the tinued for 24 h
modynamic instability, reduced plasma volume, female sex, advanced expected contrast volume after the proce-
IIa C
age, anaemia, and periprocedural bleeding, as well as on the type and is >100 mL. dure (0.5 mL/
volume of contrast administered.282–288 When the ratio of total con- kg/h if LVEF
trast volume (in mL) to glomerular filtration rate (in mL/min) exceeds <_35% or
3.7, the risk of CIN increases significantly.287,288 NYHA >2).
Adequate hydration remains the mainstay of CIN pre-
As an alternative to the
vention.289–294 High-dose statins, as indicated for secondary preven-
pre- and post- hydration
tion irrespective of the risk of CIN are also beneficial.293 All other
regimen, tailored hydra- IIb B
strategies for the prevention of CIN do not have sufficient evidence
tion regimensd may be
to justify a recommendation in favour or against.293,294 For more
considered.295–297
detailed discussion refer to the Supplementary Data.
Continued
122 ESC/EACTS Guidelines

..
Patients with severe CKD (National Kidney Foundation .. 11.2 Primary indication for myocardial
.. revascularization
stage 4) ..
.. 11.2.1 Aortic valve disease
Prophylactic haemofiltra- Fluid replace- ..
.. The recommendations for patients undergoing CABG for the clini-
tion 6 h before complex ment rate 1000 .. cally leading problem of CAD, who also have coexisting severe aortic
PCI may be mL/h without ..
.. stenosis or regurgitation, remain unchanged from those of the 2014
considered.298–300 negative loss .. Guidelines and support replacement of the aortic valve.305 However,
and saline IIb B ..
.. in the current era of rapid developments in transcatheter valve
hydration con- .. implantation technologies, a decision regarding replacement of the
tinued for 24 h ..
.. aortic valve for moderate stenosis/regurgitation should be carefully
after the .. considered on a case-by-case basis in discussion with the Heart
procedure. ..
.. Team. The patient’s age, type of prosthesis, pathogenesis of aortic

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.. stenosis/regurgitation, aortic annular size, predicted size of implanted
Haemodialysis is not rec- ..
ommended as a preven- III B .. valve, transcatheter aortic valve implantation (TAVI) access routes,
.. and technical feasibility of a TAVI procedure in the future in case of
tive measure.300,301 ..
.. disease progression should all be taken into account.306
..
CKD = chronic kidney disease; GFR = glomerular filtration rate; LVEF = left ven- ..
tricular ejection fraction; MSCT = multi-slice computed tomography; NYHA = ..
New York Heart Association; PCI = percutaneous coronary angiography. .. 11.2.2 Mitral valve disease
a
Class of recommendation.
.. Patients with concomitant severe primary mitral regurgitation (MR)
b ..
c
Level of evidence. .. should undergo mitral valve repair at the time of CABG in keeping
Example: 370 mL of contrast medium in a patient with a GFR of 100 mL/min will .. with guidance for the surgical repair of primary MR.305 There is also
yield a ratio of 3.7. ..
d
Options are: infusion of normal saline adjusted to central venous pressure295 or .. consensus based on expert opinion on the surgical repair of severe
furosemide with matched infusion of normal saline296,297 (for details see the .. secondary MR at the time of CABG.305,307 However, considerable
Supplementary Data). ..
.. controversy exists about the treatment of moderate secondary or
.. ischaemic MR in patients undergoing CABG. Until the publication of
..
.. 2 year outcomes of the CTSN (Cardiothoracic Surgical Trials
.. Network) randomized trial on treatment of ‘moderate’ ischaemic
11 Revascularization in ..
.. MR, the literature in this field was limited to small single-centre
patients requiring valve .. randomized trials, observational studies, and case series, and failed to
..
interventions .. provide clear direction. The CTSN trial showed that addition of sur-
.. gical mitral valve repair to CABG made no significant difference to
..
11.1 Primary indication for valve .. survival, overall reduction of adverse events, or LV reverse remodel-
.. ling at 2 years.308,309 Increased length of intensive care and hospital
interventions ..
Myocardial revascularization in patients undergoing primary valve .. stay and perioperative morbidity, including neurological complica-
.. tions and supraventricular arrhythmias, were reported in the CTSN
interventions, either by surgery or transcatheter routes, is addressed ..
by the 2014 ESC/EACTS Guidelines on myocardial revascularization.
.. and other randomized trials in this group of patients.308–310 Because
.. the CTSN trial used a very broad definition of moderate MR, includ-
After reviewing the subsequent literature, the current Task Force ..
endorses the recommendations of the 2014 Guidelines and has not
.. ing an effective regurgitant orifice area (EROA) <_0.2 cm2 plus addi-
..
found any evidence to support a major update. These recommenda- .. tional criteria, no firm conclusions can be drawn concerning patients
tions are included below for ease of reference. Of note, the available
.. with an EROA >0.2 cm2. Observational data suggest that in secon-
..
evidence on invasive functional assessment of CAD (with FFR or .. dary MR, an EROA >0.2 cm2 and regurgitant volume >30 mL indi-
iwFR) in patients with severe aortic stenosis (AS) is limited to a few
.. cates greater risk of cardiovascular events.311,312 In the absence of
..
small-scale observational studies. These studies support the feasibility .. dedicated trials in this setting, the decision to combine mitral valve
.. surgery with CABG in patients with an EROA >0.2 cm2 and regurgi-
of FFR and iwFR in this setting.302–304 Notwithstanding, the available ..
evidence is insufficient to support the use of invasive functional .. tant volume >30 mL needs to be made on a case-by-case basis by the
.. Heart Team. For a more detailed discussion of this issue, please refer
assessment of coronary lesions in patients with AS, particularly in ..
consideration of the altered haemodynamic condition related to the .. to the Supplementary Data.
..
presence of AS. Therefore, the Task Force is in consensus that indica- ..
tions for myocardial revascularization based on angiographic assess- .. 11.3 Gaps in the evidence
..
ment of CAD should be maintained, consistent with the 2014 ESC/ .. In patients with concomitant valvular and coronary disease, the possi-
EACTS Guidelines on myocardial revascularization and the 2017 .. bility of future transcatheter therapy for the aortic and mitral valves
..
ESC/EACTS Guidelines for the management of valvular heart .. has made a significant impact on decision-making for patients with
disease.305 .. predominantly coronary disease with moderate valve lesions.
..
. However, there is currently little evidence on this topic. The need
ESC/EACTS Guidelines 123

..
for and timing of PCI in patients undergoing TAVI is also an area with .. 12 Associated peripheral artery
limited evidence. The long-term outcomes of patients with concomi-
..
.. diseases
tant surgical repair of ischaemic MR are also awaited. ..
..
.. 12.1 Prevention of stroke associated with
..
.. carotid artery disease and myocardial
Recommendations for combined valvular and coronary ..
interventions .. revascularization
.. The early risk of stroke after myocardial revascularization is higher
..
Recommendations Classa Levelb
.. after CABG than after PCI.313 After 30 days, stroke rates between
.. revascularization techniques were similar in a recent individual
..
Primary valve intervention and coro- .. patient data meta-analysis of 11 randomized trials.313
nary revascularization ..
.. Ischaemic stroke after CABG is multifactorial: thrombo-embolism

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.. from the aorta, its branches, or the heart; atrial arrhythmias; inflam-
CABG is recommended in patients with a ..
primary indication for aortic/mitral valve .. matory pro-thrombogenic milieu; lower levels of antiplatelet therapy
I C .. perioperatively; and haemodynamic instability. However, the most
surgery and coronary artery diameter ..
stenosis >70%. .. consistent predictor of perioperative stroke is previous stroke or
.. TIA. There is no strong evidence that carotid artery stenosis is a sig-
CABG should be considered in patients
..
.. nificant cause of perioperative stroke except for bilateral severe car-
with a primary indication for aortic/mitral .. otid bifurcation stenosis.314 Therefore, indications for preoperative
IIa C ..
valve surgery and coronary artery diameter .. carotid bifurcation screening by duplex ultrasound are limited.315
stenosis of 50–70%. .. Also, there is no evidence that prophylactic revascularization of uni-
..
PCI should be considered in patients with a
.. lateral asymptomatic carotid stenoses in CABG candidates reduces
.. the risk of perioperative stroke. It may be reasonable to restrict pro-
primary indication to undergo TAVI and ..
coronary artery diameter stenosis >70% in
IIa C .. phylactic carotid revascularization to patients at highest risk of post-
.. operative stroke, i.e. patients with severe bilateral lesions or a history
proximal segments. ..
.. of prior stroke/TIA.316 Hence, the indication for revascularization,
PCI should be considered in patients with a .. and the choice between carotid endarterectomy or carotid artery
..
primary indication to undergo transcatheter .. stenting in these patients, should be made by a multidisciplinary team
mitral valve interventions and coronary IIa C ... including a neurologist.
artery diameter stenosis >70% in proximal
.. The 2017 Guidelines on the diagnosis and treatment of peripheral
..
segments. .. arterial diseases in collaboration with the European Society of
.. Vascular Surgery cover the screening for and management of carotid
Primary myocardial revascularization ..
.. artery disease in patients scheduled for CABG, including screening,
and valve intervention ..
.. indications, and the timing and type of carotid revascularization.317 Its
SAVR is indicated in patients with .. recommendations are reproduced here.
..
severe AS undergoing CABG, or
I C .. Particularly for patients at high risk for perioperative stroke after
surgery of the ascending aorta or .. CABG, such as elderly patients or patients with previous TIA/stroke,
..
another valve. .. specific preventive measures have been suggested. CT scan screening
.. of the ascending aorta/arch atheroma has been proposed to better
Mitral valve surgery is indicated in patients ..
I C
.. assess risk stratification and guide the surgical strategy in elderly
with severe secondary MR undergoing .. patients.318 It is recommended that acetylsalicylic acid is restarted 6
CABG and LVEF >30%. ..
.. h, or at the latest 24 h, after surgery, and that clopidogrel or ticagrelor
Mitral valve surgery should be considered in
.. are added in patients with ACS. New-onset atrial fibrillation (AF) is
..
symptomatic patients with severe secondary .. associated with a risk of stroke that increased two-to-three times
MR and LVEF <30%, but with evidence of IIa C
.. after CABG. Its management is discussed in section 14.
..
myocardial viability and an option for surgi- ..
cal revascularization.
.. 12.2 Associated coronary and peripheral
..
.. artery diseases
..
AS = aortic stenosis; CABG = coronary artery bypass grafting; LVEF = left ven- .. Of all patients with CAD, 7–16% have lower extremity artery disease
tricular ejection fraction; MR = mitral regurgitation; PCI = percutaneous coronary .. (LEAD), which is associated with a worse prognosis, even if it remains
intervention; SAVR = surgical aortic valve replacement; TAVI = transcatheter ..
aortic valve implantation. .. frequently asymptomatic, masked by cardiac symptoms. On the
a
Class of recommendation.
.. other hand, in patients with LEAD, CAD is present in up to 70% of
b ..
Level of evidence. .. patients.317 The choice between CABG and PCI is controversial and,
.. in the absence of solid data, it should follow a multidisciplinary
124 ESC/EACTS Guidelines

approach.127 In patients undergoing CABG, the saphenous vein


Preoperative strategies to reduce the incidence of
should be preserved or harvested guided by the results of clinical
stroke in patients undergoing coronary artery bypass
examination including the ankle-brachial index. In addition, inter-arm grafting
blood pressure asymmetry should lead to the investigation of subcla-
vian artery stenosis. Further details are provided in the 2017 periph-
Recommendations Classa Levelb
eral arterial diseases Guidelines.317
In patients undergoing CABG, carotid DUS
Recommendations on the management of carotid is recommended in patients with recent (<6 I B
stenosis in patients undergoing coronary artery bypass
months) history of stroke/TIA.321,322
grafting
In patients with no recent (<6 months) his-
Recommendations Classa Levelb tory of TIA/stroke, carotid DUS may be

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considered before CABG in the following
In patients scheduled for CABG, it is recom- IIb B
cases: age >_70 years, multivessel coronary
mended that the indication (and if so the
artery disease, concomitant LEAD, or caro-
method and timing) for carotid revasculari-
I C tid bruit.321,322
zation be individualized after discussion
within a multidisciplinary team, including a Screening for carotid stenosis is not indi-
neurologist. cated in patients requiring urgent CABG III C
with no recent stroke/TIA.
In patients scheduled for CABG, with recent
(<6 months) history of TIA/stroke:
CABG = coronary artery bypass grafting; DUS = duplex ultrasound; LEAD =
• Carotid revascularization should be con- lower extremity artery disease; TIA = transient ischaemic attack.
a
sidered in patients with 50 - 99% carotid Class of recommendation.
IIa B b
Level of evidence.
stenosis.319,320
• Carotid revascularization with CEA
should be considered as first choice in
patients with 50 - 99% carotid IIa B
stenosis.319,320 ..
.. 13 Repeat revascularization
• Carotid revascularization is not recom- ..
mended in patients with carotid stenosis ..
III C .. 13.1 Early graft failure
<50%. ..
.. Early graft failure after CABG is reported in up to 12% of grafts, as
In neurologically asymptomatic patients .. evaluated by intraoperative angiography.323 However, only a minority
..
scheduled for CABG: .. (around 3%) are clinically apparent. Graft failure can be due to con-
• Carotid revascularization may be consid- .. duit defects, anastomotic technical errors, poor native vessel run-off,
..
ered in patients with bilateral 70 - 99%
IIb C
.. or competitive flow with the native vessel. When clinically relevant,
carotid stenosis or 70 - 99% carotid .. acute graft failure may result in MI with consequently increased mor-
..
stenosis and contralateral occlusion. .. tality and major cardiac events. The suspicion of early graft failure
• Carotid revascularization may be consid- .. should arise in the presence of ECG signs of ischaemia, ventricular
..
ered in patients with a 70 - 99% carotid .. arrhythmias, biomarker changes, new wall motion abnormalities, or
stenosis, in the presence of one or more .. haemodynamic instability.324,325 Owing to the low specificity of ECG
..
characteristics that may be associated IIb C .. changes and echocardiographic wall motion abnormalities during the
with an increased risk of ipsilateral stro-
.. post-operative course, and the delay in the appearance of biomarker
..
ke,c in order to reduce stroke risk .. changes, a careful assessment of all variables will influence decision-
beyond the perioperative period.
..
.. making for angiographic evaluation.
• Routine prophylactic carotid revasculari- ... Perioperative angiography is recommended in cases of suspected
zation in patients with a 70 - 99% carotid III C
.. severe myocardial ischaemia to detect its cause and aid decision-
..
stenosis is not recommended. .. making on the most appropriate treatment.323,325,326 In symptomatic
.. patients, early post-operative graft failure can be identified as the
..
CABG = coronary artery bypass grafting; CEA = carotid endarterectomy; TIA = .. cause of ischaemia in 40 - 80% of cases.324,326–328 The optimal treat-
transient ischaemic attack. .. ment strategy in patients with acute graft failure should be decided by
a
Class of recommendation. ..
b
Level of evidence. .. ad hoc consultation between the cardiovascular surgeon and the
c
Contralateral TIA/stroke, ipsilateral silent infarction on cerebral imaging, intraplaque .. interventional cardiologist, on the basis of the patient’s clinical condi-
haemorrhage or lipid-rich necrotic core on magnetic resonance angiography, or any of
..
.. tion and the extent of myocardium at risk. In the case of early post-
the following ultrasound imaging findings: stenosis progression (>20%), spontaneous .. operative graft failure, emergency ad hoc PCI may limit the extent of
embolization on transcranial Doppler, impaired cerebral vascular reserve, large pla- ..
ques, echolucent plaques, or increased juxta-luminal hypoechogenic area.317 .. infarction, if technically feasible. The target for PCI is the native vessel
.. or the internal mammary artery (IMA) graft, while the acutely
..
ESC/EACTS Guidelines 125

..
occluded saphenous vein graft (SVG) and any anastomotic site should .. The IMA is the conduit of choice for revascularization during redo
be avoided, if possible, due to concerns regarding embolization or .. CABG if not previously used, or can be salvaged and reused in spe-
..
perforation. Redo surgery should be favoured if the anatomy is .. cific cases.344,345
unsuitable for PCI, if several important grafts are occluded, or in the ..
..
case of clear anastomotic errors. In asymptomatic patients, repeat .. 13.3.2 Percutaneous coronary intervention for saphenous
revascularization should be considered if the artery is of an appropri- ..
.. vein graft lesions
ate size and supplies a large territory of myocardium. .. PCI in SVGs is associated with an increased risk of distal coronary
Further details on the diagnosis and management of perioperative ..
.. embolization, frequently resulting in periprocedural MI.346 PCI of de
MI are provided in a recent ESC position paper.329 .. novo SVG stenosis is considered a high-risk intervention because SVG
..
.. atheroma is friable and more prone to distal embolization. Several
13.2 Acute percutaneous coronary .. different approaches have been evaluated to prevent the distal embo-
..
intervention failure .. lization of particulate debris, including distal occlusion/aspiration,

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The need for urgent surgery to manage PCI-related complications is
.. proximal occlusion, suction, filter devices, or covered stents. Distal
..
uncommon (<1%) and only required in patients with major complica- .. protection devices using filters have shown the most encouraging
tions that cannot be adequately resolved by percutaneous techni-
.. results. However, although a single randomized trial supports the use
..
ques.330,331 The need for emergency CABG is mainly confined to .. of distal embolic protection during SVG PCI, observational studies
patients with a large, evolving MI due to iatrogenic vessel occlusion
.. including data from large-scale registries are conflicting.347–349
..
that cannot be salvaged percutaneously, or in patients with recurrent .. Outcomes from studies with other devices used for SVG PCI are not
.. sufficient to recommend its use.350–353
cardiac tamponade after pericardiocentesis following PCI-related ..
vessel rupture.330,332,333 .. Based on data from a small number of randomized trials, implanta-
.. tion of DES in SVG lesions is associated with a lower risk of repeat
..
13.3 Disease progression and late graft .. revascularization than with BMS at 1 year follow-up.354–356 In the
..
failure .. only trial powered for a clinical endpoint—the ISAR-CABG (Is Drug-
.. Eluting-Stenting Associated with Improved Results in Coronary
Ischaemia after CABG may be due to the progression of disease in ..
native vessels or de novo disease of bypass grafts.334 Repeat revascula- .. Artery Bypass Grafts) trial354—the primary endpoint of death, MI,
.. and target lesion revascularization was significantly reduced with DES
rization in these patients is indicated in the presence of significant ..
symptoms despite medical treatment, and in asymptomatic patients .. vs. BMS. However, at 5 year follow-up, the advantage of DES over
.. BMS was lost due to a higher incidence of target lesion revasculariza-
with objective evidence of large myocardial ischaemia (>10% of the ..
LV).32,87
.. tion between years 1 and 5 in patients treated with DES.357 Longer-
.. term follow-up of the two smaller trials is available; one suggested
..
.. sustained superiority of DES over BMS, while the other suggested
13.3.1 Redo coronary artery bypass grafting or .. loss of the efficacy advantage of the DES.358,359
percutaneous coronary intervention
..
..
PCI in patients with prior CABG has worse acute and long-term out- ..
comes than in patients without prior CABG.335,336 Likewise, redo
.. 13.4 Repeat percutaneous coronary
.. intervention
CABG has a two- to four-fold increased mortality compared with ..
first-time CABG, and repeat CABG is generally performed
.. Recurrence of symptoms or ischaemia after PCI is the result of reste-
.. nosis, incomplete initial revascularization, or disease progression.334
infrequently.334,337–339 There are limited data comparing the efficacy ..
of PCI vs. redo CABG in patients with previous CABG. The propor-
.. Patients may require repeat PCI due to late and very late stent
..
tion of patients undergoing PCI, redo CABG, or conservative treat- .. thrombosis.
..
ment differs significantly between studies; in one study, PCI was ..
favoured in 50% of patients with only 22% undergoing redo CABG, .. 13.4.1 Restenosis
..
while another study favoured CABG in 67% of patients.340,341 In the .. Restenosis associated with angina or ischaemia should be treated by
AWESOME (Angina With Extremely Serious Operative Mortality .. repeat revascularization, and repeat PCI remains the strategy of
..
Evaluation) RCT and registry, overall 3 year mortality was compara- .. choice for most of these patients. In this setting, the results from DES
ble between redo CABG and PCI.341,342 A more recent study also .. are superior to those obtained with balloon angioplasty, BMS implan-
..
found comparable rates of death and MI between redo CABG and .. tation, or brachytherapy.360–364
PCI, although there were significantly more repeat revascularizations .. For restenosis within BMS, drug-coated balloon (DCB) proved
..
with PCI.341,343 .. superior to plain balloon angioplasty365–367 and comparable to first-
In view of the higher risk of procedural mortality with redo CABG .. generation DES.365,366,368–372 One trial showed inferior angiographic
..
and the similar long-term outcome, PCI is the preferred revasculari- .. outcomes in comparison to new-generation DES,373 while a second
zation strategy in patients with amenable anatomy.340 PCI via the .. trial showed comparable outcomes.374 For restenosis within DES,
..
bypassed native artery should be the preferred approach. If PCI in .. DCBs also proved superior to plain balloon angioplasty367,369,371 and
the native vessel fails or is not an option, PCI in the diseased SVG .. comparable to first-generation DES.371 In one study, DCBs were infe-
..
should be considered. CABG should be considered for patients with .. rior to new-generation DES in terms of the primary angiographic out-
extensively diseased or occluded bypass grafts and diffuse native ves-
.. come measure.375 In a more recent study, including patients with any
..
sel disease, especially in the absence of patent arterial grafts.340 . type of in-stent restenosis, outcomes between DCB and repeat
126 ESC/EACTS Guidelines

stenting with new-generation DES were comparable.376 A single .. associated multivessel disease, especially in the presence of other
..
randomized trial of patients undergoing DCB for restenosis within .. complex lesions such as chronic total occlusions—CABG should be
DES showed superior angiographic outcomes in patients who under-
.. considered before a new PCI attempt.
..
went lesion preparation with scoring balloons vs. standard angio- ..
plasty balloons.377
..
.. 13.4.2 Disease progression
Network meta-analysis suggests that repeat stenting with new- ..
generation DES (with EES) and DCB are ranked first and second as
.. Patients with symptomatic disease progression after PCI account for
.. up to 50% of reinterventions.383,384 They should be managed using
the highest efficacy treatments.378,379 The superior angiographic anti- ..
restenotic efficacy of new-generation DES should be weighed against
.. criteria similar to those applied to patients without previous
.. revascularization.
a possible excess of long-term adverse events with repeat stenting ..
..
during longer-term follow-up of these trials.380,381 However, obser- ..
vations in relation to clinical events must be interpreted with caution, .. 13.4.3 Stent thrombosis
..

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as none of the trials was powered for clinical endpoints and the com- .. Although stent thrombosis is very rare, particularly since the advent of
parator stent in studies with long-term follow-up was an early- .. new-generation DES, it may have devastating clinical consequences.
..
generation DES. .. Stent thrombosis usually presents as a large MI and patients should be
The use of intracoronary imaging provides unique insights into the .. treated according to the principles outlined in section 8.385 Aggressive,
..
underlying mechanisms of in-stent restenosis (see section 16.2). .. high-pressure balloon dilation should be used to correct underlying,
OCT is able to detect the presence of neoatherosclerosis in a signifi- .. stent-related, predisposing mechanical problems.386,387 Liberal use of
..
cant number of these patients. Underexpanded stents should be .. intracoronary imaging in order to detect and modify underlying
aggressively tackled with high-pressure dilatations using non- .. mechanical factors is recommended (Figure 7) (see section 16.2).
..
compliant balloons. The optimization of the final results remains cru- .. Although repeat stenting in patients with stent thrombosis may be
cial during reinterventions for in-stent restenosis and, in this regard, .. avoided when satisfactory results are obtained with balloon dilation,
..
the use of intracoronary imaging may be particularly helpful. .. a new stent may be required to overcome edge-related dissections
Outcomes of patients with in-stent restenosis after DES are poorer .. and adjacent lesions, or to optimize final results.388
..
than those in patients with BMS in-stent restenosis, independently of .. There is no evidence that the post-interventional management of
the therapeutic modality.382 In patients with recurrent episodes of
.. patients with stent thrombosis should differ from that of patients
..
diffuse in-stent restenosis in large vessels—and in those with . with thrombosis of a de novo lesion resulting in STEMI.

Figure 7 Intracoronary imaging for the assessment of stent failure.


ESC/EACTS Guidelines 127

Recommendations on repeat revascularization

Recommendations Classa Levelb

Early post-operative ischaemia and graft failure

Coronary angiography post-CABG is recommended for patients with:


• symptoms of ischaemia and/or abnormal biomarkers suggestive of perioperative MI
• ischaemic ECG changes indicating large area of risk I C
• new significant wall motion abnormalities
• haemodynamic instability.

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It is recommended that either emergency reoperation or PCI is decided upon by ad hoc consultation in the Heart
I C
Team, based on the feasibility of revascularization, area at risk, comorbidities, and clinical status.

Disease progression and late graft failure

Repeat revascularization is indicated in patients with a large area of ischaemia or severe symptoms despite medical
I B
therapy.84,334

If considered safe, PCI should be considered as first choice over CABG. IIa C

Procedural aspects of the revascularization modalities

CABG

IMA is the conduit of choice for redo CABG in patients in whom the IMA was not used previously.344 I B

Redo CABG should be considered for patients without a patent IMA graft to the LAD.340,341,344 IIa B

PCI

Distal protection devices should be considered for PCI of SVG lesions.348,350,351 IIa B

PCI of the bypassed native artery should be considered over PCI of the bypass graft. IIa C

Restenosis

DES are recommended for the treatment of in-stent restenosis of BMS or DES.373,375,378,379 I A
373,375,378,379
Drug-coated balloons are recommended for the treatment of in-stent restenosis of BMS or DES. I A

In patients with recurrent episodes of diffuse in-stent restenosis, CABG should be considered by the Heart Team over
IIa C
a new PCI attempt.

IVUS and/or OCT should be considered to detect stent-related mechanical problems leading to restenosis. IIa C

BMS = bare-metal stent; CABG = coronary artery bypass grafting; DES = drug-eluting stent; ECG = electrocardiogram; IMA = internal mammary artery; IVUS = intravascular
ultrasound; LAD = left anterior descending artery; MI = myocardial infarction; OCT = optical coherence tomography; PCI = percutaneous coronary intervention; SVG = saphe-
nous vein graft.
a
Class of recommendation.
b
Level of evidence.

14 Arrhythmias .. patients with CAD and LVEF <_35%.391 Indirect evidence for a pro-
..
.. tective effect of revascularization was demonstrated in the MADIT II
14.1 Ventricular arrhythmias ..
.. (Multicenter Automatic Defibrillator Implantation Trial II) and SCD-
14.1.1 Revascularization for the prevention of sudden .. HEFT studies (Sudden Cardiac Death in Heart Failure Trial), where
cardiac death in patients with stable coronary artery ..
.. the efficacy of implantation cardioverter defibrillators (ICDs) was
disease and reduced left ventricular function .. reduced if revascularization was performed prior to implanta-
..
Revascularization plays an important role in reducing the frequency .. tion.392,393 CABG in patients with reduced EF reduces cardiac and
of ventricular arrhythmias in patients with normal or mildly reduced .. overall mortality for a follow-up of 10 years.78,81 In view of the pro-
LV function,389,390 as well as the risk of sudden cardiac death in
..
.. tective effect of revascularization on ventricular arrhythmias, patients
.
128 ESC/EACTS Guidelines

..
with ischaemic LV dysfunction (LVEF <_35%) who are considered for .. impaired prognosis and a more than doubling of the risk of death,
primary preventive ICD implantation should be evaluated for ischae- .. congestive HF, and stroke.403
..
mia and/or for potential revascularization targets. .. The use of oral anticoagulation (OAC) for stroke prevention in
.. patients with AF occurring during or after PCI should follow the ESC
..
14.1.2 Revascularization for the treatment of electrical .. Guidelines on Atrial Fibrillation for antithrombotic treatment of AF
storm
.. that occurs outside the setting of PCI,405 although prospective stud-
..
Electrical storm is a life-threatening syndrome related to incessant .. ies are scarce. The combination and duration of anticoagulation and
ventricular arrhythmias, which is most frequently observed in
.. antiplatelet therapy should be assessed according to the clinical situa-
..
patients with ischaemic heart disease, advanced systolic HF, valve dis- .. tion, as outlined in section 17 as well as in the ESC Guidelines on
ease, corrected congenital heart disease, and genetic disorders such
.. Atrial Fibrillation405 and the ESC Focused Update on Dual
..
as Brugada syndrome, early repolarization, and long QT syn- .. Antiplatelet Therapy.410
..
drome.394 Urgent coronary angiography and revascularization should ..

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be part of the management of patients with electrical storm, as well ..
..
as antiarrhythmic drug therapy and/or ablation of ventricular .. 14.2.2 Atrial fibrillation complicating coronary artery
tachycardia. .. bypass grafting
..
.. Post-operative AF affects one-third of patients undergoing cardiac
14.1.3 Revascularization after out-of-hospital cardiac
.. surgery.411–414 The main risk factor for post-operative AF is age, and
..
arrest .. it is associated with an increased immediate risk of stroke, increased
Approximately 70% of survivors of out-of-hospital cardiac arrest
.. morbidity, and 30 day mortality.415–417 In the long-term, patients
..
have CAD, with acute vessel occlusion observed in 50%.395 Multiple .. with an episode of post-operative AF have a two-fold increase in car-
non-randomized studies suggest that emergency coronary angiogra-
.. diovascular mortality, and a substantially increased risk of future AF
..
phy and, if appropriate, PCI after out-of-hospital cardiac arrest yield a .. and ischaemic stroke compared with patients who remain in SR after
favourable survival rate of <_60% at 1 year, which is considerably
.. surgery.416,418–422
..
higher than the 25% overall survival rate in patients with aborted car- .. Post-operative AF is a common complication, in which prophylac-
..
diac arrest.396,397 More recent data suggest that almost one-quarter .. tic treatment has a moderate effect. Pre-operative anti-arrhythmic
of patients, resuscitated from cardiac arrest but without ST-segment .. drug treatment may be initiated but will have to be weighed against
.. side effects. Beta-blockers decrease the incidence of post-operative
elevation, show a culprit lesion (either vessel occlusion or irregular ..
lesion).398–401 Recent large-scale observational studies have shown .. AF after CABG.412,423–429
..
an impact on mortality of early angiography after out-of-hospital car- ..
diac arrest.402,403 Thus, in survivors of out-of-hospital cardiac arrest, ..
..
early coronary angiography and PCI, if appropriate, should be per- .. 14.2.3 Post-operative atrial fibrillation and stroke risk
formed irrespective of the ECG pattern if no obvious non-cardiac .. Patients with post-operative AF have an increased stroke risk post-
..
cause of the arrhythmia is present.404 .. operatively as well as during follow-up,419,430 and warfarin medication
.. at discharge has been associated with a reduced long-term mortal-
..
14.2 Atrial arrhythmias .. ity.431 To date, there are no studies indicating that post-operative AF
The management of AF in patients with ischaemic heart disease is
..
.. is less harmful than any other form of AF, and good quality data are
addressed by the 2016 ESC Guidelines for the management of AF .. needed. Anticoagulation treatment with warfarin or non-vitamin K
developed in collaboration with EACTS.405 After reviewing the sub-
..
.. antagonist oral anticoagulants (NOACs) for stroke prevention in
sequent literature, the current Task Force endorses the recommen- .. patients with post-operative AF should therefore follow the guide-
dations of the 2016 Guidelines and has not identified a need for any
..
.. lines for the antithrombotic treatment of AF occurring outside the
major update. Accordingly, the recommendation tables are taken .. setting of CABG using the CHA2DS2-VASc [Cardiac failure,
from the 2016 Guidelines. For a detailed discussion, we refer to the
..
.. Hypertension, Age >_75 (Doubled), Diabetes, Stroke (Doubled) –
previous Guidelines.405 ... Vascular disease, Age 65–74 and Sex category (Female)] score. The
.. duration and timing of OAC in post-operative AF patients should be
..
14.2.1 Atrial fibrillation complicating percutaneous .. assessed individually.
coronary intervention .. Whether or not surgical left atrial appendage (LAA) obliteration
..
New-onset AF in patients undergoing PCI occurs in 2–6% of proce- .. reduces stroke risk has been studied in smaller trials and registry
dures and increases with age, pre-existing HF, AMI, and arterial .. studies with conflicting results,432–434 and is currently under investi-
..
hypertension.406–409 Notably, new-onset AF [defined as change from .. gation in a large randomized trial.435 Removal or closure of the LAA
sinus rhythm (SR) at admission to AF during/after PCI] typically
.. should be considered as an adjunct to anticoagulation and not as an
..
occurs during the first 4 days after AMI, and is associated with . alternative until more data are available.
ESC/EACTS Guidelines 129

Recommendations for the prevention of ventricular arrhythmias by revascularization

Recommendations Classa Levelb

A primary PCI strategy is recommended in patients with resuscitated cardiac arrest and an ECG consistent with
I B
STEMI.395,397,436,437

Urgent angiography (and PCI if indicated) should be considered in patients with resuscitated cardiac arrest without diagnostic
IIa C
ST-segment elevation but with a high suspicion of ongoing myocardial ischaemia.

In patients with electrical storm, urgent coronary angiography and revascularization (as required) should be considered. IIa C

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ECG = electrocardiogram; STEMI = ST-elevation myocardial infarction; PCI = percutaneous coronary intervention.
a
Class of recommendation.
b
Level of evidence.

Recommendations for the prevention and treatment of atrial fibrillation in the setting of myocardial revascularization

Recommendations Classa Levelb

Perioperative oral beta-blocker therapy is recommended for the prevention of post-operative AF after CABG surgery.412,438 I B

Restoration of sinus rhythm by electrical cardioversion or antiarrhythmic drugs is recommended in post-operative AF with hae-
I C
modynamic instability.

Perioperative amiodarone should be considered as prophylactic therapy to prevent AF after CABG surgery.412,439 IIa A

Long-term anticoagulation should be considered in patients with AF after CABG or PCI who are at risk of stroke, considering
IIa B
the individual stroke and bleeding risk.440,441

Rate control and anticoagulation should be considered as the initial management of asymptomatic post-operative AF.442 IIa B

Antiarrhythmic drugs should be considered for symptomatic post-operative AF after CABG or PCI in an attempt to restore
IIa C
sinus rhythm.

Surgical occlusion or exclusion of the LAA may be considered for stroke prevention in patients with AF undergoing CABG
IIb B
surgery.432–434

AF = atrial fibrillation; CABG = coronary artery bypass grafting; LAA = left atrial appendage; PCI = percutaneous coronary intervention.
a
Class of recommendation.
b
Level of evidence.

..
14.3 Gaps in the evidence .. Perioperative medication and blood management are covered in sep-
The duration of anticoagulation and their combination with antiplate-
.. arate Guidelines.410,444
..
let therapy in patients with new-onset AF after PCI or CABG has not ..
..
been studied sufficiently. Likewise, the role of routine left atrial exclu- .. 15.1 Surgical techniques
sion at surgery for the prevention of stroke is currently unclear. ..
.. 15.1.1 Completeness of revascularization
.. Current surgical practice is largely based on an anatomical definition
..
.. of complete revascularization, and aims to bypass all epicardial vessels
15 Procedural aspects of coronary .. with a diameter exceeding >_1.5 mm and a luminal reduction of >_50%
..
artery bypass grafting .. in at least one angiographic view.131 Depending on the definition of
.. completeness of revascularization, the outcome after CABG in
..
CABG remains the most common cardiac surgical procedure, and .. patients with incomplete revascularization was either similar445–449
the techniques have been refined during 50 years of evolution.443
.. or inferior131,132,449–451 to that of patients with complete
130 ESC/EACTS Guidelines

..
revascularization. Certainly, in some patients with a stenosis in small .. grafting should be considered in patients with a reasonable life
vessels with little myocardium at risk, complete revascularization may .. expectancy and a low risk of sternal wound complications.
..
not be necessary. .. The radial artery constitutes an alternative as the second arterial
FFR-guided surgical revascularization has been associated with .. graft in patients in whom BIMA grafting is not feasible, patients with a
..
improved graft patency, but more studies are needed to investigate .. high risk of sternal wound complications, or as a third arterial graft.
whether it improves clinical outcomes.28,452 Further discussion of .. There is a strong, adverse influence on radial artery patency when
..
FFR-guided revascularization is provided in sections 3.2.1.1 and .. the native coronary artery stenosis is <70%, and therefore its use
5.3.1.3. .. should be limited to coronary artery stenosis >70% and ideally
..
.. >90%.477 Use of the radial artery as the second conduit of choice has
.. been linked to improved survival in registry studies.478–480 Available
..
15.1.2 Conduit selection .. RCTs testing the radial artery vs. saphenous vein graft used angio-
.. graphic patency as the primary endpoint, and none was powered to
In addition to patient-related factors, the outcome following CABG ..

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is related to the long-term patency of grafts and therefore is maxi- .. detect differences in clinical outcomes.481 A recently published
..
mized with the use of arterial grafts, specifically the IMA.453,454 .. patient-level meta-analysis pooling six RCTs comparing radial artery
Except in rare circumstances, all patients should receive at least one .. vs. saphenous vein graft showed that the use of the radial artery was
..
arterial graft—the left IMA (LIMA)— preferentially to the LAD.453,455 .. associated with a lower rate of the primary endpoint (composite of
SVG patency rates for non-LAD targets have been reported to be .. death, myocardial infarction, and repeat revascularization) at mean
..
suboptimal.456 Bilateral IMA (BIMA) and radial artery for non-LAD .. follow-up of 50 months, mainly driven by a significantly strong reduc-
targets have been shown to provide better patency rates than SVG, .. tion of need for reintervention and a more modest reduction in sub-
..
particularly for the left coronary artery system.457 Therefore, a sec- .. sequent MI.482 Despite a significantly lower risk of occlusion at
ond arterial graft should be considered depending on the patient’s life .. follow-up angiography, no difference in all-cause mortality was found.
..
expectancy, risk factors for sternal wound complications, coronary ..
anatomy, degree of target vessel stenosis, graft quality, and surgical .. 15.1.3 Mammary artery harvesting
..
expertise. .. While the skeletonized technique of harvesting the IMA has a higher
Whether or not the use of additional arterial grafts can translate
.. theoretical potential for injury, the potential benefits include a longer
..
into prolonged survival remains debatable. Data from non- .. conduit, more versatility (sequential anastomosis), higher blood flow,
randomized studies suggest that the use of BIMA over single IMA
.. and fewer wound-healing problems.471,483–488 Therefore, in patients
..
(SIMA) use is associated with improved long-term survival, as well as .. at higher risk of sternal wound complications, skeletonization is
fewer non-fatal events such as MI, recurrent angina, and the need for
.. recommended.
..
re-operation.458–465 However, observational studies are subject to ..
selection bias, despite propensity matching, and the effect of pro-
.. 15.1.4 Radial artery harvesting
..
longed survival with additional arterial grafts has not been confirmed .. Radial artery harvesting is associated with negligible morbidity if pre-
..
in randomized trials.466 .. ceded by assessment of the hand’s collateral circulation. Endoscopic
The ART trial (Arterial Revascularization Trial) has been designed .. radial harvesting is possible, but robust evidence concerning its safety
..
to answer the question of whether BIMA can improve 10 year sur- .. and efficacy is scarce.489,490 Use of the radial artery after recent coro-
vival when compared with SIMA. Interim analysis showed no differ- .. nary angiography with radial access should be discouraged due to
..
ence at 5 years in the rate of death or the composite of death, MI, or .. potential endothelial damage.491 Harvesting of the whole radial artery
stroke, and 10 year results are warranted to draw final conclu- .. pedicle, together with the intraluminal and subadventitial injection of
..
sions.467 Limitations of the ART trial include a high crossover rate .. vasodilators, are useful steps to prevent spasm.
from the BIMA arm to the SIMA arm and a high rate of radial artery ..
..
use in the SIMA arm that may have diluted the benefit of .. 15.1.5 Saphenous vein harvesting
BIMA.468–470 The use of BIMA grafting is associated with an increase .. Saphenous vein harvesting can be accomplished using open and mini-
..
in sternal dehiscence, and an increased rate of mediastinitis in obese .. mally invasive techniques, which include interrupted incisions and
patients and patients with diabetes.458,464,471–475 In the ART trial, the .. partial or full endoscopic procedures. Endoscopic vein graft harvest-
..
use of BIMA was associated with a 1.0 - 1.5% absolute risk increase in .. ing leads to a reduced rate of leg wound complications,492–495 but
the need for sternal would reconstruction, and a subsequent subanal-
.. the short- and long-term patency of endoscopically harvested vein
..
ysis has found that this risk is minimized with skeletonized harvest- .. grafts, compared with openly harvested grafts, has been
ing.476 While we await the 10 year data of the ART trial, BIMA
.. challenged.456,496–498 Although there is no unequivocal evidence
ESC/EACTS Guidelines 131

concerning patency rates, most data from meta-analyses and .. 15.1.9 Minimally invasive and hybrid procedures
..
randomized and non-randomized trials do not demonstrate inferior .. Minimally invasive coronary surgery with LIMA, harvested either
clinical outcomes with endoscopic vein harvest.492,493,499,500 If an .. directly or under video-assisted vision, may represent an attractive
..
endoscopic vein graft harvest is performed, it should be undertaken .. alternative to a sternotomy.530 It has a similar safety and efficacy pro-
by experienced surgeons or physician assistants with appropriate
.. file to conventional on-pump and off-pump procedures, with a mark-
..
training and reasonable caseloads.501–503 If an open technique is used, .. edly reduced post-operative length of stay and an early quality of life
the ‘no-touch’ technique has shown superior patency rates in multi-
.. benefit, although spreading of the ribs is associated with increased
..
ple randomized trials,504–507 with a patency rate >80% after 16 .. post-operative pain.531–533 It has been shown to be safe and effective
years.507
.. in the treatment of proximal LAD stenosis or chronically occluded
..
.. LAD arteries.144 Moreover, when compared with PCI in a setting of
..
15.1.6 Cross-Clamping .. single-vessel proximal LAD disease, minimally invasive coronary sur-
.. gery was associated with less need for coronary reinterven-
..

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A single cross-clamp technique may be preferred to multiple manipu-
lations of the aorta, with the aim of reducing atheroembolic events,
.. tion.143,534,535 When combined with PCI to non-LAD vessels, it
.. provides the opportunity for hybrid coronary revascularization to be
but a strict no-touch technique most effectively reduces embolization ..
of atherosclerotic material.508–510 In cases of off-pump surgery, devi-
.. performed in selected patients with multivessel disease.536
.. Hybrid revascularization can be performed consecutively in a
ces that allow a clampless procedure may help reduce the incidence ..
of cerebral vascular complications.511,512
.. hybrid operating room, or sequentially on separate occasions in the
.. conventional surgical and PCI environments.537–540 In a small
..
.. randomized trial of 200 patients, 1 year and 5 year rates of death, MI,
15.1.7 Intraoperative quality control .. stroke, and major bleeding or repeat revascularization were not sig-
..
Besides continuous ECG monitoring and transoesophageal echocar- .. nificantly different between hybrid revascularization and
diography immediately after revascularization, intraoperative quality
.. CABG.536,541 Heart Team discussion and the prospective planning of
..
control may also include graft flow measurement to confirm or .. a joint strategy are critical for the success of a hybrid revascularization
exclude a technical graft problem.513 Transit-time flow measurement
.. strategy.542
..
is the most frequently used technique for graft assessment and has ..
been able to detect 2 - 4% of grafts that require revision.513,514
..
..
In observational studies, the use of intraoperative graft assessment .. 15.2 Reporting perioperative outcomes
has been shown to reduce the rate of adverse events and graft failure,
.. Perioperative reporting of outcomes after CABG procedures should
..
although interpretation can be challenging in sequential and T-graft .. be done on a risk-adjusted basis. The early risk period after CABG
.. extends up to 3 months, is multifactorial, and depends on the inter-
configurations.513,515–517 ..
.. face between technical variability and patient comorbidity.543
..
..
15.1.8 On-pump and off-pump procedures ..
Two large, international randomized trials have shown no difference .. 15.3 Gaps in the evidence
..
in 30 day or 1 year clinical outcomes between on- and off-pump sur- .. The role of FFR and iwFR in guiding surgical revascularization needs
gery when performed by experienced surgeons.518–520 There is also .. further investigation into whether it improves clinical outcomes.
..
evidence to conclude that, for most patients and surgeons, on-pump .. Likewise, there are insufficient data on the impact of intraoperative
surgery provides excellent short- and long-term outcomes.518,520–523 .. assessment of graft flow on outcomes.
..
For some surgeons, off-pump surgery is associated with inferior early .. In view of the limitations of observational studies comparing BIMA
and late graft patency rates, and possibly compromised long-term .. with SIMA and the limitations of the ART trial, the ROMA
..
survival; however, aortic no-touch/clampless off-pump procedures in .. (Randomization of Single vs. Multiple Arterial Grafts) trial is recruiting
the hands of highly trained teams appear to be associated with a .. to answer the question of whether the use of additional arterial con-
..
reduced risk of early morbidity, such as stroke, and fewer trans- .. duits (either BIMA or radial artery) translates into superior clinical
fusions.508–510,524–528 In the subgroup of patients with end-stage .. outcomes when compared with SIMA supplemented by SVG only.
..
CKD, there is some evidence that off-pump surgery is associated .. Hybrid procedures, which combine minimally invasive arterial
with lower in-hospital mortality and less need for new renal replace-
.. grafting with PCI, proved feasible and safe. However, multicentre
..
ment therapy.529 .. studies are required to prove the efficacy and superiority of this
A summary of these technical aspects can be found in Figure 8.
.. approach in stable, multivessel coronary disease.
132 ESC/EACTS Guidelines

Recommendations on procedural aspects of coronary artery bypass grafting

Recommendations Classa Levelb

General considerations

Complete myocardial revascularization is recommended.c 131,132 I B


508,509,544,545
Minimization of aortic manipulation is recommended. I B

Routine intraoperative graft flow measurement should be considered.516,517 IIa B

CT scans of the ascending aorta should be considered in patients over 70 years of age and/or with signs of extensive
IIa C

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generalized atherosclerosis.

Prior to aortic manipulation, epiaortic ultrasound should be considered to identify atheromatous plaques and select the
IIa C
optimal surgical strategy.

Conduit selection

Arterial grafting with IMA to the LAD system is recommended.453,454,546 I B

An additional arterial graft should be considered in appropriate patients.467,482,547–551 IIa B

The use of the radial artery is recommended over the saphenous vein in patients with high-grade coronary artery
I B
stenosis.d 482,549,550,552,553

BIMA grafting should be considered in patients who do not have a high risk of sternal wound infection.e 467,547,548,551 IIa B

Vessel harvesting

Skeletonized IMA dissection is recommended in patients with a high risk of sternal wound infection.471,484,485 I B

Endoscopic vein harvesting, if performed by experienced surgeons, should be considered to reduce the incidence of
IIa A
wound complications.490,493,494,500,554

No-touch vein harvesting should be considered when an open technique is used.506,507,555,556 IIa B

Minimally invasive techniques

Off-pump CABG and preferably no-touch techniques on the ascending aorta, by experienced operators, are recom-
I B
mended in patients with significant atherosclerotic aortic disease.508,509,544,557–559

Off-pump CABG should be considered for subgroups of high-risk patients by experienced off-pump teams.525,557–560 IIa B

Where expertise exists, minimally invasive CABG through limited thoracic access should be considered in patients with
IIa B
isolated LAD lesions or in the context of hybrid revascularization.143,534,535,561

Hybrid procedures, defined as consecutive or combined surgical and percutaneous revascularization, may be consid-
IIb B
ered in specific patient subsets at experienced centres.536,561–563

BIMA = bilateral internal mammary artery; CABG = coronary artery bypass grafting; CT = computed tomography; IMA = internal mammary artery; LAD = left anterior
descending coronary artery.
a
Class of recommendation.
b
Level of evidence.
c
Definitions of complete revascularization are provided in section 5.3.1.3.
d
Particularly in patients with poor vein grafts. The radial artery should not be used if previously catheterized, if the Allen test is positive or if calcific degeneration is present.
e
Patients with diabetes mellitus, chronic pulmonary obstructive disease, previous mediastinal radiation, and obesity, particularly when multiples of these are present.
ESC/EACTS Guidelines 133

Minimize aortic manipulation IB


Off-pump if calcified aorta IB
Off-pump if high-risk IIaB

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LIMA to LAD IB
BIMA if low risk of sternal
complications IIaB
Skeletonize if risk of
sternal complications IB

Complete revascularization IB
Graft flow measurement IIaB
ml/min
93 ml/min PI 1.3
180
160
140
120
100
80
60
40
20 Radial artery
0
-20
in high-grade
LITA- LAD DF 74%
stenosis IB

Endoscopic vein harvesting IIaA


No-touch vein harvesting IIaB
©ESC 2018

Figure 8 Technical aspects of CABG. BIMA = bilateral internal mammary artery; CABG = coronary artery bypass grafting; IMA = internal mam-
mary artery; LAD = left anterior descending coronary artery.

...
16 Procedural aspects of .. selected patients in whom implantation of stents is not technically
.. feasible, or in a vessel that is considered to be too small to be stented.
percutaneous coronary .. Balloon angioplasty is no longer preferred to stenting with DES for
..
intervention ..
..
patients who require urgent non-cardiac surgery as short-duration
.. DAPT may be reasonable with both strategies.565,566
16.1 Percutaneous coronary intervention ..
..
devices .. 16.1.2 Choice of coronary stents
16.1.1 Balloon angioplasty .. Stenting with BMS results in an approximately 30% lower rate of resteno-
..
Plain balloon angioplasty has been superseded in the treatment of de .. sis in comparison with plain balloon angioplasty.564 Although many efforts
novo coronary lesions after demonstration of the superiority of stent- .. have been made to further reduce restenosis by the modification of stent
..
ing in terms of the requirement for repeat revascularization.564 .. designs and materials, reducing the thickness of stent struts has been the
Balloon angioplasty might be considered for the treatment of .. only proven modification capable of reducing restenosis of BMS.567,568
134 ESC/EACTS Guidelines

..
A major reduction in the risk of restenosis has been achieved with .. of reducing or eliminating stent-related adverse events at long-term
DES technology. Early-generation DES released sirolimus569 or pacli- .. follow-up. Current scaffold platforms to have reached clinical testing
..
taxel570 from a permanent polymer matrix coating on a relatively .. are based on two different technologies: bioresorbable, polymer-
thick-strut (120–140 mm) stainless steel backbone. These devices .. based scaffolds (resorption up to 3–4 years) and resorbable, metallic
..
reduced angiographic and clinical restenosis by approximately .. (magnesium) scaffolds (resorption up to 1 year).595 Although a num-
50–70%, but increased the risk of very late stent thrombosis com- .. ber of devices have received approval for use in Europe (see
..
pared with BMS.336,571 .. Supplementary Table 7), randomized trial data are available only with
Early-generation DES have now been supplanted by new-generation .. the Absorb bioresorbable vascular scaffold (BVS) (Abbott Vascular).
..
DES. These stents represented an iterative development of early gener- .. The safety and efficacy profile of the Absorb BVS has been com-
ation technology, including polymers with enhanced biocompatibility .. pared with contemporary DES in several trials. Findings of these trials
..
(permanent or biodegradable), exclusively sirolimus-analogue active .. as well as meta-analyses consistently indicate the inferior efficacy and
drugs, and stent backbones with thin struts (50–100 mm) composed of .. safety of Absorb BVS compared with contemporary DES during
..

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stainless steel, cobalt chromium, or platinum chromium.572–577 New- .. long-term follow-up. Specifically, the Absorb BVS is associated with a
generation DES have higher efficacy and safety in comparison with both .. significantly increased risk of target lesion revascularization and
..
early-generation DES and BMS.336,571,578 Although stenting with new- .. device thrombosis, with numbers needed to harm of 40–60.596,597
generation DES confers a similar risk of death or MI at mid- to long-
.. Of note, commercial use of the Absorb BVS was stopped in 2017
..
term follow-up in comparison with BMS,579 the risk of subacute and late .. (for additional details see the Supplementary Data).
stent thrombosis is significantly lower.579,580 Moreover, the risk of very
.. Available evidence on the magnesium scaffold is limited to small
..
late stent thrombosis is at least comparable to that of BMS and lower .. observational studies. Initial results appear encouraging, but further
than that of early-generation DES.336,571,579,580 These observations
.. evaluation is needed. Therefore, the Task Force endorses the recom-
..
were confirmed in a recent trial enrolling patients aged 75 years or older .. mendation of the recent ESC/European Association for Percutaneous
..
and demonstrating superior outcomes (composite of all-cause mortal- .. Cardiovascular Interventions (EAPCI) document on bioresorbable
ity, MI, stroke, or ischaemia-driven target lesion revascularization) with .. scaffolds that any BRS should not be used outside well-controlled clin-
..
DES as compared with BMS with similar duration of intended DAPT (1 .. ical studies. In patients who have been treated with BRS, prolonged-
month or 6 months) in both treatment arms.581 Similarly, there is no .. duration DAPT for 3 years or longer may be considered.
..
clear evidence of a difference between DES and BMS on the risk of stent ..
thrombosis following unplanned disruption of DAPT.565 Accordingly, ..
.. 16.1.4 Drug-coated balloons
new-generation DES should be preferred to BMS for routine use. .. The rationale for using DCBs is based on the concept that with highly
A large number of new-generation DES have received approval ..
.. lipophilic drugs, even short contact times between the balloon surface
for use and CE mark in Europe.578 Supplementary Table 6 displays a .. and the vessel wall are sufficient for effective drug delivery. There are
list of new-generation DES with the CE mark and evidence from ..
.. various types of DCB that are approved for use in Europe and their
large-scale clinical trials powered for clinical primary endpoints. .. main characteristics are listed in Supplementary Table 8. Although spe-
Biodegradable polymer and polymer-free DES offer the potential to ..
.. cifically designed comparative randomized trials are lacking, a class effect
reduce late adverse events after PCI by eliminating inflammatory reac- .. for all DCBs cannot be assumed.598 Randomized trial data supporting
tions to permanent polymer coatings. A number of large-scale trials ..
.. the use of DCB angioplasty are limited to the treatment of in-stent
showed comparable efficacy and safety compared with permanent poly- .. restenosis (see section 13.4). In terms of the use of DCB angioplasty for
mer stents.575,576,582–590 However, at the moment, there is no evidence
..
.. de novo disease, a number of small randomized trials have been reported
of differential efficacy with new-generation biodegradable polymer DES .. with somewhat conflicting results.599–601 At present, there are no con-
in comparison with new-generation permanent polymer DES in large-
..
.. vincing data to support the use of DCB angioplasty for this indication.
scale randomized trials with follow-up out to 5 years.591–594 ..
Regarding polymer-free DES, two large-scale trials with different
..
.. 16.1.5 Devices for lesion preparation
devices showed comparable results with new-generation DES and ..
superior results to BMS.173,577 Long-term follow-up from randomized
.. Lesion preparation is critical for successful PCI. In addition to plain
.. balloon angioplasty (with standard or non-compliant balloons), cut-
trials vs. new-generation permanent polymer DES is only available for a ..
.. ting or scoring balloon angioplasty or rotational atherectomy may be
single device and shows comparable outcomes between the devices.591 .. required in selected lesions—particularly those with heavy
The high clinical efficacy and safety of new-generation DES support ..
.. calcification—in order to adequately dilate lesions prior to stent
their preferred use in patients with an indication for PCI, including ..
patients with diabetes, CKD, multivessel and LMS disease, AMI, vein .. implantation. However, studies investigating the systematic use of
.. these adjunctive technologies, such as rotational atherectomy, have
grafts, restenotic lesions, and chronic total occlusions. New- ..
generation DES should therefore be considered as the default stent .. failed to show clear clinical benefit.602
..
type for PCI regardless of clinical presentation, lesion subtype, con- ..
comitant therapies, or comorbidities. .. 16.2 Invasive imaging tools for
..
.. procedural guidance
16.1.3 Bioresorbable scaffolds .. 16.2.1 Intravascular ultrasound
..
Completely bioresorbable scaffolds (BRS), which degrade to predomi- .. The majority of the existing clinical trial data relate to the use of IVUS
nantly inert end products after fulfilling their scaffold function in the
.. guidance during PCI. In the BMS era, several RCTs addressed the
..
lesion site of the coronary vessel, have been developed with the goal . potential of IVUS in reducing restenosis and adverse events after
ESC/EACTS Guidelines 135

..
stenting, with somewhat conflicting results. Findings from one meta- .. this rule, where upfront side branch stenting may be preferable, include
analysis of randomized trials suggested better outcomes with IVUS .. the presence of a large side branch (>_2.75 mm) with a long ostial side
..
guidance in terms of acute procedural results and reduced angiographic .. branch lesion (>5 mm) or anticipated difficulty in accessing an important
restenosis, repeat revascularization, and MACE, with no effect on .. side branch after main branch stenting, and true distal LM bifurcations.
..
death and MI.603,604 In the DES era, meta-analysis of randomized and .. Recently, a multicentre trial conducted in China directly compared a
observational studies also suggests better clinical outcomes with IVUS- .. double-kissing crush two-stent strategy with provisional stenting of the
..
guided vs. angiography-guided PCI.605,606 However, the contribution of .. main branch in 482 patients with distal LM bifurcation disease. Double-
findings from observational studies must be weighed against the likeli- .. kissing crush resulted in a lower risk of the primary endpoint target lesion
..
hood of considerable residual confounding due to treatment selection .. failure at 1 year compared with provisional stenting.620
bias. Similarly, findings of improved outcome in patients undergoing LM .. When a two-stent strategy is necessary, which two-stent technique
..
stem PCI with IVUS-guided PCI vs. angiography-guided PCI from a pro- .. should be preferred is debated. The three most widely used contem-
pensity score matched analysis must be interpreted with caution.35 .. porary two-stent techniques are culotte, crush (classic or double-
..

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In cases of stent failure, including restenosis and stent thrombosis, .. kissing crush), and T and protrusion (TAP).621,622 Several RCTs have
the use of IVUS should be considered in order to identify and correct .. compared these techniques. In non-LM bifurcation lesions, there is no
..
underlying mechanical factors (see section 13).386 .. compelling evidence that one technique is superior to the others in
.. terms of major clinical endpoints.621,622 In LM true bifurcation lesions,
..
.. double-kissing crush has the most favourable outcome data.623
16.2.2 Optical coherence tomography .. Final ‘kissing’ balloon dilation is generally recommended when two
A number of studies have assessed OCT imaging for PCI guidance. Two ..
.. stents are eventually required, with no advantage from final kissing
observational studies show that while OCT imaging changes operator .. with the one-stent technique.624,625 Several stents, designed specifi-
behaviour, its impact on clinical outcomes is unclear.607,608 Indeed, OCT ..
.. cally for the treatment of bifurcation lesions, have undergone exten-
is more accurate than angiography or IVUS in detecting subtle morpho- ..
.. sive evaluation with promising angiographic and clinical results,
logical details including malapposition, residual thrombus, plaque prolapse, .. though RCTs against current recommended therapy are limited.626
and residual dissections, although many of these additional findings may ..
have a benign course.609,610 A single randomized trial compared OCT
.. Further technical details relating to bifurcation PCI are described in
.. the consensus document of the European Bifurcation Club.627
with IVUS and coronary angiography, and showed that OCT-guided PCI ..
was safe and resulted in a similar minimum stent area to that of IVUS-
..
.. 16.3.2 Chronic total coronary occlusion
guided PCI.611 However, OCT guidance was not superior to either IVUS ..
or angiography alone. An additional randomized trial that enrolled
.. Dedicated RCTs examining the outcomes of patients with chronic
.. total occlusion (CTO) allocated to revascularization or conservative
patients with NSTE-ACS compared OCT-guided PCI with angiography- ..
.. therapy are scarce. One trial randomized patients with STEMI and
guided PCI and found no signal of impact on clinical outcomes.612 ..
.. CTO in a non-culprit vessel to CTO-PCI vs. conservative therapy, and
A number of observational studies have shown that OCT is feasi-
.. found no difference in the primary endpoint of LVEF and LV end-
ble and safe in the assessment of stent failure due to thrombosis, and .. diastolic volume at 4 months.628 More recently, the prospective
may yield information that may be clinically useful.386,387,613,614 ..
.. randomized EUROCTO (Randomized Multicentre Trial to Compare
Likewise, in cases of in-stent restenosis, intrastent neointimal tissue .. Revascularization With Optimal Medical Therapy for the Treatment
may be characterized by OCT, enabling for example the detection of ..
.. of Chronic Total Occlusions) trial showed symptomatic improvement
neoatherosclerosis.386,615,616 In cases of stent failure, the use of OCT ..
.. by PCI of CTO.629 This trial included 396 patients who were ran-
should be considered in order to identify and correct underlying .. domly assigned to PCI of CTO with optimal medical therapy, or opti-
mechanical factors (see section 13). .. mal medical therapy alone. During the 12 month follow-up, the
..
.. primary endpoint-the change in health status assessed by the Seattle
16.3 Specific lesion subsets ..
.. angina questionnaire-showed significantly greater improvement of
16.3.1 Bifurcation stenosis .. angina frequency and quality of life with CTO PCI as compared with
..
A number of RCTs have investigated the optimal intervention strategy in .. optimal medical therapy alone. Yet, MACE were comparable between
patients with bifurcation lesions and showed no benefit for the systematic .. the two groups. A systematic review of 25 observational studies
..
two-stent approach vs. main branch-only stenting with provisional stent- .. showed that at median follow-up of 3 years, successful CTO-PCI was
ing of the side branch in terms of clinical outcomes.617 A recent pooled .. associated with improved clinical outcomes in comparison with failed
..
analysis of two RCTs showed lower 5 year survival in patients random- .. revascularization, including overall survival, angina burden, and the
ized to a systematic two-stent approach.618 In addition, procedure time, .. requirement for bypass surgery.630 Broadly speaking, the treatment of
..
contrast volume, radiation exposure, and cost are higher with a two- .. CTOs may be considered analogous to the treatment of non-CTO
stent approach.618 The EBC TWO (European Bifurcation Coronary .. lesions (see recommendations in section 5). In cases of regional wall
..
TWO) trial found no difference between a provisional T-stent strategy .. motion abnormalities in the territory of the CTO, objective evidence
and a systematic two-stent strategy (culotte technique) in terms of the .. of viability should be sought. The decision to attempt CTO-PCI
..
composite endpoint of death, MI, and TVR at 12 months among 200 .. should be considered against the risk of greater contrast volume, lon-
patients with large-calibre true bifurcation lesions (side branch diameter .. ger fluoroscopy time, and higher MACE rates in comparison with
..
>_2.5 mm) and significant ostial disease length (>_5 mm).619 Thus, main .. non-CTO PCI patients.631 Ad hoc PCI is generally not recommended
branch-only stenting with provisional stenting of the side branch should
.. for CTOs, although it may be necessary in selected cases (e.g. acute
..
be the preferred approach for most bifurcation lesions. Exceptions to . bypass graft failure not amenable to recanalization of the bypass graft).
136 ESC/EACTS Guidelines

Recent developments in catheter and wire technology, and


.. stroke, or non-CABG-related major bleeding at 30 days occurred at a
..
increasing operator expertise with both antegrade and retrograde .. similar rate in radial vs. femoral access (HR 0.92, 95% CI 0.72–1.17, P =
..
approaches as well as wire escalation and dissection/re-entry techni- .. 0.50).638 In the MATRIX trial, 8404 ACS patients were randomly allo-
ques, have translated into increasing success rates of CTO-PCI with ... cated to radial or femoral access.172 In terms of the first co-primary
low rates of MACE.631–633 Success rates are strongly dependent on .. endpoint of 30 day MACE, there was no significant difference between
..
operator skills, depending on experience with specific procedural .. radial access and femoral access (RR 0.85, 95% CI 0.74–0.99, two-
techniques, and the availability of dedicated equipment, and vary .. sided P = 0.031; non-significant at a pre-specified a of 0.025). The sec-
..
from 60–70% to >90%.631–633 .. ond co-primary outcome of 30 day net adverse clinical events [MACE
.. or non-CABG BARC (Bleeding Academic Research Consortium
..
16.3.3 Ostial lesions
.. (major bleeding] was significantly lower with radial access (RR 0.83,
.. 95% CI 0.73–0.96; P = 0.009). Major BARC 3 or 5 bleeding was signifi-
In ostial coronary lesions, additional judgement and caution is essen- ..
.. cantly reduced in the radial group (1.6 vs. 2.3%; RR 0.67, 95% CI

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tial before proceeding to PCI. In particular, a catheter-induced coro- ..
.. 0.49–0.92; P = 0.013), and radial access was associated with a lower
nary spasm must be rigorously excluded. Lesion assessment with
IVUS may be helpful, particularly in LM ostial stenosis. FFR measure-
.. risk of all-cause mortality (1.6 vs. 2.2%; RR 0.72, 95% CI 0.53–0.99,
.. P = 0.045). However, the benefit of radial over femoral access depends
ment may also be valuable in the assessment of ostial lesions of bor- ..
.. upon the operator’s expertise in the radial technique.639
derline significance,634 taking special care to avoid a wedge position ..
.. Treatment of restenotic and saphenous vein graft lesions are dis-
of the guiding catheter and using i.v., rather than intracoronary,
.. cussed in section 13.3.
adenosine. When performing an intervention, due to interaction .
between the guide catheter and the proximal stent edge, the risk of Recommendations on intravascular imaging for proce-
longitudinal stent deformation must be considered635 and avoided dural optimization
with careful catheter manipulation. The accurate positioning of the
stent, precisely in the coronary ostium, may be technically challenging Recommendations Classa Levelb
and some specialized techniques that may help to achieve optimal
stent placement have been described.636,637 IVUS or OCT should be considered in
selected patients to optimize stent IIa B
implantation.603,612,651–653
16.4 Vascular access
A number of RCTs have compared radial access with femoral access IVUS should be considered to optimize
for diagnostic angiography and PCI. The two largest were RIVAL treatment of unprotected left main IIa B
(Radial versus femoral access for coronary angiography and interven- lesions.35
tion in patients with acute coronary syndromes) and MATRIX
(Minimizing Adverse Haemorrhagic Events by Transradial access Site IVUS = intravascular ultrasound; OCT = optical coherence tomography.
and Systemic Implementation of AngioX).172,638 In the RIVAL trial, a
Class of recommendation.
b
Level of evidence.
which enrolled 7021 patients, the primary outcome of death, MI,

Recommendations on choice of stent and access site

Recommendations Classa Levelb Recommendations on specific lesion subsets

DES are recommended over BMS for any


Recommendations Classa Levelb
PCI irrespective of:
• clinical presentation Stent implantation in the main vessel only,
• lesion type
I A
followed by provisional balloon angioplasty
• planned non-cardiac surgery with or without stenting of the side branch, I A
• anticipated duration of DAPT is recommended for PCI of bifurcation
• concomitant anticoagulant lesions.654–658
100,578,579,640
therapy.
Percutaneous revascularization of CTOs
Radial access is recommended as the stand- should be considered in patients with angina
ard approach, unless there are overriding I A resistant to medical therapy or with a large IIa B
procedural considerations.172,638,641 area of documented ischaemia in the terri-
tory of the occluded vessel.629,659–663
BRS are currently not recommended for
III C
clinical use outside of clinical studies.642–650 In true bifurcation lesions of the left main,
the double-kissing crush technique may be IIb B
BMS = bare-metal stents; BRS = bioresorbable scaffolds; DAPT = dual antiplatelet preferred over provisional T-stenting.620
therapy; DES = drug-eluting stents; PCI = percutaneous coronary intervention.
a
Class of recommendation.
b
Level of evidence. CTO = chronic total occlusion; PCI = percutaneous coronary intervention.
a
Class of recommendation.
b
Level of evidence.
ESC/EACTS Guidelines 137

..
17 Antithrombotic treatments .. ischaemic and bleeding events significantly influence the outcome
.. of CAD patients and their overall mortality risk during and after
Antithrombotic treatment is mandatory in CAD patients undergoing
.. myocardial revascularization.664 Thus, the choice of treatment should
..
myocardial revascularization. The choice of treatment, the combination, .. reflect the ischaemic and bleeding risk. The recommended drugs
the time point of initiation, and the duration depend on the patient’s
..
.. (Figure 9) and doses (Table 7) for anticoagulant and antiplatelet
characteristics, comorbidities, the clinical setting (elective revasculariza- .. drugs used in conjunction with myocardial revascularization are
tion vs. ACS), and the mode (PCI vs. CABG) of revascularization. Both
..
. summarized below.

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Figure 9 Antithrombotic treatment for myocardial revascularization and its pharmacological targets.

Table 7 Doses of antiplatelet and anticoagulant drugs used during and after myocardial revascularization

Antiplatelet drugs

Aspirin Loading dose of 150–300 mg orally or 75–150 mg i.v. if oral ingestion is not possible, followed by
a maintenance dose of 75–100 mg/day.

Clopidogrel Loading dose of 600 mg orally, followed by a maintenance dose of 75 mg/day.

Prasugrel Loading dose of 60 mg orally, followed by a maintenance dose of 10 mg/day.


In patients with body weight <60 kg, a maintenance dose of 5 mg is recommended.
In patients aged >75 years, prasugrel is generally not recommended, but a dose of 5 mg should
be used if treatment is deemed necessary.
Continued
138 ESC/EACTS Guidelines

Ticagrelor Loading dose of 180 mg orally, followed by a maintenance dose of 90 mg b.i.d.

Abciximab Bolus of 0.25 mg/kg i.v. and 0.125 lg/kg/min infusion (maximum 10 lg/min) for 12 h.

Eptifibatide Double bolus of 180 lg/kg i.v. (given at a 10 min interval) followed by an infusion of 2.0 lg/kg/min
for up to18 h.

Tirofiban Bolus of 25 lg/kg over 3 min i.v., followed by an infusion of 0.15 lg/kg/min for up to 18 h.

Cangrelor Bolus of 30 mg/kg i.v. followed by 4 mg/kg/min infusion for at least 2 h or duration of procedure,
whichever is longer.

Anticoagulant drugs for PCI

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Unfractionated heparin • 70–100 U/kg i.v. bolus when no GP IIb/IIIa inhibitor is planned.
• 50–70 U/kg i.v. bolus with GP IIb/IIIa inhibitors.

Enoxaparin 0.5 mg/kg i.v. bolus.

Bivalirudin 0.75 mg/kg i.v. bolus followed by i.v. infusion of 1.75 mg/kg/h for up to 4 h after the procedure
as clinically warranted.

Oral anticoagulant drugs (concomitant treatment after PCI)

Vitamin K antagonists (e.g. warfarin, Dosing is based on INR value and the respective clinical indication.
phenprocoumon)

Apixaban Maintenance doses of 5 and 2.5a mg b.i.d.

Dabigatran Maintenance doses of 150 and 110 mg b.i.d.

Edoxaban Maintenance doses of 60 and 30a mg/day

Rivaroxaban Maintenance doses of 20 and 15a mg/day, and 2.5 mg b.i.d. (vascular dose).

a
Specific criteria for reduced dose apply (see recommendation table on page 61).
b.i.d. = twice daily; GP = glycoprotein; INR = international normalized ratio; i.v. = intravenous; PCI = percutaneous coronary intervention.

..
17.1 Percutaneous coronary intervention .. and bivalirudin, have been evaluated for their use in clinical practice.
.. The REPLACE-2 (Randomised Evaluation in PCI Linking Angiomax to
in stable coronary artery disease ..
17.1.1 Choice of treatment and pre-treatment
.. Reduced Clinical Events 2) trial demonstrated that the outcome with
.. bivalirudin and provisional glycoprotein (GP) IIb/IIIa blockade is simi-
DAPT consisting of aspirin and a P2Y12 receptor inhibitor represents ..
the cornerstone of treatment in patients undergoing elective PCI.665
.. lar to that of UFH plus planned GP IIb/IIIa inhibition during elective
.. PCI.669 The ISAR-REACT (Intracoronary Stenting and
The P2Y12 receptor inhibitor clopidogrel is recommended for elec- ..
.. Antithrombotic Regimen Rapid Early Action for Coronary
tive stenting procedures. For routine clopidogrel pre-treatment .. Treatment) 3 trial also showed a similar outcome for bivalirudin vs.
(administration of the drug when the coronary anatomy is unknown), ..
.. UFH treatment.670 In ISAR REACT 3A,671 evaluating a lower dose of
there is no compelling evidence for a significant clinical benefit in .. 100 U/kg UFH, this lower dose showed net clinical benefit compared
SCAD patients.666–668 Thus, pre-treatment may only be an option in ..
.. with the historical control cohort and this benefit was mostly driven
selected patients with high probability of PCI or before staged PCI .. by a reduction in bleeding events. In view of the primary endpoint
procedures. Figures 9 and 10 summarize the commonly used antipla- ..
.. results of the RCTs and in view of a trend towards a lower risk of MI,
telet and anticoagulant drugs in SCAD patients undergoing PCI. ..
.. UFH remains the standard anticoagulant for elective PCI. Based on
.. the results of the STEEPLE (Safety and Efficacy of Intravenous
..
17.1.2 Peri-interventional treatment .. Enoxaparin in Elective Percutaneous Coronary Intervention
While aspirin and clopidogrel are indicated for elective stenting pro- .. Randomised Evaluation) trial, enoxaparin should be considered as an
..
cedures, prasugrel or ticagrelor may only be considered in selected .. alternative anticoagulant drug.672
patients for specific high-risk situations of elective stenting (e.g. com- .. Drugs for parenteral antiplatelet treatment include cangrelor
..
plex PCI procedures such as LM stenting and CTO procedures) or in .. and GP IIb/IIIa inhibitors. Cangrelor is a direct reversible, short-
patients with a history of stent thrombosis on clopidogrel treatment. .. acting P2Y12-inhibitor that has been evaluated during PCI for
..
In parallel with antiplatelet treatment, the use of anticoagulants is .. SCAD and ACS in clinical trials comparing cangrelor with clopi-
standard of care during elective PCI to inhibit thrombin generation
.. dogrel, administered before PCI [CHAMPION (Cangrelor versus
..
and activity. Different agents, including unfractionated heparin (UFH) . Standard Therapy to Achieve Optimal Management of Platelet
ESC/EACTS Guidelines 139

..
Inhibition) PCI] or after PCI (CHAMPION PLATFORM and .. An algorithm for the use of antithrombotic drugs in patients under-
CHAMPION PHOENIX).673 A meta-analysis showed a benefit .. going PCI is shown in Figure 10.
..
with respect to major ischaemic endpoints that is counter- ..
balanced by an increase in relevant bleeding.673 Moreover, the .. 17.1.3 Post-interventional and maintenance treatment
..
benefit of cangrelor with respect to ischaemic endpoints was atte- .. Following elective stenting, DAPT consisting of clopidogrel in addi-
nuated in CHAMPION PCI with upfront administration of clopi- ..
.. tion to aspirin is generally recommended for 6 months, irrespective
dogrel. Nevertheless, due to its proven efficacy in preventing .. of the stent type. In specific clinical scenarios, this standard DAPT
intraprocedural and post-procedural stent thrombosis in P2Y12- ..
.. duration can be shortened (<6 months) or extended (>6–12
inhibitor naı̈ve patients, cangrelor may be considered in P2Y12- .. months). For a more detailed description of the pertinent clinical tri-
inhibitor naı̈ve patients undergoing PCI (for more detailed discus- ..
.. als in the field of DAPT duration, we refer the reader to the 2017
sion see the Supplementary Data). .. ESC Focused Update on Dual Antiplatelet Therapy in Coronary
Available GP IIb/IIIa inhibitors include abciximab, eptifibatide, and tir- ..
.. Artery Disease.410 Following DAPT, a life-long single antiplatelet

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ofiban. In a setting of elective PCI, clinical trials did not demonstrate an .. therapy (usually with aspirin) is recommended, and patients should
additional benefit of GP IIb/IIIa inhibitor administration in SCAD
..
.. be advised not to prematurely discontinue oral antiplatelet therapy
patients in a setting of DAPT treatment that includes loading with clo- .. after stenting due to the risks of stent thrombosis and recurrent
pidogrel.674,675 A meta-analysis on this topic revealed no mortality ben-
..
.. MI.677 Recently, the value of a vascular dose of rivaroxaban (2.5 mg
efit of GP IIb/IIIa treatment and while non-fatal MIs were reduced, .. b.i.d.) in conjunction with aspirin was demonstrated in the large-scale
(minor) bleeding events were significantly higher when utilizing these
..
.. COMPASS (Rivaroxaban for the Prevention of Major Cardiovascular
agents.676 Thus, GP IIb/IIIa inhibitors may only be considered in specific .. Events in Coronary or Peripheral Artery Disease) trial.678 However,
‘bail-out’ situations including high intraprocedural thrombus burden,
..
.. its utilization in SCAD patients is a matter of secondary prevention
slow flow, or no-flow with closure of the stented coronary vessel. .. and is not linked to myocardial revascularization procedures.

Figure 10 Algorithm for the use of antithrombotic drugs in patients undergoing percutaneous coronary intervention. High bleeding risk is consid-
ered as an increased risk of spontaneous bleeding during DAPT (e.g. PRECISE-DAPT score >_25). Colour-coding refers to the ESC classes of recom-
mendations (green = class I; yellow = class IIa; and orange = class IIb).
140 ESC/EACTS Guidelines

Recommendations for antithrombotic treatment in stable coronary artery disease patients undergoing percutaneous
coronary intervention

Recommendations Classa Levelb

Pre-treatment and antiplatelet therapy

Treatment with 600 mg clopidogrel is recommended in elective PCI patients once the coronary anatomy is known and
I A
a decision is made to proceed with PCI.667,679,680

Pre-treatment with clopidogrel may be considered if the probability of PCI is high. IIb C

In patients on a maintenance dose of 75 mg clopidogrel, a new loading dose of 600 mg may be considered once the indi-
IIb C

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cation for PCI is confirmed.

Peri-interventional treatment

Aspirin is indicated before elective stenting.681–683 I A

An oral loading dose of aspirin (150–300 mg p.o. or 75–250 mg i.v.) is recommended if the patient is not pre-treated. I C

Clopidogrel (600 mg loading dose, 75 mg daily maintenance dose) is recommended for elective stenting.684–688 I A

Glycoprotein IIb/IIIa antagonists should be considered only for bail-out. IIa C

Prasugrel or ticagrelor may be considered in specific high-risk situations of elective stenting (e.g. history of stent throm-
IIb C
bosis or left main stenting).

Unfractionated heparin is indicated as the standard anticoagulant (70–100 U/kg).670,671 I B

Bivalirudin (0.75 mg/kg bolus, followed by 1.75 mg/kg/h for up to 4 h after the procedure) is indicated in the case of hep-
I C
arin-induced thrombocytopenia.

Enoxaparin (i.v. 0.5 mg/kg) should be considered as an alternative agent.672,689 IIa B

Cangrelor may be considered in P2Y12-inhibitor naı̈ve patients undergoing PCI.673 IIb A

Post-interventional and maintenance treatment

Life-long single antiplatelet therapy, usually aspirin, is recommended.681,683 I A

Instruction of patients about the importance of complying with antiplatelet therapy is recommended. I C

In patients with SCAD treated with coronary stent implantation, DAPT consisting of clopidogrel in addition to aspirin is
I A
generally recommended for 6 months, irrespective of the stent type.c 690–694

In patients with SCAD treated with BRS, DAPT should be considered for at least 12 months and up to the presumed
IIa C
full absorption of the BRS, based on an individual assessment of bleeding and ischaemic risk.

In patients with SCAD treated with DCB, DAPT should be considered for 6 months.369,371 IIa B

In patients with SCAD considered at high bleeding risk (e.g. PRECISE-DAPT >_25), DAPT should be considered for 3
IIa A
months.d 695,696

In patients with SCAD who have tolerated DAPT without a bleeding complication and who are at low bleeding risk but
high thrombotic risk, continuation of DAPT with clopidogrel for >6 months and up to 30 months may be IIb A
considered.697–700

In patients with SCAD in whom 3 month DAPT poses safety concerns, DAPT may be considered for 1 month. IIb C

BRS = bioresorbable scaffold; CAD = coronary artery disease; DAPT = dual antiplatelet therapy; DCB = drug-coated balloon; i.v. = intravenous; MI = myocardial infarction;
PCI = percutaneous coronary intervention; p.o. = orally; PRECISE-DAPT = PREdicting bleeding Complications In patients undergoing Stent implantation and subsEquent Dual
Anti Platelet Therapy; SCAD = stable coronary artery disease.
a
Class of recommendation.
b
Level of evidence.
c
These recommendations refer to stents that are supported by large-scale randomized trials with clinical endpoint evaluation leading to an unconditional CE mark.
d
The evidence supporting this recommendation comes from two studies where the zotarolimus-eluting Endeavour stent was investigated in conjunction with a 3 month DAPT
regimen.
ESC/EACTS Guidelines 141

..
17.2 Non-ST-segment elevation acute .. not confirmed in VALIDATE-SWEDEHEART and in a contemporary
.. setting of preferred radial access and selective use of GP IIb/IIIa inhibi-
coronary syndrome ..
The activation of blood platelets and the coagulation cascade plays a .. tors. More recently, a meta-analysis updated for the results of
.. VALIDATE-SWEDEHEART confirmed that bivalirudin compared
key role in the initial phase and evolution of an ACS. Hence, sufficient ..
platelet inhibition and anticoagulation is essential during ACS, and .. with heparin was associated with a similar incidence of all-cause death
.. and ischaemic events after PCI for ACS.710 A significant association of
especially in ACS patients undergoing PCI. ..
.. bivalirudin with decreased risk of bleeding was only found with unbal-
.. anced use of GP IIb/IIIa inhibitors in conjunction with heparin. In sum-
17.2.1 Choice of treatment and pre-treatment
..
.. mary and based on the above-mentioned trials, UFH is primarily
For NSTE-ACS patients, DAPT including aspirin and a potent P2Y12 .. recommended as an anticoagulant for PCI. Due to its short half-life
receptor inhibitor (prasugrel or ticagrelor) is recommended (see the
..
.. and favourable results in some of the studies, bivalirudin may be con-
Supplementary Data).701,702 Clopidogrel should only be used when .. sidered as an alternative to UFH in selected cases.
..

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prasugrel or ticagrelor are not available or are contraindicated. Based .. Patients may undergo cardiac catheterization after a conservative
on the results of the ACCOAST (Comparison of Prasugrel at the .. treatment phase and these patients are commonly treated with fon-
Time of Percutaneous Coronary Intervention or as Pretreatment at
..
.. daparinux during the conservative treatment phase. This regimen is
the Time of Diagnosis in Patients with Non-ST Elevation Myocardial .. based on the OASIS-5 (Optimal Antiplatelet Strategy for
..
Infarction) trial,165 it is not recommended that prasugrel is adminis- .. Interventions 5) trial.711 Of note, catheter thrombus formation was
tered in patients in whom coronary anatomy is not known. .. an issue with fondaparinux and therefore full-dose UFH must be
..
Nevertheless, pre-treatment with ticagrelor was part of the PLATO .. added to prevent thrombus formation when the patient proceeds to
trial (Study of Platelet Inhibition and Patient Outcomes) and was .. PCI. Enoxaparin should be considered as anticoagulant for PCI in
..
associated with an early benefit over clopidogrel.702 For these rea- .. patients pre-treated with subcutaneous enoxaparin. A benefit of
sons, pre-treatment with ticagrelor can be used, although there is no ..
.. enoxaparin over UFH in reducing mortality and bleeding complica-
direct evidence from head-to-head comparisons between pre- .. tions was recently reported in a meta-analysis including NSTE-ACS
treatment strategies. ..
.. patients.689 Yet, this meta-analysis did not include a dedicated
.. randomized study in NSTE-ACS and was largely based on non-
..
17.2.2 Peri-interventional treatment .. randomized comparisons.
Anticoagulation is recommended for all patients in addition to anti- .. Most of the trials evaluating GP IIb/IIIa inhibitors in PCI-treated
..
platelet therapy during PCI for NSTE-ACS.703 In general, a crossover .. patients pre-date the era of routine oral DAPT treatment. These
between anticoagulants should be avoided [especially between UFH .. early trials demonstrated a reduction in the incidence of ischaemic
..
and low-molecular-weight heparin (LMWH)], with the exception of .. events in favour of GP IIb/IIIa treatment in combination with UFH
adding UFH to fondaparinux when a patient proceeds to PCI.704,705 .. compared with UFH alone, primarily through a reduction in MI.712
..
The respective agents should be discontinued after PCI except for .. However, coronary angiography and PCI were delayed compared
specific clinical settings, such as the presence of an LV aneurysm with
.. with what is recommended now, and a consistent major bleeding risk
..
thrombus or AF requiring anticoagulation. .. was observed. Overall, there is no compelling evidence for an addi-
A number of trials have compared bivalirudin with UFH in ACS
.. tional benefit of routine upstream use of GP IIb/IIIa inhibitors in
..
patients undergoing PCI (see the Supplementary Data). Some of .. NSTE-ACS patients scheduled for coronary angiography and receiv-
these trials pursued a balanced use of adjunctive GP IIb/IIIa inhibitors
.. ing DAPT treatment.713,714 In a setting of potent platelet inhibition
..
with both bivalirudin and heparin, whereas others, predominantly the .. with ticagrelor or prasugrel, where randomized data on GP IIb/IIIa
older ones, had selective use of GP IIb/IIIa inhibitors in the heparin
.. inhibitor use is limited, routine use of these agents cannot be recom-
..
arm. These trials have been reviewed extensively in a number of .. mended. Nevertheless, it should be considered for bail-out situations
..
meta-analyses.706–708 A meta-analysis that included the MATRIX trial .. or thrombotic complications, and may be used for high-risk PCI in
but not VALIDATE-SWEDEHEART (Bivalirudin versus Heparin in .. patients without pre-treatment with P2Y12-inhibitors. The available
.. evidence on cangrelor suggests that the potential benefit is independ-
ST-Segment and Non-ST-Segment Elevation Myocardial Infarction in ..
Patients on Modern Antiplatelet Therapy on the Swedish Web- .. ent of the clinical presentation. Thus, similar to SCAD patients, can-
..
system for Enhancement and Development of Evidence-based care .. grelor may be considered in specific settings in P2Y12-naı̈ve patients
in Heart disease Evaluated According to Recommended Therapies) .. undergoing PCI.
..
showed no significant benefit of bivalirudin compared with UFH with ..
respect to death, MACE, and MI.708 Nevertheless, bivalirudin was ..
..
associated with a significant increase in the risk of stent thrombosis .. 17.2.3 Post-interventional and maintenance treatment
and a significant decrease in the risk of bleeding. However, the reduc- .. Following PCI for NSTE-ACS, DAPT consisting of a P2Y12 receptor
..
tion of bleeding risk was linked to unbalanced use of GP IIb/IIa inhibi- .. inhibitor in addition to aspirin is generally recommended for 12
tors predominantly with UFH. Recently, the VALIDATE- .. months, irrespective of the stent type. Recently, the SMART-DATE
..
SWEDEHEART study709 compared UFH vs. bivalirudin in a back- .. (Smart Angioplasty Research Team-safety of 6-month duration of
ground of radial access and limited use of GP IIb/IIIa inhibitors. The .. Dual Antiplatelet Therapy after percutaneous coronary intervention
..
study demonstrated similar risk patterns for both ischaemia and .. in patients with acute coronary syndromes) prospective multicentre
bleeding when comparing the two drugs. Of note, while prior studies
.. randomized trial supported this notion in the setting of contempo-
..
reported a reduced bleeding risk with bivalirudin vs. UFH, this was . rary interventional practice. The study randomly assigned 2712
142 ESC/EACTS Guidelines

patients undergoing PCI for NSTE-ACS or STEMI to either 6 month


.. inhibition on chronic antiplatelet treatment for acute coronary syn-
..
DAPT or 12 month or longer DAPT. Although the primary .. dromes) trial717, an approach of DAPT de-escalation guided by plate-
..
endpoint—a composite of all-cause death, MI, or stroke—did not .. let function testing may be considered in ACS patients (NSTE-ACS
confirm the benefit of prolonged DAPT over 6 month DAPT (cumu- .. and STEMI) as an alternative to 12 months potent platelet inhibition,
..
lative event rate 4.7 vs. 4.2%; absolute risk difference 0.5%; upper limit .. especially for patients deemed unsuitable for maintained potent pla-
of one-sided 95% CI 1.8%; Pnon-inferiority = 0.03 with a predefined non- .. telet inhibition. For a more detailed description of the pertinent clini-
..
inferiority margin of 2.0%), MI occurred more frequently in the 6 .. cal trials in the field of DAPT duration and switching antiplatelet
month DAPT group than in the prolonged DAPT group (1.8 vs. 0.8%; .. drugs, we refer the reader to the International Expert Consensus
..
P = 0.02). The rate of BARC type 2 - 5 bleeding was not significantly .. document on Switching Platelet P2Y12 Receptor-Inhibiting
affected by prolonged DAPT (HR 0.69, 95% CI 0.45–1.05, P = 0.09). .. Therapies718 and the 2017 ESC Focused Update on Dual Antiplatelet
..
The authors stated that the increased risk of MI with 6 month DAPT .. Therapy in Coronary Artery Disease.410 Following DAPT, lifelong
and the wide non-inferiority margin prevented them from concluding .. single antiplatelet therapy (usually with aspirin) is recommended and
..

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that short-term DAPT was safe in this setting, and suggested that pro- .. patients should be advised not to prematurely discontinue oral anti-
longed DAPT should remain the standard of care in patients with .. platelet therapy after stenting.677,719
..
ACS without excessive risk of bleeding.715 .. Based on the results of the ATLAS-ACS 2–TIMI 51 (Anti-Xa
In specific clinical scenarios, this standard DAPT duration can be
.. Therapy to Lower cardiovascular events in Addition to Standard
..
shortened (<12 months) or extended (>12 months). Further on, .. therapy in subjects with Acute Coronary Syndrome–Thrombolysis
switching and especially a de-escalation of DAPT (switching from
.. In Myocardial Infarction 51) trial in NSTE-ACS and STEMI patients,720
..
potent P2Y12-inhibitors to clopidogrel) was subject to a number of .. low-dose rivaroxaban may be considered after discontinuation of
randomized clinical trials.716,717 Triggers for DAPT de-escalation
.. parenteral anticoagulation for patients with no prior stroke/TIA, and
..
include clinical (bleeding events or presumed high bleeding risk) and .. at high ischaemic risk as well as low bleeding risk, receiving aspirin
socio-economic factors.716 Based on recent results from the
.. and clopidogrel. Of note, rivaroxaban has not been investigated in a
..
randomized TROPICAL-ACS (Testing responsiveness to platelet .. background of potent P2Y12-inhibitors.

Recommendations for antithrombotic treatment in patients with non-ST-elevation acute coronary syndromes under-
going percutaneous coronary intervention

Recommendations Classa Levelb

Pre-treatment and antiplatelet therapy

Aspirin is recommended for all patients without contraindications at an initial oral loading dose of 150–300 mg (or
I A
75–250 mg i.v.), and at a maintenance dose of 75–100 mg daily long-term.681,683,721

A P2Y12 inhibitor is recommended in addition to aspirin, maintained over 12 months unless there are contraindica-
I A
tions such as an excessive risk of bleeding.701,702,722,723 Options are:

 Prasugrel in P2Y12-inhibitor naı̈ve patients who proceed to PCI (60 mg loading dose, 10 mg daily dose).701 I B
 Ticagrelor irrespective of the preceding P2Y12 inhibitor regimen (180 mg loading dose, 90 mg b.i.d.).702
I B
 Clopidogrel (600 mg loading dose, 75 mg daily dose) only when prasugrel or ticagrelor are not available or are
contraindicated.722–724 I B

GP IIb/IIIa antagonists should be considered for bail-out if there is evidence of no-reflow or a thrombotic
IIa C
complication.

For pre-treatment in patients with NSTE-ACS undergoing invasive management, ticagrelor administration (180 mg
loading dose, 90 mg b.i.d.), or clopidogrel (600 mg loading dose, 75 mg daily dose) if ticagrelor is not an option, IIa C
should be considered as soon as the diagnosis is established.

Cangrelor may be considered in P2Y12-inhibitor naı̈ve patients undergoing PCI.673 IIb A

GP IIb/IIIa antagonists may be considered in P2Y12-inhibitor naı̈ve patients undergoing PCI. IIb C

Pre-treatment with GP IIb/IIIa antagonists in patients in whom coronary anatomy is not known is not
III A
recommended.713,714,725

Administration of prasugrel in patients in whom coronary anatomy is not known is not recommended.165 III B
Continued
ESC/EACTS Guidelines 143

Peri-interventional therapy

Anticoagulation is recommended for all patients in addition to antiplatelet therapy.703,726 I A

It is recommended that anticoagulation is selected according to both ischaemic and bleeding risks, and according to
I C
the efficacy–safety profile of the chosen agent.

UFH is recommended. I C

In patients on fondaparinux, a single bolus UFH (85 IU/kg, or 60 IU in the case of concomitant use of GP IIb/IIIa
I B
receptor inhibitors) is indicated.727

Enoxaparin should be considered in patients pre-treated with subcutaneous enoxaparin.689 IIa B

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Discontinuation of parenteral anticoagulation should be considered immediately after an invasive procedure. IIa C

Bivalirudin (0.75 mg/kg bolus, followed by 1.75 mg/kg/h for up to 4 h after the procedure) may be considered as an
IIb A
alternative to UFH.163,708,710,714,728

Crossover of UFH and LMWH is not recommended.705 III B

b.i.d. = twice daily; GP = glycoprotein; i.v. = intravenous; LMWH = low-molecular-weight heparin; NSTE-ACS = non-ST-segment elevation acute coronary syndromes; PCI =
percutaneous coronary intervention; UFH = unfractionated heparin.
a
Class of recommendation.
b
Level of evidence.

Recommendations for post-interventional and maintenance treatment in patients with non-ST-elevation acute coro-
nary syndromes and ST-elevation myocardial infarction undergoing percutaneous coronary intervention

Recommendations Classa Levelb

In patients with ACS treated with coronary stent implantation, DAPT with a P2Y12 inhibitor on top of aspirin is rec-
ommended for 12 months unless there are contraindications such as an excessive risk of bleeding (e.g. PRECISE- I A
DAPT >_25).701,702,722,723

In patients with ACS and stent implantation who are at high risk of bleeding (e.g. PRECISE-DAPT >_25), discontinua-
IIa B
tion of P2Y12 inhibitor therapy after 6 months should be considered.729,730

In patients with ACS treated with BRS, DAPT should be considered for at least 12 months and up to the presumed
IIa C
full absorption of the BRS, based on an individual assessment of bleeding and ischaemic risk.

De-escalation of P2Y12 inhibitor treatment (e.g. with a switch from prasugrel or ticagrelor to clopidogrel) guided by
platelet function testing may be considered as an alternative DAPT strategy, especially for ACS patients deemed IIb B
unsuitable for 12-month potent platelet inhibition.717

In patients with ACS who have tolerated DAPT without a bleeding complication, continuation of DAPT for longer
IIb A
than 12 months may be considered.700,731

In patients with MI and high ischaemic riskc who have tolerated DAPT without a bleeding complication, ticagrelor
IIb B
60 mg b.i.d. for longer than 12 months on top of aspirin may be preferred over clopidogrel or prasugrel.732–734

In ACS patients with no prior stroke/TIA, and at high ischaemic risk as well as low bleeding risk, receiving aspirin
and clopidogrel, low-dose rivaroxaban (2.5 mg b.i.d. for approximately 1 year) may be considered after discontinua- IIb B
tion of parenteral anticoagulation.720

ACS = acute coronary syndrome; b.i.d. = twice daily; BRS = bioresorbable scaffold; DAPT = dual antiplatelet therapy; MI = myocardial infarction; PCI = percutaneous coronary
intervention; PRECISE-DAPT = PREdicting bleeding Complications In patients undergoing Stent implantation and subsEquent Dual Anti Platelet Therapy; TIA = transient ischae-
mic attack.
a
Class of recommendation.
b
Level of evidence.
c
Defined as >_50 years of age and having one of the following additional high-risk features: age >_65 years or older, diabetes mellitus requiring medication, a second prior sponta-
neous MI, multivessel coronary artery disease, or chronic renal dysfunction, defined as an estimated creatinine clearance <60 mL/min.
144 ESC/EACTS Guidelines

.. administration—regardless of whether treatment starts upstream or


17.3 ST-segment elevation myocardial ..
.. in the catheterization laboratory—cannot be recommended.
infarction ..
.. Especially in a setting where potent P2Y12-inhibitors like prasugrel or
17.3.1 Choice of treatment and pre-treatment
.. ticagrelor are used, the value of GP IIb/IIIa inhibitors remains uncer-
STEMI patients undergoing primary PCI should receive aspirin and a ..
tain as these agents exhibit a fast onset of action (usually <1 h). GP
P2Y12 receptor inhibitor as soon as the diagnosis of STEMI is estab- ...
lished. In line with the treatment recommendations for NSTE-ACS .. IIb/IIIa inhibitors remain an option as bail-out therapy or in high-risk
.. PCI without pre-treatment with P2Y12-inhibitors. Of note, the bail-
patients, DAPT is the cornerstone of treatment for STEMI patients ..
and includes aspirin and a potent P2Y12 receptor inhibitor (prasugrel .. out scenarios have never been addressed in randomized controlled
.. trials. For reasons discussed above (see sections 17.1 and 17.2), can-
or ticagrelor).701,702 For both antiplatelet drugs, published subgroup ..
analyses on STEMI patients are available (see the Supplementary .. grelor may be considered in specific settings in P2Y12-naı̈ve patients
.. undergoing PCI.
Data). Randomized data on a comparison of ticagrelor vs. prasugrel ..
..

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in STEMI patients are limited, but the recently published randomized ..
PRAGUE-18 (Comparison of Prasugrel and Ticagrelor in the ..
Treatment of Acute Myocardial Infarction) trial735 with limited statis-
.. 17.3.3 Post-interventional and maintenance treatment
..
tical power found similar safety and efficacy profiles of ticagrelor and .. Following PCI for STEMI, DAPT consisting of a P2Y12 receptor inhibi-
prasugrel in a setting of primary PCI. When potent P2Y12 receptor
.. tor in addition to aspirin is generally recommended for 12 months.
..
inhibitors are contraindicated or are not available, clopidogrel should .. Recommendations for maintenance DAPT treatment are generally
be given for primary PCI instead.724 The value of pre-treatment with
.. consistent with those for NSTE-ACS patients and are detailed in sec-
..
ticagrelor was addressed in the ATLANTIC (Administration of . tion 17.2.3.
Ticagrelor in the Cath Lab or in the Ambulance for New ST-
Elevation Myocardial Infarction to Open the Coronary Artery) Recommendations for antithrombotic treatment in ST-
trial.736 No significant differences were observed in the levels of the elevation myocardial infarction patients undergoing per-
two co-primary surrogate endpoints measured before PCI (throm- cutaneous coronary intervention
bolysis in Myocardial Infarction flow and ST-segment resolution).
Likewise, the incidence of a combined ischaemic endpoint (death, MI, Recommendations Classa Levelb
stroke, stent thrombosis, and urgent revascularization) did not differ
Pre-treatment and antiplatelet therapy
between the two treatment arms. Nevertheless, in both the
TRITON (TRial to Assess Improvement in Therapeutic Outcomes Aspirin is recommended for all patients
by Optimizing Platelet InhibitioN with Prasugrel–Thrombolysis In without contraindications at an initial
Myocardial Infarction) and PLATO trials, pre-treatment was part of oral loading dose of 150–300 mg (or
the therapeutic regimen in STEMI. 75–250 mg i.v.), and at a maintenance I A
dose of 75–100 mg daily long-term
regardless of treatment
17.3.2 Peri-interventional treatment strategy.681,683,721
Immediate and sufficient anticoagulation is mandatory in the setting
of primary PCI for STEMI and available options include UFH, bivaliru- A potent P2Y12 inhibitor (prasugrel or
din, and enoxaparin. A number of RCTs compared bivalirudin vs. ticagrelor), or clopidogrel if these are
UFH in different settings and with different utilization of GP IIb/IIIa not available or are contraindicated, is
inhibitors (see the Supplementary Data). The primary recommenda- recommended before (or at latest at the
I A
tion of UFH, reserving bivalirudin for selected cases, is essentially the time of) PCI and maintained over 12
same for primary PCI as for PCI in NSTE-ACS, and is mostly based months, unless there are contraindica-
on the same clinical trials706,709 (see section 17.2.2). tions such as excessive risk of
Enoxaparin was compared with UFH in the randomized open- bleeding.701,702,724,743
label ATOLL (Acute STEMI Treated with primary PCI and intrave-
GP IIb/IIIa inhibitors should be consid-
nous enoxaparin Or UFH to Lower ischaemic and bleeding events at
ered for bail-out if there is evidence of
short- and Long-term follow-up) trial,737 and based on the trial IIa C
no-reflow or a thrombotic
results, enoxaparin should be considered as an alternative to UFH
complication.
treatment in STEMI patients.
A number of clinical trials, performed at a time when pre- Cangrelor may be considered in P2Y12-
treatment and potent platelet inhibition was not part of routine clini- inhibitor naı̈ve patients undergoing IIb A
cal practice, have documented clinical benefits of GP IIb/IIIa inhibitors PCI.673
as an adjunct to primary PCI performed with UFH.738,739 A meta-
GP IIb/IIIa antagonists may be consid-
analysis showed a significant survival benefit, especially in high-risk
ered in P2Y12-inhibitor naı̈ve patients IIb C
STEMI patients, but also a higher risk of bleeding with GP IIb/IIIa
undergoing PCI.
administration.740 Dedicated trials have investigated the value of
upstream treatment in the past.741,742 Based upon the available evi- Continued
dence, the routine use of i.v. or intracoronary GP IIb/IIIa inhibitor
ESC/EACTS Guidelines 145

Peri-interventional therapy In patients with ACS (NSTE-ACS or


STEMI) treated with DAPT who are
Anticoagulation is recommended for all
undergoing CABG and do not require
patients in addition to antiplatelet ther- I A
long-term OAC therapy, resumption of
apy during PCI.703,726 I C
P2Y12 inhibitor therapy as soon as
Routine use of UFH is recommended. I C deemed safe after surgery and its contin-
uation up to 12 months is
Routine use of enoxaparin should be
737
IIa B recommended.
considered.
In patients on P2Y12 inhibitors who
Routine use of bivalirudin may be
IIb A need to undergo non-emergent cardiac
considered.708,710,728,744–746
surgery, postponing surgery for at least

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3 days after discontinuation of ticagre- IIa B
GP = glycoprotein; i.v. = intravenous; PCI = percutaneous coronary intervention; lor, at least 5 days after clopidogrel, and
UFH = unfractionated heparin.
a
Class of recommendation. at least 7 days after prasugrel should be
b
Level of evidence. considered.747–749

In CABG patients with prior MI who are


at high risk of severe bleeding (e.g.
17.4 Coronary artery bypass grafting PRECISE-DAPT >_25), discontinuation of IIa C
Antithrombotic treatment before and after CABG is addressed in P2Y12 inhibitor therapy after 6 months
the 2017 ESC Focused Update on Dual Antiplatelet Therapy in should be considered.
Coronary Artery Disease.410 After reviewing the subsequent litera-
Platelet function testing may be consid-
ture, the current Task Force endorses the recommendations of the
ered to guide the decision on the timing
update on DAPT and does not identify a need for any major update.
of cardiac surgery in patients who have IIb B
Accordingly, the recommendation tables in this section are taken
recently received P2Y12
from the Focused Update. For a detailed discussion, we refer the
inhibitors.193,750–752
reader to the Focused Update.
In patients perceived to be at high
ischaemic risk with prior MI and CABG,
Dual antiplatelet therapy in patients undergoing cardiac
who have tolerated DAPT without a
surgery IIb C
bleeding complication, treatment with
DAPT for longer than 12 months and up
Recommendations Classa Levelb
to 36 months may be considered.
It is recommended that the Heart Team
estimates the individual bleeding and ACS = acute coronary syndrome; CABG = coronary artery bypass grafting;
ischaemic risks, and guides the timing of I C DAPT = dual antiplatelet therapy; MI = myocardial infarction; NSTE-ACS = non-
ST-elevation acute coronary syndrome; OAC = oral anticoagulant; STEMI = ST-
CABG as well as the anti-thrombotic elevation myocardial infarction. PRECISE-DAPT = PREdicting bleeding
management. Complications In patients undergoing Stent implantation and subsEquent Dual
Anti Platelet Therapy.
a
In patients on aspirin who need to Class of recommendation.
b
undergo non-emergent cardiac surgery, Level of evidence.

it is recommended to continue aspirin at I C


a low daily regimen throughout the peri-
operative period.
..
In patients treated with DAPT after cor-
.. 17.5 Special conditions
.. 17.5.1 Antithrombotic therapy after percutaneous
onary stent implantation who subse- ..
quently undergo cardiac surgery, it is
.. coronary intervention in patients requiring oral
..
recommended to resume P2Y12 inhibi- .. anticoagulation
I C .. Compared with OAC therapy alone, the addition of DAPT to OAC
tor therapy post-operatively as soon as ..
it is deemed safe, so that DAPT contin- .. therapy results in a two- to three-fold increase in bleeding complica-
.. tions, suggesting that every effort should be undertaken to avoid
ues until the recommended duration of ..
therapy is completed. .. bleeding (Table 8).753 Assessing the balance of ischaemic and bleeding
.. risks of relatively short (i.e. <_6 months) triple therapy duration com-
Continued ..
.. pared with double therapy consisting of clopidogrel and an OAC
146 ESC/EACTS Guidelines

requires patient-by-patient decisions. Of note, previous randomized ... relevant bleeding events. However, as compared with triple therapy,
..
studies evaluating the duration of triple therapy or the benefit of .. an increase in both MI (4.5 vs. 3.0%, P = 0.09) and stent thrombosis
NOACs vs. vitamin K antagonists (VKAs) were not adequately pow- .. risk (1.5 vs. 0.8%, P = 0.15) was reported for the lower dabigatran
..
ered to assess ischaemic events, and data are lacking on the efficacy .. dose (110 mg b.i.d.), but not for the higher dabigatran dose (150 mg
of dual therapy in patients at high risk of stroke or recurrent .. b.i.d.). Although statistical significance was missed, these findings raise
..
ACS.754–757 In the major trials, there was no interaction between the .. concern about the efficacy of the lower dabigatran dose in combina-
duration of triple therapy and clinical presentation (ACS vs. no ACS). .. tion with single antiplatelet therapy in preventing coronary events.
..
The rate of bleeding events peaked within the first 30 days of initia- .. Thus, the 150 mg b.i.d. dose of dabigatran is preferred. At present,
tion of triple therapy, and was twice as high when compared with the .. evidence for a dual treatment approach is available for VKA,755 rivar-
..
rate of acute coronary events including recurrent MI and stent .. oxaban,756 and dabigatran,757 but none of these studies were pow-
thrombosis. For these reasons, the duration of triple therapy should .. ered to assess the efficacy of preventing stent thrombosis or
..
be minimized depending on bleeding and ischaemic risks (see Tables 8 .. thrombo-embolic events and only RE-DUAL used a NOAC dose

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to 10 for guidance in decision-making). In stabilized event-free .. that was previously shown to be effective in the prevention of
..
patients, discontinuation of any antiplatelet agent at 1 year after stent- .. thrombo-embolic events. The ongoing AUGUSTUS trial
ing is encouraged, while dual therapy may be continued beyond 1
.. (ClinicalTrials.gov Identifier: NCT02415400) will address the value of
..
year according to the stent-driven risk shown in Table 9. .. apixaban in a similar setting, and with and without aspirin. Edoxaban
Based on the favourable bleeding risk in the large phase 3 studies, a
.. is currently being investigated in a setting of triple treatment in the
..
NOAC should be preferred over a VKA. The PIONEER756 .. ENTRUST-AF-PCI (Evaluation of the safety and efficacy of an edoxa-
(Prevention of bleeding in patients with AF undergoing PCI) trial and
.. ban-based antithrombotic regimen in patients with atrial fibrillation
..
the more recent RE-DUAL (Randomised Evaluation of Dual .. following successful percutaneous coronary intervention) trial
Antithrombotic Therapy with Dabigatran versus Triple Therapy with
.. (ClinicalTrials.gov Identifier: NCT02866175).
..
Warfarin in Patients with Nonvalvular Atrial Fibrillation Undergoing .. Figure 11 illustrates applicable DAPT algorithms in patients with an
Percutaneous Coronary Intervention)757 trial compared a NOAC ... indication for OAC undergoing PCI with the respective classes of
..
plus single antiplatelet therapy with triple therapy with a VKA plus .. recommendations for the different treatment regimens. For more
DAPT and consistently showed significantly lower bleeding risks with .. details on the pertinent studies in the field of triple treatment (DAPT
..
the dual antithrombotic regimen. In RE-DUAL, both dosing regimens .. plus OAC) and the associated issues, we refer the reader to the 2017
for dabigatran (150 mg and 110 mg b.i.d.) vs. warfarin triple therapy .. ESC Focused Update on Dual Antiplatelet Therapy in Coronary
..
were associated with a significant reduction of major or clinically .. Artery Disease.410
.

Table 8 Strategies to avoid bleeding complications in oral anticoagulation patients

Assess ischaemic and bleeding risks using validated risk predictors (e.g. CHA2DS2-VASc, ABC, and HAS-BLED) with a focus on modifiable risk
factors.

Keep triple therapy duration as short as possible; dual therapy after PCI (OAC and clopidogrel) to be considered instead of triple therapy.

One should consider the use of a NOAC instead of a VKA when NOACs are not contraindicated.

Consider a target INR in the lower part of the recommended target range and maximize time in the therapeutic range (i.e. >65%)
when a VKA is used.

Clopidogrel is the P2Y12 inhibitor of choice.

Use low-dose (<_100 mg daily) aspirin.

Routine use of PPIs.

Adapted from Valgimigli et al.410


ABC = Age, Biomarkers, Clinical history; CHA2DS2-VASc = Congestive heart failure, Hypertension, Age >_75 years (doubled), Diabetes mellitus, prior Stroke or transient
ischaemic attack or thromboembolism (doubled), Vascular disease, Age 65–74 years, Sex category (female); HAS-BLED = Hypertension, Abnormal renal/liver function, Stroke,
Bleeding history or predisposition, Labile INR, Elderly, Drugs/alcohol concomitantly; INR = international normalized ratio; NOAC = non-vitamin K antagonist OAC; OAC =
oral anticoagulant; PPIs = proton pump inhibitors; VKA = vitamin K antagonist.
ESC/EACTS Guidelines 147

Table 9 High-risk features for ischaemic events Dual antiplatelet therapy duration in patients with indi-
cation for oral anticoagulation
Prior stent thrombosis on adequate antiplatelet therapy
Recommendations Classa Levelb
Stenting of the last remaining patent coronary artery
It is recommended that periprocedural aspirin
Diffuse multivessel disease, especially in diabetic patients and clopidogrel are administered to patients I C
undergoing coronary stent implantation.
Chronic kidney disease (i.e. creatinine clearance <60 mL/min)
In patients treated with coronary stent implan-
At least three stents implanted tation, triple therapy with aspirin, clopidogrel,
IIa B
and an OAC should be considered for 1 month,
At least three lesions treated
irrespective of the type of stent used.755

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Bifurcation with two stents implanted
Triple therapy with aspirin, clopidogrel, and
Total stented length >60 mm an OAC for longer than 1 month and up to 6
months should be considered in patients
IIa B
Treatment of a chronic total occlusion with high ischaemic risk due to ACS or other
anatomical/procedural characteristics, which
History of STEMI
outweigh the bleeding risk.755

STEMI = ST-elevation myocardial infarction. Dual therapy with clopidogrel 75 mg/day and
an OAC should be considered as an alterna-
tive to 1-month triple antithrombotic ther- IIa A
apy in patients in whom the bleeding risk
outweighs the ischaemic risk.754,756,757

In patients with non-valvular AF requiring anti-


coagulation and antiplatelet treatment, a IIa A
Table 10 Unfavourable patient profile for a combina-
NOAC should be preferred over VKAs.758–760
tion of oral anticoagulant and antiplatelet therapy
In patients with an indication for a VKA in com-
Short life expectancy bination with aspirin and/or clopidogrel, the
dose intensity of the VKA should be carefully
IIa B
Ongoing malignancy regulated with a target INR in the lower part of
the recommended target range and time in the
Poor expected adherence
therapeutic range >65%.754,755
Poor mental status Discontinuation of antiplatelet treatment in
patients treated with OAC should be consid- IIa B
End-stage renal failure
ered at 12 months.753
Advanced age
When a NOAC is used in combination with
Prior major bleeding/prior haemorrhagic stroke aspirin and/or clopidogrel, the lowest approved
IIa C
dose effective for stroke prevention tested in
Chronic alcohol abuse AF trials should be considered.c

Anaemia When rivaroxaban is used in combination with


aspirin and/or clopidogrel, rivaroxaban 15 mg q.d. IIb B
Clinically significant bleeding on dual antithrombotic therapy
may be used instead of rivaroxaban 20 mg q.d.756

When dabigatran is used in combination with


aspirin or clopidogrel, a dose of 150 mg b.i.d. IIb B
may be preferred over a dose of 110 mg b.i.d.757

The use of ticagrelor or prasugrel is not rec-


ommended as part of triple antithrombotic III C
therapy with aspirin and an OAC.

ACS = acute coronary syndrome; AF = atrial fibrillation; b.i.d. = twice daily; INR
= international normalized ratio; OAC = oral anticoagulant; NOAC = non-vita-
min K oral anticoagulant; q.d. = once daily; VKA = vitamin K antagonist.
a
Class of recommendation.
b
Level of evidence.
c
Apixaban 5 mg b.i.d. or apixaban 2.5 mg b.i.d. if at least two of the following: age
>_80 years, body weight <_60 kg, or serum creatinine level >_1.5 mg/dL (133 mmol/
L); dabigatran 110 mg or 150 mg b.i.d.; and edoxaban 60 mg q.d. or edoxaban 30
mg q.d. if any of the following: creatinine clearance of 30–50 mL/min; body weight
<_60 kg; concomitant use of verapamil, quinidine, or dronedarone; and rivaroxa-
ban 20 mg q.d. or rivaroxaban 15 mg q.d. if creatinine clearance 30–49 mL/min.
148 ESC/EACTS Guidelines

Patients with an indication for oral anticoagulation1


undergoing PCI2

Concerns about
ischaemic risk3 Concerns about bleeding risk4 prevailing
prevailing

Time from
treatment
initiation

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A C O A C O C O
1 month Triple Therapy 1 month Triple Therapy Dual Therapy
Class IIa B Class IIa B up to 12 months
1 month Class IIa A

3 months A C O C O OR A O
Triple Therapy Dual Therapy
up to 6 months up to 12 months
Class IIa B Class IIa A
6 months
C O A O
Dual Therapy up to 12 months
Class IIa A
12 months

Beyond O
12 months OAC monotherapy
Class IIa B

©ESC 2018
A = Aspirin C = Clopidogrel O = Oral anticoagulation1

Colour-coding refers to the number of concomitant antithrombotic medication(s). Triple therapy denotes treatment with DAPT plus oral anticoagulant (OAC). Dual
therapy denotes treatment with a single antiplatelet agent (aspirin or clopidogrel) plus OAC.
ABC = Age, Biomarkers, Clinical history; AF = atrial fibrillation; HAS-BLED = Hypertension, Abnormal renal/liver function, Stroke, Bleeding history or predisposition,
Labile INR, Elderly, Drugs/alcohol concomitantly; VKA = vitamin K antagonist.
1
Non-vitamin K antagonist oral anticoagulant (NOAC) preferred over VKA in patients with non-valvular AF. (Class IIaA).
2
Periprocedural administration of aspirin and clopidogrel during PCI is recommended irrespective of the treatment strategy.
3
High ischaemic risk is considered as an acute clinical presentation or anatomical/procedural features which might increase the risk for myocardial infarction.
4
Bleeding risk can be estimated by HAS-BLED or ABC score.

Figure 11 Algorithm for dual antiplatelet therapy in patients with an indication for oral anticoagulation undergoing percutaneous coronary
intervention.

17.5.2 Revascularization in patients with renal .. 17.5.4 Surgery in patients on dual antiplatelet therapy
..
failure .. See 2017 ESC Focused Update on Dual Antiplatelet Therapy in
See the Supplementary Data.
.. Coronary Artery Disease.410
..
..
..
17.5.3 Monitoring of antiplatelet drugs (platelet function .. 17.6 Gaps in the evidence
testing and genotyping)
.. The value of pre-hospital pre-treatment with prasugrel in STEMI
..
See the Supplementary Data. . patients, as well as the safety and efficacy of ticagrelor given at
ESC/EACTS Guidelines 149

hospital admission in NSTE-ACS patients, has not been addressed in


.. hospitals strongly predicted mortality, irrespective of surgeon or hos-
..
dedicated randomized studies. .. pital case volumes.767 Therefore, it is recommended that such quality
The safety and efficacy of short-term potent antiplatelet treatment
.. measures (as an example see Supplementary Table 9) are
..
with either prasugrel or ticagrelor in SCAD patients is unknown, and .. adopted and reported to facilitate focused quality improvement.768
is subject to ongoing clinical trials [the ALPHEUS (Assessment of
..
..
Loading With the P2Y12 Inhibitor Ticagrelor or Clopidogrel to Halt .. 18.2 Percutaneous coronary
Ischemic Events in Patients Undergoing Elective Coronary Stenting) ... intervention
..
trial: NCT02617290 and the SASSICAIA (Comparison of Loading .. Numerous studies have investigated the relationship between the
Strategies With Antiplatelet Drugs in Patients Undergoing Elective .. volume of procedures and outcomes of PCI, suggesting a
..
Coronary Intervention) trial: NCT02548611]. .. volume–outcome relationship at the operator level, as well as at the
The clinical benefit of a short-term DAPT duration followed by .. institutional level.761,769–773 A population-based study from the PCI
..
long-term ticagrelor monotherapy (and stopping aspirin) remains .. reporting system of New York indicated that hospital case volumes

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unknown. The ongoing GLOBAL LEADERS (Long-term ticagrelor ..
.. <400 PCIs per year and operator case volumes <75 PCIs per year
monotherapy versus standard dual antiplatelet therapy followed .. were associated with impaired outcomes.769
by aspirin monotherapy in patients undergoing biolimus-eluting ..
.. Among patients with ACS, particularly STEMI, operator and hospi-
stent implantation) and TWILIGHT (Ticagrelor With Aspirin or .. tal volumes play important roles. A large study in the USA reported
Alone in High-Risk Patients After Coronary Intervention) trials aim ..
.. that, in a cohort of 36 535 patients undergoing primary PCI, in-
to close this gap in our current knowledge (NCT01813435 and .. hospital mortality was significantly lower in institutions with higher
NCT02270242, respectively). ..
.. primary PCI volumes (5.7% in hospitals performing >33 primary
.. PCIs/year vs. 7.7% in hospitals performing <12 primary PCIs/year).774
..
.. Operator volume has also been shown to impact outcomes in LM
18 Volume outcome relationship .. PCI. A single-centre study of 1948 patients who underwent unpro-
..
for revascularization procedures .. tected LM PCI, performed by 25 operators over a 7 year period,
.. showed reduced 30 day and 3 year mortality for patients who had
..
Operator experience influences outcomes, particularly in critical, .. their PCI performed by a high-volume operator (defined as >_15 LM
complex situations. Greater total experience of an entire hospital
.. PCI/year; mean 25/year) vs. a low-volume operator (<15 LM PCI/
..
team—consisting of the supporting members in the operating room .. year).775
or catheterization laboratory and those responsible for postopera-
.. An example of quality measures for PCI is provided in
..
tive care—results in more favourable outcomes. .. Supplementary Table 10.
..
..
18.1 Coronary artery bypass grafting .. 18.3 Training in cardiac surgery and
..
Studies have suggested that the volume of CABG surgery in a hos- .. interventional cardiology for myocardial
.. revascularization
pital significantly impacts in-hospital mortality, although no consis- ..
tent cut-offs for volume were used in these studies.761–762 This .. A European training programme in interventional cardiology has
..
increase in mortality observed in lower volume centres seems to .. been proposed by the EAPCI in order to ensure the high quality of
be attributable to so-called ‘failure to rescue’: although patients .. patient care and clinical excellence.776 The programme should last
..
operated on at low-volume centres are not at particularly higher .. 1–2 years at high-volume institutions that handle >_800 PCIs per year
risk of suffering a major complication, they are more likely to die .. and that have an established 24 h/7 day service for the treatment of
..
from such a complication should it occur.763 Therefore, consider- .. patients with ACS.
ation should be given to the performance of CABG in centres .. For CABG, no standardized European programme exists at
..
with an annual volume of at least 200 CABG cases. Apart from .. this time. However, the pace at which proficiency reaches certain
hospital volume, higher surgeon volume also appears to be inver- .. acceptable standards differs from trainee to trainee. Therefore,
..
sely related to operative mortality. Birkmeyer et al. provided evi- .. although it is recommended that trainees perform >_200 CABG pro-
dence suggesting that both hospitals and surgeons have some .. cedures under supervision before becoming completely independ-
..
impact on outcomes.764 .. ent, a competency-driven residency programme with regular
Several studies suggest that quality measures are more
.. evaluation of progress is recommended over a volume-driven
..
important than volume per se.765,766 Missing quality indicators in . programme.
150 ESC/EACTS Guidelines

Recommendations for operator/institutional volume in myocardial revascularization

Recommendations Classa Levelb

CABG

It should be considered that CABG be performed at institutions with annual institutional volumes of >_200 CABG cases. IIa C

PCI

It should be considered that PCI for ACS be performed by trained operators with annual volumes of >_75 procedures
at institutions performing >_400 PCIs per year with an established 24 h/7 day service for the treatment of patients with IIa C
ACS.

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It should be considered that PCI for SCAD be performed by trained operators with annual volumes of >_75 procedures
IIa C
at institutions performing >_200 PCIs per year.

It should be considered that institutions with annual volumes of <400 PCIs collaborate in networks with higher-volume
IIa C
institutions (>400 PCIs per year), with shared written protocols and exchange of operators and support staff.

It should be considered that PCI for LM be performed by trained operators with an annual volume of >_25 LM PCI cases
IIa C
per year.

It should be considered that non-emergency high-risk PCI procedures—such as for LM disease, single remaining patent
coronary artery, and complex chronic total occlusions—are only performed by adequately experienced operators at IIa C
centres that have access to circulatory support and intensive care treatment.

ACS = acute coronary syndromes; CABG = coronary artery bypass grafting; LM = left main; PCI = percutaneous coronary intervention; SCAD = stable coronary artery
disease.
a
Class of recommendation.
b
Level of evidence.

Recommendations for training in myocardial revascularization

Recommendations Classa Levelb

Training in CABG

It is recommended that trainees in cardiac surgery and interventional cardiology follow a competency-driven residency
I C
programme with regular evaluation of progression.

It should be considered that trainees in cardiac surgery perform >_200 CABG procedures under supervision before
IIa C
being independent.

Training in PCI

It should be considered that trainees in interventional cardiology perform >_200 PCI procedures as first operator, with
IIa C
one-third of PCI procedures in emergency or ACS patients under supervision, before being independent.

It should be considered that trainees in interventional cardiology complete formal training according to a 1–2 year cur-
riculum at institutions with >_800 PCIs per year and an established 24 h/7 day service for the treatment of patients with IIa C
ACS.

ACS = acute coronary syndrome; CABG = coronary artery bypass grafting; PCI = percutaneous coronary intervention.
a
Class of recommendation.
b
Level of evidence.
ESC/EACTS Guidelines 151

Recommendations for outcome registration, monitor- Strategies for follow-up and management in patients
ing, and benchmarking after myocardial revascularization

Recommendations Classa Levelb Recommendations Classa Levelb

It is recommended that specific quality per- After CABG or PCI for AMI, participation in
formance measures for CABG are adopted a cardiac rehabilitation programme is rec-
I C I A
at a national level to allow outcome moni- ommended to improve patient
toring and benchmarking. outcomes.777

It is recommended that national societies It is recommended that secondary preven-


establish national databases on CABG prac- I C tion measures, including medical therapy

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tice and outcomes. and lifestyle changes, are started and rein- I A
forced after myocardial
It is recommended that CABG outcome
revascularization.683,778–785
data are reported by hospitals to national I C
databases. It is recommended that patients are re-eval-
uated after myocardial revascularization
CABG = coronary artery bypass grafting. (e.g. at 3 months and thereafter, at least on
a
Class of recommendation. an annual basis) in order to reassess symp-
b
Level of evidence. I C
toms and adherence to secondary preven-
tion measures, and reinforce medical
therapy and lifestyle changes when
appropriate.

19 Medical therapy, secondary Symptomatic patients

prevention, and strategies for Coronary angiography is recommended in


patients with intermediate- to high-risk fin- I C
follow-up dingsc at stress testing.
Myocardial revascularization must be accompanied by medical ther-
An imaging stress test should be considered
apy and other secondary prevention strategies for risk factor modifi- IIa B
in patients with prior revascularization over
cation and permanent lifestyle changes.42 Secondary prevention and
stress ECG.786
cardiac rehabilitation are an integral part of management after revas-
cularization because such measures reduce future morbidity and Asymptomatic patients
mortality in a cost-effective way, and can further improve symptoms.
Surveillance by non-invasive imaging-based
These measures are discussed in detail in the European Guidelines
stress testing may be considered in high-risk
on Cardiovascular Disease Prevention that were published in 2016.42 IIb C
patient subsets 6 months after
The need to detect restenosis has reduced in the DES era.
revascularization.
Likewise, the durability of CABG results have increased with the use
of arterial grafts, and ischaemia stems mainly from SVG attrition and/ After high-risk PCI (e.g. unprotected LM
or progression of CAD in native vessels. Nevertheless, the recur- stenosis), late (3–12 months) surveillance
IIb C
rence of symptoms or ischaemia due to disease progression or reste- angiography may be considered, irrespective
nosis deserves attention. of symptoms.

Routine non-invasive imaging-based stress


testing may be considered 1 year after PCI IIb C
and >5 years after CABG.

AMI = acute myocardial infarction; CABG = coronary artery bypass grafting;


ECG = electrocardiogram; LM = left main; PCI = percutaneous coronary
intervention.
a
Class of recommendation.
b
Level of evidence.
c
Intermediate- and high-risk findings at stress imaging are ischaemia at low work-
load with exercise stress testing, early-onset ischaemia with pharmacological
stress testing, an inducible wall motion abnormality, or a reversible perfusion
defect in >_10% of LV myocardium.
152 ESC/EACTS Guidelines

..
19.1 Gaps in the evidence .. (5) In some instances, both PCI and CABG are equally reasonable, or
In all studies to date on the optimal follow-up after PCI, the gain from
.. sometimes even equally problematic, options. This calls for the
..
discovering patients with restenosis is obscured by the high rate .. Heart Team to be consulted to develop individualized treatment
.. concepts, with respect for the preferences of the patient who has
of false positive exercise ECG tests indicating ischaemia. Therefore, ..
simple exercise ECG testing is not recommended for follow-up and .. been informed about early and late outcomes.
.. (6) Timely PCI of the culprit lesion remains the mainstay of treatment
a non-invasive imaging approach is preferred. Specific studies to ..
clarify which subset of patients benefits more from a specific follow- .. of ACS.
.. (7) After PCI of the culprit lesion in ACS, the choice of further revas-
up approach are missing. More studies are needed to assess the role ..
of CT angiography in patient surveillance after myocardial .. cularization modality should follow the criteria applied to patients
.. with SCAD.
revascularization. ..
.. (8) Radial access is preferred for any PCI irrespective of clinical pre-
.. sentation, unless there are overriding procedural considerations.
..

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20 Key messages .. (9) DES are recommended for any PCI irrespective of clinical presen-
.. tation, lesion type, anticipated duration of DAPT, or concomitant
..
(1) Myocardial revascularization is performed for the relief of symp- .. anticoagulant therapy.
toms of myocardial ischaemia and the improvement of prognosis.
.. (10) Even though 6 months of DAPT is generally recommended after
..
In SCAD, the prognostic benefit is dependent on the extent of .. PCI in SCAD and 12 months of DAPT after ACS, the type and
myocardium subject to ischaemia.
.. duration of DAPT should be individualized according to the ischae-
..
(2) The prognostic and symptomatic benefits of myocardial revascula- .. mic and bleeding risks, and appropriately adapted during follow-
.. up. Based on this judgement, treatment durations for DAPT after
rization critically depend on the completeness of revascularization. ..
Therefore, the ability to achieve complete revascularization is a .. DES that are as short as 1 month or even as long as lifelong may be
.. reasonable.
key issue when choosing the appropriate treatment strategy. ..
(3) Apart from issues of individual operative risk and technical feasibil- .. (11) Off-pump surgery with no-touch aorta for high-risk patients
..
ity, diabetes mellitus and the anatomical complexity of CAD deter- .. should be considered when expertise exists.
mine the relative benefits of PCI and CABG. .. (12) Multiple arterial grafting should be considered using the radial
..
(4) The SYNTAX score is the recommended tool to gauge the ana- .. artery for high-grade stenosis and/or BIMA grafting for patients
tomical complexity of coronary disease. .. who do not have an increased risk of sternal wound infection.
..
..

21 Evidence-based ‘to do’ and ‘not to do’ messages from the Guidelines

Risk models to assess short- and long-term outcomes after myocardial revascularization Classa Levelb

When evidence of ischaemia is not available, FFR or iwFR are recommended to assess the haemodynamic relevance
I A
of intermediate-grade stenosis.

It is recommended that the STS score is calculated to assess in-hospital or 30 day mortality, and in-hospital morbidity,
I B
after CABG.

In patients with LM or multivessel disease, it is recommended that the SYNTAX score is calculated to assess the
I B
anatomical complexity of CAD and the long-term risk of mortality and morbidity after PCI.

Indications for revascularization in patients with stable angina or silent ischaemia

For prognosis LM disease with stenosis >50%.c I A

Any proximal LAD stenosis >50%.c I A

Two- or three-vessel disease with stenosis >50%c with impaired LV function (LVEF <_35%).c I A
d
Large area of ischaemia detected by functional testing (>10% LV) or abnormal invasive FFR. I B

For symptoms Any haemodynamically significant coronary stenosis in the presence of limiting angina or angina equivalent,
I A
with an insufficient response to optimized medical therapy.

Continued
ESC/EACTS Guidelines 153

Type of revascularization (CABG or PCI) in patients with SCAD with suitable coronary anatomy for both
procedures and low predicted surgical mortality

Recommendations according to the extent of CAD CABG PCI

Classa Levelb Classa Levelb

One-vessel CAD

With proximal LAD stenosis I A I A

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Two-vessel CAD

With proximal LAD stenosis I B

LM CAD

LM with low SYNTAX score 0 - 22 I A I A

LM with intermediate SYNTAX score >22 and <_32 I A

LM with high SYNTAX score >32.e I A III B

Three-vessel CAD without diabetes mellitus

Three-vessel disease with low SYNTAX score 0 - 22 I A I A

Three-vessel disease with intermediate or high SYNTAX score >22e I A III A

Three-vessel CAD with diabetes mellitus

Three-vessel disease with low SYNTAX score 0 - 22 I A


e
Three-vessel disease with intermediate or high SYNTAX score >22 I A III A

Invasive evaluation and revascularization in NSTE-ACS

An early invasive strategy (<24 h) is recommended in patients with at least one high-risk criterion (Figure 4). I A

An invasive strategy (<72 h after first presentation) is indicated in patients with at least one intermediate-risk
I A
criterion (Figure 4) or recurrent symptoms.

It is recommended that the revascularization strategy (ad hoc culprit-lesion PCI/multivessel PCI/CABG) is based
on the patient’s clinical status and comorbidities, as well as the disease severity, i.e. distribution and I B
angiographic lesion characteristics (e.g. SYNTAX score), according to the principles for SCAD.

In cardiogenic shock, routine revascularization of non-IRA lesions is not recommended during primary PCI. III B

Continued
154 ESC/EACTS Guidelines

Primary PCI for myocardial reperfusion in STEMI

Indication

Reperfusion therapy is indicated in all patients with time from symptom onset <12 h duration and persistent ST-seg-
I A
ment elevation.

A primary PCI strategy is recommended over fibrinolysis within indicated timeframes. I A

Logistics

It is recommended that the pre-hospital management of STEMI patients be based on regional networks that are

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I B
designed to timely and effectively deliver reperfusion therapy, and to offer primary PCI to as many patients as possible.

It is recommended that primary PCI-capable centres deliver a 24 h/7 day service and ensure that primary PCI is per-
I B
formed as fast as possible.

Patients transferred to a PCI-capable centre for primary PCI should bypass the emergency department and be trans-
I B
ferred directly to the catheterization laboratory.

Strategy/technique

In cardiogenic shock, routine revascularization of non-IRA lesions is not recommended during primary PCI. III B

Routine use of thrombus aspiration is not recommended. III A

Recommendations on revascularizations in patients with chronic heart failure and systolic LV dysfunction (EF 35%)

In patients with severe LV systolic dysfunction and coronary artery disease suitable for intervention, myocardial revas-
I B
cularization is recommended.

CABG is recommended as the first revascularization strategy choice in patients with multivessel disease and acceptable
I B
surgical risk.

Revascularizations in patients with cardiogenic shock

Emergency invasive evaluation is indicated in patients with acute heart failure or cardiogenic shock complicating ACS. I B

Emergency PCI is indicated for patients with cardiogenic shock due to STEMI or NSTE-ACS, independent of time delay
I B
of symptom onset, if coronary anatomy is amenable.

Emergency CABG is recommended for patients with cardiogenic shock if the coronary anatomy is not amenable to
I B
PCI.

Routine use of IABP in patients with cardiogenic shock due to ACS is not recommended. III B

Prevention of contrast-induced nephropathy

Patients with moderate-to-severe CKD

Use of low- or iso-osmolar contrast media is recommended. I A

It is recommended that the volume of contrast media is minimized. I B

Severe CKD

Haemodialysis therapy is not recommended as a preventative measure. III B

Pre-operative strategies to reduce the incidence of stroke in patients undergoing CABG

In patients undergoing CABG, carotid DUS is recommended in patients with recent (<6 months) history of stroke/TIA. I B
Continued
ESC/EACTS Guidelines 155

Disease progression and late graft failure

Repeat revascularization is indicated in patients with extensive ischaemia or severe symptoms despite medical therapy. I B

IMA is the conduit of choice for redo CABG in patients in whom the IMA was not used previously. I B

DES are recommended for the treatment of in-stent restenosis within BMS or DES. I A

Drug-coated balloons are recommended for the treatment of in-stent restenosis within BMS or DES. I A

Prevention of ventricular arrhythmias by revascularization

A primary PCI strategy is recommended in patients with resuscitated cardiac arrest and an ECG consistent with STEMI. I B

Perioperative oral b-blocker therapy is recommended for the prevention of post-operative AF after CABG surgery. I B

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Procedural aspects of CABG

Arterial grafting with an IMA to the LAD system is recommended. I B

Use of the radial artery is recommended over the saphenous vein in patients with high-degree stenosis. I A

Skeletonized IMA dissection is recommended in patients with high risk of sternal wound infection. I B

Minimization of aortic manipulation is recommended. I B

Procedural aspects of PCI

DESf are recommended over BMS for any PCI irrespective of:
• clinical presentation
• lesion type
I A
• planned non-cardiac surgery
• anticipated duration of DAPT
• concomitant anticoagulant therapy.

Radial access is recommended as the standard approach, unless there are overriding procedural considerations. I A

Stent implantation in the main vessel only, followed by provisional balloon angioplasty with or without stenting of the
I A
side branch, is recommended for PCI of bifurcation lesions.

Antithrombotic treatment in SCAD patients undergoing PCI

Treatment with 600 mg clopidogrel is recommended in elective PCI patients once anatomy is known and the decision
I A
has been made to proceed with PCI.

Aspirin is indicated before elective stenting. I A

Clopidogrel (600 mg loading dose and 75 mg daily maintenance dose) is recommended for elective stenting. I A

UFH is indicated as a standard anticoagulant (70–100 U/kg). I B

Life-long single antiplatelet therapy, usually aspirin, is recommended. I A

In patients with SCAD treated with coronary stent implantation, DAPT consisting of clopidogrel in addition to aspirin is
I A
generally recommended for 6 months, irrespective of the stent type.

Antithrombotic treatment in NSTE-ACS patients undergoing PCI

Aspirin is recommended for all patients without contraindications at an initial oral loading dose of 150–300 mg (or
I A
75–250 mg i.v.) and at a maintenance dose of 75–100 mg daily long-term, regardless of treatment strategy.
Continued
156 ESC/EACTS Guidelines

A P2Y12 inhibitor is recommended in addition to aspirin, maintained over 12 months unless there are contraindications
I A
such as an excessive risk of bleeding. Options are:

 Prasugrel in P2Y12-naı̈ve patients who proceed to PCI (60 mg loading dose and 10 mg daily dose) I B

 Ticagrelor irrespective of the pre-treatment and revascularization strategy (180 mg loading dose, 90 mg twice daily) I B

 Clopidogrel (600 mg loading dose and 75 mg daily dose), only when prasugrel or ticagrelor are not available or are
I B
contraindicated.

Pre-treatment with GP IIb/IIIa antagonists in patients in whom coronary anatomy is not known is not recommended. III A

Administration of prasugrel to patients in whom coronary anatomy is not known is not recommended. III B

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Peri-interventional anticoagulation is recommended for all patients in addition to antiplatelet therapy. I A

In patients on fondaparinux (2.5 mg daily s.c.), a single bolus UFH (85 IU/kg, or 60 IU in the case of concomitant use of
I B
GP IIb/IIIa receptor inhibitors) is indicated.

Crossover of UFH and LMWH is not recommended. III B

In patients with ACS treated with coronary stent implantation, DAPT with a P2Y12 inhibitor on top of aspirin is recom-
mended for 12 months unless there are contraindications such as an excessive risk of bleeding (e.g. PRECISE-DAPT I A
>_25).

Antithrombotic treatment in STEMI patients undergoing PCI

Aspirin is recommended for all patients without contraindications at an initial oral loading dose of 150–300 mg (or
I A
75–250 mg i.v.), and at a maintenance dose of 75–100 mg daily long-term regardless of treatment strategy.

A potent P2Y12 inhibitor (prasugrel or ticagrelor), or clopidogrel if these are not available or are contraindicated, is rec-
ommended before (or at the time of PCI at the latest) PCI and should be maintained over 12 months, unless there are I A
contraindications such as an excessive risk of bleeding.

Strategies for follow-up and management

After CABG or PCI for AMI, participation in a cardiac rehabilitation programme is recommended to improve patient
I A
outcomes.

It is recommended that secondary prevention measures, including medical therapy and lifestyle changes, are started and
I A
reinforced after myocardial revascularization.

ACS = acute coronary syndrome; AF = atrial fibrillation; AMI = acute myocardial infarction; BMS = bare-metal stent; CABG = coronary artery bypass grafting; CAD = coronary
artery disease; CKD = chronic kidney disease; DAPT = dual antiplatelet therapy; DES = drug eluting stents; DUS = duplex ultrasound; ECG = electrocardiogram; EF = ejection
fraction; FFR = fractional flow reserve; GP = glycoprotein; IABP = intra-aortic balloon pump; iwFR = instantaneous wave-free radio; IMA = internal mammary artery; IRA =
infarct-related artery; i.v. = intravenous; LAD = left anterior descending; LM = left main; LMWH = low-molecular-weight heparin; LV = left ventricular; LVEF = left ventricular
ejection fraction; NSTE-ACS = non-ST-elevation acute coronary syndrome; PCI = percutaneous coronary intervention; PRECISE-DAPT = PREdicting bleeding Complications
In patients undergoing Stent implantation and subsEquent Dual Anti Platelet Therapy; s.c. = subcutaneous; SCAD = stable coronary artery disease; STEMI = ST-elevation myo-
cardial infarction; STS = Society of Thoracic Surgeons; SYNTAX = Synergy between Percutaneous Coronary Intervention with TAXUS and Cardiac Surgery; TIA = transient
ischaemic attack; UFH = unfractionated heparin.
a
Class of recommendation.
b
Level of evidence.
c
With documented ischaemia, a haemodynamically relevant lesion defined by FFR <_0.80 or iwFR <_0.89, or >90% stenosis in a major coronary vessel.
d
Based on FFR <0.75 indicating a prognostically relevant lesion.
e
PCI should be considered, if the Heart Team is concerned about the surgical risk or if the patient refuses CABG after adequate counselling by the Heart Team.
f
These recommendations refer to stents that are supported by large-scale randomized trials with clinical endpoint evaluation leading to an unconditional CE mark.

..
22 Appendix ..
..
Gaemperli (Switzerland), Gerhard Hindricks (Germany), Bernard
.. Iung (France), Peter Jüni (Canada), Hugo A. Katus (Germany),
ESC Committee for Practice Guidelines (CPG): .. Juhani Knuuti (Finland), Patrizio Lancellotti (Belgium), Christophe
Stephan Windecker (Chairperson) (Switzerland), Victor Aboyans .. Leclercq (France), Theresa A. McDonagh (UK), Massimo Francesco
..
(France), Stefan Agewall (Norway), Emanuele Barbato (Italy), Héctor .. Piepoli (Italy), Piotr Ponikowski (Poland), Dimitrios J. Richter
Bueno (Spain), Antonio Coca (Spain), Jean-Philippe Collet (France), .. (Greece), Marco Roffi (Switzerland), Evgeny Shlyakhto (Russia),
..
Ioan Mircea Coman (Romania), Veronica Dean (France), Victoria .. Miguel Sousa-Uva (Portugal), Iain A. Simpson (UK), Jose Luis
Delgado (The Netherlands), Donna Fitzsimons (UK), Oliver .. Zamorano (Spain).
.
ESC/EACTS Guidelines 157

EACTS Council: (On behalf of the EACTS Council): Domenico


.. 2. Min JK, Leipsic J, Pencina MJ, Berman DS, Koo BK, van Mieghem C, Erglis A, Lin
.. FY, Dunning AM, Apruzzese P, Budoff MJ, Cole JH, Jaffer FA, Leon MB,
Pagano (Secretary General) (UK), Nick Freemantle (UK), Miguel ..
Sousa-Uva (Portugal).
.. Malpeso J, Mancini GB, Park SJ, Schwartz RS, Shaw LJ, Mauri L. Diagnostic
.. accuracy of fractional flow reserve from anatomic CT angiography. JAMA
ESC National Cardiac Societies actively involved in the .. 2012;308:1237–1245.
review process of the 2018 ESC/EACTS Guidelines on myocardial
.. 3. Norgaard BL, Leipsic J, Gaur S, Seneviratne S, Ko BS, Ito H, Jensen JM, Mauri L,
.. De Bruyne B, Bezerra H, Osawa K, Marwan M, Naber C, Erglis A, Park SJ,
revascularization: Algeria: Algerian Society of Cardiology, .. Christiansen EH, Kaltoft A, Lassen JF, Botker HE, Achenbach S, Group NXTTS.
Mohamed Chettibi; Armenia: Armenian Cardiologists Association,
.. Diagnostic performance of noninvasive fractional flow reserve derived from coro-
..
Hamayak Sisakian; Austria: Austrian Society of Cardiology, .. nary computed tomography angiography in suspected coronary artery disease:
.. The NXT trial (Analysis of Coronary Blood Flow Using CT Angiography: Next
Bernhard Metzler; Azerbaijan: Azerbaijan Society of Cardiology,
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Firdovsi _Ibrahimov; Belarus: Belorussian Scientific Society of .. 4. Douglas PS, Pontone G, Hlatky MA, Patel MR, Norgaard BL, Byrne RA, Curzen N,
Cardiologists, Valeriy I. Stelmashok; Bulgaria: Bulgarian Society of .. Purcell I, Gutberlet M, Rioufol G, Hink U, Schuchlenz HW, Feuchtner G, Gilard
.. M, Andreini D, Jensen JM, Hadamitzky M, Chiswell K, Cyr D, Wilk A, Wang F,
Cardiology, Arman Postadzhiyan; Croatia: Croatian Cardiac .. Rogers C, De Bruyne B, PLATFORM Investigators. Clinical outcomes of fractional

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Society, Bosko Skoric; Cyprus: Cyprus Society of Cardiology, .. flow reserve by computed tomographic angiography-guided diagnostic strategies
.. vs. usual care in patients with suspected coronary artery disease: The prospective
Christos Eftychiou; Czech Republic: Czech Society of Cardiology, .. longitudinal trial of FFR(CT): Outcome and resource impacts study. Eur Heart J
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European Heart Journal (2019) 40, 237–269 EXPERT CONSENSUS DOCUMENT
doi:10.1093/eurheartj/ehy462

Fourth universal definition of myocardial


infarction (2018)
Kristian Thygesen* (Denmark), Joseph S. Alpert* (USA), Allan S. Jaffe (USA),
Bernard R. Chaitman (USA), Jeroen J. Bax (The Netherlands), David A. Morrow

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(USA), Harvey D. White* (New Zealand): the Executive Group on behalf of the Joint
European Society of Cardiology (ESC)/American College of Cardiology (ACC)/
American Heart Association (AHA)/World Heart Federation (WHF) Task Force for
the Universal Definition of Myocardial Infarction

Authors/Task Force Members/Chairpersons: Kristian Thygesen* (Denmark), Joseph


S. Alpert* (USA), Allan S. Jaffe (USA), Bernard R. Chaitman (USA), Jeroen J. Bax
(The Netherlands), David A. Morrow (USA), Harvey D. White* (New Zealand),
Hans Mickley (Denmark), Filippo Crea (Italy), Frans Van de Werf (Belgium), Chiara
Bucciarelli-Ducci (UK), Hugo A. Katus (Germany), Fausto J. Pinto (Portugal), Elliott
M. Antman (USA), Christian W. Hamm (Germany), Raffaele De Caterina (Italy),
James L. Januzzi Jr (USA), Fred S. Apple (USA), Maria Angeles Alonso Garcia
(Spain), S. Richard Underwood (UK), John M. Canty Jr (USA), Alexander R. Lyon
(UK), P. J. Devereaux (Canada), Jose Luis Zamorano (Spain), Bertil Lindahl
(Sweden), William S. Weintraub (USA), L. Kristin Newby (USA), Renu Virmani
(USA), Pascal Vranckx (Belgium), Don Cutlip (USA), Raymond J. Gibbons (USA),
Sidney C. Smith (USA), Dan Atar (Norway), Russell V. Luepker (USA), Rose Marie
Robertson (USA), Robert O. Bonow (USA), P. Gabriel Steg (France), Patrick T.
O’Gara (USA), Keith A. A. Fox (UK)

* Corresponding authors. Kristian Thygesen, Department of Cardiology, Aarhus University Hospital, Palle Juul-Jensens Boulevard, DK-8200 Aarhus N, Denmark. Tel: þ45
78452262, Fax: þ45 78452260, Email: kthygesen@oncable.dk; kristhyg@rm.dk. Joseph S. Alpert, Department of Medicine, University of Arizona College of Medicine, 1501 N.
Campbell Ave., P.O. Box 245037, Tucson AZ 85724-5037, USA. Tel: þ1 5206262763, Email: jalpert@email.arizona.edu. Harvey D. White, Green Lane Cardiovascular Service,
Auckland City Hospital, Private Bag 92024, 1030 Auckland, New Zealand. Tel: þ64 96309992, Fax: 00 64 9 6309915, Email: harveyw@adhb.govt.nz.
The content of this ESC/ACC/AHA/WHF Expert Consensus Document has been published for personal and educational use only. No commercial use is authorized. No part of
the ESC/ACC/AHA/WHF Expert Consensus Document may be translated or reproduced in any form without written permission from the ESC or ACC or AHA or WHF.
Permission can be obtained upon submission of a written request to Oxford University Press, the publisher of the European Heart Journal and the party authorized to handle
such permissions on behalf of the ESC, ACC, AHA and WHF (journals.permissions@oxfordjournals.org).
Disclaimer. The ESC/ACC/AHA/WHF Expert Consensus Document represents the views of the ESC, ACC, AHA, and WHF and was produced after careful consideration of
the scientific and medical knowledge and the evidence available at the time of their publication. The ESC, ACC, AHA, and WHF are not responsible in the event of any contra-
diction, discrepancy, and/or ambiguity between the ESC/ACC/AHA/WHF Expert Consensus Document and any other official recommendations or Expert Consensus Document
issued by the relevant public health authorities, in particular in relation to good use of healthcare or therapeutic strategies. Health professionals are encouraged to take the ESC/
ACC/AHA/WHF Expert Consensus Document fully into account when exercising their clinical judgment, as well as in the determination and the implementation of preventive,
diagnostic, or therapeutic medical strategies; however, the ESC/ACC/AHA/WHF Expert Consensus Document does not override, in any way whatsoever, the individual responsi-
bility of health professionals to make appropriate and accurate decisions in consideration of each patient’s health condition and in consultation with that patient and, where
appropriate and/or necessary, the patient’s caregiver. Nor does the ESC/ACC/AHA/WHF Expert Consensus Document exempt health professionals from taking into full and
careful consideration the relevant official updated recommendations or Expert Consensus Documents issued by the competent public health authorities, in order to manage
each patient’s case in light of the scientifically accepted data pursuant to their respective ethical and professional obligations. It is also the health professional’s responsibility to
verify the applicable rules and regulations relating to drugs and medical devices at the time of prescription.
This article has been co-published in European Heart Journal, Journal of the American College of Cardiology, Circulation, and Global Heart. All rights reserved.
C 2018 European Society of Cardiology, American College of Cardiology, American Heart Association, Inc., and World Heart Foundation. The articles are identical except for
V
minor stylistic and spelling differences in keeping with each journal’s style. Any citation can be used when citing this article.
238 Expert consensus document

Document Reviewers: David Hasdai (CPG Review Co-ordinator) (Israel), Victor Aboyans (France),
Stephan Achenbach (Germany), Stefan Agewall (Norway), Thomas Alexander (India), Alvaro Avezum
(Brazil), Emanuele Barbato (Italy), Jean-Pierre Bassand (France), Eric Bates (USA), John A. Bittl (USA),
Güenter Breithardt (Germany), Héctor Bueno (Spain), Raffaele Bugiardini (Italy), Mauricio G. Cohen
(USA), George Dangas (USA), James A. de Lemos (USA), Victoria Delgado (Netherlands), Gerasimos
Filippatos (Greece), Edward Fry (USA), Christopher B. Granger (USA), Sigrun Halvorsen (Norway), Mark
A. Hlatky (USA), Borja Ibanez (Spain), Stefan James (Sweden), Adnan Kastrati (Germany), Christophe
Leclercq (France), Kenneth W. Mahaffey (USA), Laxmi Mehta (USA), Christian Müller (Switzerland),
~ eiro (Argentina), Marco Roffi
Carlo Patrono (Italy), Massimo Francesco Piepoli (Italy), Daniel Pin
(Switzerland), Andrea Rubboli (Italy), Samin Sharma (USA), Iain A. Simpson (UK), Michael Tendera
(Poland), Marco Valgimigli (Switzerland), Allard C. van der Wal (Netherlands), Stephan Windecker
(Switzerland)

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The disclosure forms of all experts involved in the development of this Expert Consensus Document are
available on the ESC website www.escardio.org/guidelines

Online publish-ahead-of-print 25 August 2018

...................................................................................................................................................................................................
Keywords Expert Consensus Document • Myocardial infarction • Type 1 MI • Type 2 MI • Type 3 MI • Type 4a
MI • Type 4b MI • Type 4c MI • Type 5 MI • Cardiac troponin • High sensitivity cardiac troponin •
Myocardial injury • Prior myocardial infarction • Silent myocardial infarction • Recurrent myocardial
infarction • Re-infarction • Cardiac procedural myocardial injury • Takotsubo syndrome • Myocardial infarc-
tion with non-obstructive coronary arteries (MINOCA)

..
Table of contents .. 12 Myocardial infarction associated with coronary artery bypass
.. grafting (type 5 myocardial infarction) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 251
..
Abbreviations and acronyms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 239 .. 13 Other definitions of myocardial infarction related to percutaneous
1 What is new in the Universal Definition of Myocardial .. coronary intervention or coronary artery bypass grafting . . . . . . . . . . . 252
..
Infarction? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 240 .. 14 Recurrent myocardial infarction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 252
2 Universal definitions of myocardial injury and myocardial
.. 15 Re-infarction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 252
..
infarction: summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 241 .. 16 Myocardial injury and infarction associated with cardiac
3 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 242
.. procedures other than revascularization . . . . . . . . . . . . . . . . . . . . . . . . . . . 252
..
4 Pathological characteristics of myocardial ischaemia and .. 17 Myocardial injury and infarction associated with
infarction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 243
.. non-cardiac procedures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 252
..
5 Biomarker detection of myocardial injury and infarction . . . . . . . . . . 243 .. 18 Myocardial injury or infarction associated with heart failure . . . . . . 253
6 Clinical presentations of myocardial infarction . . . . . . . . . . . . . . . . . . . . 245
.. 19 Takotsubo syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 253
..
7 Clinical classification of myocardial infarction . . . . . . . . . . . . . . . . . . . . . 245 .. 20 Myocardial infarction with non-obstructive coronary arteries . . . . 254
7.1 Myocardial infarction type 1 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 245
.. 21 Myocardial injury and/or infarction associated with
..
7.2 Myocardial infarction type 2 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 246 .. kidney disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 254
..
7.3 Myocardial infarction type 2 and myocardial injury . . . . . . . . . . . . 248 .. 22 Myocardial injury and/or infarction in critically ill patients . . . . . . . . 254
7.4 Myocardial Infarction type 3 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 248 .. 23 Biochemical approach for diagnosing myocardial injury
..
8 Coronary procedure-related myocardial injury . . . . . . . . . . . . . . . . . . . 249 .. and infarction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 254
9 Myocardial infarction associated with percutaneous coronary .. 24 Analytical issues of cardiac troponins . . . . . . . . . . . . . . . . . . . . . . . . . . . 256
..
intervention (type 4a myocardial infarction) . . . . . . . . . . . . . . . . . . . . . . . . 250 .. 25 The 99th percentile upper reference limit . . . . . . . . . . . . . . . . . . . . . . . 256
10 Stent/scaffold thrombosis associated with percutaneous .. 26 Operationalizing criteria for myocardial injury and infarction . . . . . 256
..
coronary intervention (type 4b myocardial infarction) . . . . . . . . . . . . . . 251 .. 27 Electrocardiographic detection of myocardial infarction . . . . . . . . . 257
11 Restenosis associated with percutaneous coronary intervention .. 28 Application of supplemental electrocardiogram leads . . . . . . . . . . . . 258
..
(type 4c myocardial infarction) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 251 . 29 Electrocardiographic detection of myocardial injury . . . . . . . . . . . . . 259
Expert consensus document 239

30 Prior or silent/unrecognized myocardial infarction . . . . . . . . . . . . . . . 259 .. cTnI Cardiac troponin I


31 Conditions that confound the electrocardiographic diagnosis
..
.. cTnT Cardiac troponin T
of myocardial infarction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 259 .. CT Computed tomography
..
32 Conduction disturbances and pacemakers . . . . . . . . . . . . . . . . . . . . . . 260 .. CV Coefficient of variation
33 Atrial fibrillation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 260 .. EF Ejection fraction
..
34 Imaging techniques . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 260 .. ECG Electrocardiogram or electrocardiographic
34.1 Echocardiography . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 260 .. HF Heart failure
..
34.2 Radionuclide imaging . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 261 .. hs-cTn High-sensitivity cardiac troponin
34.3 Cardiac magnetic resonance imaging . . . . . . . . . . . . . . . . . . . . . . . 261 .. IFCC International Federation of Clinical Chemistry and
..
34.4 Computed tomographic coronary angiography . . . . . . . . . . . . . 262 .. Laboratory Medicine
35 Applying imaging in acute myocardial infarction . . . . . . . . . . . . . . . . . 262 ..
.. ISFC International Society and Federation of Cardiology
36 Applying imaging in late presentation of myocardial infarction . . . . 262 .. LAD Left anterior descending artery

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37 Regulatory perspective on myocardial infarction in ..
.. LBBB Left bundle branch block;
clinical trials . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 262 .. LoD Limit of detection
38 Silent/unrecognized myocardial infarction in epidemiological ..
.. LGE Late gadolinium enhancement
studies and quality programmes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 263 .. LGE-CMR Late gadolinium enhancement cardiac magnetic
39 Individual and public implications of the myocardial ..
.. resonance
infarction definition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 263 .. LV Left ventricular
40 Global perspectives of the definition of myocardial infarction . . . . 263
..
.. LVH Left ventricular hypertrophy
41 Using the Universal Definition of Myocardial Infarction in the .. MI Myocardial infarction
healthcare system . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 263
..
.. MINOCA Myocardial infarction with non-obstructive coronary
42 Appendix . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 264 .. arteries
43 Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 264
..
.. MONICA MONItoring of trends and determinants in
44 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 264 .. CArdiovascular disease
..
.. MPS Myocardial perfusion scintigraphy
.. NHLBI National Heart, Lung, and Blood Institute
..
Abbreviations and acronyms .. NSTEMI Non-ST-elevation myocardial infarction
.. PET Positron emission tomography
..
ACC American College of Cardiology .. PCI Percutaneous coronary intervention
ACS Acute coronary syndrome .. POC Point of care
..
AHA American Heart Association .. RBBB Right bundle branch block
ARC-2 Academic Research Consortium-2 ..
.. SPECT Single photon emission computed tomography
AUC Area under the curve .. STEMI ST-elevation myocardial infarction
CAD Coronary artery disease
..
.. ST-T ST-segment–T wave
CABG Coronary artery bypass grafting .. TIMI Thrombolysis in Myocardial Infarction
CKD Chronic kidney disease
..
.. TTS Takotsubo syndrome
CK-MB Creatine kinase MB isoform .. UDMI Universal Definition of Myocardial Infarction
CMR Cardiac magnetic resonance
..
.. URL Upper reference limit
CTCA Computed tomographic coronary angiography .. WHF World Heart Federation
cTn Cardiac troponin
..
. WHO World Health Organization
240 Expert consensus document

1 What is new in the Universal Definition of Myocardial Infarction?

What’s new in the universal definition of myocardial infarction?


New concepts

• Differentiation of myocardial infarction from myocardial injury.


• Highlighting peri-procedural myocardial injury after cardiac and non-cardiac procedures as discrete from myocardial infarction.
• Consideration of electrical remodelling (cardiac memory) in assessing repolarization abnormalities with tachyarrhythmia, pacing, and

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rate-related conduction disturbances.
• Use of cardiovascular magnetic resonance to define aetiology of myocardial injury.
• Use of computed tomographic coronary angiography in suspected myocardial infarction.

Updated concepts

• Type 1 myocardial infarction: Emphasis on the causal relationship of plaque disruption with coronary athero-thrombosis; new Figure 3.
• Type 2 myocardial infarction: Settings with oxygen demand and supply imbalance unrelated to acute coronary athero-thrombosis;
new Figures 4 and 5.
• Type 2 myocardial infarction: Relevance of presence or absence of coronary artery disease to prognosis and therapy.
• Differentiation of myocardial injury from type 2 myocardial infarction; new Figure 6.
• Type 3 myocardial infarction: Clarify why type 3 myocardial infarction is a useful category to differentiate from sudden cardiac death.
• Types 4–5 myocardial infarction: Emphasis on distinction between procedure-related myocardial injury and procedure-related
myocardial infarction.
• Cardiac troponin: Analytical issues for cardiac troponins; new Figure 7.
• Emphasis on the benefits of high-sensitivity cardiac troponin assays.
• Considerations relevant to the use of rapid rule-out and rule-in protocols for myocardial injury and myocardial infarction.
• Issues related to specific diagnostic change ('delta') criteria for the use of cardiac troponins to detect or exclude acute myocardial
injury.
• Consideration of new non-rate-related right bundle branch block with specific repolarization patterns.
• ST-segment elevation in lead aVR with specific repolarization patterns, as a STEMI equivalent.
• ECG detection of myocardial ischaemia in patients with an implantable cardiac defibrillator or a pacemaker.
• Enhanced role of imaging including cardiac magnetic resonance imaging for the diagnosis of myocardial infarction; new Figure 8.

New sections

©ESC/ACC/AHA/WHF 2018
• Takotsubo syndrome.
• MINOCA.
• Chronic kidney disease.
• Atrial fibrillation.
• Regulatory perspective on myocardial infarction.
• Silent or unrecognized myocardial infarction.

ECG = electrocardiogram; MINOCA = myocardial infarction with non-obstructive coronary arteries; STEMI = ST-elevation myocardial infarction.
Expert consensus document 241

2 Universal definitions of myocardial injury and myocardial infarction:


summary

Universal definitions of myocardial injury and myocardial infarction


Criteria for myocardial injury

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The term myocardial injury should be used when there is evidence of elevated cardiac troponin values (cTn) with at least one value above
the 99th percentile upper reference limit (URL). The myocardial injury is considered acute if there is a rise and/or fall of cTn values.

Criteria for acute myocardial infarction (types 1, 2 and 3 MI)

The term acute myocardial infarction should be used when there is acute myocardial injury with clinical evidence of acute myocardial
ischaemia and with detection of a rise and/or fall of cTn values with at least one value above the 99th percentile URL and at least one of
the following:
• Symptoms of myocardial ischaemia;
• New ischaemic ECG changes;
• Development of pathological Q waves;
• Imaging evidence of new loss of viable myocardium or new regional wall motion abnormality in a pattern consistent with an
ischaemic aetiology;
• Identification of a coronary thrombus by angiography or autopsy (not for types 2 or 3 MIs).
Post-mortem demonstration of acute athero-thrombosis in the artery supplying the infarcted myocardium meets criteria for type 1 MI.
Evidence of an imbalance between myocardial oxygen supply and demand unrelated to acute athero-thrombosis meets criteria for type 2 MI.
Cardiac death in patients with symptoms suggestive of myocardial ischaemia and presumed new ischaemic ECG changes before cTn
values become available or abnormal meets criteria for type 3 MI.

Criteria for coronary procedure-related myocardial infarction (types 4 and 5 MI)

Percutaneous coronary intervention (PCI) related MI is termed type 4a MI.


Coronary artery bypass grafting (CABG) related MI is termed type 5 MI.
Coronary procedure-related MI ≤ 48 hours after the index procedure is arbitrarily defined by an elevation of cTn values > 5 times for
type 4a MI and > 10 times for type 5 MI of the 99th percentile URL in patients with normal baseline values. Patients with elevated
pre-procedural cTn values, in whom the pre-procedural cTn level are stable (≤ 20% variation) or falling, must meet the criteria for
a > 5 or > 10 fold increase and manifest a change from the baseline value of > 20%. In addition with at least one of the following:
• New ischaemic ECG changes (this criterion is related to type 4a MI only);
• Development of new pathological Q waves;
• Imaging evidence of loss of viable myocardium that is presumed to be new and in a pattern consistent with an ischaemic aetiology;
• Angiographic findings consistent with a procedural flow-limiting complication such as coronary dissection, occlusion of a major
epicardial artery or graft, side-branch occlusion-thrombus, disruption of collateral flow or distal embolization.
Isolated development of new pathological Q waves meets the type 4a MI or type 5 MI criteria with either revascularization procedure if
cTn values are elevated and rising but less than the pre-specified thresholds for PCI and CABG.
Other types of 4 MI include type 4b MI stent thrombosis and type 4c MI restenosis that both meet type 1 MI criteria.
Post-mortem demonstration of a procedure-related thrombus meets the type 4a MI criteria or type 4b MI criteria if associated with a stent.
©ESC/ACC/AHA/WHF 2018

Criteria for prior or silent/unrecognized myocardial infarction

Any one of the following criteria meets the diagnosis for prior or silent/unrecognized MI:
• Abnormal Q waves with or without symptoms in the absence of non-ischaemic causes.
• Imaging evidence of loss of viable myocardium in a pattern consistent with ischaemic aetiology.
• Patho-anatomical findings of a prior MI.

CABG = coronary artery bypass grafting; cTn = cardiac troponin; ECG = electrocardiogram; MI = myocardial infarction; PCI = percutaneous coronary intervention; URL =
upper reference limit.
242 Expert consensus document

..
3 Introduction .. Cardiology (ACC) collaborated to redefine MI using a biochemical
.. and clinical approach, and reported that myocardial injury detected
In the late 19th century, post-mortem examinations demonstrated a
.. by abnormal biomarkers in the setting of acute myocardial ischaemia
..
possible relationship between thrombotic occlusion of a coronary ... should be labelled as MI.9 The principle was further refined by the
artery and myocardial infarction (MI).1 However, it was not until the .. Global MI Task Force, leading to the Universal Definition of
beginning of the 20th century that the first clinical descriptions
..
.. Myocardial Infarction Consensus Document in 2007, introducing a
appeared describing a connection between the formation of a throm- .. novel MI classification system with five subcategories.10 This docu-
bus in a coronary artery and its associated clinical features.2,3 Despite
..
.. ment, endorsed by the ESC, the ACC), the American Heart
these landmark observations, considerable time elapsed before gen- .. Association (AHA), and the World Heart Federation (WHF), was
..
eral clinical acceptance of this entity was achieved, in part due to one .. adopted by the WHO.11 The development of even more sensitive
autopsy study that showed no thrombi in the coronary arteries of .. assays for markers of myocardial injury made further revision of the
..
31% of deceased patients with an MI.4 The clinical entity was referred .. document necessary, particularly for patients who undergo coronary

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to as coronary thrombosis, although use of the term ‘MI’ ultimately .. procedures or cardiac surgery. As a result, the Joint ESC/ACC/AHA/
..
prevailed. Over the years, several different definitions of MI have .. WHF Task Force produced the Third Universal Definition of
been used, leading to controversy and confusion. Hence, a general .. Myocardial Infarction Consensus Document in 2012.12
..
and worldwide definition for MI was needed. This occurred for the .. Studies have shown that myocardial injury, defined by an elevated
first time in the 1950–70s, when working groups from the World .. cardiac troponin (cTn) value, is frequently encountered clinically and is
..
Health Organization (WHO) established a primarily electrocardio- .. associated with an adverse prognosis.13,14 Although myocardial injury
graphic (ECG)-based definition of MI intended for epidemiological .. is a prerequisite for the diagnosis of MI, it is also an entity in itself. To
..
use.5 The original description, with minor modifications, is still used in .. establish a diagnosis of MI, criteria in addition to abnormal biomarkers
epidemiological surveys (Figure 1).6–8 .. are required. Non-ischaemic myocardial injury may arise secondary to
..
With the introduction of more sensitive cardiac biomarkers, the .. many cardiac conditions such as myocarditis, or may be associated
European Society of Cardiology (ESC) and the American College of .. with non-cardiac conditions such as renal failure.15 Therefore, for
.

Epidemiological Approach Clinical Approach

ESC ACC Third


Re- UDMI
definition Definition

First Fifth ISFC WHO Fourth


WHO WHO WHO MONICA UDMI UDMI
Definition Definition Definition Definition Definition Definition

1950 1960 1970 1980 1990 2000 2010 2020


©ESC/ACC/AHA/WHF 2018

AHA - ESC - WHF - NHLBI


Clinical and
epidemiological definition

Figure 1 History of documents on the definition of myocardial infarction. ACC = American College of Cardiology; AHA = American Heart
Association; ESC = European Society of Cardiology; ISFC = International Society and Federation of Cardiology; MONICA = MONItoring of trends
and determinants in CArdiovascular disease; NHLBI = National Heart, Lung, and Blood Institute; UDMI = Universal Definition of Myocardial
Infarction; WHF = World Heart Federation; WHO = World Health Organization.
Expert consensus document 243

..
patients with increased cTn values, clinicians must distinguish whether .. reported to occur following injury to non-cardiac tissues. The situa-
patients have suffered a non-ischaemic myocardial injury or one of the .. tion is more complex for cTnT. Biochemical data indicate that injured
..
MI subtypes. If there is no evidence to support the presence of myo- .. skeletal muscle expresses proteins that are detected by the cTnT
cardial ischaemia, a diagnosis of myocardial injury should be made. .. assay, leading to some situations where elevations of cTnT could
..
This diagnosis can be changed if subsequent evaluation indicates crite- .. emanate from skeletal muscle.23–27 Recent data suggest that the fre-
ria for MI. The current Fourth Universal Definition of Myocardial .. quency of such elevations in the absence of ischaemic heart disease
..
Infarction Consensus Document reflects these considerations through .. may be higher than originally thought.28,29 cTnI and cTnT are the pre-
adhering to the clinical approach of the definition of MI. .. ferred biomarkers for the evaluation of myocardial injury,12,21,22,30
..
.. and high-sensitivity (hs)-cTn assays are recommended for routine
.. clinical use.22 Other biomarkers, e.g. creatine kinase MB isoform
..
Clinical criteria for MI .. (CK-MB), are less sensitive and less specific.31 Myocardial injury is
.. defined as being present when blood levels of cTn are increased
..

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The clinical definition of MI denotes the presence of acute myo-
cardial injury detected by abnormal cardiac biomarkers in the set-
.. above the 99th percentile upper reference limit (URL).12,21,22,30 The
.. injury may be acute, as evidenced by a newly detected dynamic rising
ting of evidence of acute myocardial ischaemia. ..
.. and/or falling pattern of cTn values above the 99th percentile URL,

Criteria for myocardial injury


Detection of an elevated cTn value above the 99th percentile
4 Pathological characteristics of URL is defined as myocardial injury. The injury is considered
myocardial ischaemia and acute if there is a rise and/or fall of cTn values.

infarction
MI is defined pathologically as myocardial cell death due to prolonged
ischaemia. Diminished cellular glycogen, and relaxed myofibrils and or chronic, in the setting of persistently elevated cTn levels.
sarcolemmal disruption, are the first ultrastructural changes and are Although elevated cTn values reflect injury to myocardial cells,
seen as early as 10–15 min after the onset of ischaemia.16 they do not indicate the underlying pathophysiological mechanisms,
Mitochondrial abnormalities are observed as early as 10 min after and can arise following preload-induced mechanical stretch or phys-
coronary occlusion by electron microscopy and are progressive.17 It iological stresses in otherwise normal hearts.32–34 Various causes
can take hours before myocyte necrosis can be identified by post- have been suggested for the release of structural proteins from the
mortem examination in humans; this is in contrast to animal models, myocardium, including normal turnover of myocardial cells, apopto-
in which biochemical evidence of myocardial cell death due to apop- sis, cellular release of cTn degradation products, increased cellular
tosis can be detected within 10 min of induced myocardial ischaemia wall permeability, the formation and release of membranous blebs,
in association with myocyte death.15 Experimentally, necrosis pro- and myocyte necrosis.27,35 Yet, it is not clinically possible to distin-
gresses from the subendocardium to the subepicardium over several guish which increases of cTn levels are due to which mechanisms.36
hours. The time course may be prolonged by increased collateral However, regardless of the mechanism, acute myocardial injury,
flow, reduced determinants of myocardial oxygen consumption, and when associated with a rising and/or falling pattern of cTn values with
intermittent occlusion/reperfusion, which can precondition the at least one value above the 99th percentile URL and caused by myo-
heart.18 Timely implementation of reperfusion therapy, when appro- cardial ischaemia, is designated as an acute MI.12,21,22,30 Histological
priate, reduces ischaemic injury of the myocardium.19,20 evidence of myocardial injury with myocyte death can be detected in
clinical conditions associated with non-ischaemic mechanisms of
myocardial injury as well37,38 (Figure 2).
5 Biomarker detection of Myocardial ischaemic or non-ischaemic conditions associated with
myocardial injury and infarction increased cTn values are presented in Table 1. The complexity of clin-
ical circumstances may sometimes make it difficult to discriminate
Cardiac troponin I (cTnI) and T (cTnT) are components of the con- specific individual mechanism(s) of myocardial injury. In this situation,
tractile apparatus of myocardial cells and are expressed almost exclu- the multifactorial contributions resulting in myocardial injury should
sively in the heart.21,22 Increases in cTnI values have not been be described in the patient record.
244 Expert consensus document

No myocardial injurya

Increased cTn =
Hypoxaemia myocardial injuryb Anaemia

Clinical evidence

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of acute ischaemic
Hypotension/ myocardial Ventricular
shock injury = tachyarrhythmia
myocardial
infarctionc

©ESC/ACC/AHA/WHF 2018
Kidney Heart
disease failure

Figure 2 Spectrum of myocardial injury, ranging from no injury to myocardial infarction. Various clinical entities may involve these myocardial cate-
gories, e.g. ventricular tachyarrhythmia, heart failure, kidney disease, hypotension/shock, hypoxaemia, and anaemia. cTn = cardiac troponin; URL =
upper reference limit. aNo myocardial injury = cTn values <_ 99th percentile URL or not detectable. bMyocardial injury = cTn values > 99th percentile
URL. cMyocardial infarction = clinical evidence of myocardial ischaemia and a rise and/or fall of cTn values > 99th percentile URL.
Expert consensus document 245

..
Table 1 Reasons for the elevation of cardiac troponin
.. rest, or an ischaemic equivalent such as dyspnoea or fatigue. Often,
.. the discomfort is diffuse; not localized, nor positional, nor affected by
values because of myocardial injury ..
.. movement of the region. However, these symptoms are not specific
.. for myocardial ischaemia and can be observed in other conditions
..
Myocardial injury related to acute myocardial ischaemia .. such as gastrointestinal, neurological, pulmonary, or musculoskeletal
.. complaints. MI may occur with atypical symptoms such as palpitations
Atherosclerotic plaque disruption with thrombosis. ..
.. or cardiac arrest, or even without symptoms.12 Very brief episodes
Myocardial injury related to acute myocardial ischaemia
.. of ischaemia too short to cause necrosis can also cause cTn release
..
because of oxygen supply/demand imbalance .. and elevations. The involved myocytes can subsequently die due to
.. apoptosis.42
Reduced myocardial perfusion, e.g. ..
• Coronary artery spasm, microvascular dysfunction .. If myocardial ischaemia is present clinically or detected by ECG
• Coronary embolism
.. changes together with myocardial injury, manifested by a rising and/
..

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• Coronary artery dissection .. or falling pattern of cTn values, a diagnosis of acute MI is appropriate.
• Sustained bradyarrhythmia .. If myocardial ischaemia is not present clinically, then elevated cTn lev-
• Hypotension or shock ..
.. els may be indicative of acute myocardial injury if the pattern of values
• Respiratory failure ..
• Severe anaemia .. is rising and/or falling, or related to more chronic ongoing injury if the
... pattern is unchanging.14 Similar considerations are relevant when
Increased myocardial oxygen demand, e.g. .. evaluating events that are potentially related to procedures that may
• Sustained tachyarrhythmia ..
• Severe hypertension with or without left ventricular .. cause myocardial injury and/or MI. Additional evaluations may lead to
hypertrophy
.. a need for the initial diagnosis to be revised.
..
.. Patients with suspected acute coronary syndrome (ACS) that are
Other causes of myocardial injury .. ruled out for MI with normal cardiac biomarker values (<_ 99th per-
..
Cardiac conditions, e.g. .. centile URL) may have unstable angina or an alternative diagnosis.
• Heart failure .. These patients should be evaluated and treated accordingly.11,43
• Myocarditis
..
..
• Cardiomyopathy (any type) ..
• Takotsubo syndrome ..
• Coronary revascularization procedure .. 7 Clinical classification of
• Cardiac procedure other than revascularization
..
.. myocardial infarction
• Catheter ablation ..
• Defibrillator shocks ..
• Cardiac contusion
.. For the sake of immediate treatment strategies such as reperfusion
.. therapy, it is usual practice to designate MI in patients with chest dis-
..
Systemic conditions, e.g. .. comfort or other ischaemic symptoms, who develop new ST-
• Sepsis, infectious disease .. segment elevations in two contiguous leads or new bundle branch
• Chronic kidney disease ..
.. blocks with ischaemic repolarization patterns as an ST-elevation MI
©ESC/ACC/AHA/WHF 2018

• Stroke, subarachnoid haemorrhage .. (STEMI) (see section 27). In contrast, patients without ST-segment
• Pulmonary embolism, pulmonary hypertension ..
• Infiltrative diseases, e.g. amyloidosis, sarcoidosis .. elevation at presentation are usually designated non-ST-elevation MI
• Chemotherapeutic agents .. (NSTEMI). The categories of patients with STEMI, NSTEMI, or unsta-
• Critically ill patients
..
.. ble angina are customarily included in the concept of ACS. In addition
• Strenuous exercise ..
.. to these categories, MI may be classified into various types based on
.. pathological, clinical, and prognostic differences, along with different
For a more comprehensive listing, see39–41
..
.. treatment strategies.
..
..
.. 7.1 Myocardial infarction type 1
6 Clinical presentations of ..
.. MI caused by atherothrombotic coronary artery disease (CAD) and
.. usually precipitated by atherosclerotic plaque disruption (rupture or
myocardial infarction ..
.. erosion) is designated as a type 1 MI. The relative burden of athero-
Onset of myocardial ischaemia is the initial step in the development .. sclerosis and thrombosis in the culprit lesion varies greatly, and the
..
of MI and results from an imbalance between oxygen supply and .. dynamic thrombotic component may lead to distal coronary emboli-
demand. Myocardial ischaemia in a clinical setting can most often be .. zation resulting in myocyte necrosis.44,45 Plaque rupture may
..
identified from the patient’s history and from the ECG. Possible .. not only be complicated by intraluminal thrombosis but also by
ischaemic symptoms include various combinations of chest, upper .. haemorrhage into the plaque through the disrupted surface
..
extremity, mandibular, or epigastric discomfort during exertion or at . (Figure 3).44,45
246 Expert consensus document

Myocardial Infarction Type 1

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Plaque rupture/erosion with
occlusive thrombus

©ESC/ACC/AHA/WHF 2018
Plaque rupture/erosion with
non-occlusive thrombus

Figure 3 Myocardial infarction type 1.

..
Criteria for type 1 MI .. demand has been classified as type 2 MI.10,12 By definition, acute athe-
.. rothrombotic plaque disruption is not a feature of type 2 MI. In
Detection of a rise and/or fall of cTn values with at least one ..
value above the 99th percentile URL and with at least one of the
.. patients with stable known or presumed CAD, an acute stressor
.. such as an acute gastrointestinal bleed with a precipitous drop in hae-
following: ..
.. moglobin, or a sustained tachyarrhythmia with clinical manifestations
• Symptoms of acute myocardial ischaemia; .. of myocardial ischaemia, may result in myocardial injury and a type 2
..
• New ischaemic ECG changes; .. MI. These effects are due to insufficient blood flow to the ischaemic
• Development of pathological Q waves; .. myocardium to meet the increased myocardial oxygen demand of
..
• Imaging evidence of new loss of viable myocardium or new .. the stressor. Ischaemic thresholds may vary substantially in individual
regional wall motion abnormality in a pattern consistent with .. patients depending on the magnitude of the stressor, the presence of
an ischaemic aetiology;
..
.. non-cardiac comorbidities, and the extent of underlying CAD and
• Identification of a coronary thrombus by angiography includ- .. cardiac structural abnormalities.
ing intracoronary imaging or by autopsy.a
..
.. Studies have shown variable occurrences of type 2 MI depending
.. on criteria used for diagnosis. Some reports rely on specific predeter-
..
cTn = cardiac troponin; ECG = electrocardiogram; URL = upper .. mined oxygen mismatch criteria,48,49 whereas others apply more lib-
reference limit. .. eral criteria. Most studies show a higher frequency of type 2 MI in
..
a
Post-mortem demonstration of an atherothrombus in the artery .. women. The short- and long-term mortality rates for patients with
supplying the infarcted myocardium, or a macroscopically large cir-
.. type 2 MI are generally higher than for type 1 MI patients in most but
..
cumscribed area of necrosis with or without intramyocardial hae- .. not all studies due to an increased prevalence of comorbid con-
..
morrhage, meets the type 1 MI criteria regardless of cTn values. .. ditions.49–57 Coronary atherosclerosis is a common finding in type 2
.. MI patients selected for coronary angiography. In general, these
..
It is essential to integrate the ECG findings with the aim of classify- .. patients have a worse prognosis than those without CAD.54–57
ing type 1 MI into STEMI or NSTEMI in order to establish the appro- .. Prospective evaluations of the importance of CAD with type 2 MI
priate treatment according to current Guidelines.46,47
..
.. using consistent definitions and approaches are needed.
.. It has been shown that the frequency of ST-segment elevation in
..
7.2 Myocardial infarction type 2 .. type 2 MI varies from 3–24%.53 In some cases, coronary embolism
The pathophysiological mechanism leading to ischaemic myocardial
.. caused by thrombi, calcium or vegetation from the atria or ventricles,
..
injury in the context of a mismatch between oxygen supply and . or acute aortic dissection may result in a type 2 MI. Spontaneous
Expert consensus document 247

..
coronary artery dissection with or without intramural haematoma is .. hypertrophy. In patients who undergo timely coronary angiography,
another non-atherosclerotic condition that may occur, especially in .. description of a ruptured plaque with thrombus in the infarct-related
..
young women. It is defined as spontaneous dissection of the coronary .. artery may be helpful in making the distinction between type 2 MI vs.
artery wall with accumulation of blood within the false lumen, which .. type 1 MI, but angiography is not always definitive, clinically indicated,
..
can compress the true lumen to varying degrees (Figure 4).58 .. or required to establish the diagnosis of type 2 MI.
All of the clinical information available should be considered in dis- .
tinguishing type 1 MI from type 2 MI. The context and mechanisms of
type 2 MI should be considered when establishing this diagnosis Criteria for type 2 MI
(Figure 5). The myocardial oxygen supply/demand imbalance attribut- Detection of a rise and/or fall of cTn values with at least one value
able to acute myocardial ischaemia may be multifactorial, related above the 99th percentile URL, and evidence of an imbalance
either to: reduced myocardial perfusion due to fixed coronary athe- between myocardial oxygen supply and demand unrelated to acute
rosclerosis without plaque rupture, coronary artery spasm, coronary coronary athero-thrombosis, requiring at least one of the following:

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microvascular dysfunction (which includes endothelial dysfunction,
smooth muscle cell dysfunction, and the dysregulation of sympathetic • Symptoms of acute myocardial ischaemia;
innervation), coronary embolism, coronary artery dissection with or • New ischaemic ECG changes;
without intramural haematoma, or other mechanisms that reduce • Development of pathological Q waves;
• Imaging evidence of new loss of viable myocardium or new
oxygen supply such as severe bradyarrhythmia, respiratory failure
regional wall motion abnormality in a pattern consistent with
with severe hypoxaemia, severe anaemia, and hypotension/shock; or
an ischaemic aetiology.
to increased myocardial oxygen demand due to sustained tachyar-
rhythmia or severe hypertension with or without left ventricular

Myocardial Infarction Type 2

Atherosclerosis and oxygen


supply/demand imbalance

Vasospasm or coronary
microvascular dysfunction

Non-atherosclerotic
coronary dissection
©ESC/ACC/AHA/WHF 2018

Oxygen supply/demand
imbalance alone

Figure 4 Myocardial infarction type 2.


248 Expert consensus document

Secondary to another illness or process


Context
Main reason leading to clinical presentation (e.g. chest pain)

Fixed coronary atherosclerosis

Type 2 Coronary spasm


myocardial Coronary microvascular dysfunction
infarction Coronary embolism

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Coronary artery dissection +/-
Intramural haematoma

Oxygen supply Sustained tachyarrhythmia


Mechanisms and demand
Severe hypertension +/-
imbalancea Left ventricular hypertrophy

Severe bradyarrhythmia

Respiratory failure

©ESC/ACC/AHA/WHF 2018
a
Severe anaemia
Ischaemic thresholds vary substantially in
relation to the magnitude of the stressor and the Hypotension/Shock
extent of underlying cardiac disease.

Figure 5 Framework for type 2 myocardial infarction considering the clinical context and pathophysiological mechanisms attributable to acute
myocardial ischaemia. The illustration above is modified from Januzzi and Sandoval.59

..
It appears advisable in the acute setting to treat the underlying .. Type 2 MI and non-ischaemic myocardial injury may coexist. It should
ischaemic imbalance of oxygen supply and demand. This treatment .. be recognized that some disease entities may be on both sides of the
..
may include volume adjustment, blood pressure management, admin- .. diagram, e. g. acute heart failure that may occur in the context of
istration of blood products, heart-rate control, and respiratory sup- .. acute myocardial ischaemia. Nevertheless, abnormal cTn values in
..
port.47,48 Depending on the clinical situation, coronary evaluations .. the setting of acute and/or chronic heart failure are often better cate-
may be indicated to assess the likelihood of CAD. If it is present, the .. gorized as a myocardial injury condition. Few studies have compared
..
MI Guidelines may be applied in accordance with the ECG findings of .. the incidence and clinical features of type 2 MI vs. myocardial injury
STEMI or NSTEMI.46,47 However, if CAD is absent, the benefits of .. without acute myocardial ischaemia.
..
cardiovascular risk reduction strategies with type 2 MI remain ..
uncertain. ..
.. 7.4 Myocardial infarction type 3
..
.. The detection of cardiac biomarkers in the blood is fundamental for
7.3 Myocardial infarction type 2 and .. establishing the diagnosis of MI.10,12 However, patients can manifest a
..
myocardial injury .. typical presentation of myocardial ischaemia/infarction, including pre-
Type 2 MI and myocardial injury are frequently encountered in clini- .. sumed new ischaemic ECG changes or ventricular fibrillation, and die
..
cal practice and both are related to a poor outcome.13,14,49,51,56 .. before it is possible to obtain blood for cardiac biomarker determina-
A conceptual model to facilitate the clinical distinction between acute .. tion; or the patient may succumb soon after the onset of symptoms
..
ischaemic myocardial injury with or without an acute atherothrom- .. before an elevation of biomarker values has occurred. Such patients
botic event (type 1 or type 2 MI) vs. conditions without acute ischae- .. are designated as having a type 3 MI, when suspicion for an acute
..
mic myocardial injury is displayed in Figure 6. Acute MI requires a .. myocardial ischaemic event is high, even when cardiac biomarker evi-
rising and/or falling pattern of cTn values. Acute myocardial injury
.. dence of MI is lacking.10,12 This category allows the separation of fatal
..
may also manifest such a pattern but if the injury is related to struc- .. MI events from the much larger group of sudden death episodes that
tural heart disease, the cTn values may be stable and unchanging.
.. may be cardiac (non-ischaemic) or non-cardiac in origin. When a
Expert consensus document 249

Elevated Cardiac Troponin Value(s) >99th percentile URL

Troponin rise and/or fall Troponin level stablea

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With Without
acute ischaemiab acute ischaemiab

Acute Acute Chronic


myocardial infarction myocardial injury myocardial injury

Oxygen supply
Atherosclerosis
and demand
+ thrombosis
imbalance

©ESC/ACC/AHA/WHF 2018
Type 1 MI: triggers Type 2 MI: examples Examples Examples
• Plaque rupture • Severe hypertension • Acute heart failure • Structural heart disease
• Plaque erosion • Sustained tachyarrhythmia • Myocarditis • Chronic kidney disease

Figure 6 A model for interpreting myocardial injury. Ischaemic thresholds vary substantially in relation to the magnitude of the stressor and the
extent of underlying cardiac disease. MI = myocardial infarction; URL = upper reference limit. aStable denotes <_ 20% variation of troponin values in
the appropriate clinical context. bIschaemia denotes signs and/or symptoms of clinical myocardial ischaemia.

..
type 3 MI is diagnosed and a subsequent autopsy reveals recent evi- .. 8 Coronary procedure-related
dence of an MI, with a fresh or recent thrombus in the infarct-related ..
.. myocardial injury
artery, the type 3 MI should be reclassified to a type 1 MI. Original ..
investigations addressing the incidence of type 3 MI are sparse, but a
..
.. Cardiac procedural myocardial injury related to coronary revasculari-
study showed an annual incidence below 10/100 000 person-years .. zation procedures, whether percutaneous coronary intervention
and a frequency of 3 – 4% among all types of MI.60
..
.. (PCI) or coronary artery bypass grafting (CABG), may be temporally
.. related to the procedure itself, reflecting periprocedural issues, or
..
Criteria for type 3 MI .. may occur later reflecting complications of a device, such as early or
.. late stent thrombosis or in-stent restenosis for PCI, or graft occlusion
Patients who suffer cardiac death, with symptoms suggestive of ..
myocardial ischaemia accompanied by presumed new ischaemic
.. or stenosis with CABG. Late gadolinium enhancement (LGE) cardiac
..
ECG changes or ventricular fibrillation, but die before blood sam- .. magnetic resonance (CMR) allows assessment of procedural myocar-
ples for biomarkers can be obtained, or before increases in car-
.. dial injury.61–63 When quantifying procedural injury using LGE-CMR
..
diac biomarkers can be identified, or MI is detected by autopsy .. before and shortly after PCI or CABG, it was found that 32% of
examination.
.. patients had evidence of procedural myocardial injury.63 Furthermore,
..
. it has been shown that patients with elevation of cTnI values after PCI
250 Expert consensus document

..
or after CABG have evidence of procedural myocardial injury on .. normal baseline values or, in patients with elevated pre-procedure
CMR imaging.61,62 For that reason, increased cTn values detected fol- .. cTn in whom the cTn levels are stable (<_ 20% variation) or falling, the
..
lowing a coronary revascularization procedure may reflect procedural .. post-procedure cTn must rise > 20% to an absolute value more than
myocardial injury. Of importance, if the baseline value before the pro- .. five times the 99th percentile URL. In addition, there should be evi-
..
cedure is above the 99th percentile URL, it is essential that cTn levels .. dence of new myocardial ischaemia, either from ECG changes, imag-
are stable prior to the evaluation in order to reliably establish the pres- .. ing evidence, or from procedure-related complications associated
..
ence of acute procedural myocardial injury. It is not possible to deter- .. with reduced coronary blood flow such as coronary dissection,
mine, when intervening in a patient with an acute MI event resulting in .. occlusion of a major epicardial artery or a side branch occlusion/
..
an increased cTn level, how much of any given increase is related to .. thrombus, disruption of collateral flow, slow flow or no-reflow, or
the MI and how much is due to the procedure.
.. distal embolization. The use of hs-cTn assays to diagnose type 4a MI
..
.. (and type 5 MI) is an area of active research. Many hs-cTn assays are
.. available, which have wide dynamic ranges. Different criteria may be
..

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Criteria for cardiac procedural myocar- .. required for different assays. However, it has recently been shown
.. that the optimal hs-cTnT thresholds to predict cardiovascular events
dial injury ..
.. at 30 days and 1 year were very close to the five-fold increase sug-
Cardiac procedural myocardial injury is arbitrarily defined by .. gested by the Third Universal Definition of Myocardial infarc-
increases of cTn values (> 99th percentile URL) in patients with ..
.. tion.12,66,67 These criteria are therefore retained because of a lack of
normal baseline values (<_ 99th percentile URL) or a rise of cTn ..
new scientific evidence that identifies superior criteria for defining
values > 20% of the baseline value when it is above the 99th per- ...
centile URL but it is stable or falling. .. this MI subtype. Other criteria that meet the definition of type 4a MI,
.. regardless of hs-cTn or cTn values, are the development of new
..
.. pathological Q waves or autopsy evidence of recent procedure-
.. related thrombus in the culprit artery.
A large proportion of patients have abnormal values of cTn after
..
..
PCI, ranging from 20 – 40% in stable CAD to 40 – 50% in MI.64 The ..
occurrence of procedural myocardial injury can be detected by the
.
measurement of cTn before the procedure and repeated 3 – 6 h
later. Where the second value is rising, further sampling should be Criteria for PCI-related MI  48 h
performed to document the peak cTn value. Increasing levels after after the index procedure
the procedure can only be attributed with certainty to procedural
(type 4a MI)
myocardial injury when the pre-procedural cTn values are normal
(<_ 99th percentile URL), or if they are stable or falling. For patients Coronary intervention-related MI is arbitrarily defined by an ele-
that present with an ACS and undergo a prompt coronary revascula- vation of cTn values more than five times the 99th percentile
rization procedure resulting in only a single pre-procedural baseline URL in patients with normal baseline values. In patients with ele-
value that is normal or mildly elevated, followed by subsequent post- vated pre-procedure cTn in whom the cTn level are stable
procedural values that continue to increase, the post-procedural (<_ 20% variation) or falling, the post-procedure cTn must rise by
increase should be attributed to the index event. Recent data corrob- > 20%. However, the absolute post-procedural value must still be
orate the importance of elevated pre-procedure cTn values as a at least five times the 99th percentile URL. In addition, one of the
prognostic marker in patients that have values that rise after the pro- following elements is required:
cedure.65 To diagnose procedural myocardial injury in the clinical set- • New ischaemic ECG changes;
ting of only a single pre-procedural cTn value, the cardiac Tn values • Development of new pathological Q waves;a
would need to be stable or falling post-procedure, followed by a sub- • Imaging evidence of new loss of viable myocardium or new
sequent increase that exceeds the 99th percentile URL, and if the regional wall motion abnormality in a pattern consistent with
value has not returned to baseline, the increase should be > 20% an ischaemic aetiology;
with an absolute value > the 99th percentile URL. • Angiographic findings consistent with a procedural flow-limit-
ing complication such as coronary dissection, occlusion of a
major epicardial artery or a side branch occlusion/thrombus,
9 Myocardial infarction associated disruption of collateral flow, or distal embolization.b
with percutaneous coronary a
Isolated development of new pathological Q waves meets the
intervention (type 4a myocardial type 4a MI criteria if cTn values are elevated and rising but less
infarction) than five times the 99th percentile URL.
b
Post-mortem demonstration of a procedure-related thrombus
Stand-alone post-procedural increases of cTn values are sufficient to in the culprit artery, or a macroscopically large circumscribed
establish a diagnosis of procedural myocardial injury but not for the area of necrosis with or without intra-myocardial haemorrhage
diagnosis of type 4a MI. Type 4a MI requires an elevation of cTn val- meets the type 4a MI criteria.
ues greater than five times the 99th percentile URL in patients with
Expert consensus document 251

..
10 Stent/scaffold thrombosis ..
..
especially cTn appear robust for the detection of procedural myocar-
dial injury and also, in the presence of new myocardial ischaemia, for
associated with percutaneous ..
.. the detection of type 5 MI, a specific cut-off value for all procedures
coronary intervention (type 4b .. and all cTn assays is difficult to define. However, in order to ensure
..
myocardial infarction) .. consistency with the analogous standards of the preceding definition
.. of type 5 MI12 and because of the lack of new scientific evidence that
..
A subcategory of PCI-related MI is stent/scaffold thrombosis, type 4b .. identifies superior criteria for defining this MI subtype, it is suggested
MI, as documented by angiography or autopsy using the same criteria
.. that a cTn value > 10 times the 99th percentile URL is applied as the
..
utilized for type 1 MI. It is important to indicate the time of the occur- .. cut-off point during the first 48 h following CABG, occurring from a
.. normal baseline cTn value (<_ 99th percentile URL), for diagnosing
rence of the stent/scaffold thrombosis in relation to the timing of the ..
PCI procedure. The following temporal categories are suggested: .. type 5 MI. It is important that the post-procedural elevation of cTn
.. values is accompanied by ECG, angiographic, or imaging evidence of
acute, 0–24 h; subacute, > 24 h to 30 days; late, > 30 days to 1 year; ..

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and very late > 1 year after stent/scaffold implantation.68 .. new myocardial ischaemia/new loss of myocardial viability.71 The
.. higher cut-off of MI after CABG than after PCI (10 times vs. 5 times
..
.. the 99th percentile URL) has been arbitrarily selected due to the
.. occurrence of more unavoidable myocardial injury during surgery
11 Restenosis associated with ..
.. than during PCI.
percutaneous coronary .. It should be recognized that ST-segment deviation and T wave
..
intervention (type 4c myocardial .. changes are common after CABG due to epicardial injury, and are
..
.. not reliable indicators of myocardial ischaemia in this setting.
infarction) .. However, ST-segment elevation with reciprocal ST-segment depres-
..
Occasionally MI occurs and—at angiography, in-stent restenosis, or .. sion or other specific ECG patterns may be a more reliable finding of
.. a potential ischaemic event.
restenosis following balloon angioplasty in the infarct territory—is .
the only angiographic explanation since no other culprit lesion or
thrombus can be identified. This PCI-related MI type is designated as
type 4c MI, defined as focal or diffuse restenosis, or a complex lesion
Criteria for CABG-related MI  48 h
associated with a rise and/or fall of cTn values above the 99th percen- after the index procedure (type 5 MI)
tile URL applying, the same criteria utilized for type 1 MI. CABG-related MI is arbitrarily defined as elevation of cTn values
> 10 times the 99th percentile URL in patients with normal base-
line cTn values. In patients with elevated pre-procedure cTn in
12 Myocardial infarction whom cTn levels are stable (<_ 20% variation) or falling, the post-
procedure cTn must rise by > 20%. However, the absolute post-
associated with coronary artery procedural value still must be > 10 times the 99th percentile
bypass grafting (type 5 myocardial URL. In addition, one of the following elements is required:

infarction) • Development of new pathological Q waves;a


• Angiographic documented new graft occlusion or new native
Numerous factors can lead to procedural myocardial injury during a coronary artery occlusion;
CABG procedure. Many of them are related to the details of the car- • Imaging evidence of new loss of viable myocardium or new
diac preservation, the extent of the direct traumatic injury to the regional wall motion abnormality in a pattern consistent with
myocardium, as well as any potential ischaemic injury. For that rea- an ischaemic aetiology.
son, increases in cTn values should be expected after all CABG pro- a
Isolated development of new pathological Q waves meets the
cedures,69,70 which need to be taken into account when comparing type 5 MI criteria if cTn values are elevated and rising but < 10
the extent of procedural myocardial injury after cardiac surgery with times the 99th percentile URL.
that associated with less invasive approaches. Depending on whether
it is off-pump or on-pump surgery, procedural myocardial injury is
observed among 32 – 44% of CABG patients when quantified by Marked isolated elevation of cTn values within the 48 h post-
LGE-CMR.61,63 The area under the curve (AUC) and routine cTn operative period, even in the absence of ECG/angiographic or other
sampling has demonstrated an excellent linear relationship with the imaging evidence of MI, indicates prognostically significant cardiac
mass of the new injury as defined by LGE-CMR. AUC for CK-MB is procedural myocardial injury.72 The presence of significant proce-
also good, although clearly inferior to cTnI.69 However, these rela- dural myocardial injury in patients with operative problems (e.g. diffi-
tionships vary depending on the nature of the procedure, the nature culty coming off bypass, technically difficult anastomoses in a heavily
of the cardioplegia, and the specific assay used to measure cTn. Very calcified aorta, of perioperative evidence of myocardial ischaemia,
high cTn values are most often associated with coronary artery- etc.) should prompt clinical review of the procedure and/or consider-
related events.61,63,69 Thus, although cardiac biomarkers and ation of additional diagnostic testing for possible type 5 MI.
252 Expert consensus document

..
13 Other definitions of myocardial ..
..
is recommended. A second sample should be obtained 3–6 h later or
earlier with more sensitive cTn assays. If the cTn concentration is ele-
infarction related to percutaneous ..
.. vated, but stable or decreasing at the time of suspected re-infarction,
coronary intervention or coronary .. the diagnosis of re-infarction requires a > 20% increase of the cTn
..
.. value in the second sample.74 If the initial cTn concentration is nor-
artery bypass grafting .. mal, the criteria for new acute MI apply.12
..
There is no universal consensus on the cTn or hs-cTn cut-off points ..
that clearly distinguish cardiac procedural myocardial injury from MI.
..
..
The distinction is made on the basis of an injury created by a flow- .. 16 Myocardial injury and
limiting complication during the procedure that results in sufficient
..
.. infarction associated with cardiac
myocardial ischaemia to generate a procedure-related MI. The size of ..
.. procedures other than
the insult will determine the magnitude of the cTn release. Various ..

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groups have used multiples of the 99th percentile URL and set ..
thresholds to diagnose periprocedural MIs for clinical trials.68,73
.. revascularization
..
Unless a standard assay is used for all analyses, given the heterogene- .. Cardiac procedures such as transcatheter valve interventions may
..
ity of cTn assays, this approach could lead to very different values .. cause myocardial injury, both by direct trauma to the myocardium
depending on the assay used locally. The Academic Research .. and by creating regional ischaemia secondary to coronary obstruc-
..
Consortium-2 (ARC-2) suggests a post-procedural cTn value >_ 35 .. tion or embolization. Ablation of arrhythmias involves controlled
times the 99th percentile URL for both PCI and CABG in patients .. procedural myocardial injury by application of warming or cooling of
..
that have a normal baseline cTn value or in patients with elevated .. the tissue. The extent of procedural myocardial injury can be
pre-procedure cTn values in whom the cTn levels are stable or falling. .. assessed by serial cTn measurements. Increases of cTn values in this
..
ARC-2 proposes that one ancillary criterion be required in addition .. context should be considered as a procedural myocardial injury and
to the >_ 35 cTn rise to fulfill the definition of periprocedural MI. The .. not labelled as an MI unless the biomarker criteria and one of the
..
ancillary criteria are one or more of the following: new significant Q .. ancillary criteria for acute myocardial ischaemia listed for type 5 MI
waves (or equivalent), flow-limiting angiographic complications in a .. are present.75,76
..
major epicardial vessel or > 1.5 mm diameter branch, or a substantial ..
new loss of viable myocardium on echocardiography related to the
..
..
procedure.68 Furthermore, ARC-2 has defined stand-alone criteria .. 17 Myocardial injury and
for significant procedural myocardial injury if the rise in cTn is >_ 70
..
..
times the 99th percentile URL (where the baseline is lower than the .. infarction associated with
URL, elevated and stable, or falling).68
..
.. non-cardiac procedures
..
.. Perioperative MI is one of the most important complications in major
..
14 Recurrent myocardial .. non-cardiac surgery and it is associated with a poor prognosis.77,78
.. Most patients who have a perioperative MI will not experience
infarction ..
.. ischaemic symptoms due to anaesthesia, sedation, or pain relieving
.. medications. Nevertheless, asymptomatic perioperative MI is as
Incident MI is defined as the individual’s first MI. When features of MI ..
occur in the first 28 days after an incident event, the second event is
.. strongly associated with 30 day mortality as symptomatic MI.77,78
.. Knowledge about hs-cTn values at baseline can help to identify
not counted as a new MI for epidemiological purposes. If characteris- ..
tics of MI occur after 28 days following an incident MI, it is considered
.. patients having chronic cTn elevation before surgery, as well as those
..
to be a recurrent MI.11 .. at increased risk during and after the procedure.79,80 Measurement of
.. hs-cTn in post-operative samples reveals that as many as 35% of
..
.. patients have levels above the 99th percentile URL, and 17% have an
..
15 Re-infarction .. elevation and a rising pattern of values indicative of evolving myocar-
.. dial injury.81 Those with a rising pattern of elevated hs-cTn values are
The term re-infarction is used clinically for an acute MI that occurs .. at particular risk; the greater the rise, the greater the risk.82,83
..
within 28 days of an incident or recurrent MI.11 The ECG diagnosis of .. The pathophysiological mechanism of perioperative MI is subject
suspected re-infarction following the initial MI may be confounded by .. to debate. It is recognized that the perioperative period is character-
..
the initial evolutionary ECG changes. Re-infarction should be consid- .. ized by increased cardiac metabolic demand that may lead to MI in
ered when ST-elevation >_ 1 mm recurs or new pathognomonic Q .. patients with otherwise stable CAD.84,85 Thus, an angiographic inves-
..
waves appear in at least two contiguous leads, particularly when asso- .. tigation has identified demand myocardial ischaemia as the predomi-
ciated with ischaemic symptoms. However, re-elevation of the ST- .. nant aetiology of perioperative MI,84,85 which together with a rise
..
segment can also be seen in threatened myocardial rupture or in .. and/or fall of cTn values indicates type 2 MI. However, other angio-
cases of pericarditis, and should lead to additional diagnostic .. graphic studies have detected coronary plaque rupture in 50–60%
..
evaluation. .. of patients with perioperative MI,86,87 which qualifies as type 1 MI. On
In patients where re-infarction is suspected from clinical signs or
.. the other hand, perioperative myocardial injury without ancillary
..
symptoms following the initial MI, an immediate measurement of cTn . ischaemic evidence indicative of MI is a common complication after
Expert consensus document 253

non-cardiac surgery that is associated with substantial short- and


.. CMR—is often required to better understand the cause of deviant
..
long-term mortality on a level with perioperative MI.83 .. cTn values.
Post-operative cTn surveillance is recommended for high-risk indi-
..
..
viduals. In order to properly interpret the aetiology of elevated post- ..
operative values, a baseline pre-operative value is necessary to deter-
..
.. 19 Takotsubo syndrome
mine whether the increase is acute or more chronic. However, a ..
diagnosis of MI still requires, in addition to an increase of cTn values,
..
.. Takotsubo syndrome (TTS) can mimic MI and is found in 1 – 2% of
evidence of myocardial ischaemia that may be evident from the peri- .. patients presenting with suspected STEMI.90 The onset of TTS is
..
and post-operative period, e.g. ST-segment changes on telemetry/ .. often triggered by intense emotional or physical stresses, such as
ECG, repeated episodes of hypoxia, hypotension, tachycardia, or .. bereavement. Over 90% of patients are post-menopausal women.
..
imaging evidence of MI. In the absence of evidence for acute myocar- .. Cardiovascular complications occur in 50% of patients presenting
dial ischaemia, a diagnosis of acute myocardial injury is more appro- .. with TTS, and the inpatient mortality is similar to STEMI (4 – 5%) due
..

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priate. Ongoing research suggests the possibility that interventions .. to cardiogenic shock, ventricular rupture, or malignant arrhythmias.90
may be helpful in this clinical situation. .. TTS usually presents similar to ACS. ST-segment elevation is fre-
..
.. quent (44%), but the extent of the ST-segment elevation is usually
..
.. widespread across the lateral and precordial leads, beyond that of a
18 Myocardial injury or infarction ..
.. single coronary artery distribution. ST-segment depression occurs in
associated with heart failure ..
..
< 10% of patients and after 12 – 24 h, deep, symmetric T wave inver-
sion and QTc prolongation are typically observed.91,92
..
Depending on the assay used, detectable to clearly elevated cTn val- .. There are usually transient elevations in cTn levels (> 95% of
ues being indicative of myocardial injury may be seen in patients with .. cases), but the peak cTn values observed are modest, and contrast
..
heart failure (HF), both with reduced ejection fraction (EF) and with .. with the large territory of ECG changes or left ventricular (LV) dys-
preserved EF.88 Using hs-cTn assays, measurable hs-cTn concentra- .. function. The rise and fall in cTn levels support an acute myocardial
..
tions may be present in nearly all patients with HF, with a significant .. injury, secondary to the high catecholamine surges that are known to
percentage exceeding the 99th percentile URL, particularly in those .. trigger cTn release from cardiomyocytes. Coronary vasospasm, high
..
patients with more severe HF syndromes, such as in acutely decom- .. myocardial strain hypercontractility, or high ventricular afterload may
pensated HF.87 .. also contribute to myocardial ischaemia. The diagnosis of TTS should
..
Beyond type 1 MI, multiple mechanisms have been proposed to .. be suspected when the clinical manifestations and ECG abnormalities
explain measurable to pathologically elevated cTn concentrations in .. are out of proportion to the degree of elevation of cTn values, and
..
patients with HF.88,89 For example, type 2 MI may result from .. when the distribution of the LV wall motion abnormalities does not
increased transmural pressure, small-vessel coronary obstruction,
.. correlate with a single coronary artery distribution. However, coro-
..
endothelial dysfunction, anaemia, or hypotension. Besides type 1 MI .. nary angiography and ventriculography are often needed to secure
or type 2 MI, cardiomyocyte apoptosis and autophagy due to wall
.. the diagnosis.
..
stretch have been experimentally demonstrated. Direct cellular tox- .. In most cases, the coronary arteries are angiographically normal,
icity related to inflammation, circulating neurohormones, and infiltra-
.. and where CAD is present (15% cases) it is not sufficient to explain
..
tive processes may present with HF and abnormal cTn .. the observed pattern of regional wall motion abnormalities. Left ven-
measurements indicating myocardial injury. Finally, exocytosis of the
.. triculography during catheterization and/or echocardiography may
..
early releasable cytosolic troponin pool into the blood stream from .. show a variety of LV regional wall motion abnormalities including api-
..
stressed cardiomyocytes has also been suggested as a cause of ele- .. cal (82% of patients), mid-ventricular (14.6%), basal (2.2%), or focal
vated cTn values.89 .. (1.5%) akinesis or hypokinesis in a circumferential pattern involving
..
In the context of an acutely decompensated HF presentation, cTn .. more than one coronary artery territory. Evidence of myocardial
should always be promptly measured and the ECG recorded, with .. oedema is often seen on CMR imaging during the acute phase but
..
the goal of identifying or excluding myocardial ischaemia as the pre- .. LGE is usually absent. The recovery time for LV function varies from
cipitant. In this setting, elevated cTn values should be interpreted .. hours to several weeks.93 Cardiac function may not return to normal,
..
with a high level of suspicion for type 1 MI if a significant rise and/or .. with persisting abnormalities of diastolic function, myocardial reserve
fall of the marker is seen, especially if it is accompanied by chest dis- .. during exercise, or rhythm disturbances at long-term follow-up in
..
comfort or other symptoms suggestive of myocardial ischaemia, and/ .. 10 – 15% of patients. In the absence of recovery of regional wall
or if new ischaemic ECG changes or loss of myocardial function on .. motion abnormalities, LGE-CMR is recommended to exclude MI
..
non-invasive testing are found. Shortness of breath, the cardinal .. with spontaneous recanalization.
symptom of acutely decompensated HF, may be an ischaemic equiva- .. The distinction between MI and TTS can be challenging, particu-
..
lent, but in the absence of corroborating evidence for a coronary .. larly when concurrent CAD is present (15% in the International
mechanism, caution is advised in its interpretation. Coronary artery .. Takotsubo Registry).91 Two additional features that are helpful in dis-
..
anatomy may be known and this knowledge may be used to interpret .. tinguishing TTS from acute MI are QTc prolongation > 500 ms
abnormal cTn results. However, further information—such as renal
.. during the acute phase and the recovery of LV function over
..
function, myocardial perfusion studies, coronary angiography, or . 2 – 4 weeks. There are rare cases described where MI and TTS
254 Expert consensus document

..
coexist, e.g. MI-induced TTS or TTS with secondary plaque rupture, .. Diagnosing MI in patients with CKD and elevated cTn levels may
but this occurs where the acute regional wall motion abnormalities .. be difficult if symptoms or ECG changes indicating myocardial ischae-
..
are more extensive than the culprit coronary artery territory, and ful- .. mia are absent. However, studies suggest that serial changes in cTn
fil the pattern and definition of TTS.94 .. levels are equally effective in diagnosing MI in patients with CKD and
..
.. in those with normal renal function.106 If the level of elevated cTn val-
.. ues is unchanging, and the timing of the event makes a rising and/or
..
.. falling pattern unlikely, the elevated level, even if substantial, is likely a
20 Myocardial infarction with ..
.. reflection of chronic myocardial injury. This does not imply that these
non-obstructive coronary arteries ..
..
patients are free of CAD, since renal dysfunction and CAD are corre-
.. lated. However, if a rising and/or falling pattern is present then the
It is increasingly recognized that there is a group of MI patients with .. aetiology of the abnormal cTn values could be acute volume over-
no angiographic obstructive CAD (>_ 50% diameter stenosis in a .. load, congestive HF, or MI. If a rising and falling pattern is seen, and it
..

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major epicardial vessel), and the term myocardial infarction with non- .. is accompanied by ischaemic symptoms, new ischaemic ECG
obstructive coronary arteries (MINOCA) has been coined for this .. changes, or loss of viable myocardium on imaging, a diagnosis of acute
..
entity.95,96 The diagnosis of MINOCA, like the diagnosis of MI, indi- .. MI is likely. There are no data to suggest that different criteria for the
cates that there is an ischaemic mechanism responsible for the myo- .. cTn decision levels are needed for these patients. At times, additional
..
cyte injury (i.e. non-ischaemic causes such as myocarditis have been .. imaging studies may be necessary to determine the appropriate diag-
excluded). Furthermore, the diagnosis of MINOCA necessitates that .. nosis. It should be noted that if CKD patients present late after the
..
obstructive CAD has not been inadvertently overlooked (e.g. sponta- .. onset of chest pain, it may be difficult to observe a rise and/or fall of
neous coronary artery dissection). The prevalence of MINOCA is ..
.. cTn values in the short-term, particularly when the baseline value is
estimated to be 6 – 8% among patients diagnosed with MI and more ... elevated. Such a situation should not obviate the diagnosis of MI
common in women than men, as well as in patients presenting with .. when the clinical evidence is strong.
NSTEMI compared with those presenting with STEMI.96–98 ..
..
Atherosclerotic plaque disruption and coronary thrombosis may be ..
a cause of MINOCA, i.e. type 1 MI. However, coronary spasm and
..
spontaneous coronary dissection may be involved as well, i.e. type 2
..
..
22 Myocardial injury and/or
MI, along with other possible causes. Additional coronary imaging
.. infarction in critically ill patients
..
and functional testing methods may be useful to elucidate the mecha- ..
nisms of ischaemia in MINOCA.46
.. Elevations of cTn values are common in patients in the intensive care
.. unit and are associated with adverse prognosis regardless of the
..
.. underlying disease state.107,108 Some elevation of cTn values may
.. reflect type 2 MI due to underlying CAD and increased myocardial
..
21 Myocardial injury and/or .. oxygen demand,109 whereas in other patients, type 1 MI may occur
.. because of plaque disruption leading to thrombosis in a coronary
infarction associated with kidney ..
.. artery. However, other patients may have elevated cTn values and
disease .. marked decreases in EF due to sepsis caused by endotoxin, with
..
.. myocardial function recovering completely with normal EF once the
Many patients with chronic kidney disease (CKD) have elevation of .. sepsis is treated. It is frequently challenging for the clinician caring for
..
cTn values.99,100 With hs-cTn assays, the majority of patients with .. a critically ill patient with a severe single organ or multiorgan patho-
end-stage renal disease will have elevation of hs-cTn values above the .. logical condition to decide on a plan of action when the patient has
..
99th percentile URL.99,101 This is particularly the case for hs-cTnT, .. elevated cTn values. If and when the patient recovers from the critical
which is more often elevated compared with hs-cTnI.99,102 It has .. illness, clinical judgement should be employed to decide whether,
..
been shown using hs-cTn assays that renal dysfunction is commonly .. and to what extent, further evaluation for CAD or structural heart
associated with cardiovascular abnormalities.102–104 In autopsy stud- ..
.. disease is indicated.110
ies, elevation of cTn values was invariably associated with evidence of ..
myocardial injury.15 Recently, a minor effect on renal clearance of ..
..
cTn has been shown when levels are low, but not in response to .. 23 Biochemical approach for
acute episodes of myocardial injury.105 The mechanisms include ..
..
increased ventricular pressure, small-vessel coronary obstruction, .. diagnosing myocardial injury and
..
anaemia, hypotension, and possibly direct toxic effects on the myo- .. infarction
cardium associated with the uraemic state.89 Cardiomyocyte apopto- ..
sis and autophagy due to acute wall stretch have been demonstrated .. cTnI and cTnT are the preferred biomarkers recommended to
..
experimentally.18 Thus, baseline elevation of cTn values is common, .. both rule in and rule out myocardial injury, and thus to define MI and
and because they reflect myocardial injury, such elevation is highly
.. each specific subtype of MI.12,22,23,31 Detection of a rise and/or fall of
..
prognostic over time.99 . cTn values is essential, and a key early component along with other
Expert consensus document 255

Very early
sampling Early sampling Later sampling Very late sampling

Rising cTn values


from below to
>99th percentile
Delta is
detectable
cTn values
>99th percentile
Delta may not
be seen over a Acute

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short period cTn values myocardial
Cardiac >99th percentile infarction
Declining delta
Troponin Chronic
(cTn) myocardial
injury
Low
cTn
values
Hard to
detect
delta

99th

©ESC/ACC/AHA/WHF 2018
percentile
URL

Time from onset of symptoms (hours)

Figure 7 Illustration of early cardiac troponin kinetics in patients after acute myocardial injury including acute myocardial infarction. The timing of
biomarker release into the circulation is dependent on blood flow and how soon after the onset of symptoms samples are obtained. Thus, the ability
to consider small changes as diagnostic can be problematic. In addition, many comorbidities increase cTn values and, in particular, hs-cTn values, so
that elevations can be present at baseline even in those with myocardial infarction who present early after the onset of symptoms. Changes in cTn
values or deltas can be used to define acute compared with chronic events, and the ability to detect these is indicated in the figure. Increased cTn val-
ues can often be detected for days after an acute event. cTn = cardiac troponin; URL = upper reference limit.

..
elements of the clinical evaluation to establish the diagnosis of acute .. deviation around the measurement of the individual assay at relevant
MI. Criteria for determining a pathological rise between two serial .. values.12,22 For hs-cTn assays, biological variation also needs to be
..
cTn values are assay-dependent and continue to evolve. An idealized .. considered. In most studies, conjoint analytical and biological varia-
view of troponin kinetics in patients with acute MI is shown in
.. tion is in the range of 50 – 60%.
..
Figure 7. .. For that reason, this percentage has been suggested for use when
It should be appreciated that because biomarker release is sub-
.. initial baseline values are <_ the 99th percentile URL.23,31,113
..
stantially dependent on blood flow,111,112 there is significant variabil- .. However, for individuals with an initial value greater than the 99th
ity in the time to peak value (velocity), the time when a normal value
.. percentile URL, a lesser degree of change during serial measurements
..
may become greater than the 99th percentile URL, or when a chang- .. is necessary to achieve improved clinical sensitivity (as compared
ing pattern of values can be observed. The ability to define a changing
.. with individuals with initial values <_ the 99th percentile URL). Thus,
..
pattern will also depend on timing. For example, around peak values, .. an expert consensus group has recommended serial changes > 20%
..
it may be difficult to observe a changing pattern of values. Similarly, .. be used in this situation.22 Absolute changes are assay dependent but
the downslope of the time–concentration curve is much slower than .. appear superior to relative per cent changes with hs-cTn assays,114
..
the upslope. These issues need to be taken into account when defin- .. and in some studies this is especially the case when the initial value is
ing whether or not a changing pattern is present. In addition, it is .. increased.115 The use of a fixed absolute value change criteria trans-
..
important to make sure that a given change is greater than can be .. lates into a smaller percentage or relative change as absolute values
anticipated by variability alone. This is defined for conventional cTn ... rise, and therefore provides greater sensitivity. The use of a changing
assays as a change greater than or equal to three times the standard .. pattern is important in allowing clinicians to differentiate an acute
256 Expert consensus document

..
from a chronic cTn increase above the 99th percentile URL.113–115 .. be difficult to observe over short periods of time in those who
Using criteria less than conjoint analytical and biological variation will .. present early after the onset of symptoms of acute MI, those who
..
reduce the clinical specificity of hs-cTn assays.113,116 An imprecision .. present late and are on the downslope of the time-concentration
of <_ 10% coefficient of variation (CV) at the 99th percentile URL is .. curve, and those who have values near peak where they may be tran-
..
also mandatory for hs-cTn assays.31 The use of non-hs-cTn assays .. sitioning from a rising to a falling pattern.113,123
that do not have imprecision (<_ 10% CV at the 99th percentile URL) ..
..
makes the determination of a significant serial change more difficult ..
but does not cause false positive results. Assays with CVs between .. 25 The 99th percentile upper
..
10 – 20% are acceptable for clinical use. However, assays with CVs > .. reference limit
20% at the 99th percentile URL should not be used.117 ..
..
If a cTn assay is not available, the best alternative is CK-MB meas- .. The 99th percentile URL is designated as the decision level for the
ured by a mass assay. As with cTn, an increased CK-MB value is .. presence of myocardial injury and must be determined for each spe-
..

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defined as a measurement above the 99th percentile URL, which is .. cific assay with quality control materials used at the URL to validate
designated as the decision level for the diagnosis of MI. Sex-specific .. appropriate assay imprecision. The cTn assay 99th percentile URL
..
CK-MB values should be employed.118 .. values used in clinical practice and research can be found both in
.. manufacturers’ package inserts, in peer-reviewed publications, and
..
.. on the IFCC website.118–120 Clinicians should be aware that for all
24 Analytical issues of cardiac .. cTn assays, including hs-cTn assays, there is still no expert opinion or
..
..
troponins ..
consensus about specific criteria for how the 99th percentile URL
.. should be defined.124 We endorse IFCC guidelines on the technical
The analytical sensitivity [limit of detection (LoD)] of cTnI and cTnT .. issues related to hs-cTn assays, including how studies should be con-
..
assays varies 10-fold.31,119 Because assays are not standardized, values .. figured to determine 99th percentile URLs.119 The guidelines include
from one assay cannot be directly compared with those from .. the clinical or surrogate biomarker screening that may be needed to
..
another assay. Furthermore, values may be different between assay .. better define the 99th percentile URL and the statistical methods
generations120 and changes can even occur when the same assay .. that can be applied, but do not include a requirement for cardiac
..
reagents are measured on different instruments.121 Thus, clinicians .. imaging.119 Screening of apparently healthy subjects with imaging has
must learn about their local assay and should look for reliable infor- .. been shown to lower the observed 99th percentile URL value, but is
..
mation, e.g. available on the International Federation of Clinical .. not a practical standard for the in vitro diagnostic industry to
Chemistry and Laboratory Medicine (IFCC) website (http://www. .. use.124,125 Thus, there is the possibility of false negative values using
..
ifcc.org/executive-board-and-council/eb-task-forces/task-force-on-cli .. the manufacturer’s reported 99th percentile URL values. hs-cTn
nical-applications-of-cardiac-bio-markers-tf-cb/), when they have .. assays demonstrate shifts to higher values for the 99th percentile
..
questions concerning analytical issues. The current guidelines accom- .. URL in association with comorbidities and age over > 60
modate all assays, whether hs-cTn, contemporary (conventional)
.. years.101,125–127 However, at present, age-dependent cut-off points
..
cTn, or point of care (POC) cTn. While hs-cTn assays are able to .. are not recommended for clinical use. Clinicians should rely instead
measure relatively low values and document small increases above
.. on changing values during serial measurements of cTn for the diagno-
..
the 99th percentile URL, many contemporary and POC cTn assays .. sis of acute myocardial injury, including MI. Significantly lower values
may not detect small increasing values within the reference interval
.. are observed among women compared with men, and therefore sex-
..
or slightly above the 99th percentile URL, leading to substantial differ- .. specific 99th percentile URLs are recommended for hs-cTn
ences in the frequency of events based solely on the cTn assay used.
.. assays.31,118–120 For some hs-cTn assays, sex-specific cut-off values
..
These differences are amplified when multiples of the 99th percentile .. have been reported to improve diagnostic and prognostic informa-
.. tion in patients with possible acute MI.128,129 However, there is con-
URL are used. At present, IFCC guidelines support the concept that ..
hs-cTn assays are differentiated from contemporary or POC cTn .. troversy as to whether this approach provides valuable additional
..
assays by their ability to measure cTn values above the assay’s LoD in .. information for all hs-cTn assays.130
>_ 50% of healthy individuals.31,118,119,122 This provides a rough esti- ..
..
mate of assay sensitivity. It is recommended that values for cTn assays ..
be reported as whole numbers in nanograms per litre to avoid inter- ..
..
26 Operationalizing criteria for
pretation problems associated with multiple zeros and decimal points .. myocardial injury and infarction
that can often result in confusion.31 Clinicians should avoid mixing ..
..
the units from contemporary assays with those from hs-cTn assays. .. Blood samples for the measurement of cTn should be drawn on first
All assays, including cTn assays, have some analytical problems result- .. assessment (designated as 0 h) and repeated 3 – 6 h later, or earlier
..
ing in false positive and false negative results, but these are uncom- .. with hs-cTn assays. The sampling interval will impact the clinical cut-
mon (< 0.5%).22 These problems are less common with hs-cTn .. off at baseline and what is determined to be a pathological rise and/or
..
assays.23 .. fall of the biomarker. Sampling beyond 6 h may be required if further
Conjoint biological and analytical variation of hs-cTn assays is in .. ischaemic episodes occur, or in high-risk patients. To establish the
..
the range of 50–60%.123 When values are elevated, analytical varia- .. diagnosis of an acute MI, a rise and/or fall in cTn values with at least
tion is less and a value of 20% can be used to determine that values
.. one value above the 99th percentile URL is required, coupled with a
..
are stable in the proper clinical context. For example, changes may . high clinical and/or ECG likelihood of myocardial ischaemia. hs-cTn
Expert consensus document 257

..
assays shorten the time to diagnosis in many patients to within 3 h of .. can be marked but do not change acutely during serial sampling.
onset of symptoms, but there are still some patients who may rule in .. However, a falling pattern may take longer to be observed in patients
..
late (at 6 h).131 Furthermore, some patients with acute myocardial .. with a high pre-test risk of MI who present late after symptom
injury presenting late after the onset of acute MI (> 12 – 18 h) and .. onset.146 These patients who have cTn values on the downslope of
..
who are on the downslope of the time-concentration curve may .. the time–concentration curve have a slow decline in values (Figure 7).
require longer periods of time for a changing pattern to be .. Thus, detecting a changing pattern over short periods of time may be
..
detected.131 In addition, it should be noted that with the implementa- .. difficult.117 Depending on the extent of myocardial injury, cTn values
tion of cTn and hs-cTn assays, the frequency of unstable angina will .. may remain above the 99th percentile URL for a longer period of
..
decrease and the diagnosis of NSTEMI will increase.132,133 The magni- .. time.22,23 An increased cTn value above the 99th percentile URL,
tude of these changes using hs-cTn assays have been reported in the .. with or without a dynamic change of values, or in the absence of clini-
..
range of 18 – 30%.134 Assuming proper timing of symptoms, acute .. cal evidence of ischaemia, should prompt a search for other diagno-
ischaemia should result in a change in hs-cTn; however, there may be .. ses associated with myocardial injury, as shown in Table 1.
..

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patients in whom it is difficult to ascertain the timing of symptom ..
onset. Thus, despite typical chest discomfort, these patients may have ..
..
hs-cTn values that are not elevated. Other patients with symptoms .. 27 Electrocardiographic detection
suggestive of unstable angina may have increased hs-cTn values as a
..
..
..
of myocardial infarction
result of structural heart disease with or without acute myocardial
ischaemia. This latter group may be particularly difficult to distinguish
..
.. The ECG is an integral part of the diagnostic workup of patients with
from patients presenting with late NSTEMI with a slow decline in tro- .. suspected MI, and should be acquired and interpreted promptly (i.e.
ponin values that can be observed in late presenters.131 Finally, some
..
.. target within 10 min) after first medical contact.47,147 Pre-hospital
patients may manifest a changing pattern of troponin values with a .. ECGs reduce the time to diagnosis and treatment, and can facilitate
..
magnitude that does not exceed the delta suggested for diagnosis or .. the triage of STEMI patients to hospitals with PCI capability if within
who fail to manifest a value greater than the 99th percentile URL. .. the recommended time interval (120 min from STEMI diagnosis).46,148
..
This is a group of patients that deserves close scrutiny because they .. Acute myocardial ischaemia is often associated with dynamic changes
may be at high risk. The triage of these patients can only be accom- .. in ECG waveform and serial ECG acquisition can provide critical infor-
..
plished based on clinical evaluation. .. mation, particularly if the ECG at initial presentation is non-diagnostic.
Strategies employing either very low levels of hs-cTn on presenta- .. Recording several standard ECGs with fixed electrode positions at
..
tion or the lack of any change and persistently normal hs-cTn values .. 15 – 30 min intervals for the initial 1 – 2 h, or the use of continuous
over a 1 – 2 h period after presentation have been advocated to .. computer-assisted 12-lead ECG recording (if available) to detect
..
exclude acute myocardial injury, and MI as well. A single sample rule .. dynamic ECG changes, is reasonable for patients with persistent or
out strategy using a very low value (in many cases the LoD of the .. recurrent symptoms or an initial non-diagnostic ECG.149 Serial or con-
..
assay) has high sensitivity for myocardial injury and therefore high .. tinuous ECG recordings may be helpful in determining reperfusion or
negative predictive value to exclude MI.135 This strategy should not .. reocclusion status. Reperfusion is usually associated with a large and
..
be used in those who present early, i.e. < 2 h after the onset of chest .. prompt reduction in ST-segment elevation.
discomfort. Some studies indicate that the single sample approach .. More profound ST-segment shifts or T wave inversions involving
..
provides optimal sensitivity and negative predictive accuracy in .. multiple leads/territories are associated with a greater degree of
patients otherwise at low risk and those with a normal ECG.136–138
.. myocardial ischaemia, and a worse prognosis. For example, ST-
..
However, one concern about very short rule out periods is that the .. segment depression >_ 1 mm in six leads, which may be associated
precision of the assays may not permit small differences to be distin-
.. with ST-segment elevation in leads aVR or lead V1 and haemody-
..
guished.139–142 These criteria have not, and should not, be applied to .. namic compromise, is suggestive evidence of multivessel disease or
patients with hs-cTn elevations.
..
.. left main disease. Pathologic Q waves increase the prognostic risk.
The clinical specificity and positive predictive value of such 1–2 h .. Other ECG signs associated with acute myocardial ischaemia include
sampling approaches for ruling in MI are limited by the substantial
..
.. cardiac arrhythmias, intraventricular bundle branch blocks, atrioven-
proportion of individuals who meet the proposed biomarker criteria .. tricular conduction delays, and loss of precordial R wave amplitude, a
..
with diagnoses other than MI.136,141 Thus, the use of a rapid rule in/ .. less specific finding. The ECG by itself is often insufficient to diagnose
out MI protocol does not absolve the clinician from considering .. acute myocardial ischaemia or infarction, since ST deviation may be
..
other causes of acute myocardial injury.142 In addition, considering a .. observed in other conditions, such as acute pericarditis, LV hypertro-
broader population of patients—inclusive of those who present .. phy (LVH), left bundle branch block (LBBB), Brugada syndrome, TTS,
..
atypically, those with end-stage renal disease, and the critically ill— .. and early repolarization patterns.150 A prior ECG is often helpful in
the cut-off points to be used will likely need to be altered.139 Such .. distinguishing a new from a chronic finding, but should not delay the
..
patients have been excluded from the majority of emergency depart- .. decision for treatment.
ment evaluation studies.108,136,142 .. Prolonged new convex ST-segment elevation, particularly when
..
The demonstration of a rising and/or falling pattern is needed to .. associated with reciprocal ST-segment depression, usually reflects
distinguish acute injury from chronic conditions associated with .. acute coronary occlusion and results in myocardial injury with
..
structural heart disease that can have chronic increases of cTn values. .. necrosis. Reciprocal changes can help to differentiate STEMI from
For example, patients with renal failure99,143,144 or LV hypertrophy145 .. pericarditis or early repolarization changes. As in cardiomyopathy, Q
..
can have significant chronic increases in cTn values. These increases . waves may also occur due to myocardial fibrosis in the absence of
258 Expert consensus document

CAD. Some of the earlier manifestations of myocardial ischaemia are


.. onset of the QRS serving as the reference point. In patients with a
..
typical T wave and ST-segment changes. Increased hyperacute T .. stable baseline, the TP segment (isoelectric interval) is a more accu-
wave amplitude, with prominent symmetrical T waves in at least two
.. rate method to assess the magnitude of ST-segment shift, and in dis-
..
contiguous leads, is an early sign that may precede the elevation of .. tinguishing pericarditis (PTa depression) from acute myocardial
..
the ST-segment. In general, the development of new Q waves indi- .. ischaemia. Tachycardia and baseline shift are common in the acute
cates myocardial necrosis, which starts minutes/hours after the myo- .. setting and can make this determination difficult. Therefore, QRS
..
cardial insult. Transient Q waves may be observed during an episode .. onset is recommended as the reference point for J-point determina-
of acute ischaemia or (rarely) during acute MI with successful reper- .. tion (Figure 8).
..
fusion. Table 2 lists ST-segment–T wave (ST-T) criteria suggestive of .. New, or presumed new, J-point elevation >_ 1 mm (1 mm = 0.1
acute myocardial ischaemia that may or may not lead to MI. The .. mV) is required in all leads other than V2 and V3 as an ischaemic
..
J-point (junction between QRS termination and ST-segment onset) is .. response. In healthy men under age 40, J-point elevation can be as
used to determine the magnitude of the ST-segment shift with the .. much as 2.5 mm in leads V2 or V3, but it decreases with increasing
..

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.. age. Sex differences require different cut-off points for women, since
.. J-point elevation in healthy women in leads V2 and V3 is less than in
..
.. men.5 The criteria in Table 2 require that the ST shift be present in
.. two or more contiguous leads. For example, >_ 2 mm of ST-elevation
..
.. in lead V2 and >_ 1 mm in lead V1 would meet the criteria of two
1 ..
©ESC/ACC/AHA/WHF 2018
.. abnormal contiguous leads in a man >_40 years old. However, >_ 1
.. mm and < 2 mm of ST-elevation, seen only in leads V2 –V3 in men (or
.. < 1.5 mm in women), may represent a normal finding.
..
2 .. It should be noted that lesser degrees of ST displacement or T
.. wave inversion than those described in Table 2 can also represent an
..
.. acute myocardial ischaemic response. In patients with known or high
.. likelihood of CAD, the clinical presentation is critical to enhance the
..
Figure 8 Electrocardiogram example of ST-segment elevation. .. specificity of these findings.
The initial onset of the Q wave shown by arrow 1 serves as the ..
.. Absence of ST-elevation in the precordial leads, tall, prominent,
reference point and arrow 2 shows the onset of the ST-segment or .. symmetrical T waves in the precordial leads, upsloping ST-segment
J-point. The difference between the two identifies the magnitude of ..
displacement. Measurements of both arrows should be made from .. depression > 1 mm at the J-point in the precordial leads, and in most
.. cases ST-segment elevation (> 1 mm) in lead aVR or the symmetrical,
the top of the electrocardiogram line tracing. ..
.. often deep (> 2 mm), T wave inversions in the anterior precordial
.. leads are associated with significant left anterior descending artery
..
.. (LAD) occlusion.151–153 ST-elevation in lead aVR > 1 mm may
.. accompany anterior or inferior STEMI, and is associated with
Table 2 Electrocardiographic manifestations sugges- ..
.. increased 30 day mortality in patients with acute MI.154 Pulmonary
tive of acute myocardial ischaemia (in the absence of .. embolism, intracranial processes, electrolyte abnormalities, hypo-
left ventricular hypertrophy and bundle branch block) ..
.. thermia, or perimyocarditis may also result in ST-T abnormalities and
.. should be considered in the differential diagnosis.
..
ST-elevation .. The ECG diagnosis of atrial infarction should be suspected in the
.. context of ventricular infarction (particularly when the right ventricle
New ST-elevation at the J-point in two contiguous leads with ..
.. is involved) if small, transient elevations and reciprocal depressions of
the cut-point: ≥ 1 mm in all leads other than leads V2 –V3 where ..
the following cut-points apply: ≥ 2mm in men ≥ 40 years; .. the PR (PTa) segment are noted associated with changes in configura-
≥ 2.5 mm in men < 40 years, or ≥ 1.5 mm in women regardless .. tion of the P wave.
of age.a
..
..
©ESC/ACC/AHA/WHF 2018

..
ST-depression and T wave changes ..
..
New horizontal or downsloping ST-depression ≥ 0 .5 mm .. 28 Application of supplemental
in two contiguous leads and/or T inversion > 1 mm in two ..
contiguous leads with prominent R wave or R/S ratio > 1 .
.. electrocardiogram leads
..
.. Supplemental leads, as well as serial ECG recordings, should be
..
a
When the magnitudes of J-point elevation in leads V2 and V3 are registered .. deployed with a very low threshold in patients who present with
from a prior electrocardiogram, new J-point elevation >_ 1 mm (as compared .. ischaemic chest pain and a non-diagnostic initial ECG.155,156 ECG evi-
with the earlier electrocardiogram) should be considered an ischaemic response.
..
For bundle branch block, see section below.
.. dence of myocardial ischaemia in the distribution of a left circumflex
.. artery is often overlooked. Isolated ST-segment depression >_ 0.5
Expert consensus document 259

mm in leads V1 –V3 may indicate left circumflex occlusion and can


Table 3 Electrocardiographic changes associated with
best be captured using posterior leads at the fifth intercostal space
prior myocardial infarction (in the absence of left ven-
(V7 at the left posterior axillary line, V8 at the left mid-scapular line, tricular hypertrophy and left bundle branch block)
and V9 at the left paraspinal border). Recording of these leads is
strongly recommended in patients with high clinical suspicion of
acute circumflex occlusion (e.g. initial ECG non-diagnostic or ST- Any Q wave in leads V2 –V3 > 0 .02 s or QS complex in leads
segment depression in leads V1–V3).156 A cut-off point of 0.5 mm ST- V2 –V3 .

©ESC/ACC/AHA/WHF 2018
elevation is recommended in leads V7 –V9; specificity is increased at a Q wave ≥ 0 .03 s and ≥ 1 mm deep or QS complex in leads I,
cut-off point >_ 1 mm ST-elevation and this cut-off point should be II, aVL, aVF or V4 –V6 in any two leads of a contiguous lead
used in men < 40 years old. ST-segment depression in leads V1 –V3 grouping (I, aVL; V1 –V6 ; II, III, aVF).a
may be suggestive of inferobasal myocardial ischaemia (previously
R wave > 0 .04 s in V1 –V2 and R/S > 1 with a concordant
termed posterior infarction), especially when the terminal T wave is positive T wave in absence of conduction defect.

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positive (ST-elevation equivalent); however, this is non-specific.
In patients with inferior and suspected right ventricular infarction, a
The same criteria are used for supplemental leads V7 –V9. s = seconds.
leads aVR or V1 may exhibit ST-segment elevation >_ 1 mm. The early
recording of right precordial leads V3R and V4R should be performed,
since ST-elevation >_ 0.5 mm (>_ 1 mm in men < 30 years old) pro-
vides supportive criteria for the diagnosis.157 Changes in right precor-
dial leads may be transient, and an absence of ECG changes in leads .. Asymptomatic patients who develop new Q wave criteria for MI
V3R and V4R does not exclude right ventricular infarction. Myocardial
..
.. detected during routine ECG follow-up, or reveal evidence of MI by
imaging can be helpful in this clinical setting. .. cardiac imaging that cannot be directly attributed to an interim coro-
..
.. nary revascularization procedure or an ACS admission, should be
..
.. termed ‘silent or unrecognized MI’. In studies where serial ECG analy-
29 Electrocardiographic detection .. sis was applied, silent or unrecognized Q wave MI accounted for
..
of myocardial injury .. 9–37% of all non-fatal MI events and was associated with a signifi-
.. cantly increased mortality risk.163,164 Improper lead placement, QRS
It is not possible to initially distinguish ECG manifestations of acute or ..
.. abnormalities, or technical errors (e.g. lead reversal) may result in the
chronic myocardial injury from acute myocardial ischaemia. Rapidly .. appearance of new Q waves or QS complexes, as compared with a
developing dynamic ECG changes that temporally match the clinical ..
.. prior tracing. Thus, the diagnosis of a new silent Q wave MI should be
presentation may be helpful in diagnosing a symptomatic patient with .. confirmed by a repeat ECG recording with correct lead placement,
elevated cTn values as having acute myocardial ischaemia resulting in ..
.. focused questioning about potential interim ischaemic symptoms, or
MI. However, ECG abnormalities are also common in patients who .. by an imaging study. Imaging techniques are useful if there is abnormal
have myocardial injury, e.g. myocarditis or TTS.158–160 ..
.. myocardial motion, thickening, or thinning in the region of interest,
.. but the absence of these does not exclude MI.165
..
30 Prior or silent/unrecognized
myocardial infarction Criteria for prior or silent/unrecognized
Q wave criteria associated with MI and an increased relative risk of
MI
death are illustrated in Table 3, and are contained in Q wave coding Any one of the following criteria meets the diagnosis for prior or
algorithms such as the Minnesota Code and the WHO MONItoring silent/unrecognized MI:
of trends and determinants in CArdiovascular disease (MONICA)
• Pathological Q waves as described in Table 3, with or without
code.11,161,162 symptoms, in the absence of non-ischaemic causes;
The specificity of the ECG diagnosis for MI is greatest when Q • Imaging evidence of loss of viable myocardium in a pattern
waves occur in several leads or lead groupings, or are > 0.04 s. When consistent with ischaemic aetiology;
the Q waves are associated with ST deviations or T wave changes in • Pathological findings of a prior MI.
the same leads, the likelihood of MI is increased; for example, minor
Q waves >_ 0.02 s and < 0.03 s that are >_ 1 mm deep are suggestive
of prior MI if accompanied by inverted T waves in the same lead
group. Non-invasive imaging techniques also provide important sup-
portive evidence of prior MI. In the absence of non-ischaemic causes,
31 Conditions that confound the
regional myocardial thinning, scar or reduced wall motion shown by electrocardiographic diagnosis of
echocardiography, myocardial perfusion scintigraphy (MPS) with sin- myocardial infarction
gle photon emission computed tomography (SPECT) or positron
emission tomography (PET), or magnetic resonance imaging provide A QS complex in lead V1 is normal. A Q wave < 0.03 s and < 0.25 of
strong evidence for prior MI, particularly when ECG criteria are the R wave amplitude in lead III is normal if the frontal QRS axis is
equivocal. between -30 and 0 . A Q wave may also be normal in aVL if the
260 Expert consensus document

..
frontal QRS axis is between 60–90 . Septal Q waves are small, non- .. depression should not automatically be classified as type 2 MI without
pathological Q waves < 0.03 s and < 0.25 of the R-wave amplitude in .. additional information. In this clinical setting, signs of overt ischaemic
..
leads I, aVL, aVF, and V4–V6. Pre-excitation, cardiomyopathy, TTS, .. symptoms, the timing of symptoms relative to atrial fibrillation onset,
cardiac amyloidosis, LBBB, left anterior hemiblock, LVH, right ventric- .. a changing pattern of cTn, and imaging and/or angiographic findings
..
ular hypertrophy, myocarditis, acute cor pulmonale, or hyperkalae- .. may be helpful in establishing the diagnosis. However, in the absence
mia may be associated with Q waves or QS complexes in the .. of evidence for myocardial ischaemia, the aetiology of the elevated
..
absence of MI. Clinicians should be aware of confounders to the .. cTn values should be attributed to myocardial injury.
ECG diagnosis of myocardial ischaemia, since ST-T wave abnormal-
..
..
ities are commonly observed with different pathological cardiac con- ..
..
ditions, such as pre-excitation, pericarditis, and cardiomyopathy. .. 34 Imaging techniques
..
.. Non-invasive imaging plays many roles in patients with known or sus-
..

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32 Conduction disturbances and .. pected MI, but this section concerns only its role in the diagnosis and
.. characterization of myocardial injury and MI. The underlying rationale
..
pacemakers .. is that regional myocardial hypoperfusion and ischaemia lead to a cas-
.. cade of events including myocardial dysfunction, cell death, and heal-
The diagnosis of MI is more difficult in the presence of conduction ..
.. ing by fibrosis. Important imaging parameters are therefore
disturbances, related in part to ST-T wave changes caused by the .. myocardial perfusion, myocyte viability, myocardial thickness, thick-
conduction disturbance and the fact that the conduction disturbance ..
.. ening and motion, and the effects of myocyte loss on the kinetics of
itself may be heart-rate dependent.166,167 Comparison to a pre- ..
admission ECG may be helpful in determining if the conduction .. paramagnetic or radio-opaque contrast agents indicating myocardial
.. fibrosis or scar.
defect or ST-T wave changes are new, as long as it does not delay ..
time to treatment. Ischaemic symptoms, and presumed new LBBB or .. Commonly used imaging techniques in acute and prior MI are
.. echocardiography, MPS using SPECT or PET, CMR, and possibly
right bundle branch block (RBBB) that is not rate-related, are associ- ..
ated with an adverse prognosis. In patients with LBBB, ST-segment .. computed tomography (CT).173 There is considerable overlap in
.. their capabilities and each of the techniques can assess myocardial
elevation >_ 1 mm concordant with the QRS complex in any lead may ..
be an indicator of acute myocardial ischaemia. Similar findings can be .. viability, perfusion, and function to a greater or lesser extent. Only
.. the radionuclide techniques provide a direct assessment of myocyte
useful in detecting ECG evidence for acute myocardial ischaemia in ..
patients with right ventricular paced rhythms.167 Recording an ECG
.. viability because of the inherent properties of the tracers used.
.. Other techniques provide indirect assessments of myocardial viabil-
trace with the pacemaker temporarily switched off may also be useful ..
in patients who are not pacemaker dependent, but careful interpreta-
.. ity, such as the contractile response to dobutamine by echocardiog-
.. raphy, or increased extracellular space secondary to myocyte loss by
tion of repolarization is needed due to the possible presence of ..
stimulation-induced changes (electrical memory). The ECG diagnosis
.. CMR or CT.
..
of acute myocardial ischaemia in patients with biventricular pacing is ..
more difficult. In patients with RBBB, new or presumed new ST-
.. 34.1 Echocardiography
..
segment elevation >_ 1 mm, or ST-segment or T wave abnormalities .. The strength of echocardiography is the combined assessment of car-
.. diac structure and function, in particular myocardial thickness, thick-
(excluding leads V1 –V4) (Table 2), may indicate acute myocardial ..
ischaemia. New, or presumed new, RBBB without associated ST- .. ening/thinning, and motion. Regional wall motion abnormalities
.. induced by ischaemia can be detected by echocardiography almost
segment or T wave changes is associated with thrombolysis in myo- ..
cardial infarction (TIMI) 0–2 flow in as many as 66% of patients (com- .. immediately after onset when > 20% transmural myocardial thick-
..
pared with > 90% in those with ST-segment or T wave changes).168 .. ness is affected.174–176 These abnormalities, when new and without
.. alternative aetiology, support the diagnosis of MI when cTn values
..
.. show a rising and/or falling pattern. Echocardiography also allows
.. detection of non-coronary cardiac pathologies known to cause chest
33 Atrial fibrillation ..
.. pain, e.g. acute pericarditis, severe aortic stenosis, and hypertrophic
In patients with atrial fibrillation and rapid ventricular rate or paroxys- .. cardiomyopathy among others. The technique is useful in diagnosing
..
mal supraventricular tachycardia, ST-segment depression or T wave .. mechanical complications in patients with MI and haemodynamic
inversion may occur in the absence of CAD.169,170 The causes are .. compromise (shock), or other potentially fatal entities such as acute
..
not completely understood. Cardiac memory, an electrical remodel- .. aortic dissection or massive pulmonary embolism where the clinical
ling phenomenon characterized by marked diffuse T wave inversions .. presentation might be similar to that seen with acute MI.
..
following periods of abnormal ventricular activation, which may also .. Intravenous echocardiographic contrast agents can improve visual-
be caused by transient rate-related conduction disturbances or pac- .. ization of the endocardial border, and can be used to assess myocar-
..
ing, may explain these findings. In some patients, the tachycardia may .. dial perfusion and microvascular obstruction. Tissue Doppler and
result in an insufficient increase in coronary flow to match myocardial .. strain imaging permit the quantification of global and regional func-
..
oxygen demand, resulting in cellular hypoxia and abnormal repolari- .. tion.177,178 Intravascular echocardiographic contrast agents that are
zation.171,172 For these reasons, a patient with new-onset atrial fibril-
.. targeted at specific molecular processes have been developed, but
..
lation, elevated baseline cTn concentration, and new ST-segment . these techniques have not yet been applied in the setting of MI.179
Expert consensus document 261

..
34.2 Radionuclide imaging .. meta-iodobenzylguanidine,181 imaging of matrix metalloproteinase
.. activation in ventricular remodelling,182,183 and the assessment of
Several radionuclide tracers allow viable myocytes to be imaged ..
directly, including the SPECT tracers 201TI chloride, 99mTc sestamibi, .. myocardial metabolism.184
..
and tetrofosmin, and the PET tracers 18F 2-fluorodeoxyglucose and ..
82
Rb.173 A strength of the radionuclide techniques is that they are the .. 34.3 Cardiac magnetic resonance
..
only commonly available methods for assessing viability directly, .. imaging
although the relatively low resolution of the images limits them for .. The high tissue contrast and resolution of CMR provides an accurate
..
detecting the smallest areas of MI. Phantom studies suggest that myo- .. assessment of myocardial structure and function. Although less com-
cyte loss as little as 4% of the myocardium can be detected, corre- .. monly used in the acute setting, it has similar capabilities to echocar-
..
sponding to 5 – 10 g of muscle.180 ECG-gated imaging provides a .. diography in suspected MI. Paramagnetic contrast agents can be used
reliable assessment of myocardial motion, thickening, and global func-
.. to assess myocardial perfusion and the increase in extracellular space
..
tion. Evolving radionuclide techniques relevant to the assessment of .. that is associated with the fibrosis of prior MI (detected by LGE-

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MI include imaging of sympathetic innervation using 123I-labelled
.. CMR). These techniques have been used in the setting of acute

ISCHAEMIC
Transmural Subendocardial Focal Subendocardial

NON-ISCHAEMIC

©ESC/ACC/AHA/WHF 2018

Subepicardial Mid-wall Insertion points

Figure 9 Post-contrast cardiac magnetic resonance images. The gadolinium-based contrasts wash out slowly from myocardium with increased
extracellular space such as fibrosis, thus enhancing areas of scarring (white arrows). The different patterns of scarring are divided into ischaemic and
non-ischaemic. Typically, an ischaemic scar/fibrosis (upper panel) extends from the subendocardium to the epicardium (subendocardial, non-trans-
mural scar vs. transmural scar). Conversely, a non-ischaemic fibrosis/scar can be encountered at the epicardium, in the mid-wall, or at the insertion
points of the right ventricle (lower panel).
262 Expert consensus document

..
MI185,186 and localized delay in contrast enhancement is able to .. be excluded, and unless a new abnormality is detected or can be pre-
detect even small areas of subendocardial MI, thought to be as little .. sumed to have arisen in the setting of other features of acute MI.
..
as 1 g.187 CMR also has the ability to identify the presence and extent .. In the setting of acute MI, CMR can also be used to assess the pres-
of myocardial oedema/inflammation, allowing the distinction of acute .. ence and extent of myocardium at risk (myocardial oedema), myo-
..
vs. chronic myocardial injury. The patterns of LGE when reflecting .. cardial salvage, microvascular obstruction, intramyocardial
ischaemic and non-ischaemic myocardial injury are shown in Figure 9. .. haemorrhage, and infarct size, all markers of myocardial injury that
..
The gadolinium-based contrasts wash out slowly from myocar- .. have prognostic value.190 In patients with possible acute MI but unob-
dium with increased extracellular space such as fibrosis, thus enhanc- .. structed coronary arteries, CMR can help to diagnose alternative
..
ing areas of scarring (white arrows). The different patterns of scarring .. conditions such as myocarditis, TTS, embolic infarction, or MI with
are divided into ischaemic and non-ischaemic. Typically, an ischaemic .. spontaneous recanalization.189
..
scar/fibrosis (upper panel) extends from the subendocardium to the ..
epicardium (subendocardial, non-transmural scar vs. transmural ..
..

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scar). Conversely, a non-ischaemic fibrosis/scar can be encountered ..
..
36 Applying imaging in late
at the epicardium, in the mid-wall, or at the insertion points of the
right ventricle (lower panel).
..
..
presentation of myocardial
.. infarction
..
34.4 Computed tomographic coronary ..
.. In the case of late presentation after suspected MI, the presence of a
angiography .. regional abnormality of myocardial motion, thickening, thinning, or
..
Infarcted myocardium is initially visible as a focal area of decreased LV .. scar in the absence of a non-ischaemic cause provides supportive evi-
myocardial enhancement, but later imaging shows hyper-
.. dence of past MI. The resolution and specificity of CMR for the detec-
..
enhancement as with LGE-CMR.188 This finding is clinically relevant .. tion of myocardial scarring has made this a valuable technique. In
because contrast-enhanced CT may be performed for suspected pul-
.. particular, the ability to distinguish between subendocardial and
..
monary embolism and aortic dissection, conditions with clinical fea- .. other patterns of scars helps to differentiate between ischaemic heart
tures that overlap with those of acute MI, but the technique is not
.. disease and other myocardial pathologies. Imaging techniques are
..
used routinely. Similarly, CT assessment of myocardial perfusion is .. also useful for risk stratification after a definitive diagnosis of MI.
..
technically feasible but not widely applied.189 CT coronary angiogra- ..
phy (CTCA) may be used to diagnose CAD in patients with an ACS ..
.. 37 Regulatory perspective on
in the emergency department or chest pain unit, particularly in low- ..
to intermediate-risk patients with normal cTn at presentation.189–193 ..
.. myocardial infarction in clinical
The only randomized trial in these patients that included both hs-cTn ..
and CTCA found that imaging did not reduce the length of stay in .. trials
..
hospital, but it did decrease subsequent outpatient testing and .. In drug and device development programmes, MI may be an entry cri-
costs.189 A diagnosis of MI cannot be established based on a CTCA ..
.. terion or be used as an efficacy endpoint, commonly as a component
scan alone. .. of the primary endpoint, as well as a safety endpoint of interest in
..
.. drug development programmes.195,196 A universal definition of MI is
.. of great benefit for clinical studies, since it will allow a standardized
..
35 Applying imaging in acute .. approach for meaningful interpretation and comparison across differ-
..
myocardial infarction ..
..
ent trials, or the pooling of results for the detection of safety signals.
For the harmonization of the MI definition it is important to standard-
..
Imaging techniques can be useful in the diagnosis of acute MI because .. ize the reporting of MI events by clinical events committees. This
of the ability to detect wall motion abnormalities or loss of viable .. would allow a more optimal comparison of MI rates among drug and
..
myocardium in the presence of elevated cardiac biomarker values. .. device trials.
Demonstration of new loss of myocardial viability in the absence of .. One cannot presume that values from one cTn assay are equiva-
..
non-ischaemic causes supports the diagnosis of MI. Normal function .. lent to those of another. These differences are amplified when multi-
practically excludes significant MI, but a small MI cannot be ruled .. ples of the values are used. This could affect results, especially in trials
..
out.194 Thus, imaging techniques are useful for early triage and dis- .. that compare strategies such as PCI and CABG. The use of one single
charge of patients with suspected MI. However, if biomarkers have .. assay and/or a central core laboratory within a trial could help to
..
been measured at appropriate times and are normal, this excludes .. decrease this variability, and might be particularly relevant in decreas-
acute MI and takes precedence over the imaging criteria. .. ing variability in trials of a drug or intervention in which cTn concen-
..
Abnormal regional myocardial motion and thickening may be .. tration is a principal safety endpoint. However, the uniform use of a
caused by acute MI, or by one or more of several other conditions .. single assay is generally not feasible in trials with follow-up post-dis-
..
including prior infarction, acute ischaemia, stunning, or hibernation. .. charge, since recurrent ischaemic events may occur in different hos-
Non-ischaemic conditions such as cardiomyopathy, and inflammatory .. pitals using different cTn assays. In clinical trials, a standardized
..
or infiltrative diseases, can also lead to regional loss of viable myocar- .. approach to establish the 99th percentile URL for a particular assay
dium or functional abnormality. Therefore, the positive predictive
.. should be established. One approach in large multicentre trials is to
..
value of imaging for acute MI is not high unless these conditions can . use the manufacturer’s recommended 99th percentile URL for a
Expert consensus document 263

..
particular assay to reduce site-to-site variability in the selection of the .. respect to psychological status, life and health insurance, and profes-
MI decision cut-off point. .. sional career, as well as driving and pilot licences. The diagnosis is also
..
Multiples for hs-cTn vs. conventional cTn could have markedly dif- .. associated with societal implications with regards to diagnosis-related
ferent prognostic implications. The assay types should be reported .. coding, hospital reimbursement, public health statistics, sick leave,
..
when possible. Multiples of the 99th percentile URL should be indi- .. and disability attestation. In order to meet these challenges, physi-
cated and reported, both for those with cardiac procedural myocar- .. cians must be adequately informed of the diagnostic criteria. Hence,
..
dial injury and those diagnosed with types 4a and 5 MI. Cumulative .. educational materials will need to be created and treatment guide-
frequency distribution of peak cTn measurements for MI endpoint .. lines must be appropriately adapted.
..
assessments by treatment group should also be provided. This will ..
facilitate the comparison of trials and meta-analyses. ..
..
.. 40 Global perspectives of the
..
.. definition of myocardial infarction

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38 Silent/unrecognized ..
..
myocardial infarction in .. Cardiovascular disease is a global health problem and prevalence is
.. increasing in the developing world. Understanding the burden and
..
epidemiological studies and .. effects of CAD in populations is of critical importance. Changing clini-
..
quality programmes .. cal definitions, criteria, and biomarkers add challenges to our under-
.. standing and ability to improve the health of the public. For clinicians,
ECG monitoring for unrecognized or silent Q wave MI is usually .. the definition of MI has important and immediate therapeutic implica-
..
acquired annually in epidemiological studies and clinical trials that .. tions. For epidemiologists, the data are often retrospective, so consis-
assess cardiovascular endpoints. These events are associated with
.. tent case definitions are critical for comparisons and trend analysis.
..
adverse outcomes.197 There is no firm consensus on how frequently .. The standards described in this report are suitable for epidemiology
..
to monitor for ECG evidence of silent Q wave MI or whether surveil- .. studies and for international classification of diseases.199 However, to
lance for silent MI events should be routinely implemented. Serial .. analyse trends over time, it is important to have consistent definitions
monitoring of patients who have had a symptomatic Q wave MI event
..
.. and to quantify adjustments when biomarkers or other diagnostic
revealed Q wave regression in a substantial number of patients.198 .. methods change,200 considering that the advent of cTn has dramati-
An annual ECG is reasonable in clinical trials to monitor for silent Q
..
.. cally increased the number of diagnosable MIs for
wave MI events if the study population is expected to have an accel- .. epidemiologists.11,201
..
erated rate of atherosclerotic events. The review should consider .. In countries with limited economic resources, cardiac biomarkers
the baseline tracing, interim event ECG tracings, and protocol- .. and imaging techniques may not be available except in a few centres,
..
mandated annual tracings, along with the review of imaging studies if .. and even the option of ECG recordings may be lacking. The WHO
available. .. recommends the use of the ESC/ACC/AHA/WHF Universal
..
.. Definition of MI in countries without resource constraints, but rec-
.. ommends more flexible standards in resource-constrained locations.
..
39 Individual and public .. Thus, when the only information available is the clinical history and
.. ECG, and when data on cardiac biomarkers are not available or
implications of the myocardial ..
.. incomplete, the diagnosis of MI can be confirmed by the development
infarction definition .. of pathological Q waves.11
..
..
Revision of the definition of MI has a number of implications for indi- ..
..
viduals, health professionals, and society at large. A tentative or final ..
diagnosis is the basis for advice about further diagnostic testing, life- .. 41 Using the Universal Definition
.. of Myocardial Infarction in the
style changes, treatment, and prognosis for the patient. The aggregate ..
..
of patients with a particular diagnosis is the basis for healthcare plan-
.. healthcare system
ning, and policy and resource allocation. ..
One of the goals of good clinical practice is to reach a definitive .. Arriving at a diagnosis of MI using the criteria set forth in this docu-
..
and specific diagnosis, which is supported by current scientific knowl- .. ment requires the integration of clinical findings, patterns on the
edge. The approach to the definition of myocardial injury and MI out- .. ECG, laboratory data, observations from imaging procedures, and on
..
lined in this document meets this goal. In general, the conceptual .. occasion pathological findings, all viewed in the context of the time
meaning of the term myocardial infarction has not changed, although .. horizon over which the suspected event unfolds. Contemporary
..
new sensitive methods have been developed to diagnose this entity. .. healthcare systems are increasingly using electronic medical records
Thus, the diagnosis of an acute MI is a clinical diagnosis based on .. where medical information is entered, curated, and available for
..
patient symptoms, ECG changes, and highly sensitive biochemical .. retrieval at a later date. This evolution offers the advantages of a
markers, as well as information gleaned from various imaging .. modern electronic database that is useful for a variety of purposes,
..
techniques. .. including scientific discovery and quality improvement in clinical care,
It should be appreciated that the universal definition of MI may be
.. but carries with it the challenges of sifting through variable locations
..
associated with consequences for patients and their families with . and formats where key data elements for confirming a diagnosis of MI
264 Expert consensus document

..
are located. Also, use of the electronic medical record as an epide- .. Society of Cardiology, Alexey Yakovlev; San Marino: San Marino
miological and research tool of the future is likely to require efforts .. Society of Cardiology, Marco Zavatta; Serbia: Cardiology Society of
..
to verify the accuracy of an acute MI diagnosis, rather than accepting .. Serbia, Milan Nedeljkovic; Slovenia: Slovenian Society of
the coded diagnoses used for administrative and billing purposes. .. Cardiology, Peter Radsel; Spain: Spanish Society of Cardiology,
..
Such an effort to create a computable phenotype of MI (further cate- .. Alessandro Sionis; Sweden: Swedish Society of Cardiology, Tomas
gorized as types 1 – 5 MI) will require input from informaticians and .. Jemberg; Switzerland: Swiss Society of Cardiology, Christian
..
experts in implementation science to translate the recommendations .. Müller; Tunisia: Tunisian Society of Cardiology and Cardio-Vascular
from this Universal Definition of MI into the routine practice of .. Surgery, Leila Abid; Turkey: Turkish Society of Cardiology, Adnan
..
healthcare delivery and documentation. .. Abaci; Ukraine: Ukrainian Association of Cardiology, Alexandr
Given the evolution of biomarker assays used to support the diag- .. Parkhomenko; United Kingdom: British Cardiovascular Society,
..
nosis of MI, it is important that a consistent approach be used in the .. Simon Corbett.
construction of the computable phenotype of MI so as to reliably ..
.. Approved by the ACC Clinical Policy Approval Committee.

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make comparisons across institutions and track epidemiological ..
trends. Ideally, the information provided should include the assay .. Approved by the AHA Science Advisory and Coordinating
..
used to make the diagnosis of MI, the 99th percentile of the URL, and .. Committee.
the full sequence of values obtained to discern a rise and fall in bio-
..
.. Approved by the WHF Board.
marker levels.196 ..
..
..
..
.. 43 Acknowledgements
42 Appendix .. We are indebted to Karen A. Hicks for valuable advice.
..
..
Approved by the ESC Committee for Practice Guidelines .. 44 References
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European Heart Journal (2016) 37, 2893–2962 ESC GUIDELINES
doi:10.1093/eurheartj/ehw210

2016 ESC Guidelines for the management of atrial


fibrillation developed in collaboration with EACTS
The Task Force for the management of atrial fibrillation of the
European Society of Cardiology (ESC)

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Developed with the special contribution of the European Heart
Rhythm Association (EHRA) of the ESC

Endorsed by the European Stroke Organisation (ESO)


Authors/Task Force Members: Paulus Kirchhof* (Chairperson) (UK/Germany),
Stefano Benussi*1 (Co-Chairperson) (Switzerland), Dipak Kotecha (UK),
Anders Ahlsson1 (Sweden), Dan Atar (Norway), Barbara Casadei (UK),
Manuel Castella1 (Spain), Hans-Christoph Diener2 (Germany), Hein Heidbuchel
(Belgium), Jeroen Hendriks (The Netherlands), Gerhard Hindricks (Germany),
Antonis S. Manolis (Greece), Jonas Oldgren (Sweden), Bogdan Alexandru Popescu
(Romania), Ulrich Schotten (The Netherlands), Bart Van Putte1 (The Netherlands),
and Panagiotis Vardas (Greece)
Document Reviewers: Stefan Agewall (CPG Review Co-ordinator) (Norway), John Camm (CPG Review
Co-ordinator) (UK), Gonzalo Baron Esquivias (Spain), Werner Budts (Belgium), Scipione Carerj (Italy),
Filip Casselman (Belgium), Antonio Coca (Spain), Raffaele De Caterina (Italy), Spiridon Deftereos (Greece),
Dobromir Dobrev (Germany), José M. Ferro (Portugal), Gerasimos Filippatos (Greece), Donna Fitzsimons (UK),

* Corresponding authors: Paulus Kirchhof, Institute of Cardiovascular Sciences, University of Birmingham, SWBH and UHB NHS trusts, IBR, Room 136, Wolfson Drive, Birmingham
B15 2TT, United Kingdom, Tel: +44 121 4147042, E-mail: p.kirchhof@bham.ac.uk; Stefano Benussi, Department of Cardiovascular Surgery, University Hospital Zurich, Rämistrasse
100, 8091 Zürich, Switzerland, Tel: +41(0)788933835, E-mail: stefano.benussi@usz.ch.
1
Representing the European Association for Cardio-Thoracic Surgery (EACTS)
2
Representing the European Stroke Association (ESO)
ESC Committee for Practice Guidelines (CPG) and National Cardiac Societies Reviewers can be found in the Appendix.
ESC entities having participated in the development of this document:
Associations: European Association for Cardiovascular Prevention and Rehabilitation (EACPR), European Association of Cardiovascular Imaging (EACVI), European Heart Rhythm
Association (EHRA), Heart Failure Association (HFA).
Councils: Council on Cardiovascular Nursing and Allied Professions, Council for Cardiology Practice, Council on Cardiovascular Primary Care, Council on Hypertension.
Working Groups: Cardiac Cellular Electrophysiology, Cardiovascular Pharmacotherapy, Grown-up Congenital Heart Disease, Thrombosis, Valvular Heart Disease.
The content of these European Society of Cardiology (ESC) Guidelines has been published for personal and educational use only. No commercial use is authorized. No part of the ESC
Guidelines may be translated or reproduced in any form without written permission from the ESC. Permission can be obtained upon submission of a written request to Oxford Uni-
versity Press, the publisher of the European Heart Journal and the party authorized to handle such permissions on behalf of the ESC (journals.permissions@oup.com).
Disclaimer. The ESC Guidelines represent the views of the ESC and were produced after careful consideration of the scientific and medical knowledge and the evidence available at
the time of their publication. The ESC is not responsible in the event of any contradiction, discrepancy and/or ambiguity between the ESC Guidelines and any other official recom-
mendations or guidelines issued by the relevant public health authorities, in particular in relation to good use of healthcare or therapeutic strategies. Health professionals are encour-
aged to take the ESC Guidelines fully into account when exercising their clinical judgment, as well as in the determination and the implementation of preventive, diagnostic or
therapeutic medical strategies; however, the ESC Guidelines do not override, in any way whatsoever, the individual responsibility of health professionals to make appropriate and
accurate decisions in consideration of each patient’s health condition and in consultation with that patient and, where appropriate and/or necessary, the patient’s caregiver. Nor
do the ESC Guidelines exempt health professionals from taking into full and careful consideration the relevant official updated recommendations or guidelines issued by the competent
public health authorities, in order to manage each patient’s case in light of the scientifically accepted data pursuant to their respective ethical and professional obligations. It is also the
health professional’s responsibility to verify the applicable rules and regulations relating to drugs and medical devices at the time of prescription.
& The European Society of Cardiology 2016. All rights reserved. For permissions please email: journals.permissions@oup.com.
2894 ESC Guidelines

Bulent Gorenek (Turkey), Maxine Guenoun (France), Stefan H. Hohnloser (Germany), Philippe Kolh (Belgium),
Gregory Y. H. Lip (UK), Athanasios Manolis (Greece), John McMurray (UK), Piotr Ponikowski (Poland), Raphael Rosenhek
(Austria), Frank Ruschitzka (Switzerland), Irina Savelieva (UK), Sanjay Sharma (UK), Piotr Suwalski (Poland),
Juan Luis Tamargo (Spain), Clare J. Taylor (UK), Isabelle C. Van Gelder (The Netherlands), Adriaan A. Voors (The
Netherlands), Stephan Windecker (Switzerland), Jose Luis Zamorano (Spain), and Katja Zeppenfeld (The Netherlands)
The disclosure forms of all experts involved in the development of these guidelines are available on the ESC website
http://www.escardio.org/guidelines.
Online publish-ahead-of-print 27 August 2016

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Keywords Guidelines † Atrial fibrillation † Anticoagulation † Vitamin K antagonists † Non-vitamin K antagonist oral
anticoagulants † Left atrial appendage occlusion † Rate control † Cardioversion † Rhythm control †
Antiarrhythmic drugs † Upstream therapy † Catheter ablation † AF surgery † Valve repair † Pulmonary
vein isolation † Left atrial ablation

Table of Contents
Abbreviations and acronyms . . . . . . . . . . . . . . . . . . . . . . . . 4 7.1.1 Patients with atrial fibrillation and heart failure with
1. Preamble . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5 reduced ejection fraction . . . . . . . . . . . . . . . . . . . . . . 16
2. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7 7.1.2 Atrial fibrillation patients with heart failure with
3. Epidemiology and impact for patients . . . . . . . . . . . . . . . . . 7 preserved ejection fraction . . . . . . . . . . . . . . . . . . . . . 16
3.1 Incidence and prevalence of atrial fibrillation . . . . . . . . 7 7.1.3 Atrial fibrillation patients with heart failure with mid-
3.2 Morbidity, mortality, and healthcare burden of atrial range ejection fraction . . . . . . . . . . . . . . . . . . . . . . . . 16
fibrillation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7 7.1.4 Prevention of atrial fibrillation in heart failure . . . . . 16
3.3 Impact of evidence-based management on outcomes in 7.2 Hypertension . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17
atrial fibrillation patients . . . . . . . . . . . . . . . . . . . . . . . . 8 7.3 Valvular heart disease . . . . . . . . . . . . . . . . . . . . . . . 17
3.4 Gender . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9 7.4 Diabetes mellitus . . . . . . . . . . . . . . . . . . . . . . . . . . 18
4. Pathophysiological and genetic aspects that guide management 9 7.5 Obesity and weight loss . . . . . . . . . . . . . . . . . . . . . . 18
4.1 Genetic predisposition . . . . . . . . . . . . . . . . . . . . . . 9 7.5.1 Obesity as a risk factor . . . . . . . . . . . . . . . . . . . 18
4.2 Mechanisms leading to atrial fibrillation . . . . . . . . . . . . 9 7.5.2 Weight reduction in obese patients with atrial
4.2.1 Remodelling of atrial structure and ion channel fibrillation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18
function . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9 7.5.3 Catheter ablation in obese patients . . . . . . . . . . . 18
4.2.2 Electrophysiological mechanisms of atrial fibrillation . 9 7.6 Chronic obstructive pulmonary disease, sleep apnoea, and
4.2.2.1 Focal initiation and maintenance of atrial other respiratory diseases . . . . . . . . . . . . . . . . . . . . . . . 18
fibrillation. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9 7.7 Chronic kidney disease . . . . . . . . . . . . . . . . . . . . . . 19
4.2.2.2 The multiple wavelet hypothesis and rotors as 8. Integrated management of patients with atrial fibrillation . . . . 19
sources of atrial fibrillation . . . . . . . . . . . . . . . . . . . 10 8.1 Evidence supporting integrated atrial fibrillation care . . . 20
5. Diagnosis and timely detection of atrial fibrillation . . . . . . . . 10 8.2 Components of integrated atrial fibrillation care . . . . . . 21
5.1 Overt and silent atrial fibrillation . . . . . . . . . . . . . . . . 10 8.2.1 Patient involvement . . . . . . . . . . . . . . . . . . . . . . 21
5.2 Screening for silent atrial fibrillation . . . . . . . . . . . . . . 11 8.2.2 Multidisciplinary atrial fibrillation teams . . . . . . . . . 21
5.2.1 Screening for atrial fibrillation by electrocardiogram in 8.2.3 Role of non-specialists . . . . . . . . . . . . . . . . . . . . 21
the community . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11 8.2.4 Technology use to support atrial fibrillation care . . . 21
5.2.2 Prolonged monitoring for paroxysmal atrial 8.3 Diagnostic workup of atrial fibrillation patients . . . . . . . 21
fibrillation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12 8.3.1 Recommended evaluation in all atrial fibrillation
5.2.3 Patients with pacemakers and implanted devices . . . 12 patients . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21
5.2.4 Detection of atrial fibrillation in stroke survivors . . . 13 8.3.2 Additional investigations in selected patients with
5.3 Electrocardiogram detection of atrial flutter . . . . . . . . . 13 atrial fibrillation . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22
6. Classification of atrial fibrillation . . . . . . . . . . . . . . . . . . . . 13 8.4 Structured follow-up . . . . . . . . . . . . . . . . . . . . . . . . 22
6.1 Atrial fibrillation pattern . . . . . . . . . . . . . . . . . . . . . 13 8.5 Defining goals of atrial fibrillation management . . . . . . . 22
6.2 Atrial fibrillation types reflecting different causes of the 9. Stroke prevention therapy in atrial fibrillation patients . . . . . . 22
arrhythmia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14 9.1 Prediction of stroke and bleeding risk . . . . . . . . . . . . . 22
6.3 Symptom burden in atrial fibrillation . . . . . . . . . . . . . . 14 9.1.1 Clinical risk scores for stroke and systemic embolism 22
7. Detection and management of risk factors and concomitant 9.1.2 Anticoagulation in patients with a CHA2DS2-VASc
cardiovascular diseases . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15 score of 1 in men and 2 in women . . . . . . . . . . . . . . . . 22
7.1 Heart failure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15 9.1.3 Clinical risk scores for bleeding . . . . . . . . . . . . . . 23
ESC Guidelines 2895

9.2 Stroke prevention . . . . . . . . . . . . . . . . . . . . . . . . . . 24 11.1.2 ‘Pill in the pocket’ cardioversion performed by


9.2.1 Vitamin K antagonists . . . . . . . . . . . . . . . . . . . . 24 patients . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 40
9.2.2 Non-vitamin K antagonist oral anticoagulants . . . . . 24 11.1.3 Electrical cardioversion . . . . . . . . . . . . . . . . . . 40
9.2.2.1 Apixaban . . . . . . . . . . . . . . . . . . . . . . . . . 25 11.1.4 Anticoagulation in patients undergoing
9.2.2.2 Dabigatran . . . . . . . . . . . . . . . . . . . . . . . . 25 cardioversion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 41
9.2.2.3 Edoxaban . . . . . . . . . . . . . . . . . . . . . . . . . 25 11.2 Long-term antiarrhythmic drug therapy . . . . . . . . . . . 41
9.2.2.4 Rivaroxaban . . . . . . . . . . . . . . . . . . . . . . . 26 11.2.1 Selection of antiarrhythmic drugs for long-term
9.2.3 Non-vitamin K antagonist oral anticoagulants or therapy: safety first! . . . . . . . . . . . . . . . . . . . . . . . . . . 42
vitamin K antagonists . . . . . . . . . . . . . . . . . . . . . . . . . 27 11.2.1.1 Amiodrone . . . . . . . . . . . . . . . . . . . . . . . 42
9.2.4 Oral anticoagulation in atrial fibrillation patients with 11.2.1.2 Dronedarone . . . . . . . . . . . . . . . . . . . . . 42
chronic kidney disease . . . . . . . . . . . . . . . . . . . . . . . . 27 11.2.1.3 Flecainide and propafenone . . . . . . . . . . . . 42

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9.2.5 Oral anticoagulation in atrial fibrillation patients on 11.2.1.4 Quinidine and disopyramide . . . . . . . . . . . . 42
dialysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27 11.2.1.5 Sotalol . . . . . . . . . . . . . . . . . . . . . . . . . . 43
9.2.6 Patients with atrial fibrillation requiring kidney 11.2.1.6 Dofetilide . . . . . . . . . . . . . . . . . . . . . . . . 43
transplantation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 28 11.2.2 Twelve-lead electrocardiogram as a tool to identify
9.2.7 Antiplatelet therapy as an alternative to oral patients at risk of pro-arrhythmia . . . . . . . . . . . . . . . . . 43
anticoagulants . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 28 11.2.3 New antiarrhythmic drugs . . . . . . . . . . . . . . . . . 43
9.3 Left atrial appendage occlusion and exclusion . . . . . . . . 29 11.2.4 Antiarrhythmic effects of non-antiarrhythmic drugs 44
9.3.1 Left atrial appendage occlusion devices . . . . . . . . . 29 11.3 Catheter ablation . . . . . . . . . . . . . . . . . . . . . . . . . 46
9.3.2 Surgical left atrial appendage occlusion or exclusion . 29 11.3.1 Indications . . . . . . . . . . . . . . . . . . . . . . . . . . . 46
9.4 Secondary stroke prevention . . . . . . . . . . . . . . . . . . 29 11.3.2 Techniques and technologies . . . . . . . . . . . . . . . 46
9.4.1 Treatment of acute ischaemic stroke . . . . . . . . . . 29 11.3.3 Outcome and complications . . . . . . . . . . . . . . . 47
9.4.2 Initiation of anticoagulation after transient ischaemic 11.3.3.1 Outcome of catheter ablation for atrial
attack or ischaemic stroke . . . . . . . . . . . . . . . . . . . . . 29 fibrillation. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 47
9.4.3 Initiation of anticoagulation after intracranial 11.3.3.2 Complications of catheter ablation for atrial
haemorrhage . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 30 fibrillation. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 47
9.5 Strategies to minimize bleeding on anticoagulant therapy 31 11.3.4 Anticoagulation: – before, during, and after ablation 47
9.5.1 Uncontrolled hypertension . . . . . . . . . . . . . . . . . 31 11.3.5 Ablation of atrial fibrillation in heart failure patients 48
9.5.2 Previous bleeding event . . . . . . . . . . . . . . . . . . . 31 11.3.6 Follow-up after catheter ablation . . . . . . . . . . . . 48
9.5.3 Labile international normalized ratio and adequate 11.4 Atrial fibrillation surgery . . . . . . . . . . . . . . . . . . . . . 48
non-vitamin K antagonist oral anticoagulant dosing . . . . . 31 11.4.1 Concomitant atrial fibrillation surgery . . . . . . . . . 48
9.5.4 Alcohol abuse . . . . . . . . . . . . . . . . . . . . . . . . . 31 11.4.2 Stand-alone rhythm control surgery . . . . . . . . . . 49
9.5.5 Falls and dementia . . . . . . . . . . . . . . . . . . . . . . 31 11.5 Choice of rhythm control following treatment failure . . 50
9.5.6 Genetic testing . . . . . . . . . . . . . . . . . . . . . . . . . 31 11.6 The atrial fibrillation Heart Team . . . . . . . . . . . . . . . 50
9.5.7 Bridging periods off oral anticoagulation . . . . . . . . 31 12. Hybrid rhythm control therapy . . . . . . . . . . . . . . . . . . . . 51
9.6 Management of bleeding events in anticoagulated patients 12.1 Combining antiarrhythmic drugs and catheter ablation . 51
with atrial fibrillation . . . . . . . . . . . . . . . . . . . . . . . . . . . 32 12.2 Combining antiarrhythmic drugs and pacemakers . . . . 52
9.6.1 Management of minor, moderate, and severe 13. Specific situations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 52
bleeding . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 32 13.1 Frail and ‘elderly’ patients . . . . . . . . . . . . . . . . . . . . 52
9.6.2 Oral anticoagulation in atrial fibrillation patients at risk 13.2 Inherited cardiomyopathies, channelopathies, and
of or having a bleeding event . . . . . . . . . . . . . . . . . . . 33 accessory pathways . . . . . . . . . . . . . . . . . . . . . . . . . . . 52
9.7 Combination therapy with oral anticoagulants and 13.2.1 Wolff– Parkinson– White syndrome . . . . . . . . . . 52
antiplatelets . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 34 13.2.2 Hypertrophic cardiomyopathy . . . . . . . . . . . . . . 53
9.7.1 Antithrombotic therapy after acute coronary 13.2.3 Channelopathies and arrhythmogenic right
syndromes and percutaneous coronary intervention in ventricular cardiomyopathy . . . . . . . . . . . . . . . . . . . . 53
patients requiring oral anticoagulation . . . . . . . . . . . . . . 34 13.3 Sports and atrial fibrillation . . . . . . . . . . . . . . . . . . . 54
10. Rate control therapy in atrial fibrillation . . . . . . . . . . . . . . 36 13.4 Pregnancy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 54
10.1 Acute rate control . . . . . . . . . . . . . . . . . . . . . . . . 36 13.4.1 Rate control . . . . . . . . . . . . . . . . . . . . . . . . . 54
10.2 Long-term pharmacological rate control . . . . . . . . . . 36 13.4.2 Rhythm control . . . . . . . . . . . . . . . . . . . . . . . 54
10.2.1 Beta-blockers . . . . . . . . . . . . . . . . . . . . . . . . . 36 13.4.3 Anticoagulation . . . . . . . . . . . . . . . . . . . . . . . 54
10.2.2 Non-dihydropyridine calcium channel blockers . . . 37 13.5 Post-operative atrial fibrillation . . . . . . . . . . . . . . . . 55
10.2.3 Digitalis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 38 13.5.1 Prevention of post-operative atrial fibrillation . . . . 55
10.2.4 Amiodarone . . . . . . . . . . . . . . . . . . . . . . . . . . 38 13.5.2 Anticoagulation . . . . . . . . . . . . . . . . . . . . . . . 55
10.3 Heart rate targets in atrial fibrillation . . . . . . . . . . . . 39 13.5.3 Rhythm control therapy in post-operative atrial
10.4 Atrioventricular node ablation and pacing . . . . . . . . . 39 fibrillation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 55
11. Rhythm control therapy in atrial fibrillation . . . . . . . . . . . . 40 13.6 Atrial arrhythmias in grown-up patients with congenital
11.1 Acute restoration of sinus rhythm . . . . . . . . . . . . . . 40 heart disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 56
11.1.1 Antiarrhythmic drugs for acute restoration of sinus 13.6.1 General management of atrial arrhythmias in grown-
rhythm (‘pharmacological cardioversion’) . . . . . . . . . . . . 40 up patients with congenital heart disease . . . . . . . . . . . . 56
2896 ESC Guidelines

13.6.2 Atrial tachyarrhythmias and atrial septal defects . . . 56 APACHE-AF Apixaban versus Antiplatelet drugs or no
13.6.3 Atrial tachyarrhythmias after Fontan operation . . . 56 antithrombotic drugs after anticoagulation-
13.6.4 Atrial tachyarrhythmias after tetralogy of Fallot associated intraCerebral HaEmorrhage in
correction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 56 patients with Atrial Fibrillation
13.7 Management of atrial flutter . . . . . . . . . . . . . . . . . . 57 ARB angiotensin receptor blocker
14. Patient involvement, education, and self-management . . . . . 57 ARISTOTLE Apixaban for Reduction in Stroke and Other
14.1 Patient-centred care . . . . . . . . . . . . . . . . . . . . . . . 57 Thromboembolic Events in Atrial Fibrillation
14.2 Integrated patient education . . . . . . . . . . . . . . . . . . 57 ARNI angiotensin receptor neprilysin inhibition
14.3 Self-management and shared decision-making . . . . . . . 57 ARTESiA Apixaban for the Reduction of Thrombo-Em-
15. Gaps in evidence . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 58 bolism in Patients With Device-Detected
15.1 Major health modifiers causing atrial fibrillation . . . . . . 58 Sub-Clinical Atrial Fibrillation

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15.2 How much atrial fibrillation constitutes a mandate for ATRIA AnTicoagulation and Risk factors In Atrial
therapy? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 58 fibrillation
15.3 Atrial high-rate episodes and need for anticoagulation . 58 AV Atrioventricular
15.4 Stroke risk in specific populations . . . . . . . . . . . . . . . 58 AXAFA Anticoagulation using the direct factor Xa in-
15.5 Anticoagulation in patients with severe chronic kidney hibitor apixaban during Atrial Fibrillation
disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 58 catheter Ablation: Comparison to vitamin K
15.6 Left atrial appendage occlusion for stroke prevention . . 58 antagonist therapy
15.7 Anticoagulation in atrial fibrillation patients after a BAFTA Birmingham Atrial Fibrillation Treatment of
bleeding or stroke event . . . . . . . . . . . . . . . . . . . . . . . . 58 the Aged Study
15.8 Anticoagulation and optimal timing of non-acute BMI body mass index
cardioversion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 58 b.p.m. beats per minute
15.9 Competing causes of stroke or transient ischaemic attack CABANA Catheter Ablation versus Antiarrhythmic
in atrial fibrillation patients . . . . . . . . . . . . . . . . . . . . . . . 58 Drug Therapy for Atrial Fibrillation Trial
15.10 Anticoagulation in patients with biological heart valves CABG coronary artery bypass graft
(including transcatheter aortic valve implantation) and non- CAD coronary artery disease
rheumatic valve disease . . . . . . . . . . . . . . . . . . . . . . . . . 59 CHA2DS2-VASc Congestive Heart failure, hypertension, Age
15.11 Anticoagulation after ‘successful’ catheter ablation . . . 59 ≥75 (doubled), Diabetes, Stroke (doubled),
15.12 Comparison of rate control agents . . . . . . . . . . . . . 59 Vascular disease, Age 65–74, and Sex (female)
15.13 Catheter ablation in persistent and long-standing CHADS2 Cardiac failure, Hypertension, Age, Diabetes,
persistent AF . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 59 Stroke (Doubled)
15.14 Optimal technique for repeat catheter ablation . . . . . 59 CI confidence interval
15.15 Combination therapy for maintenance of sinus rhythm 59 CKD chronic kidney disease
15.16 Can rhythm control therapy convey a prognostic CPG Committee for Practice Guidelines
benefit in atrial fibrillation patients? . . . . . . . . . . . . . . . . . 59 CrCl creatinine clearance
15.17 Thoracoscopic ‘stand-alone’ atrial fibrillation surgery . 59 CT computed tomography
15.18 Surgical exclusion of the left atrial appendage . . . . . . 59 CV cardiovascular
15.19 Concomitant atrial fibrillation surgery . . . . . . . . . . . 59 CYP2D6 cytochrome P450 2D6
16. To do and not to do messages from the Guidelines . . . . . . 60 CYP3A4 cytochrome P450 3A4
17. A short summary of the management of atrial fibrillation DIG Digitalis Investigation Group
patients . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 62 EACTS European Association for Cardio-Thoracic
18. Web addenda . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 62 Surgery
19. Appendix . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 62 EAST Early treatment of Atrial fibrillation for Stroke
20. References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 63 prevention Trial
ECG electrocardiogram/electrocardiography
EHRA European Heart Rhythm Association
ENGAGE AF-TIMI Effective Anticoagulation with Factor Xa
Abbreviations and acronyms 48 Next Generation in Atrial Fibrillation –
Thrombolysis in Myocardial Infarction 48
ABC age, biomarkers, clinical history EORP EURObservational Research Programme
ACE angiotensin-converting enzyme ESC European Society of Cardiology
ACS acute coronary syndromes ESO European stroke Organisation
AF atrial fibrillation FAST Atrial Fibrillation Catheter Ablation vs. Surgi-
AFFIRM Atrial Fibrillation Follow-up Investigation of cal Ablation Treatment
Rhythm Management FEV1 forced expiratory volume in 1 s
AFNET German Competence NETwork on Atrial FFP four-factor prothrombin complex concentrates
Fibrillation FXII factor XII
AngII angiotensin II GDF-15 growth differentiation factor 15
AHRE atrial high rate episodes GFR glomerular filtration rate
ESC Guidelines 2897

GUCH grown-up congenital heart disease PREVAIL Prospective Randomized Evaluation of the
HARMONY A Study to Evaluate the Effect of Ranolazine Watchman LAA Closure Device In Patients
and Dronedarone When Given Alone and with AF Versus Long Term Warfarin Therapy
in Combination in Patients With Paroxysmal trial
Atrial Fibrillation PROTECT AF Watchman Left Atrial Appendage System for
HAS-BLED hypertension, abnormal renal/liver function Embolic Protection in Patients With AF trial
(1 point each), stroke, bleeding history or PUFA polyunsaturated fatty acid
predisposition, labile INR, elderly (.65 PVI pulmonary vein isolation
years), drugs/alcohol concomitantly (1 point QoL quality of life
each) RACE Rate Control Efficacy in Permanent Atrial
HEMORR2HAGES Hepatic or renal disease, ethanol abuse, Fibrillation

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malignancy history, older age .75, reduced RATE-AF Rate Control Therapy Evaluation in Perman-
platelet count/function/antiplatelet, rebleed- ent Atrial Fibrillation
ing risk (scores double), hypertension RCT randomized controlled trial
(uncontrolled), anaemia, genetic factors, ex- RE-CIRCUIT Randomized Evaluation of Dabigatran Etexi-
cessive fall risk, stroke history late Compared to warfarIn in pulmonaRy
HF heart failure Vein Ablation: Assessment of an Uninterrupt-
HFmrEF heart failure with mid-range ejection fraction ed periproCedUral antIcoagulation sTrategy
HFpEF heart failure with preserved ejection fraction RE-LY Randomized Evaluation of Long-Term Antic-
HFrEF heart failure with reduced ejection fraction oagulation Therapy
HR hazard ratio RF radiofrequency
ICD implantable cardioverter defibrillator ROCKET-AF Rivaroxaban Once Daily Oral Direct Factor
IHD ischaemic heart disease Xa Inhibition Compared with Vitamin K
IL-6 interleukin 6 Antagonism for Prevention of Stroke and
INR international normalized ratio Embolism Trial in Atrial Fibrillation
i.v. intravenous RR risk ratio
LA left atrium/atrial rtPA recombinant tissue plasminogen activator
LAA left atrial appendage SAMe-TT2R2 Sex (female), age (,60 years), medical history
LAAOS Left Atrial Appendage Occlusion Study (two of the following: hypertension, diabetes,
LV left ventricular mi, pad, congestive heart failure, history of
LVEF left ventricular ejection fraction stroke, pulmonary disease, hepatic or renal dis-
LVH left ventricular hypertrophy ease), treatment (interacting medications e.g.
MANTRA-PAF Medical ANtiarrhythmic Treatment or Radio- amiodarone), tobacco use (within 2 years; scores
frequency Ablation in Paroxysmal Atrial double), race (non-Caucasian; scores double)
Fibrillation SD standard deviation
MERLIN Metabolic Efficiency With Ranolazine for Less SPAF Stroke Prevention in Atrial Fibrillation
Ischemia in Non ST-Elevation Acute Coron- SR sinus rhythm
ary Syndromes TF tissue factor
MRA Mineralocorticoid receptor antagonist TIA transient ischaemic attack
MRI magnetic resonance imaging TIMI Thrombolysis in Myocardial Infarction
NIHSS National Institutes of Health stroke severity TOE transoesophageal echocardiography
scale TTR time in therapeutic range
NOAC non-vitamin K antagonist oral anticoagulant UFH unfractionated heparin
NOAH Non vitamin K antagonist Oral anticoagulants VKA vitamin K antagonist
in patients with Atrial High rate episodes VT Ventricular tachycardia
(NOAH) VVI Ventricular pacing, ventricular sensing, inhib-
NYHA New York Heart Association ited response pacemaker
OAC oral anticoagulation/oral anticoagulant WOEST What is the Optimal antiplatElet and anti-
OR odds ratio coagulant therapy in patients with oral anti-
ORBIT Outcomes Registry for Better Informed coagulation and coronary StenTing
Treatment of Atrial Fibrillation WPW Wolff-Parkinson-White syndrome
PAFAC Prevention of Atrial Fibrillation After Cardio-
version trial
PAI-1 plasminogen activator inhibitor 1
PCI percutaneous coronary intervention
1. Preamble
PCC prothrombin complex concentrates Guidelines summarize and evaluate all available evidence on a par-
PICOT Population, Intervention, Comparison, Out- ticular issue at the time of the writing process, with the aim of assist-
come, Time ing health professionals in selecting the best management strategies
2898 ESC Guidelines

Table 1 Classes of recommendations

Classes of Definition Suggested wording to


recommendations use

Class I Evidence and/or general agreement Is recommended/is


that a given treatment or indicated
procedure is beneficial, useful,
effective.

Class II Conflicting evidence and/or a


divergence of opinion about the
usefulness/efficacy of the given

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treatment or procedure.

Class IIa Weight of evidence/opinion is in Should be considered


favour of usefulness/efficacy.

Class IIb Usefulness/efficacy is less well May be considered


established by evidence/opinion.

Class III Evidence or general agreement that Is not recommended


the given treatment or procedure
is not useful/effective, and in some
cases may be harmful.

care of patients with this pathology. Selected experts in the field


Table 2 Levels of evidence undertook a comprehensive review of the published evidence
for management (including diagnosis, treatment, prevention and
Level of Data derived from multiple randomized rehabilitation) of a given condition according to ESC Committee
evidence A clinical trials or meta-analyses.
for Practice Guidelines (CPG) policy and approved by the EACTS
Data derived from a single randomized and ESO. A critical evaluation of diagnostic and therapeutic proce-
Level of
clinical trial or large non-randomized dures was performed, including assessment of the risk – benefit ra-
evidence B
studies.
tio. Estimates of expected health outcomes for larger populations
Consensus of opinion of the experts and/ were included, where data exist. The level of evidence and the
Level of
or small studies, retrospective studies, strength of the recommendation of particular management op-
evidence C
registries.
tions were weighed and graded according to predefined scales,
as outlined in Tables 1 and 2.
The experts of the writing and reviewing panels provided declar-
ation of interest forms for all relationships that might be perceived as
for an individual patient with a given condition, taking into account real or potential sources of conflicts of interest. These forms were
the impact on outcome, as well as the risk–benefit ratio of particular compiled into one file and can be found on the ESC website (http
diagnostic or therapeutic means. Guidelines and recommendations ://www.escardio.org/guidelines). Any changes in declarations of
should help health professionals to make decisions in their daily prac- interest that arise during the writing period must be notified to
tice. However, the final decisions concerning an individual patient the ESC and EACTS and updated. The Task Force received its entire
must be made by the responsible health professional(s) in consult- financial support from the ESC and EACTS without any involvement
ation with the patient and caregiver as appropriate. from the healthcare industry.
A great number of Guidelines have been issued in recent years by The ESC CPG supervises and co-ordinates the preparation of
the European Society of Cardiology (ESC) and by the European As- new Guidelines produced by task forces, expert groups or consen-
sociation for Cardio-Thoracic Surgery (EACTS), as well as by other sus panels. The Committee is also responsible for the endorsement
societies and organisations. Because of the impact on clinical prac- process of these Guidelines. The ESC Guidelines undergo extensive
tice, quality criteria for the development of guidelines have been es- review by the CPG and external experts, and in this case by EACTS
tablished in order to make all decisions transparent to the user. The and ESO-appointed experts. After appropriate revisions the Guide-
recommendations for formulating and issuing ESC Guidelines can be lines are approved by all the experts involved in the Task Force. The
found on the ESC website (http://www.escardio.org/Guidelines- finalized document is approved by the CPG, EACTS and ESO for
&-Education/Clinical-Practice-Guidelines/Guidelines-development/ publication in the European Heart Journal, Europace, and in the
Writing-ESC-Guidelines). ESC Guidelines represent the official pos- European Journal of Cardio-Thoracic Surgery. The Guidelines
ition of the ESC on a given topic and are regularly updated. were developed after careful consideration of the scientific and
Members of this Task Force were selected by the ESC, including medical knowledge and the evidence available at the time of their
representation from the European Heart Rhythm Association dating.
(EHRA), and EACTS as well as by the European Stroke Organisa- The task of developing ESC and EACTS Guidelines covers not
tion (ESO) to represent professionals involved with the medical only integration of the most recent research, but also the creation
ESC Guidelines 2899

of educational tools and implementation programmes for the re- 3. Epidemiology and impact for
commendations. To implement the guidelines, condensed pocket
guideline versions, summary slides, booklets with essential mes- patients
sages, summary cards for non-specialists and an electronic version
for digital applications (smartphones, etc.) are produced. These ver- 3.1 Incidence and prevalence of atrial
sions are abridged and thus, if needed, one should always refer to fibrillation
the full text version, which is freely available on the ESC website. In 2010, the estimated numbers of men and women with AF world-
The National Societies of the ESC are encouraged to endorse, wide were 20.9 million and 12.6 million, respectively, with higher in-
translate and implement all ESC Guidelines. Implementation pro- cidence and prevalence rates in developed countries.1,2 One in four
grammes are needed because it has been shown that the outcome middle-aged adults in Europe and the US will develop AF.3 – 5 By 2030,
of disease may be favourably influenced by the thorough application 14 – 17 million AF patients are anticipated in the European Union,
with 120 000–215 000 newly diagnosed patients per year.2,6,7 Esti-

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of clinical recommendations.
Surveys and registries are needed to verify that real-life daily prac- mates suggest an AF prevalence of approximately 3% in adults aged
tice is in keeping with what is recommended in the guidelines, thus 20 years or older,8,9 with greater prevalence in older persons1 and
completing the loop between clinical research, writing of guidelines, in patients with conditions such as hypertension, heart failure, coron-
disseminating them and implementing them into clinical practice. ary artery disease (CAD), valvular heart disease, obesity, diabetes
Health professionals are encouraged to take the ESC and EACTS mellitus, or chronic kidney disease (CKD).7,10 – 15 The increase
Guidelines fully into account when exercising their clinical judgment, in AF prevalence can be attributed both to better detection of
as well as in the determination and the implementation of prevent- silent AF16 – 18, alongside increasing age and conditions predisposing
ive, diagnostic or therapeutic medical strategies. However, the ESC to AF.19
and EACTS Guidelines do not override in any way whatsoever the
individual responsibility of health professionals to make appropriate 3.2 Morbidity, mortality, and healthcare
and accurate decisions in consideration of each patient’s health con-
burden of atrial fibrillation
dition and in consultation with that patient and the patient’s care-
AF is independently associated with a two-fold increased risk of
giver where appropriate and/or necessary. It is also the health
all-cause mortality in women and a 1.5-fold increase in men20 – 22
professional’s responsibility to verify the rules and regulations
(Table 3). Death due to stroke can largely be mitigated by anticoa-
applicable to drugs and devices at the time of prescription.
gulation, while other cardiovascular deaths, for example due to
heart failure and sudden death, remain common even in AF pa-
2. Introduction tients treated according to the current evidence base.23 AF is
Despite good progress in the management of patients with atrial fib- also associated with increased morbidity, such as heart failure
rillation (AF), this arrhythmia remains one of the major causes of and stroke.21,24,25 Contemporary studies show that 20 – 30% of pa-
stroke, heart failure, sudden death, and cardiovascular morbidity tients with an ischaemic stroke have AF diagnosed before, during,
in the world. Furthermore, the number of patients with AF is pre-
dicted to rise steeply in the coming years. To meet the growing de-
mand for effective care of patients with AF, new information is Table 3 Cardiovascular morbidity and mortality
continually generated and published, and the last few years have associated with atrial fibrillation
seen substantial progress. Therefore, it seems timely to publish
this 2nd edition of the ESC guidelines on AF. Event Association with AF
Reflecting the multidisciplinary input into the management of Death Increased mortality, especially cardiovascular
patients with AF, the Task Force includes cardiologists with varying sub- mortality due to sudden death, heart failure or
specialty expertise, cardiac surgeons, stroke neurologists, and specialist stroke.
nurses amongst its members. Supplementing the evidence review Stroke 20–30% of all strokes are due to AF. A growing
as outlined in the preamble, this Task Force defined three Population, number of patients with stroke are diagnosed with
Intervention, Comparison, Outcome, Time (PICOT) questions on ‘silent’, paroxysmal AF.
relevant topics for the guidelines. The ESC commissioned external sys- Hospitalizations 10–40% of AF patients are hospitalized every year.
tematic reviews to answer these questions, and these reviews have Quality of life Quality of life is impaired in AF patients independent
informed specific recommendations. of other cardiovascular conditions.
Further to adhering to the standards for generating recommenda- Left ventricular Left ventricular dysfunction is found in 20–30% of all
tions that are common to all ESC guidelines (see preamble), this dysfunction and AF patients. AF causes or aggravates LV dysfunction
Task Force discussed each draft recommendation during web-based heart failure in many AF patients, while others have completely
preserved LV function despite long-standing AF.
conference calls dedicated to specific chapters, followed by consen-
sus modifications and an online vote on each recommendation. Cognitive decline Cognitive decline and vascular dementia can
and vascular develop even in anticoagulated AF patients.
Only recommendations that were supported by at least 75% of dementia Brain white matter lesions are more common in
the Task Force members were included in the guidelines. AF patients than in patients without AF.
We hope that these guidelines will help to deliver good care to
all patients with AF based on the current state-of-the-art evidence AF ¼ atrial fibrillation; LV ¼ left ventricular.
in 2016.
2900 ESC Guidelines

or after the initial event.17,26,27 White matter lesions in the brain, anticoagulation (OAC) with vitamin K antagonists (VKAs) or non-
cognitive impairment, 28 – 30 decreased quality of life, 31,32 and VKA oral anticoagulants (NOACs) markedly reduces stroke and
depressed mood 33 are common in AF patients, and between mortality in AF patients.38,39 Other interventions such as rhythm
10 – 40% of AF patients are hospitalized each year.23,34,35 control and rate control improve AF-related symptoms and may
The direct costs of AF already amount to approximately 1% of to- preserve cardiac function, but have not demonstrated a reduction
tal healthcare spending in the UK, and between 6.0 –26.0 billion US in long-term morbidity or mortality.40,41
dollars in the US for 2008,36,37 driven by AF-related complications In contemporary, well-controlled, randomized clinical trials
(e.g. stroke) and treatment costs (e.g. hospitalizations). These costs in AF, the average annual stroke rate is about 1.5% and the
will increase dramatically unless AF is prevented and treated in a annualized death rate is around 3% in anticoagulated AF patients.40
timely and effective manner. In real life, the annual mortality can be different (both higher and
lower).42 A minority of these deaths are related to stroke, while

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sudden cardiac death and death from progressive heart failure
3.3 Impact of evidence-based are more frequent, emphasizing the need for interventions beyond
management on outcomes in atrial anticoagulation.43,44 Furthermore, AF is also associated with high
fibrillation patients rates of hospitalization, commonly for AF management, but often
Figure 1 depicts the major milestones in the management of AF. also for heart failure, myocardial infarction, and treatment-
Despite these advances, substantial morbidity remains. Oral associated complications.34,45

First maze surgery


95

VKA superior to aspirin for AF treatment


19

for stroke prevention in published


AF
PVI can suppress AF
ACE-I/ARBs prevent
RF based maze
AF in heart failure
maintains SR after
00
20

Rate control not inferior to rhythm control cardiovascular


VKA reduces stroke in surgery
ARBs prevent AF in AF by 2/3 PVI maintains SR
hypertension & LVH better than
Ximelagatran as antiarrhythmic drugs
05

effective as VKA
20

Amiodarone not
superior to rate
ARBs do not prevent Dabigatran at least as control in heart Dronedarone
AF or adverse effective as VKA in AF failure improves outcomes
outcomes in patients in non-permanent AF
without hypertension
Lenient rate control AF ablation
acceptable improves Qol
10
20

PUFA do not Rixaroxaban and


prevent AF Apixaban at least as Dronedarone harms
effective as VKA in AF in permanent AF
MRA prevent AF in First-line PVI
HFrEF patients pre- maintains SR better Bipolar RF more
treated with ACE-I/ Edoxaban at least as than antiarrhythmic effective than
beta-blockers effective as VKA in AF drugs conventional RF
for stand-alone
ACE-I/ARB prevent AF surgery
AF in hypertension Meta-analysis and PVI alone as
healthcare databases: Beta-blockers effective as
Beta-blockers NOACs safer and without prognostic complex ablation in Concomitant maze
prevent AF in HFrEF slightly more effective benefit in AF patients persistent AF surgery maintains SR
with HFrEF but increases risk of
15

patients pre-treated compared to VKA


20

with ACE-I Cryoenergy as permanent pacemaker


effective as RF
for PVI

LVH = left ventricular hypertrophy; NOAC = non-vitamin K antagonist oral anticoagulant; PUFA = polyunsaturated fatty acid; PVI = pulmonary vein isolation;
QoL = quality of life; RF = radiofrequency; SR = sinus rhythm;VKA = vitamin K antagonist.

Figure 1 Timeline of findings from landmark trials in atrial fibrillation management, including treatment of concomitant conditions and preven-
tion (green), anticoagulation (blue), rate control therapy (orange), rhythm control therapy (red), and atrial fibrillation surgery (purple).
ESC Guidelines 2901

3.4 Gender While genomic analysis may provide an opportunity to improve the
In both developed and developing countries, the age-adjusted inci- diagnosis and management of AF in the future,75,76 routine genetic
dence and prevalence of AF are lower in women, while the risk of testing for common gene variants associated with AF cannot be re-
death in women with AF is similar to or higher than that in men with commended at present.77
AF.1,46,47 Female AF patients who have additional stroke risk factors
(particularly older age) are also at greater risk than men of having a 4.2 Mechanisms leading to atrial
stroke,48,49 even those anticoagulated with warfarin50 (see Chapter fibrillation
9 for details). Women with diagnosed AF can be more symptomatic 4.2.1 Remodelling of atrial structure and ion channel
than men and are typically older with more comorbidities.51,52 function
Bleeding risk on anticoagulation is similar in both sexes,49,50,53 but External stressors such as structural heart disease, hypertension,
women appear less likely to receive specialist care and rhythm con- possibly diabetes, but also AF itself induce a slow but progressive

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trol therapy,54 while the outcomes of catheter ablation or AF sur- process of structural remodelling in the atria (Figure 2). Activation
gery are comparable to those in men.55,56 These observations of fibroblasts, enhanced connective tissue deposition, and fibrosis
highlight the need to offer effective diagnostic tools and therapeutic are the hallmarks of this process.78 – 80 In addition, atrial fatty infiltra-
management equally to women and men. tion, inflammatory infiltrates, myocyte hypertrophy, necrosis, and
amyloidosis are found in AF patients with concomitant conditions
Recommendations relating to gender predisposing to AF.81 – 84 Structural remodelling results in electrical
dissociation between muscle bundles and local conduction hetero-
Recommendations Class a Level b Ref C geneities,85 favouring re-entry and perpetuation of the arrhythmia.86
In many patients, the structural remodelling process occurs before
AF clinicians must offer effective
diagnostic tools and therapeutic the onset of AF.78 As some of the structural remodelling will be ir-
I A 39, 46, 57
management to women and men reversible, early initiation of treatment seems desirable.87 Table 4
equally to prevent stroke and death. gives an overview of the most relevant pathophysiological altera-
Catheter or surgical ablation tions in atrial tissue associated with AF, and lists corresponding clin-
techniques should be regarded as IIa B 55, 56 ical conditions that can contribute to these changes.
equally effective in women and men.
The functional and structural changes in atrial myocardium and
stasis of blood, especially in the left atrial appendage (LAA), generate
AF ¼ atrial fibrillation. a prothrombotic milieu. Furthermore, even short episodes of AF
a
Class of recommendation.
b
Level of evidence. lead to atrial myocardial damage and the expression of prothrom-
c
Reference(s) supporting recommendations. botic factors on the atrial endothelial surface, alongside activation
of platelets and inflammatory cells, and contribute to a generalized
prothrombotic state.88,89 The atrial and systemic activation of the
coagulation system can partially explain why short episodes of AF
4. Pathophysiological and genetic convey a long-term stroke risk.
aspects that guide management 4.2.2 Electrophysiological mechanisms of atrial fibrillation
4.1 Genetic predisposition AF provokes a shortening of the atrial refractory period and AF cy-
cle length during the first days of the arrhythmia, largely due to
AF, especially early-onset AF, has a strong heritable component that
downregulation of the Ca2+-inward current and upregulation of
is independent of concomitant cardiovascular conditions.58,59 A few
inward rectifier K+ currents.94,95 Structural heart disease, in con-
young AF patients suffer from inherited cardiomyopathies or chan-
trast, tends to prolong the atrial refractory period, illustrating the
nelopathies mediated by disease-causing mutations. These mono-
heterogeneous nature of mechanisms that cause AF in different pa-
genic diseases also convey a risk for sudden death (see Chapter
tients.96 Hyperphosphorylation of various Ca2+-handling proteins
6). Up to one-third of AF patients carry common genetic variants
may contribute to enhanced spontaneous Ca2+ release events and
that predispose to AF, albeit with a relatively low added risk. At least
triggered activity,97,98 thus causing ectopy and promoting AF. Al-
14 of these common variants, often single nucleotide polymorphisms,
though the concept of Ca2+-handling instability has been chal-
are known to increase the risk of prevalent AF in populations.60 – 62
lenged recently, 106,107 it may mediate AF in structurally
The most important variants are located close to the paired-like home-
remodelled atria and explain how altered autonomic tone can gen-
odomain transcription factor 2 (Pitx2) gene on chromosome 4q25.63,64
erate AF.80,105
These variants modify the risk of AF up to seven-fold.64 Several of the
AF risk variants are also associated with cardioembolic or ischaemic 4.2.2.1 Focal initiation and maintenance of atrial fibrillation
stroke, possibly due to silent AF (see chapter 5 and 5.2).62,65,66 The seminal observation by Haissaguerre et al.108 was that a
Changes in atrial action potential characteristics,67 – 70 atrial remodel- focal source in the pulmonary veins can trigger AF, and ablation
ling, and modified penetration of rare gene defects61 have been of this source can suppress recurrent AF. The mechanism of
suggested as potential mechanisms mediating increased AF risk in car- focal activity might involve both triggered activity and localized
riers of common gene variants. Genetic variants could, in the future, reentry.109,110 Hierarchic organization of AF with rapidly activated
become useful for patient selection of rhythm or rate control.71 – 74 areas driving the arrhythmia has been documented in patients
2902 ESC Guidelines

Stroke

Diabetes
Heart

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failure
Obesity
Coronary
artery
disease
Hypertension
Ageing
Genetic
predisposition

Atrial
fibrillation

AngII = angiotensin II; TF = tissue factor; FXII = factor XII; IL-6 = interleukin 6; PAI-1 = plasminogen activator inhibitor 1;VCAM-1 = vascular cell adhesion molecule 1.

Figure 2 Major mechanisms causing atrial fibrillation that can be considered when choosing therapy. The various aetiological factors (left) cause
a complex array of pathophysiological changes in the atria, including stretch-induced atrial fibrosis, hypocontractility, fatty infiltration, inflamma-
tion, vascular remodelling, ischaemia, ion channel dysfunction, and Ca2+-instability. These changes enhance both ectopy and conduction distur-
bances, increasing the propensity of the atria to develop or maintain AF. At the same time, some of these alterations are involved in the occurrence
of the hypercoagulable state associated with AF. For example, hypocontractility reduces local endothelial shear stress, which increases PAI-1 ex-
pression, and ischaemia-induced inflammation enhances the expression of endothelial adhesion molecules or promotes shedding of endothelial
cells, resulting in tissue factor exposure to the blood stream. These changes contribute to the thrombogenic milieu in the atria of AF patients. AF in
itself can aggravate many of the mechanisms shown, which may explain the progressive nature of the arrhythmia.

with paroxysmal AF,111,112 but is less obvious in unselected patients these phenomena may generate ‘rotors’ picked up by intracar-
with persistent AF.113 diac116,117 or body surface117 recordings.
4.2.2.2 The multiple wavelet hypothesis and rotors as sources of atrial
fibrillation
Moe and Abildskov114 proposed that AF can be perpetuated by
5. Diagnosis and timely detection
continuous conduction of several independent wavelets propagat- of atrial fibrillation
ing through the atrial musculature in a seemingly chaotic manner.
As long as the number of wavefronts does not decline below a crit- 5.1 Overt and silent atrial fibrillation
ical level, they will be capable of sustaining the arrhythmia. Numer- The diagnosis of AF requires rhythm documentation using an elec-
ous experimental and clinical observations can be reconciled with trocardiogram (ECG) showing the typical pattern of AF: Absolutely
the multiple wavelet hypothesis.115 All localized sources of AF (ec- irregular RR intervals and no discernible, distinct P waves. ECG-
topic foci, rotors, or other stable re-entry circuits) cause fibrillatory documented AF was the entry criterion in trials forming the evi-
conduction remote from the source, which is difficult to distinguish dence for these guidelines. By accepted convention, an episode last-
from propagation sustaining AF by multiple wavelets, and either of ing at least 30 s is diagnostic. Individuals with AF may be
ESC Guidelines 2903

Table 4 Pathophysiological alterations in atrial tissue associated with atrial fibrillation and clinical conditions that could
contribute to such alterations

Pathophysiological Clinical conditions contributing Pro-arrhythmic mechanism/ References


alteration to the alteration functional consequence
Changes of the extracellular matrix, fibroblast function and fat cells
Interstitial and replacement AF (especially forms with a high AF burden), Electrical dissociation, conduction block, 78, 79, 90, 91
fibrosis hypertension, heart failure, valvular heart disease (via enhanced AF complexity.
pressure and volume overload).
Inflammatory infiltration Profibrotic responses, enhanced AF 81
complexity.

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Fatty infiltration Obesity. Profibrotic / proinflammatory responses, 82, 92
localized conduction block.
Amyloid deposition Aging, heart failure, coronary artery disease (via atrial Conduction disturbances. 83, 93
scarring), genetic factors.
Ion channel alterations
Ion channel remodelling AF (especially forms with a high AF burden), genetic AF cycle shortening (if due to atrial 94–96
predisposition to AF. tachycardia), AF cycle length prolongation (if
due to heart failure), enhanced heterogeneity
of atrial repolarization.
Ca2+ handling instability AF (especially forms with a high AF burden), heart Enhanced propensity to ectopy. 97, 98
failure and hypertension (possibly through increased
sympathetic activation).
Gap-junction redistribution AF Conduction disturbances. 99
Myocyte alterations
Apoptosis and necrosis Coronary artery disease, heart failure (through May induce replacement fibrosis. 100
cardiomyocyte death and atrial scarring).
Myocyte hypertrophy Atrial dilatation, AF. Aggravates conduction disturbances. 84, 101
Endothelial and vascular alterations
Microvascular changes Atherosclerosis, coronary and peripheral artery disease, Aggravation of atrial ischaemia, heterogeneity 102
possibly atrial fibrillation. of electrical function, structural remodelling.
Endocardial remodelling Enhanced risk for thrombus formation. 103,104
Changes of the autonomic nervous system
Sympathetic Heart failure, hypertension. Enhanced propensity to ectopy. 80, 105
hyperinnervation

AF ¼ atrial fibrillation; CAD ¼ coronary artery disease.

symptomatic or asymptomatic (‘silent AF’). Many AF patients have monitoring of drug effects on ventricular rate; and (4) monitoring of
both symptomatic and asymptomatic episodes of AF.118 – 121 antiarrhythmic drug effects or catheter ablation for rhythm control.
Silent, undetected AF is common,120,122 with severe consequences
such as stroke and death.123 – 125 Prompt recording of an ECG is an ef- 5.2 Screening for silent atrial fibrillation
fective and cost-effective method to document chronic forms of 5.2.1 Screening for atrial fibrillation by electrocardiogram
AF.126 The technology to detect paroxysmal, self-terminating AF epi- in the community
sodes is rapidly evolving (see Chapter 6.1 for a definition of AF pat- Undiagnosed AF is common, especially in older populations and
terns). There is good evidence that prolonged ECG monitoring in patients with heart failure.130 Opportunistic screening for silent AF
enhances the detection of undiagnosed AF, e.g. monitoring for 72 h seems cost-effective in elderly populations (e.g. . 65 years),131 and simi-
after a stroke,27,127 or even longer periods.18,128 Daily short-term lar effects have been reported using single-lead ECG screening in other
ECG recordings increase AF detection in populations over 75 years at-risk populations.132,133 Screening of older populations (mean age 64
of age129 (Web Figure 1). Ongoing studies will determine whether years) yielded a prevalence of 2.3% for chronic forms of AF in 122,571
such early detection alters management (e.g. initiation of anticoagu- participants using either short-term ECG or pulse palpation (followed
lation) and improves outcomes. by ECG in those with an irregular pulse).134 Previously undiagnosed
Once the ECG diagnosis of AF has been established, further ECG AF was found in 1.4% of those aged .65 years, suggesting a number
monitoring can inform management in the context of: (1) a change needed to screen of 70. These findings encourage the further evaluation
in symptoms or new symptoms; (2) suspected progression of AF; (3) of systematic AF screening programmes in at-risk populations.
2904 ESC Guidelines

5.2.2 Prolonged monitoring for paroxysmal atrial detected in 10–15% of pacemaker patients.141 AHRE are associated
fibrillation with an increased risk of overt AF [hazard ratio (HR) 5.56; 95% con-
Paroxysmal AF is often missed.120 Repeated daily ECG recordings fidence interval (CI) 3.78–8.17; P , 0.001] and ischaemic stroke or
increased the detection of silent, asymptomatic paroxysmal AF in systemic embolism (HR 2.49; 95% CI 1.28 – 4.85; P ¼ 0.007). The
an unselected Swedish population aged .75 years.120,135 Several stroke risk in AHRE patients seems lower than the stroke risk in pa-
patient-operated devices136,137 and extended continuous ECG tients with diagnosed AF, and not all AHRE represent AF.142 Strokes
monitoring using skin patch recorders138 have been validated for often occur without AHRE detected within 30 days before the
the detection of paroxysmal AF (Web Figure 1).139 The detection event.143 – 147 Consequently, it is unclear whether AHRE imply the
of asymptomatic AF by new technologies, such as smartphone cases same therapeutic requirements as overt AF,148 and the benefit of
with ECG electrodes, smart watches, and blood pressure machines OAC in patients with AHRE is tested in ongoing clinical trials [e.g.
with AF detection algorithms, has not yet been formally evaluated Apixaban for the Reduction of Thrombo-Embolism in Patients With
against an established arrhythmia detection method.140

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Device-Detected Sub-Clinical Atrial Fibrillation (ARTESiA)
(NCT01938248) and Non vitamin K antagonist Oral anticoagulants
5.2.3 Patients with pacemakers and implanted devices in patients with Atrial High rate episodes (NOAH – AFNET 6)
Implanted pacemakers or defibrillators with an atrial lead allow (NCT02618577)]. At present, pacemakers and implanted devices
continuous monitoring of atrial rhythm. Using this technology, pa- should be interrogated on a regular basis for AHRE, and patients
tients with atrial high rate episodes (AHRE) can be identified. De- with AHRE should undergo further assessment of stroke risk factors
pending on the risk profile of the population studied, such AHRE are and for overt AF, including ECG monitoring (Figure 3).149

Patient without known AF presenting with atrial high rate episode


(AHRE, >5–6 min and >180 bpm) detected by an implanted device

Assess eligibility for oral anticoagulation using CHA2DS2-VASc score


Stroke risk low

Verify presence of AF by ECG documentation


e.g. resting ECG
Ambulatory ECG recorder
Patient-operated devices
Review device electrograms (if available) to determine whether it is AF

No AF detected AF diagnosed

Consider patient characteristics


*
(e.g. stroke risk score)
and patient preference

No antithrombotic Initiate oral anticoagulation


therapy (IB) (IA)

2DS2-VASc = Congestive
Heart failure, hypertension, Age ≥75 (doubled), Diabetes, Stroke (doubled),Vascular disease, Age 65–74, and Sex (female); ECG = electrocardiogram; EHRA = European Heart
Rhythm Association.
*In rare individual circumstances, oral anticoagulation may be considered in patients with AHRE, but without diagnosed AF. This clearly needs discussion with the patient and careful

a
Adapted from the report of the 3rd AFNET/EHRA consensus conference.150

Figure 3 Management of AHRE detected by an implanted device.


ESC Guidelines 2905

5.2.4 Detection of atrial fibrillation in stroke survivors often show a ‘saw tooth’ morphology, especially in the inferior leads
Sequential stratified ECG monitoring detected AF in 24% (95% CI (II, III, aVF). The ventricular rate can be variable (usual ratio of atrial
17 – 31) of stroke survivors,151 and in 11.5% (95% CI 8.9% – 14.3%) to ventricular contraction 4:1 to 2:1, in rare cases 1:1) and
in another meta-analysis,17 with large variations depending on the macro-re-entrant tachycardias may be missed in stable 2:1 conduc-
timing, duration, and method of monitoring. AF detection is not tion. Vagal stimulation or intravenous adenosine can therefore
uncommon in unselected stroke patients (6.2%, 95% CI 4.4 – be helpful to unmask atrial flutter. The management of atrial flutter
8.3),128 but is more likely in patients with cryptogenic stroke im- is discussed in chapter 13.7. Left or right atrial macro re-entrant
planted with loop recorders or who have had ECG monitors tachycardia is mainly found in patients after catheter ablation for
for several weeks. 18,128,152 Cryptogenic stroke is defined as a AF, AF surgery, or after open heart surgery.158
stroke in which the cause could not be identified after extensive
investigations.153 A broader definition is embolic stroke of un-
determined source.154 Several studies have also found AF in pa- 6. Classification of atrial fibrillation

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tients in whom another competing cause for stroke has been
identified clinically (e.g. hypertension or carotid artery sten- 6.1 Atrial fibrillation pattern
osis).27,127 Hence, prolonged ECG monitoring seems reasonable In many patients, AF progresses from short, infrequent episodes to
in all survivors of an ischaemic stroke without an established diag- longer and more frequent attacks. Over time, many patients will de-
nosis of AF. velop sustained forms of AF. In a small proportion of patients, AF
will remain paroxysmal over several decades (2 – 3% of AF pa-
Recommendations for screening for atrial fibrillation tients).161 The distribution of paroxysmal AF recurrences is not ran-
dom, but clustered.162 AF may also regress from persistent to
paroxysmal AF. Furthermore, asymptomatic recurrences of AF
Recommendations Class a Level b Ref C
are common in patients with symptomatic AF.120
Opportunistic screening for AF is Based on the presentation, duration, and spontaneous termin-
recommended by pulse taking or 130, 134,
I B ation of AF episodes, five types of AF are traditionally distin-
ECG rhythm strip in patients 155
>65 years of age. guished: first diagnosed, paroxysmal, persistent, long-standing
In patients with TIA or ischaemic persistent, and permanent AF (Table 5). If patients suffer from
stroke, screening for AF is both paroxysmal and persistent AF episodes, the more common
recommended by short-term ECG I B 27, 127 type should be used for classification. Clinically determined AF
recording followed by continuous
patterns do not correspond well to the AF burden measured
ECG monitoring for at least 72 hours.
It is recommended to interrogate
pacemakers and ICDs on a regular
basis for atrial high rate episodes Table 5 Patterns of atrial fibrillation
(AHRE). Patients with AHRE should I B 141, 156
undergo further ECG monitoring to
AF pattern Definition
document AF before initiating AF
therapy. First diagnosed AF that has not been diagnosed before, irrespective
AF of the duration of the arrhythmia or the presence
In stroke patients, additional ECG
and severity of AF-related symptoms.
monitoring by long-term non-
invasive ECG monitors or implanted IIa B 18, 128 Paroxysmal AF Self-terminating, in most cases within 48 hours.
loop recorders should be considered Some AF paroxysms may continue for up to 7 days.a
to document silent atrial fibrillation. AF episodes that are cardioverted within
7 days should be considered paroxysmal.a
Systematic ECG screening may be
considered to detect AF in patients 130, 135, Persistent AF AF that lasts longer than 7 days, including episodes
IIb B that are terminated by cardioversion, either with
aged >75 years, or those at high 157
stroke risk. drugs or by direct current cardioversion, after
7 days or more.

AF ¼ atrial fibrillation; AHRE ¼ atrial high rate episodes; Long-standing Continuous AF lasting for ≥1 year when it is decided
ECG ¼ electrocardiogram; ICD ¼ implantable cardioverter defibrillator; persistent AF to adopt a rhythm control strategy.
TIA ¼ transient ischaemic attack. Permanent AF AF that is accepted by the patient (and physician).
a
Class of recommendation. Hence, rhythm control interventions are, by
b
Level of evidence.
c definition, not pursued in patients with permanent
Reference(s) supporting recommendations.
AF. Should a rhythm control strategy be adopted, the
arrhythmia would be re-classified as ‘long-standing
persistent AF’.
5.3 Electrocardiogram detection of atrial
flutter AF ¼ atrial fibrillation.
a
Right atrial isthmus-dependent flutter has a typical ECG pattern and The distinction between paroxysmal and persistent AF is often not made correctly
without access to long-term monitoring.163 Hence, this classification alone is often
ventricular rate.158 The prevalence of atrial flutter is less than one-
insufficient to select specific therapies. If both persistent and paroxysmal episodes
tenth of the prevalence of AF.159 Atrial flutter often coexists with or are present, the predominant pattern should guide the classification.
precedes AF.160 In typical, isthmus-dependent flutter, P waves will
2906 ESC Guidelines

Table 6 Clinical types of atrial fibrillationa

AF type Clinical presentation Possible pathophysiology


AF secondary to AF in patients with LV systolic or diastolic dysfunction, long-standing Increased atrial pressure and atrial structural remodelling,
structural heart hypertension with LVH, and/or other structural heart disease. together with activation of the sympathetic and renin-
disease The onset of AF in these patients is a common cause of hospitalization angiotensin system.
and a predictor of poor outcome.
Focal AF Patients with repetitive atrial runs and frequent, short episodes of Localized triggers, in most cases originating from the pulmonary
paroxysmal atrial fibrillation. Often highly symptomatic, younger veins, initiate AF.
patients with distinguishable atrial waves (coarse AF), atrial ectopy, and/ AF due to one or a few re-entrant drivers is also considered to
or atrial tachycardia deteriorating in AF. be part of this type of AF.

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Polygenic AF AF in carriers of common gene variants that have been associated with Currently under study. The presence of selected gene variants
early onset AF. may also influence treatment outcomes.
Post-operative AF New onset of AF (usually self-terminating) after major (typically Acute factors: inflammation, atrial oxidative stress, high
cardiac) surgery in patients who were in sinus rhythm before surgery sympathetic tone, electrolyte changes, and volume overload,
and had no prior history of AF. possibly interacting with a pre-existing substrate.
AF in patients with AF in patients with mitral stenosis, after mitral valve surgery and in Left atrial pressure (stenosis) and volume (regurgitation) load
mitral stenosis or some cases other valvular disease. are the main drivers of atrial enlargement and structural atrial
prosthetic heart valves remodelling in these patients.
AF in athletes Usually paroxysmal, related to duration and intensity of training. Increased vagal tone and atrial volume.
Monogenic AF AF in patients with inherited cardiomyopathies, including The arrhythmogenic mechanisms responsible for sudden death
channelopathies. are likely to contribute to the occurrence of AF in these patients.

AF ¼ atrial fibrillation; LV ¼ left ventricular; LVH ¼ left ventricular hypertrophy. It is recognized that these types of AF will overlap in clinical practice, and that their impact for
management needs to be evaluated systematically.

by long-term ECG monitoring.163 Even less is known about the 6.3 Symptom burden in atrial fibrillation
response to therapy in patients with long-standing persistent Patients with AF have significantly poorer quality of life than
AF or long-standing paroxysmal AF. Despite these inaccuracies, healthy controls, experiencing a variety of symptoms including
the distinction between paroxysmal and persistent AF has been lethargy, palpitations, dyspnoea, chest tightness, sleeping difficul-
used in many trials and therefore still forms the basis of some ties, and psychosocial distress.32,177 – 180 Improved quality of life
recommendations.
There is some evidence suggesting that AF burden may influence
stroke risk44,124,164 and could modify the response to rhythm con-
trol therapy.76,165 The evidence for this is weak. Therefore, AF bur- Table 7 Modified European Heart Rhythm
den should not be a major factor in deciding on the usefulness of an Association symptom scale (modified from Wynn
intervention that is deemed suitable for other reasons. et al.199)

6.2 Atrial fibrillation types reflecting Modified


Symptoms Description
EHRA score
different causes of the arrhythmia
1 None AF does not cause any symptoms
The risk of developing AF is increased in a variety of physiological
Normal daily activity not affected
and disease states (Figure 2), and the historic term ‘lone AF’ is prob- 2a Mild
by symptoms related to AFa
ably misleading and should be avoided.166 Although the pattern of
Normal daily activity not affected
AF may be the same, the mechanisms underpinning AF vary substan-
2b Moderate by symptoms related to AF, but
tially between patients167 (Table 6). This suggests that stratifying AF patient troubled by symptomsa
patients by underlying drivers of AF could inform management, Normal daily activity affected by
for example, considering cardiac and systemic comorbidity (e.g. 3 Severe
symptoms related to AF
diabetes and obesity168), lifestyle factors (e.g. activity level, smoking, Normal daily activity
alcohol intake169,170), markers of cardiac structural remodelling (e.g. 4 Disabling
discontinued
fibrosis171 – 173 or electrocardiographic parameters of AF complex-
ity174), or genetic background. Table 6 provides such a taxonomy, AF ¼ atrial fibrillation; EHRA ¼ European Heart Rhythm Association.
informed by expert consensus,76,120,175 but without much evidence a
EHRA class 2a and 2b can be differentiated by evaluating whether patients are
to underpin its clinical use.176 Systematic research defining the functionally affected by their AF symptoms. AF-related symptoms are most
commonly fatigue/tiredness and exertional shortness of breath, or less frequently
major drivers of AF is clearly needed to better define different types palpitations and chest pain.42,194,200 – 202
of AF.176
ESC Guidelines 2907

has been noted with both pharmacological and interventional


therapies, 181 – 185 but there are limited data to compare the Table 8 Cardiovascular and other conditions
benefit of different treatments. 32,186 Assessment of quality of independently associated with atrial fibrillation
life is further constrained by a lack of cross-validation of the
Characteristic/comorbidity Association with AF
several AF-specific quality of life tools. 187 – 191 With regard to
symptom assessment, EHRA suggested the EHRA symptom Genetic predisposition (based on HR range 0.4–3.2
multiple common gene variants
scale (Table 7) to describe symptom severity in AF patients.192
associated with AF)64
A similar scale (the Canadian Cardiovascular Society Severity of
Older age19 HR:
Atrial Fibrillation Scale) is used in Canada.193 The EHRA scale has 50–59 years 1.00 (reference)
been used and validated.194 – 199 A modification was proposed in 60–69 years 4.98 (95% CI 3.49–7.10)
2014, subdividing EHRA class 2 into mild (2a) or moderate (2b) 70–79 years 7.35 (95% CI 5.28–10.2)
impact.199 As symptoms in class 2b (‘troubling’ symptoms) iden- 80–89 years 9.33 (95% CI 6.68–13.0)

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tified patients with a health utility benefit of rhythm control in Hypertension (treated) vs. none19 HR 1.32 (95% CI 1.08–1.60)
that study, this modification may provide a threshold for potential 19
Heart failure vs. none HR 1.43 (95% CI 0.85–2.40)
treatment decisions, pending independent validation. While 205
Valvular heart disease vs. none RR 2.42 (95% CI 1.62–3.60)
some AF patients had no or minimal symptoms (25 – 40%),
many (15 – 30%) report severe or disabling symptoms. 194,196 Myocardial infarction vs. none 19
HR 1.46 (95% CI 1.07–1.98)
The modified EHRA scale should be used to guide symptom- Thyroid dysfunction206, 207 (reference: euthyroid)
orientated treatment decisions and for longitudinal patient Hypothyroidism HR 1.23 (95% CI 0.77–1.97)
profiling. Subclinical hyperthyroidism RR 1.31 (95% CI 1.19–1.44)
Overt hyperthyroidism RR 1.42 (95% CI 1.22–1.63)
Obesity19, 208 HR:
Recommendation on use of the modified European None (BMI <25 kg/m²) 1.00 (reference)
Heart Rhythm Association symptom scale Overweight (BMI 25–30 kg/m²) 1.13 (95% CI 0.87–1.46)
Obese (BMI ≥31 kg/m²) 1.37 (95% CI 1.05–1.78)
Recommendation Class a Level b Ref C Diabetes mellitus vs. none19 HR 1.25 (95% CI 0.98–1.60)

Use of the modified EHRA Chronic obstructive pulmonary RR:


symptom scale is recommended disease209
in clinical practice and research I C 192, 199 FEV1 ≥80% 1.00 (reference)
studies to quantify AF-related FEV1 60–80% 1.28 (95% CI 0.79–2.06)
symptoms. FEV1 <60% 2.53 (95% CI 1.45–4.42)
Obstructive sleep apnoea vs. none210 HR 2.18 (95% CI 1.34–3.54)
AF ¼ atrial fibrillation; EHRA ¼ European Heart Rhythm Association. Chronic kidney disease211 OR:
a
Class of recommendation. None 1.00 (reference)
b
Level of evidence. Stage 1 or 2 2.67 (95% CI 2.04–3.48)
c
Reference(s) supporting recommendations. Stage 3 1.68 (95% CI 1.26–2.24)
Stage 4 or 5 3.52 (95% CI 1.73–7.15)
Smoking212 HR:
7. Detection and management of Never
Former
1.00 (reference)
1.32 (95% CI 1.10–1.57)
risk factors and concomitant Current 2.05 (95% CI 1.71–2.47)
Alcohol consumption213
cardiovascular diseases None
RR:
1.00 (reference)
Many cardiovascular diseases and concomitant conditions increase 1– 6 drinks/week 1.01 (95% CI 0.94–1.09)
7–14 drinks/week 1.07 (95% CI 0.98–1.17)
the risk of developing AF (Table 8), recurrent AF, and AF-associated 15–21 drinks/week 1.14 (95% CI 1.01–1.28)
complications. The identification of such conditions, their preven- >21 drinks/week 1.39 (95% CI 1.22–1.58)
tion and treatment is an important leverage to prevent AF and Habitual vigorous exercise214 RR:
its disease burden. Knowledge of these factors and their manage- Non-exercisers 1.00 (reference)
ment is hence important for optimal management of AF <1 day/week 0.90 (95% CI 0.68−1.20)
patients.203,204 1−2 days/week 1.09 (95% CI 0.95−1.26)
3−4 days/week 1.04 (95% CI 0.91−1.19)
5−7 days/week 1.20 (95% CI 1.02−1.41)
7.1 Heart failure
Heart failure and AF coincide in many patients.215 – 217 They are AF ¼ atrial fibrillation; BMI ¼ body mass index; CI ¼ confidence interval;
linked by similar risk factors and share a common pathophysi- FEV1 ¼ forced expiratory volume in 1 second; HR ¼ hazard ratio; OR ¼ odds
ology.218 Heart failure and AF can cause and exacerbate each other ratio; RR ¼ risk ratio.

through mechanisms such as structural cardiac remodelling,


2908 ESC Guidelines

activation of neurohormonal mechanisms, and rate-related impair- rhythm.229 Catheter ablation may be a useful method to restore
ment of left ventricular (LV) function. Patients with AF and concomi- LV function and quality of life in AF patients with HFrEF,185,226 –
228
tant heart failure, both with preserved ejection fraction [LV ejection but further data are needed. Figure 4 summarizes the approach
fraction (LVEF) ≥50%] and reduced ejection fraction (LVEF to patients with AF and heart failure.
,40%),219,220 suffer from a worse prognosis, including increased
mortality.16,221 The recent ESC Guidelines on heart failure222
7.1.2 Atrial fibrillation patients with heart failure with
have also introduced a new category of heart failure with mid-range preserved ejection fraction
ejection fraction (HFmrEF; LVEF 40 – 49%), although data on AF The diagnosis of heart failure with preserved ejection fraction
patients in this group are limited. Prevention of adverse outcomes (HFpEF) in patients with AF is problematic because of the difficulty
and maintenance of a good quality of life are the aims of manage- in separating symptoms that are due to HF from those due to AF.
ment in all patients with AF and concomitant heart failure, regard- Although diagnostic differentiation can be achieved by cardioversion
less of LVEF.223 The general approach to AF management does

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and clinical reassessment but should be reserved for symptomatic
not differ between heart failure patients and others, but a few con- improvement as a specific therapy that improves prognosis in HFpEF
siderations are worthwhile. Of note, the only therapy with proven is currently lacking. Echocardiography can support the detection of
prognostic value in these patients is anticoagulation, and appropriate HFpEF in patients with symptomatic AF by providing evidence of
OAC should be prescribed in all patients at risk of stroke (see relevant structural heart disease [e.g. LV hypertrophy (LVH)] and/
Chapter 9). or measurement of diastolic dysfunction. Reduced early diastolic
myocardial velocity e’ by tissue Doppler reflects impaired LV relax-
7.1.1 Patients with atrial fibrillation and heart failure with ation, while the ratio of E/e’ is correlated with invasive measurement of
reduced ejection fraction LV filling pressures.230 – 234 Natriuretic peptide levels are part of the
In addition to OAC, standard heart failure therapy should be used diagnostic assessment of HFpEF,222 although natriuretic peptide levels
in patients with heart failure with reduced ejection fraction are elevated in AF patients and the optimum diagnostic cut-off is still
(HFrEF), as detailed in the ESC Guidelines. 222 This includes unknown.235 The management of patients with AF
angiotensin-converting enzyme (ACE) inhibitors or angiotensin and concomitant HFpEF should focus on the control of fluid
receptor blockers (ARBs), mineralocorticoid antagonists, balance and concomitant conditions such as hypertension and
defibrillators, cardiac resynchronization therapy,218 and combined myocardial ischaemia.
angiotensin receptor neprilysin inhibition (ARNI) in patients
able to tolerate an ACE inhibitor or ARB with ongoing
symptoms.224 7.1.3 Atrial fibrillation patients with heart failure with
mid-range ejection fraction
Rate control of AF is discussed in detail in Chapter 10. In brief,
HFmrEF is a recently defined entity, describing patients with symp-
only beta-blockers and digoxin are suitable in HFrEF because of
toms and signs of heart failure, LVEF 40 – 49%, elevated levels of
the negative inotropic potential of verapamil and diltiazem. Beta-
natriuretic peptides, and either LV hypertrophy, left atrial (LA) en-
blockers are usually the first-line option in patients with clinically
largement, or evidence of diastolic dysfunction.222 However, diag-
stable HFrEF, although a meta-analysis using individual patient data
nosis is more difficult in patients with AF, as natriuretic peptides
from randomized controlled trials (RCTs) found no reduction in
are elevated in AF and LA dilatation is common, regardless of con-
mortality from beta-blockers vs. placebo in those with AF at base-
comitant heart failure. LVEF is also variable and difficult to assess in
line (HR 0.97, 95% CI 0.83 – 1.14). 23 Digoxin is commonly pre-
AF patients because of AF-induced reduction in systolic LV function
scribed in clinical practice, but no head-to-head RCTs in AF
and variable cardiac cycle length. Further study of this group is re-
patients have been performed. In a meta-analysis of observational
quired before particular treatment strategies in AF patients with
studies, digoxin had a neutral effect on mortality in patients with
HFmrEF can be recommended.
AF and concomitant heart failure (adjusted observational studies
HR 0.90, 95% CI 0.70 – 1.16; propensity-matched observational
studies RR 1.08, 95% CI 0.93–1.26).225 Therefore, initial and com- 7.1.4 Prevention of atrial fibrillation in heart failure
bination rate control therapy for AF in HFrEF should take account of Retrospective analyses from large randomized trials have reported a
individual patient characteristics and symptoms; beta-blocker initi- lower incidence of new-onset AF in patients treated with ACE inhi-
ation should be delayed in patients with acute decompensated heart bitors/ARBs compared with placebo.236 – 238 The reduced incidence
failure, and digoxin can accumulate and provoke adverse effects in of AF with ACE inhibitors/ARBs is less evident in patients with
patients with kidney dysfunction (see Chapter 10). HFpEF239 and is lost in patients without heart failure.240 – 242 Nepri-
Patients with AF and HFrEF who present with severe symp- lysin inhibition does not seem to add to this effect.224 Beta-blocker
toms may require rhythm control therapy in addition to rate con- therapy was associated with a 33% reduction in the adjusted odds of
trol therapy. For patients who develop HFrEF as a result of rapid incident AF in HFrEF patients pre-treated with ACE inhibitors/ARBs,
AF (tachycardiomyopathy), a rhythm control strategy is pre- reinforcing the importance of beta-blocker therapy in HFrEF pa-
ferred, based on several relatively small patient cohorts and trials tients in sinus rhythm.23 Eplerenone, a mineralocorticoid receptor
reporting improved LV function after restoration of sinus antagonist, also reduced the risk of new-onset AF in patients with
rhythm. 185,226 – 228 The diagnosis of tachycardiomyopathy can LVEF ≤35%, New York Heart Association (NYHA) Class II, when
be challenging, and at times requires the restoration of sinus added to ACE inhibitors/ARBs and beta-blockers.243
ESC Guidelines 2909

Management of patients presenting acutely with AF and heart failure


Acute management Chronic management

Cardiovert if unstable

Anticoagulate according to stroke risk

Normalise fluid balance with diuretics to improve symptoms

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Control rate: Initial rate target <110 bpm; stricter if persistent HF/AF symptoms

Inhibit the renin–angiotensin–aldosterone systema

Early consideration of rhythm control

Advanced HF therapies, including devices a

Treatment of other cardiovascular disease, especially ischaemia and hypertension

heart failure.
a
In patients with heart failure and reduced ejection fraction. Also consider combined ARNI in patients able to tolerate an ACE inhibitor or ARB with ongoing symptoms.

Figure 4 Initial management of patients presenting acutely with atrial fibrillation and heart failure. (Adapted from Kotecha and Piccini.128)

7.2 Hypertension some form of valvular heart disease, often detected only by
Hypertension is a stroke risk factor in AF; uncontrolled high blood echocardiogram. 201,253 – 255 AF worsens prognosis in patients
pressure enhances the risk of stroke and bleeding events and may with severe valvular heart disease,256 including those undergoing
lead to recurrent AF. Therefore, good blood pressure control should surgery or transcatheter interventions for aortic or mitral valve
form an integral part of the management of AF patients.247 Inhibition disease.257 – 262 Valvular heart disease can be associated with an in-
of the renin–angiotensin–aldosterone system can prevent structural creased thrombo-embolic risk, which probably also adds to the
remodelling and recurrent AF.236,244 A recent analysis of the Danish stroke risk in AF patients.263 Similar to heart failure, valvular dis-
healthcare database with long-term monitoring of the effect of differ- ease and AF interact with and sustain each other through volume
ent antihypertensive agents on the occurrence of overt AF suggests a and pressure overload, tachycardiomyopathy, and neurohumoral
beneficial effect of ACE inhibitors or ARBs.245 Secondary analyses of factors. 264 – 270 When valve dysfunction is severe, AF can be
ACE inhibitors or ARBs in patients with heart failure or LVH show a regarded as a marker for progressive disease, thus favouring valve
lower incidence of new-onset AF.238,246 In patients with established repair or replacement.271
AF, but without LV dysfunction or heart failure, ARBs do not prevent Traditionally, patients with AF have been dichotomized into
recurrent AF better than placebo.240,241 ACE inhibitors or ARBs may ‘valvular’ and ‘non-valvular’ AF.272 Although slightly different defini-
reduce recurrent AF after cardioversion when co-administered with tions have been used, valvular AF mainly refers to AF patients that
antiarrhythmic drug therapy compared with an antiarrhythmic drug have either rheumatic valvular disease (predominantly mitral sten-
alone.248,249 Meta-analyses driven by these studies suggested a lower osis) or mechanical heart valves. In fact, while AF implies an incre-
risk of recurrent AF,236 – 238,250 but at least one controlled trial failed mental risk for thrombo-embolism in patients with mitral valve
to demonstrate benefit.240,251 stenosis,263,273,274 there is no clear evidence that other valvular dis-
eases, including mitral regurgitation or aortic valve disease, need to
be considered when choosing an anticoagulant or indeed to esti-
7.3 Valvular heart disease mate stroke risk in AF.275 Therefore, we have decided to replace
Valvular heart disease is independently associated with the historic term ‘non-valvular’ AF with reference to the specific
incident AF. 252 Approximately 30% of patients with AF have underlying conditions.
2910 ESC Guidelines

7.5.3 Catheter ablation in obese patients


Recommendations for patients with valvular heart Obesity may increase the rate of AF recurrence after catheter abla-
disease and atrial fibrillation tion,298 – 301 with obstructive sleep apnoea as an important potential
confounder. Obesity has also been linked to a higher radiation dose
Recommendations Class a Level b Ref C and complication rate during AF ablation.302,303 Notably, the symp-
Early mitral valve surgery should tomatic improvement after catheter ablation of AF in obese patients
be considered in severe mitral seems comparable to the improvement in normal-weight pa-
regurgitation, preserved LV function,
IIa C 276 tients.298 In view of the potential to reduce AF episodes by weight
and new-onset AF, even in the
absence of symptoms, particularly reduction (see chapter 7.5.2.), AF ablation should be offered to ob-
when valve repair is feasible. ese patients in conjunction with lifestyle modifications that lead to
Mitral valvulotomy should be weight reduction.

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considered for asymptomatic
patients with severe mitral stenosis IIa C
Recommendation for obese patients with atrial
and suitable valve anatomy who
have new-onset AF. fibrillation

AF ¼ atrial fibrillation; LV ¼ left ventricular. Recommendation Class a Level b Ref C


a
Class of recommendation. In obese patients with AF, weight
b
Level of evidence.
c loss together with management
Reference(s) supporting recommendations. 204, 288,
of other risk factors should be IIa B
296
considered to reduce AF burden
and symptoms.

7.4 Diabetes mellitus


AF ¼ atrial fibrillation.
Diabetes and AF frequently coexist because of associations with a
Class of recommendation.
other risk factors.277 – 283 Diabetes is a risk factor for stroke and b
Level of evidence.
c
other complications in AF.284 In patients with AF, a longer duration Reference(s) supporting recommendation.

of diabetes appears to confer a higher risk of thrombo-embolism,


albeit without greater risk of OAC-related bleeding.285 Unfortu-
nately, intensive glycaemic control does not affect the rate of
7.6 Chronic obstructive pulmonary
new-onset AF,284 while treatment with metformin seems to be disease, sleep apnoea, and other
associated with a decreased long-term risk of AF in diabetic respiratory diseases
patients286 and may even be associated with a lower long-term AF has been associated with obstructive sleep apnoea.304,305 Mul-
stroke risk.13 Diabetic retinopathy, a measure of disease severity, tiple pathophysiological mechanisms can contribute to AF in
does not increase the risk of ocular bleeding in anticoagulated obstructive sleep apnoea, including autonomic dysfunction, hypoxia,
patients.287 hypercapnia, and inflammation.96,304 – 307 Obstructive sleep apnoea
exaggerates intrathoracic pressure changes, which in itself and via
vagal activation can provoke shortening of the atrial action potential
7.5 Obesity and weight loss and induce AF. Risk factor reduction and continuous positive airway
7.5.1 Obesity as a risk factor pressure ventilation can reduce AF recurrence.308 – 312 It seems rea-
Obesity increases the risk for AF (Table 8)288 – 291 with a progressive sonable to consider obstructive sleep apnoea screening in AF pa-
increase according to body mass index (BMI).288,290 – 292 Obese pa- tients with risk factors. Obstructive sleep apnoea treatment
tients may have more LV diastolic dysfunction, increased sympathet- should be optimized to improve AF treatment results in appropriate
ic activity and inflammation, and increased fatty infiltration of the patients. Servo-controlled pressure support therapy should not be
atria.293 – 295 Obesity may also be a risk factor for ischaemic stroke, used in HFrEF patients with predominantly central sleep apnoea (of
thrombo-embolism, and death in AF patients.292 which 25% had concomitant AF).313
Patients with chronic obstructive pulmonary disease often suffer
7.5.2 Weight reduction in obese patients with atrial from atrial tachycardias, which need to be differentiated from AF
fibrillation by ECG. Agents used to relieve bronchospasm, notably theophyl-
Intensive weight reduction in addition to the management of other lines and beta-adrenergic agonists, may precipitate AF and make con-
cardiovascular risk factors (in the range of 10 – 15 kg weight loss trol of the ventricular response rate difficult. Non-selective
achieved), led to fewer AF recurrences and symptoms compared beta-blockers, sotalol, propafenone, and adenosine should be used
with an approach based on general advice in obese patients with with caution in patients with significant bronchospasm, while they
AF.203,204,296 Improved cardiorespiratory fitness can further de- can safely be used in patients with chronic obstructive pulmonary dis-
crease AF burden in obese patients with AF.297 Although the find- ease. Beta-1 selective blockers (e.g. bisoprolol, metoprolol, and nebi-
ings in these studies have to be confirmed, they underpin the volol), diltiazem, and verapamil are often tolerated and effective (see
positive effect of weight reduction in obese AF patients. Chapter 10).
ESC Guidelines 2911

Recommendations for patients with atrial fibrillation Recommendations for patients with kidney disease and
and respiratory diseases atrial fibrillation

Recommendations Class a Level b Ref C Recommendations Class a Level b Ref C


Correction of hypoxaemia and The assessment of kidney function
acidosis should be considered as by serum creatinine or creatinine
initial management for patients clearance is recommended in all AF 316,
IIa C I A
who develop AF during an acute patients to detect kidney disease 318−321
pulmonary illness or exacerbation and to support correct dosing of
of chronic pulmonary disease. AF therapy.
Interrogation for clinical signs of All AF patients treated with
304, 305,

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obstructive sleep apnoea should be IIa B oral anticoagulation should be
314, 315
considered in all AF patients. considered for at least yearly IIa B
renal function evaluation to detect
Obstructive sleep apnoea treatment
chronic kidney disease.
should be optimized to reduce
IIa B 307–311
AF recurrences and improve AF
treatment results. AF ¼ atrial fibrillation.
a
Class of recommendation.
b
Level of evidence.
AF ¼ atrial fibrillation. c
Reference(s) supporting recommendations.
a
Class of recommendation.
b
Level of evidence.
c
Reference(s) supporting recommendations.

8. Integrated management of
7.7 Chronic kidney disease patients with atrial fibrillation
AF is present in 15 – 20% of patients with CKD.316 The definition of Most patients initially access the healthcare system through pharma-
CKD in most AF trials is relatively strict. Although an estimated cists, community health workers, or primary care physicians. As AF
creatinine clearance (CrCl) rate of ,60 mL/min is indicative of is often asymptomatic (“silent AF”), these healthcare professionals
CKD, a number of trials in AF patients have used CrCl ,50 mL/ are important stakeholders to enable the adequate detection of
min to adapt NOAC dosage, usually estimated using the Cock- AF and to ensure consistent management. The initial assessment
roft – Gault formula. CrCl in AF patients can deteriorate over should be performed at the point of first contact with the healthcare
time.317 The management of OAC in patients with CKD is dis- system, and is feasible in most healthcare settings (when an ECG is
cussed in chapter 9.2.4. available). We propose to consider five domains in the initial

Treatment Desired outcome Patient benefit

Acute rate
and rhythm Haemodynamic stability
control
Manage Lifestyle changes, treatment of Cardiovascular risk Improved life
precipitating underlying cardiovascular conditions reduction expectancy
factors

Assess stroke Oral anticoagulation in


patients at risk for stroke Stroke prevention
risk
Improved quality of life,
Assess heart Rate control therapy Symptom improvement, autonomy, social
rate preservation of LV function functioning

Antiarrhythmic drugs,
Assess cardioversion, catheter Symptom
symptoms ablation, AF surgery improvement

Figure 5 Acute and chronic management of atrial fibrillation patients, desired cardiovascular outcomes, and patient benefits. Adapted from the
report on the 4th AFNET/EHRA consensus conference.76
2912 ESC Guidelines

assessment of patients presenting with newly diagnosed AF (Fig-


ure 5). These domains are:
(1) Haemodynamic instability or limiting, severe symptoms;
Provision of all therapy options a (2) Presence of precipitating factors (e.g. thyrotoxicosis, sepsis, or
postoperative AF) and underlying cardiovascular conditions;
(3) Stroke risk and need for anticoagulation;
Measurable high service quality b
(4) Heart rate and need for rate control;
(5) Symptom assessment and decision for rhythm control.
Optimal AF
management An integrated, structured approach to AF care, as applied suc-
Multidisciplinary service, shared cessfully to other domains of medicine,322 – 324 will facilitate consist-
decision making
ent, guideline-adherent AF management for all patients325 (Figure 6),

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with the potential to improve outcomes.42,326,327 Such approaches
are consistent with the Innovative Care for Chronic Conditions
Service accessible for all patients
Framework proposal put forward by the World Health Organiza-
tion.328 Review by an AF service, or at least referral to a cardiologist,
will usually be required after the initial assessment to fully evaluate
a
the effect of AF on cardiovascular health.329 There may also be rea-
On-site or through institutionalized cooperation.
b
Safety outcomes should be collected in published and monitored central sons for early or urgent referral (Table 9). Integrated care of all pa-
databases. tients with newly diagnosed AF should help to overcome the
current shortcomings of AF management, such as underuse of anti-
Figure 6 Achieving optimal management of atrial fibrillation coagulation, access to rate and rhythm control therapy, and incon-
patients. sistent approaches to cardiovascular risk reduction. Integrated AF
care requires the cooperation of primary care physicians, cardiolo-
gists, cardiac surgeons, AF specialists, stroke specialists, allied health
Table 9 Clinical signs calling for urgent involvement of practitioners, and patients, encompassing lifestyle interventions,
a specialized atrial fibrillation servicea treatment of underlying cardiovascular diseases, and AF-specific
therapy (Figure 7).
Clinical conditions
Haemodynamic instability 8.1 Evidence supporting integrated atrial
Uncontrollable rate fibrillation care
Symptomatic bradycardia not amenable to reduction of rate control agents Several structured approaches to AF care have been developed.
Severe angina or worsening left ventricular function Some evidence underpins their use, while more research is needed
Transient ischaemic attack or stroke into the best way of delivering integrated AF care. Integrated AF
management in an RCT increased the use of evidence-based care,
a
Anticoagulation should be initiated early in all suitable patients and will not and reduced by approximately one-third the composite outcome
routinely require specialist input. of cardiovascular hospitalization and cardiovascular death over a
mean follow-up of 22 months (14.3% vs. 20.8%, HR 0.65; 95% CI

Integrated AF management
Access to all treatment
Patient involvement Multidisciplinary teams Technology tools
options for AF

• Central role in care process • Phycisians (general physicians, • Information on AF • Structured support for lifestyle
• Patient education cardiology and stroke AF • Clinical decision support changes
• Encouragement and empowerment specialists, surgeons) and allied • Checklist and communication tools • Anticoagulation
for self-management health professionals work in a • Used by healthcare professionals • Rate control
• Advice and education on lifestyle collaborative practice model and patients • Antiarrhythmic drugs
and risk factor management • • Monitoring of therapy adherence • Catheter and surgical interventions
• Shared decision making skills, education, and experience and effectiveness (ablation, LAA occluder, AF surgery,
etc.)

• Informed, involved, • Working together in a • Navigation system to support • Complex management


empowered patient multidisciplinary chronic AF decision making in treatment decisions underpinned by an
care team team AF Heart Team

Figure 7 Fundamentals of integrated care in atrial fibrillation patients.


ESC Guidelines 2913

0.45–0.93; P ¼ 0.017) compared with usual care in a large tertiary 8.2.4 Technology use to support atrial fibrillation care
care centre.330 Integrated AF management appeared cost-effective Technology, such as decision support software, has the potential
in that study.331 However, an Australian RCT showed only a margin- to enhance the implementation of evidence-based care and im-
al effect on unplanned admissions and death using integrated AF prove outcomes, when used to enhance expert advice.338 Elec-
care limited to the initial care period, possibly emphasizing the tronic tools can also ensure coherent communication within the
need for sustained integration of AF care.332 Two observational AF team. With a view to support the wider use of such technol-
studies of integrated AF care found fewer hospitalizations,333,334 ogy, this Task Force is providing digital decision tools, in the form
one study showed fewer cases of stroke,333 and a further non- of freely accessible smartphone apps, to AF healthcare profes-
randomized study identified a trend for a lower rate of the compos- sionals and to AF patients.
ite outcome of death, cardiovascular hospitalization, and AF-related
emergency visits.335 More research is needed, and integrated AF Recommendations for an integrated approach to care

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care is likely to require different designs in different healthcare
settings. Recommendations Class a Level b Ref C
An integrated approach with
structured organization of care and
8.2 Components of integrated atrial follow-up should be considered in all
IIa B
patients with AF, aiming to improve 330–332
fibrillation care guidelines adherence and to reduce
8.2.1 Patient involvement hospitalizations and mortality.
Patients should have a central role in the care process. As treatment Placing patients in a central role
of AF requires patients to change their lifestyles and adhere to in decision-making should be
330,
chronic therapy, at times without an immediately tangible benefit, considered in order to tailor
IIa C 332,
they need to understand their responsibilities in the care process. management to patient preferences
334
and improve adherence to
Physicians and healthcare professionals are responsible for provid- long-term therapy.
ing access to evidence-based therapy, but adherence to therapy is
ultimately the responsibility of informed and autonomous patients,
AF ¼ atrial fibrillation
best described as ‘shared accountability’.336 Hence, information and a
Class of recommendation.
b
the education of patients, and often of their partners and relatives, is Level of evidence.
c
Reference(s) supporting recommendations.
indispensable to encourage a self-management role and to em-
power patients to participate in shared decision-making,326,328 and
to support understanding of the disease and the suggested
treatments.337
8.3 Diagnostic workup of atrial fibrillation
8.2.2 Multidisciplinary atrial fibrillation teams patients
Delegation of tasks from specialists to general physicians and from AF is often found in patients with other, at times undiagnosed, car-
physicians to allied health professionals is a fundamental concept of diovascular conditions. Thus, all AF patients will benefit from a
integrated care models. A multidisciplinary AF team approach in- comprehensive cardiovascular assessment.339
cludes an efficient mix of interpersonal and communication skills,
education, and expertise in AF management, as well as the use of
8.3.1 Recommended evaluation in all atrial fibrillation
dedicated technology. This approach underlines the importance of
patients
redesigning daily practice in a way that encourages non-specialists
A complete medical history should be taken and all patients should
and allied professionals to have an important role in educating pa-
undergo clinical evaluation that includes thorough assessment for
tients and co-ordinating care, while the specialist remains medically
concomitant conditions, establishing the AF pattern, estimation
responsible. Cultural and regional differences will determine the
of stroke risk and AF-related symptoms, and assessment of
composition of AF teams.
arrhythmia-related complications such as thrombo-embolism or
LV dysfunction. A 12-lead ECG is recommended to establish a sus-
8.2.3 Role of non-specialists pected diagnosis of AF, to determine rate in AF, and to screen for
Some non-specialist health care professionals, e.g. physicians in conduction defects, ischaemia, and signs of structural heart disease.
primary care have extensive expertise in stroke prevention and Initial blood tests should evaluate thyroid and kidney function, as
initial management of AF patients. Others may seek training to well as serum electrolytes and full blood count. Transthoracic echo-
acquire such knowledge. Other components of AF management cardiography is recommended in all AF patients to guide treatment
(e.g. assessment of concomitant cardiovascular conditions, decisions. Transthoracic echocardiography should be used to iden-
antiarrhythmic drug therapy, or interventional treatment) often tify structural disease (e.g. valvular disease) and assess LV size and
require specialist input. Integrated AF care structures should function (systolic and diastolic), atrial size, and right heart func-
support treatment initiation by non-specialists where appropriate, tion.339,340 Although biomarkers such as natriuretic peptides are
and provide ready access to specialist knowledge to optimize elevated in AF patients, there is insufficient data to suggest that
AF care. blood-based parameters are independent markers for AF.341 – 343
2914 ESC Guidelines

8.3.2 Additional investigations in selected patients with benefit need careful explanation to patients when their benefits
atrial fibrillation are not directly felt. Rhythm control therapy can be successful if
Ambulatory ECG monitoring in AF patients can assess the adequacy symptoms are controlled, even when AF recurs. Explaining the
of rate control, relate symptoms with AF recurrences, and detect expected benefits to each patient at the start of AF management
focal induction of bouts of paroxysmal AF. Transoesophageal echo- will prevent unfounded expectations and has the potential to
cardiography (TOE) is useful to further assess valvular heart disease optimize quality of life.
and to exclude intracardiac thrombi, especially in the LAA, to facili-
tate early cardioversion or catheter ablation.344 Patients with symp-
toms or signs of myocardial ischaemia should undergo coronary 9. Stroke prevention therapy in
angiography or stress testing as appropriate. In patients with AF atrial fibrillation patients
and signs of cerebral ischaemia or stroke, computed tomography
(CT) or magnetic resonance imaging (MRI) of the brain is recom- OAC therapy can prevent the majority of ischaemic strokes in AF

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mended to detect stroke and support decisions regarding acute patients and can prolong life.38,39,42,194,201,329,350 – 352 It is superior
management and long-term anticoagulation. Delayed-enhancement to no treatment or aspirin in patients with different profiles for
MRI of the left atrium using gadolinium contrast,345 – 347 T1 mapping stroke risk. 353,354 The net clinical benefit is almost universal,
using cardiac MRI,347 and intracardiac echo348 may help to guide with the exception of patients at very low stroke risk, and OAC
treatment decisions in AF, but require external validation in multi- should therefore be used in most patients with AF (Figure 8). Des-
centre studies. pite this evidence, underuse or premature termination of OAC
therapy is still common. Bleeding events, both severe and nuis-
8.4 Structured follow-up ance bleeds, a perceived ‘high risk of bleeding’ on anticoagulation,
Most AF patients need regular follow-up to ensure continued and the efforts required to monitor and dose-adjust VKA therapy
optimal management. Follow-up may be undertaken in primary are among the most common reasons for withholding or ending
care, by specially trained nurses, by cardiologists, or by AF specia- OAC.352,355 – 359 However, the considerable stroke risk without
lists.325,330 A specialist should co-ordinate care and follow-up. OAC often exceeds the bleeding risk on OAC, even in the elderly,
Follow-up should ensure implementation of the management plan, in patients with cognitive dysfunction, or in patients with frequent
continued engagement of the patient, and therapy adaptation where falls or frailty.360,361 The bleeding risk on aspirin is not different to
needed. the bleeding risk on VKA362 or NOAC therapy,354,363 while VKA
and NOACs, but not aspirin, effectively prevent strokes in AF
Recommendations for diagnostic workup of atrial patients.38,354,362,363
fibrillation patients
9.1 Prediction of stroke and bleeding
Recommendations Class a Level b Ref C
risk
ECG documentation is required to 9.1.1 Clinical risk scores for stroke and systemic
I B 349
establish the diagnosis of AF.
embolism
A full cardiovascular evaluation, Simple, clinically applicable stroke risk-stratification schemes
including an accurate history, careful
clinical examination, and assessment I C in AF patients were developed in the late 1990s in small cohort
of concomitant conditions, is studies, and have later been refined and validated in larger
recommended in all AF patients. populations. 364 – 368 The introduction of the CHA 2 DS 2 -VASc
Transthoracic echocardiography is score (Table 11) has simplified the initial decision for OAC in
recommended in all AF patients to I C 339
guide management.
AF patients. Since its first incorporation in the ESC guidelines in
2010,369 it has been widely used.370 We recommend estimating
Long-term ECG monitoring should
be considered in selected patients to stroke risk in AF patients based on the CHA2DS2-VASc score.368
assess the adequacy of rate control IIa C In general, patients without clinical stroke risk factors do not need
in symptomatic patients and to relate antithrombotic therapy, while patients with stroke risk factors (i.e.
symptoms with AF episodes.
CHA2DS2-VASc score of 1 or more for men, and 2 or more for
women) are likely to benefit from OAC.
AF ¼ atrial fibrillation; ECG ¼ electrocardiogram.
a
Class of recommendation.
Other, less established risk factors for stroke include unstable
b
Level of evidence. international normalized ratio (INR) and low time in therapeutic
c
Reference(s) supporting recommendations. range (TTR) in patients treated with VKAs; previous bleed or an-
aemia; alcohol excess and other markers for decreased therapy ad-
herence; CKD; elevated high-sensitivity troponin; and elevated
8.5 Defining goals of atrial fibrillation N-terminal pro-B-type natriuretic peptide.
management
AF management comprises therapies with prognostic impact (an- 9.1.2 Anticoagulation in patients with a CHA2DS2-VASc
ticoagulation and treatment of cardiovascular conditions) and score of 1 in men and 2 in women
therapies predominantly providing symptomatic benefit (rate Controlled trials studying OAC in AF patients have been enriched
control and rhythm control, Table 10). Therapies with prognostic for patients at high risk of stroke, 38,39,42,194,201,329,351,352 and
ESC Guidelines 2915

Table 10 Goal-based follow-up

Category Intervention Follow-up aspects Performance indicator


(examples)
Prognostic Comorbidity control Obesity Weight loss
(relevant examples Arterial hypertension Blood pressure control
given) Heart failure Heart failure therapy and hospitalizations
Coronary artery disease Statin and antiplatelet therapy;
revascularization
Diabetes Glycaemic control
Valvular heart disease Valve repair or replacement
Prognostic Anticoagulation Indication (risk profile; timing, e.g. post-cardioversion). Stroke

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Adherence (NOAC or VKA) and INR (if VKA). Bleeding
NOAC dosing (co-medications; age; weight; renal function). Mortality
Mainly symptomatic Rate control Symptoms Modified EHRA score
Partly prognostic Average resting heart rate <110 bpm Heart failure status
LV function
Symptomatic at present Rhythm control Symptoms vs. side effects
Exercise capacity
Exclusion of pro-arrhythmia (PR; QRS; QTc interval)
Hospitalization
Therapy complications
Relevant for Patient education and Knowledge (about disease; about treatment; about Adherence to therapy
implementation of self-care capabilities management goals) Directed evaluation, preferably based on
therapy and adherence Capabilities (what to do if…) systematic checklists
Relevant for chronic care Caregiver involvement Who? (spouse; GP; home nurse; pharmacist) Directed evaluation of task performance
management Clearly spelling out participation roles (e.g. via patient card)
Knowledge and capabilities Dispensed medication
Log of follow-up visits

bpm ¼ beats per minute; mEHRA symptoms scale ¼ modified European Heart Rhythm Association symptoms scale; GP ¼ general practitioner; INR ¼ international normalized
ratio; LV ¼ left ventricular; NOAC ¼ non-vitamin K antagonist oral anticoagulant; VKA ¼ vitamin K antagonist.

hence there is strong evidence that patients with a CHA2DS2 - Measurement of cardiac troponin (high-sensitivity troponin T or I)
VASc risk score of 2 or more in men, and 3 or more in women, and N-terminal pro-B-type natriuretic peptide may provide
benefit from OAC. Fortunately, we now have a growing evidence additional prognostic information in selected AF patients.380 – 382
base regarding stroke risk in patients with one clinical risk factor Biomarker-based risk scores may, in the future, prove helpful to bet-
(i.e. a CHA2DS2-VASc score of 1 for men, and 2 for women), al- ter stratify patients (e.g. those at a truly low risk of stroke).75,382
though this relies largely on observed stroke rates in patients not
receiving OAC. In many of these patients, anticoagulation seems
to provide a clinical benefit. 371 – 375 The rates of stroke and 9.1.3 Clinical risk scores for bleeding
thrombo-embolism vary considerably in patients with CHA2DS2- Several bleeding risk scores have been developed, mainly in pa-
VASc scores of 1 or 2 due to differences in outcomes, populations, tients on VKAs. These include HAS-BLED [hypertension, abnor-
and anticoagulation status (Web Table 1.)371,376,377,1041 We there- mal renal/liver function (1 point each), stroke, bleeding history or
fore commissioned an analysis of stroke risk in men and women predisposition, labile INR, elderly (.65 years), drugs/alcohol con-
with one additional stroke risk factor to inform these guidelines comitantly (1 point each)], ORBIT (Outcomes Registry for Better
(Web Table 1, last line). OAC should be considered for men Informed Treatment of Atrial Fibrillation), and more recently, the
with a CHA2DS2-VASc score of 1 and women with a score of 2, ABC (age, biomarkers, clinical history) bleeding score, which also
balancing the expected stroke reduction, bleeding risk, and pa- makes use of selected biomarkers.383 – 385 Stroke and bleeding risk
tient preference. Importantly, age (65 years and older) conveys factors overlap (compare Tables 11 and 12). For example, older
a relatively high and continuously increasing stroke risk that also age is one of the most important predictors of both ischaemic
potentiates other risk factors (such as heart failure and sex). stroke and bleeding in AF patients. 386,387 A high bleeding risk
Hence, an individualized weighing of risk, as well as patient prefer- score should generally not result in withholding OAC. Rather,
ences, should inform the decision to anticoagulate patients with bleeding risk factors should be identified and treatable factors
only one CHA2DS2-VASc risk factor, apart from female sex. Fe- corrected (see chapter 8.5). Table 12 provides details of modifi-
male sex does not appear to increase stroke risk in the absence able bleeding risk factors.
of other stroke risk factors (Web Table 1).378,379
2916 ESC Guidelines

Mechanical heart valves or moderate or severe Yes


mitral stenosis

No

Estimate stroke risk based on number of


CHA 2DS2-VASc risk factors a

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0b 1 ≥2

No antiplatelet or Oral anticoagulation


anticoagulant indicated
treatment (IIIB) OAC should be Assess for contra-indications
considered (IIaB) Correct reversible
bleeding risk factors

LAA occluding devices


may be considered in
patients with clear
contra-indications
for OAC (IIbC) NOAC (IA)c VKA (IA)c,d

a
Congestive heart failure, Hypertension, Age ≥75 years (2 points), Diabetes, prior Stroke/TIA/embolus (2 points),Vascular disease, age 65–74 years, female Sex.
b
Includes women without other stroke risk factors.
c
IIaB for women with only one additional stroke risk factor.
d
IB for patients with mechanical heart valves or mitral stenosis.

Figure 8 Stroke prevention in atrial fibrillation.

Recommendations for prediction of stroke and 9.2 Stroke prevention


bleeding risk 9.2.1 Vitamin K antagonists
Warfarin and other VKAs were the first anticoagulants used in AF
Recommendations Class a Levelb Ref C patients. VKA therapy reduces the risk of stroke by two-thirds and
mortality by one-quarter compared with control (aspirin or no ther-
The CHA 2 DS 2 -VASc score is
recommended for stroke risk I A
368, 371, apy).38 VKAs have been used in many patients throughout the world
386 with good outcomes,394 – 396 and this is reflected in the warfarin
prediction in patients with AF.
Bleeding risk scores should be arms of the NOAC trials (see chapter 9.2.2.). The use of VKAs is limited
384, 386,
considered in AF patients on oral
IIa B 387,
by the narrow therapeutic interval, necessitating frequent monitoring
anticoagulation to identify modifiable and dose adjustments, but VKAs, when delivered with adequate time
389–392
risk factors for major bleeding.
in therapeutic range (TTR), are effective for stroke prevention in AF pa-
Biomarkers such as high-sensitivity
tients. Clinical parameters can help to identify patients who are likely to
troponin and natriuretic peptide
may be considered to further refine IIb B
380–382, achieve a decent TTR on VKA therapy.397 These have been summar-
387, 393
stroke and bleeding risk in AF ized in the SAMe-TT2R2 score. Patients who fare well on this score,
patients. when treated with a VKA, have on average a higher TTR than patients
who do not fare well on the score.398,399 VKAs are currently the only
AF ¼ atrial fibrillation; CHA2DS2-VASc ¼ Congestive Heart failure, treatment with established safety in AF patients with rheumatic mitral
hypertension, Age ≥75 (doubled), Diabetes, Stroke or transient ischaemic
attack or systemic embolism (doubled), Vascular disease, Age 65 –74, and Sex valve disease and/or a mechanical heart valve prosthesis.400
(female).
a
Class of recommendation. 9.2.2 Non-vitamin K antagonist oral anticoagulants
b
Level of evidence.
c
Reference(s) supporting recommendations. NOACs, including the direct thrombin inhibitor dabigatran and the
factor Xa inhibitors apixaban, edoxaban, and rivaroxaban, are
ESC Guidelines 2917

Table 11 Clinical risk factors for stroke, transient Table 12 Modifiable and non-modifiable risk factors
ischaemic attack, and systemic embolism in the for bleeding in anticoagulated patients based on
CHA2DS2-VASc score bleeding risk scores

CHA 2DS2-VASc risk factor Points Modifiable bleeding risk factors


Congestive heart failure +1 Hypertension (especially when systolic blood pressure is >160 mmHg)a,b,c
Signs/symptoms of heart failure or objective evidence of
Labile INR or time in therapeutic range <60%a in patients on vitamin
reduced left ventricular ejection fraction
K antagonists
Hypertension +1
Medication predisposing to bleeding, such as antiplatelet drugs and
Resting blood pressure >140/90 mmHg on at least two non-steroidal anti-inflammatory drugsa,d
occasions or current antihypertensive treatment
Excess alcohol (≥8 drinks/week)a,b

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Age 75 years or older +2
Potentially modifiable bleeding risk factors
Diabetes mellitus +1
Fasting glucose >125 mg/dL (7 mmol/L) or treatment Anaemiab,c,d
with oral hypoglycaemic agent and/or insulin
Impaired renal functiona,b,c,d
Previous stroke, transient ischaemic attack, or +2
Impaired liver functiona,b
thromboembolism
Reduced platelet count or functionb
Vascular disease +1
Previous myocardial infarction, peripheral artery disease, Non-modifiable bleeding risk factors
or aortic plaque Agee (>65 years)a (≥75 years)b,c,d
Age 65–74 years +1 History of major bleedinga,b,c,d
Sex category (female) +1 Previous strokea,b
Dialysis-dependent kidney disease or renal transplanta,c
CHA2DS2-VASc ¼ Congestive Heart failure, hypertension, Age ≥75 (doubled),
Diabetes, Stroke (doubled), Vascular disease, Age 65 – 74, and Sex (female).
Cirrhotic liver diseasea
Malignancyb
Genetic factorsb
suitable alternatives to VKAs for stroke prevention in AF (Table 13).
Biomarker-based bleeding risk factors
Their use in clinical practice is increasing rapidly.401 All NOACs have
High-sensitivity troponine
a predictable effect (onset and offset) without need for regular an-
ticoagulation monitoring. The phase III trials have been conducted Growth differentiation factor-15e
with carefully selected doses of the NOACs, including clear rules Serum creatinine/estimated CrCle
for dose reduction that should be followed in clinical practice
(Table 13). ABC ¼ age, biomarkers, clinical history; ATRIA ¼ AnTicoagulation and Risk
factors In Atrial fibrillation; CKD ¼ chronic kidney disease; CrCl ¼ creatinine
9.2.2.1 Apixaban clearance; HAS-BLED ¼ hypertension, abnormal renal/liver function (1 point
In the ARISTOTLE (Apixaban for Reduction in Stroke and Other each), stroke, bleeding history or predisposition, labile INR, elderly (.65 years),
drugs/alcohol concomitantly (1 point each); HEMORR2HAGES ¼ hepatic or renal
Thrombo-embolic Events in Atrial Fibrillation) trial,319 apixaban 5 mg disease, ethanol abuse, malignancy, older (age .75), reduced platelet count or
twice daily reduced stroke or systemic embolism by 21% compared function, rebleeding risk (prior bleed; 2 points), hypertension (uncontrolled),
with warfarin, combined with a 31% reduction in major bleeding and anaemia, genetic factors (CYP 2C9 polymorphisms), excessive fall risk (including
neuropsychiatric disease), and stroke; INR ¼ international normalized ratio;
an 11% reduction in all-cause mortality (all statistically significant). ORBIT ¼ Outcomes Registry for Better Informed Treatment of Atrial Fibrillation;
Rates of haemorrhagic stroke and intracranial haemorrhage, but not TTR ¼ time in therapeutic range; VKA ¼ vitamin K antagonist.
a
of ischaemic stroke, were lower on apixaban. Rates of gastrointestinal Derived from the HAS-BLED score.384
b
Derived from the HEMORR2HAGES score.383
bleeding were similar between the two treatment arms.402 c
Derived from the ATRIA score.385
Apixaban is the only NOAC that has been compared with aspirin d
Derived from the ORBIT score.388
e
in AF patients; apixaban significantly reduced stroke or systemic em- Derived from the ABC bleeding score.387

bolism by 55% compared with aspirin, with no or only a small differ-


ence in rates of major bleeding or intracranial haemorrhage.354,403
by 12%, while gastrointestinal bleeding was significantly increased by
9.2.2.2 Dabigatran
50%. There was a non-significant numerical increase in the rate of
In the RE-LY (Randomized Evaluation of Long-Term Anticoagula-
myocardial infarction with both dabigatran doses,318,404 which has
tion Therapy) study,318,404 dabigatran 150 mg twice daily reduced
not been replicated in large post-authorization analyses.396 These
stroke and systemic embolism by 35% compared with warfarin with-
observational data have also replicated the benefit of dabigatran
out a significant difference in major bleeding events. Dabigatran
over VKA found in the RE-LY trial in patients who were mainly trea-
110 mg twice daily was non-inferior to warfarin for prevention of
ted with the higher dabigatran dose (150 mg twice daily).396
stroke and systemic embolism, with 20% fewer major bleeding
events. Both dabigatran doses significantly reduced haemorrhagic 9.2.2.3 Edoxaban
stroke and intracranial haemorrhage. Dabigatran 150 mg twice daily In the ENGAGE AF-TIMI 48 (Effective Anticoagulation with Fac-
significantly reduced ischaemic stroke by 24% and vascular mortality tor Xa Next Generation in Atrial Fibrillation – Thrombolysis in
2918 ESC Guidelines

Table 13 Characteristics of approved non-vitamin K antagonist oral anticoagulants compared

Dabigatran Rivaroxaban Apixaban Edoxaban


(RE-LY) (ROCKET-AF) (ARISTOTLE) (ENGAGE AF-TIMI 48)
Mechanism Oral direct thrombin inhibitor Oral direct factor Xa inhibitor Oral direct factor Xa inhibitor Oral direct factor Xa inhibitor
Bioavailability, % 6 66 fasting, 80–100 with food 50 62
Time to peak levels, hours 3 2–4 3 1–2
Half-life, hours 12–17 5–13 9–14 10–14
Excretion 80% renal 66% liver, 33% renal 27% renal 50% renal
Dose 150 mg twice daily or 110 mg twice daily 20 mg once daily 5 mg twice daily 60 mg once daily or 30 mg once daily
Dose reduction in selected Rivaroxaban 15 mg once daily if CrCl 30-49 Apixaban 2.5 mg twice daily if at least Edoxaban 60 mg reduced to 30 mg once daily, and
patients mL/min 2 of age ≥80 years, body weight ≤60 kg edoxaban 30 mg reduced to 15 mg once daily, if any of
or serum creatinine level ≥1.5 mg/dL the following: creatinine clearance of 30–50 mL/min, body
(133 µmol/L) weight ≤60 kg, concomitant use of verapamil or quinidine

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or dronedarone
Study design Randomized, open-label Randomized, double-blind Randomized, double-blind Randomized, double-blind
Number of patients 18 113 14 264 18 201 21 105
Follow-up period, years 2 1.9 1.8 2.8
Randomized groups Dose-adjusted warfarin vs. blinded doses Dose-adjusted warfarin vs. rivaroxaban Dose-adjusted warfarin vs. apixaban 5 Dose-adjusted warfarin vs. edoxaban
of dabigatran (150 mg twice daily, 110 mg twice daily) 20 mg once daily mg twice daily (60 mg once daily, 30 mg once daily)
Age, years 71.5 ± 8.7 (mean ± SD) 73 (65–78) [median (interquartile range)] 70 (63–76) [median (interquartile 72 (64–78) [median (interquartile range)]
range)]
Male sex, % 63.6 60.3 64.5 61.9
CHADS2 score (mean) 2.1 3.5 2.1 2.8
Warfarin Dabigatran 150 Dabigatran 110 Warfarin Rivaroxaban Warfarin Apixaban Warfarin Edoxaban 60 Edoxaban 30
n = 6022 n = 6076 n = 6015 n = 7133 n = 7131 n = 9081 n = 9120 n = 7036 n = 7035 n = 7034

Event rate, Event rate, %/year Event rate, %/ Event rate, %/year Event rate, %/year (HR Event rate, Event rate, %/year (HR Event rate, Event rate, %/year Event rate, %/year
%/year (RR vs. warfarin) year (RR vs. vs. warfarin) %/year vs. warfarin) %/year (HR vs. warfarin) (HR vs. warfarin)
warfarin)
1.54 (0.89,
1.12 (0.65,
0.73–1.09; 2.1 (0.88, 0.75–1.03; 1.27 (0.79, 0.66–0.95; 1.57 (0.87, 0.73–1.04; 2.04 (1.13, 0.96–1.34;
0.52–0.81;
P for non- P for non-inferiority P <0.001 for non- P <0.001 for non- P = 0.005 for non-
Stroke/systemic embolism 1.72 P for non-inferiority 2.4 1.60 1.80
inferiority <0.001, P for inferiority, inferiority, P = 0.08 for inferiority, P = 0.10
and superiority
<0.001) superiority = 0.12) P = 0.01 for superiority) superiority) for superiority)
<0.001)

0.93 (0.76, 1.34 (1.10,


1.34 (0.94; 0.75–1.17; 0.97 (0.92, 0.74–1.13; 1.25 (1.00, 0.83–1.19; 1.77 (1.41, 1.19–1.67;
Ischaemic stroke 1.22 0.59–0.97; 0.88–1.37; 1.42 1.05 1.25
P = 0.581) P = 0.42) P = 0.97) P <0.001)
P = 0.03) P = 0.42)

0.10 (0.26, 0.12 (0.31,


0.26 (0.59; 0.37–0.93; 0.24 (0.51, 0.35–0.75; 0.26 (0.54, 0.38–0.77; 0.16 (0.33, 0.22–0.50;
Haemorrhagic stroke 0.38 0.14–0.49; 0.17–0.56; 0.44 0.47 0.47
P = 0.024) P <0.001) P <0.001) P <0.001)
P <0.001) P <0.001)

2.92 (0.80,
3.40 (0.94,
0.70–0.93; 2.13 (0.69, 0.60–0.80; 2.75 (0.80, 0.71–0.91; 1.61 (0.47, 0.41–0.55;
Major bleeding 3.61 0.82–1.08; 3.45 3.60 (1.04; 0.90-2.30; 3.09 3.43
P = 0.003) P <0.001) P <0.001) P <0.001)
P = 0.41) P = 0.58)

0.32 (0.42, 0.23 (0.29


0.49 (0.67; 0.47–0.93; 0.33 (0.42, 0.30–0.58; 0.39 (0.47, 0.34–0.63; 0.26 (0.30, 0.21–0.43;
Intracranial bleeding 0.77 0.29–0.61; 0.19–0.45; 0.74 0.80 0.85
P = 0.02) P <0.001) P <0.001) P <0.001)
P <0.001) P <0.001)
1.60 (1.48, 1.13 (1.04,
Gastrointestinal major 2.00 (1.61; 1.30-1.99; 0.76 (0.89, 0.70–1.15; 1.51 (1.23, 1.02–1.50; 0.82 (0.67, 0.53–0.83;
1.09 1.19–1.86; 0.82–1.33; 1.24 0.86 1.23
bleeding P < 0.001) P = 0.37) P = 0.03) P <0.001)
P <0.001) P = 0.74)
0.81 (1.27, 0.82 (1.29, 0.96-
0.91 (0.81; 0.63–1.06; 0.53 (0.88, 0.66–1.17; 0.70 (0.94, 0.74–1.19; 0.89 (1.19, 0.95–1.49;
Myocardial infarction 0.64 0.94-1.71; 1.75; 1.12 0.61 0.75
P = 0.12) P = 0.37) P = 0.60) P = 0.13)
P = 0.12) P = 0.09)
3.64 (0.88, 3.75 (0.91,
1.87 (0.85; 0.70–1.02; 3.52 (0.89, 0.80–0.99; 3.99 (0.92, 0.83–1.01; 3.80 (0.87, 0.79–0.96;
Death from any cause 4.13 0.77–1.00; 0.80–1.03; 2.21 3.94 4.35
P = 0.07) P = 0.047) P = 0.08) P = 0.006)
P = 0.051) P = 0.13)

Myocardial Infarction 48) trial,321 edoxaban 60 mg once daily and Only the higher dose regimen has been approved for stroke pre-
edoxaban 30 mg once daily (with dose reductions in certain pa- vention in AF.
tients, Table 13), were compared with adjusted-dose warfarin.405
Edoxaban 60 mg once daily was non-inferior to warfarin (Table 13). 9.2.2.4 Rivaroxaban
In an on-treatment analysis, edoxaban 60 mg once daily significant- In the ROCKET-AF (Rivaroxaban Once Daily Oral Direct Fac-
ly reduced stroke or systemic embolism by 21% and significantly tor Xa Inhibition Compared with Vitamin K Antagonism for Pre-
reduced major bleeding events by 20% compared with warfarin, vention of Stroke and Embolism Trial in Atrial Fibrillation) trial,320
while edoxaban 30 mg once daily was non-inferior to warfarin patients were randomized to rivaroxaban 20 mg once daily
for prevention of stroke and systemic embolism but significantly or VKA, with a dose adjustment to 15 mg daily for those with
reduced major bleeding events by 53%. Cardiovascular death estimated CrCl 30 – 49 mL/min by the Cockroft – Gault formula
was reduced in patients randomized to edoxaban 60 mg once (Table 13). Rivaroxaban was non-inferior to warfarin for the pre-
daily or edoxaban 30 mg once daily compared with warfarin. vention of stroke and systemic embolism in the intent-to-treat
ESC Guidelines 2919

analysis, while the per-protocol on-treatment analysis achieved NOACs at centres with poor INR control (interaction P ¼
statistical superiority with a 21% reduction in stroke or systemic 0.022). Notably, the substantial reduction in intracranial haemor-
embolism compared with warfarin. Rivaroxaban did not reduce rhage by NOACs compared with warfarin seems unrelated to the
the rates of mortality, ischaemic stroke, or major bleeding events quality of INR control.408,409
compared to VKA. There was an increase in gastrointestinal
bleeding events, but a significant reduction in haemorrhagic stroke 9.2.4 Oral anticoagulation in atrial fibrillation patients
and intracranial haemorrhage with rivaroxaban compared with with chronic kidney disease
warfarin. Comparable event rates have been reported in post- CKD is associated with stroke and bleeding in large data sets.410,411
authorization analyses, which are part of the post-approval risk Anticoagulation can be safely used in AF patients with moderate or
management process.406,407 moderate-to-severe CKD [glomerular filtration rate (GFR) ≥15
mL/min]: the SPAF (Stroke Prevention in Atrial Fibrillation) III trial

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9.2.3 Non-vitamin K antagonist oral anticoagulants or randomized 805/1936 participants with stage 3 CKD (estimated
vitamin K antagonists GFR ,59 mL/min/1.73 m2), and reported good outcomes on war-
Both VKAs and NOACs are effective for the prevention of stroke farin (INR 2–3).412 This finding is supported by a large Swedish data-
in AF. A meta-analysis39 based on the high-dose treatment groups base, in which stroke risk was lower in CKD patients with AF treated
of the pivotal studies of warfarin vs. NOACs included 42 411 pa- with warfarin (adjusted HR 0.76; 95% CI 0.72–0.80),413 while bleed-
tients receiving a NOAC and 29 272 receiving warfarin. NOACs in ing was also slightly increased, especially during therapy initiation.414
these dosages significantly reduced stroke or systemic embolic In a meta-analysis of the major NOAC trials, patients with mild or
events by 19% compared with warfarin (RR 0.81; 95% CI 0.73 – moderate CKD suffered fewer strokes, systemic emboli, or major
0.91; P , 0.0001), mainly driven by a reduction in haemorrhagic bleeding events on NOACs than on warfarin.415 Kidney function
stroke (RR 0.49; 95% CI 0.38 – 0.64; P , 0.0001). Mortality was should be regularly monitored in AF patients on OACs to allow
10% lower in patients randomized to NOAC therapy (RR 0.90; dose adaptation for those on NOACs (Table 14) and to refine
95% CI 0.85 – 0.95; P ¼ 0.0003) and intracranial haemorrhage risk estimation.416
was halved (RR 0.48; 95% CI 0.39 – 0.59; P , 0.0001), while
gastrointestinal bleeding events were more frequent (RR 1.25; 9.2.5 Oral anticoagulation in atrial fibrillation patients on
95% CI 1.01 – 1.55; P ¼ 0.04). 39 The stroke reduction with dialysis
NOACs was consistent in all evaluated subgroups, while there Approximately one in eight dialysis patients suffer from AF, with
was a suggestion of greater relative reduction in bleeding with an incidence rate of 2.7/100 patient-years. 417 AF is associated

Table 14 Dose adjustment for NOACs as evaluated in the PHASE III trials (adapted from Hart et al.316)

Dabigatran Rivaroxaban Apixaban Edoxaban


(RE-LY) 318, 425 (ROCKET-AF) 320, 426 (ARISTOTLE) 319, 427 (ENGAGE AF-TIMI 48) 321

Renal clearance 80% 35% 25% 50%


Number of patients 18 113 14 264 18 201 21 105
Dose 150 mg or 20 mg once daily 5 mg twice daily 60 mg (or 30 mg)
110 mg twice daily once daily
Exclusion criteria CrCl <30 mL/min CrCl <30 mL/min Serum creatinine >2.5 mg/dL or CrCl <30 mL/min
for CKD CrCl <25 mL/min
Dose adjustment with None 15 mg once daily 2.5 mg twice daily if serum 30 mg (or 15 mg) once daily if
CKD if CrCl 30–49 mL/min creatinine ≥1.5 mg/dL CrCl <50 mL/min
(133 µmol/L) plus age ≥80 years
or weight ≤60 kg
Percentage of patients 20% with 21% with 15% with 19% with
with CKD CrCl 30–49 mL/min CrCl 30–49 mL/min CrCl 30–50 mL/dL CrCl <50 mL/min
Reduction of stroke No interaction with No interaction with No interaction with NA
and systemic embolism CKD status CKD status CKD status
Reduction in major Reduction in major Major haemorrhage Reduction in major NA
haemorrhages haemorrhage with dabigatran similar haemorrhage with apixaban
compared to warfarin was greater in patients
with eGFR >80 mL/min with
either dose

CKD ¼ chronic kidney disease; CrCl ¼ creatinine clearance; GFR ¼ glomerular filtration rate; NA ¼ not available.
2920 ESC Guidelines

with increased mortality in patients on dialysis.417 There are no guided by the estimated GFR of the transplanted kidney. Potential
randomized trials assessing OAC in haemodialysis patients, 418 pharmacokinetic interactions of OAC with immunosuppressive
and no controlled trials of NOACs in patients with severe CKD agents should be considered.
(CrCl ,25 – 30 mL/min).318 – 321 Warfarin use was associated ei-
ther with a neutral or increased risk of stroke in database analyses
of patients on dialysis,419 – 421 including a population-based ana- 9.2.7 Antiplatelet therapy as an alternative to oral
anticoagulants
lysis in Canada (adjusted HR for stroke 1.14; 95% CI 0.78 – 1.67,
The evidence supporting antiplatelet monotherapy for stroke pre-
adjusted HR for bleeding 1.44; 95% CI 1.13 – 1.85).422 In contrast,
vention in AF is very limited.38,428 – 430 VKA therapy prevents stroke,
data from Denmark suggest a benefit of OAC in patients on renal
systemic embolism, myocardial infarction, and vascular death better
replacement therapy.423 Hence, controlled studies of anticoagu-
than single or dual antiplatelet therapy with aspirin and clopidogrel
lants (both VKAs and NOACs) in AF patients on dialysis are
(annual risk of 5.6% for aspirin and clopidogrel vs. 3.9% with VKA
needed.424

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therapy).431 Even greater benefits were seen in VKA-treated pa-
tients with a high TTR.432 Antiplatelet therapy increases bleeding
9.2.6 Patients with atrial fibrillation requiring kidney risk, especially dual antiplatelet therapy (2.0% vs. 1.3% with antipla-
transplantation telet monotherapy; P , 0.001),433 with bleeding rates that are simi-
There are no randomized trials assessing OAC in patients after kid- lar to those on OAC.354,362,431,434 Thus, antiplatelet therapy cannot
ney transplantation. The prescription of NOAC therapy should be be recommended for stroke prevention in AF patients.

Recommendations for stroke prevention in patients with atrial fibrillation

Recommendations Class a Level b Ref C


38,
Oral anticoagulation therapy to prevent thromboembolism is recommended for all male AF patients with a CHA 2DS2 -VASc
I A 318–321,
score of 2 or more.
354, 404
38,
Oral anticoagulation therapy to prevent thromboembolism is recommended in all female AF patients with a CHA2DS2 -VASc
I A 318–321,
score of 3 or more.
354, 404
Oral anticoagulation therapy to prevent thromboembolism should be considered in male AF patients with a 371,
IIa B
CHA 2DS 2 -VASc score of 1, considering individual characteristics and patient preferences. 375–377
Oral anticoagulation therapy to prevent thromboembolism should be considered in female AF patients with a 371, 376,
IIa B
CHA 2DS2 -VASc score of 2, considering individual characteristics and patient preferences. 377
Vitamin K antagonist therapy (INR 2.0–3.0 or higher) is recommended for stroke prevention in AF patients with 274,
I B
moderate-to-severe mitral stenosis or mechanical heart valves. 435–440
39,
When oral anticoagulation is initiated in a patient with AF who is eligible for a NOAC (apixaban, dabigatran, edoxaban, or
I A 318–321,
rivaroxaban), a NOAC is recommended in preference to a vitamin K antagonist.
404
When patients are treated with a vitamin K antagonist, time in therapeutic range (TTR) should be kept as high as 395, 432,
I A
possible and closely monitored. 441-444
39, 318,
AF patients already on treatment with a vitamin K antagonist may be considered for NOAC treatment if TTR is not well
IIb A 319, 404,
controlled despite good adherence, or if patient preference without contra-indications to NOAC (e.g. prosthetic valve).
408
Combinations of oral anticoagulants and platelet inhibitors increase bleeding risk and should be avoided in AF patients III
B 429, 445
without another indication for platelet inhibition. (harm)

In male or female AF patients without additional stroke risk factors, anticoagulant or antiplatelet therapy is not III 368, 371,
B
recommended for stroke prevention. (harm) 376, 377
III 38, 429,
Antiplatelet monotherapy is not recommended for stroke prevention in AF patients, regardless of stroke risk. A
(harm) 430
NOACs (apixaban, dabigatran, edoxaban, and rivaroxaban) are not recommended in patients with mechanical heart valves III 318–321,
B C
(Level of evidence B) or moderate-to-severe mitral stenosis (Level of evidence C). (harm) 400, 404

AF ¼ atrial fibrillation; CHA2DS2-VASc ¼ Congestive Heart failure, hypertension, Age ≥75 (doubled), Diabetes, Stroke (doubled), Vascular disease, Age 65 –74, and Sex (female);
INR ¼ international normalized ratio; NOAC ¼ non-vitamin K antagonist oral anticoagulant; OAC ¼ oral anticoagulation; TTR ¼ time in therapeutic range; VKA ¼ vitamin K
antagonist.
a
Class of recommendation.
b
Level of evidence.
c
Reference(s) supporting recommendations.
ESC Guidelines 2921

9.3 Left atrial appendage occlusion and Recommendations for occlusion or exclusion of the
exclusion left atrial appendage
9.3.1 Left atrial appendage occlusion devices
Interventional LAA occlusion, 446 – 449 and limited experience Recommendations Class a Level b Ref C
with percutaneous LAA ligation, has mainly been reported in ob-
After surgical occlusion or exclusion
servational studies and registries. Only one device (Watchmanw)
of the LAA, it is recommended to
has been compared with VKA therapy in randomized trials continue anticoagulation in I B 461, 462
[PROTECT AF (Watchman Left Atrial Appendage System for at-risk patients with AF for stroke
Embolic Protection in Patients With AF trial), see Web Table 2; prevention.
and PREVAIL (Prospective Randomized Evaluation of the Watch- LAA occlusion may be considered
man LAA Closure Device In Patients with AF Versus Long Term for stroke prevention in patients

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with AF and contra-indications for
Warfarin Therapy trial)].449 – 451 In these data sets, LAA occlusion long-term anticoagulant treatment IIb B
449, 453,
was non-inferior to VKA treatment for the prevention of stroke in 454
(e.g. those with a previous
AF patients with moderate stroke risk, with a possibility of lower life-threatening bleed without a
bleeding rates in the patients who continued follow-up. 452,453 reversible cause).
These data were confirmed in a patient-level meta-analysis of Surgical occlusion or exclusion of
the two trials and their associated registries. 453 LAA occlusion the LAA may be considered for
IIb B 463
stroke prevention in patients with
may also reduce stroke risk in patients with contraindications to AF undergoing cardiac surgery.
OAC.454,455 The implantation procedure can cause serious com-
Surgical occlusion or exclusion of the
plications,446,456 – 458 with high event rates reported in analyses LAA may be considered for stroke
from insurance databases and systematic reviews, possibly identi- IIb B 468
prevention in patients undergoing
fying a certain degree of reporting bias.446,456 A large recent Euro- thoracoscopic AF surgery.
pean registry reported a high rate of implantation success (98%),
with an acceptable procedure-related complication rate of 4% at AF ¼ atrial fibrillation; LAA ¼ left atrial appendage.
a
30 days.459 Most patients who historically would be considered b
Class of recommendation.
Level of evidence.
unsuitable for OAC therapy seem to do relatively well on contem- c
Reference(s) supporting recommendations.
porarily managed OAC. 396,407,460 Adequately powered con-
trolled trials are urgently needed to inform the best use of
these devices, including LAA occluders in patients who are truly 9.4 Secondary stroke prevention
unsuitable for OAC or in patients who suffer a stroke on OAC,
The most important risk factors for stroke in patients with AF are
randomized comparisons of LAA occluders with NOACs, and as-
advanced age and previous cardioembolic stroke or TIA,382 empha-
sessment of the minimal antiplatelet therapy acceptable after LAA
sizing the need for OAC in these patients. The highest risk of recur-
occlusion.
rent stroke is in the early phase after a first stroke or TIA.469,470

9.4.1 Treatment of acute ischaemic stroke


9.3.2 Surgical left atrial appendage occlusion or Systemic thrombolysis with recombinant tissue plasminogen activator
exclusion (rtPA) is an effective and approved medical treatment for acute ischae-
Surgical LAA occlusion or exclusion concomitant to cardiac sur- mic stroke in patients presenting within 4.5 h of symptom onset.471 Sys-
gery has been performed for many decades and with various temic thrombolysis is contraindicated in patients on therapeutic
techniques. Multiple observational studies indicate the feasibility OAC.472,473 Recombinant tissue plasminogen activator can be given in
and safety of surgical LAA occlusion/exclusion, but only limited patients treated with a VKA if the INR is below 1.7,474 or in dabigatran-
controlled trial data are available.461 – 464 Residual LAA flow or in- treated patients with a normal activated partial thromboplastin time and
complete LAA exclusion can increase stroke risk. 465 In most last intake of drug .48 h previously (based on expert consensus).472
studies, LAA occlusion/exclusion was performed during other Whether specific NOAC antidotes475 could be used followed by sys-
open heart surgery, and more recently in combination with sur- temic thrombolysis needs to be investigated. Thrombectomy can be
gical ablation of AF463 or as a stand-alone thoracoscopic proced- performed in anticoagulated patients with distal occlusion of the internal
ure. One randomized trial evaluating the role of concomitant AF carotid artery or middle cerebral artery in a 6 h window.476
surgery and LAA occlusion reported in 2015, without a clear
benefit of LAA exclusion for stroke prevention in the subgroup 9.4.2 Initiation of anticoagulation after transient ischaemic
undergoing AF surgery.466 A large randomized trial is currently attack or ischaemic stroke
underway.467 Data on the optimal use of anticoagulants (heparin, low-molecular-
weight heparin, heparinoid, VKA, NOAC) in the first days after a
2922 ESC Guidelines

Patient with atrial fibrillation and acute TIA or ischaemic stroke


Exclusion of intracerebral bleeding by CT or MRI

Mild stroke Moderate stroke Severe stroke


TIA (NIHSS ≥16)
(NIHSS <8) (NIHSS 8–15)

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Consider additional clinical factors favouring early / delayed initiation of OAC
Factors favouring early initiation of OAC: Factors favouring delayed initiation of OAC:

Low NIHSS (<8): High NIHSS (≥8):


Small/no brain infarction on imaging Large/moderate brain infarction on imaging
High recurrence risk, e.g. cardiac thrombus on echo Needs gastrostomy or major surgical
No need for percutaneous endoscopic gastrostomy intervention
No need for carotid surgery Needs carotid surgery
No haemorrhagic transformation Haemorrhagic transformation
Clinically stable Neurologically unstable
Young patient Elderly patient
Blood pressure is controlled Uncontrolled hypertension

Evaluate haemorrhagic Evaluate haemorrhagic


transformation by transformation by
CT or MRI at day 6 CT or MRI at day 12

Start 1 day after 3 days after 6 days after 12 days after


OAC acute event acute event acute event acute event

NIH_Stroke_Scale.pdf); OAC = oral anticoagulation; TIA = transient ischaemic attack

Figure 9 Initiation or continuation of anticoagulation in atrial fibrillation patients after a stroke or transient ischaemic attack. This approach is
based on consensus rather than prospective data.

stroke are scarce. Parenteral anticoagulants seem to be associated strokes (OR 0.44; 95% CI 0.32–0.62).482 Detailed data for edoxaban
with a non-significant reduction in recurrent ischaemic stroke have not yet been published.321 If a patient suffers a stroke or TIA
when administered 7 – 14 days after the acute stroke [odds ratio whilst taking an anticoagulant, switching to another anticoagulant
(OR) 0.68; 95% CI 0.44 –1.06), with a significant increase in symp- should be considered.
tomatic intracranial bleeding (OR 2.89; 95% CI 1.19 – 7.01), and a
similar rate of death or disability at final follow-up.477 It seems likely 9.4.3 Initiation of anticoagulation after intracranial
that the bleeding risk on parenteral anticoagulation exceeds the haemorrhage
stroke prevention benefit in the first days after a large stroke, No prospective studies have investigated the benefit or risk of the ini-
whereas patients with a TIA or a small stroke may benefit from early tiation of OAC after intracranial haemorrhage,483 and patients with a
(immediate) initiation or continuation of anticoagulation. Therefore, history of intracranial bleeding were excluded from the randomized
we propose to initiate anticoagulation in AF patients between 1 trials comparing NOACs with VKAs. The available evidence indicates
and 12 days after an ischaemic stroke, depending on stroke severity that anticoagulation in patients with AF can be reinitiated after 4–8
(Figure 9).478 We suggest repeat brain imaging to determine the op- weeks, especially when the cause of bleeding or the relevant risk fac-
timal initiation of anticoagulation in patients with a large stroke at tor (e.g. uncontrolled hypertension, see Table 12) has been treated,
risk for haemorrhagic transformation. Long-term OAC with a and that such treatment leads to fewer recurrent (ischaemic) strokes
VKA363,479 – 481 or NOAC482 conveys benefits in AF patients who and lower mortality.460,484 If anticoagulation is resumed, it seems rea-
survived a stroke. NOACs seem to convey slightly better outcomes, sonable to consider anticoagulants with a low bleeding risk.39 Figure 10
mainly driven by fewer intracranial haemorrhages and haemorrhagic depicts a consensus opinion on the initiation or resumption of OAC
ESC Guidelines 2923

after an intracranial haemorrhage. We recommend a multidisciplinary is of particular relevance in anticoagulated patients with AF. Treat-
decision with input from stroke physicians/neurologists, cardiologists, ment according to current guidelines is recommended in patients
neuroradiologists, and neurosurgeons. with known hypertension.489

9.5.2 Previous bleeding event


Recommendations for secondary stroke prevention History of bleeding events and the presence of anaemia are import-
ant parts of the assessment of all patients receiving OAC. The ma-
Recommendations Class a Levelb Ref C jority of bleeding events are gastrointestinal. Compared with
Anticoagulation with heparin or LMWH warfarin, the risk of gastrointestinal bleeds was increased for dabiga-
III
immediately after an ischaemic stroke is
(harm)
A 477 tran 150 mg twice daily,396,490 rivaroxaban 20 mg once daily,491 and
not recommended in AF patients.
edoxaban 60 mg once daily.321 The risk of gastrointestinal bleeds
In patients who suffer a TIA or stroke was comparable to warfarin on dabigatran 110 mg twice daily490

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while on anticoagulation, adherence
IIa C and on apixaban 5 mg twice daily.319 Recent observational analyses
to therapy should be assessed and
optimized. do not replicate these findings, suggesting a smaller effect.396,492,493
In patients who suffer a moderate-
In patients in whom the source of bleeding has been identified and
to-severe ischaemic stroke while corrected, OAC can be reinitiated. This also appears true for pa-
on anticoagulation, anticoagulation tients who have had an intracranial haemorrhage, once modifiable
should be interrupted for 3–12 IIa C bleeding risk factors (e.g. uncontrolled hypertension) have been
days based on a multidisciplinary
assessment of acute stroke and
corrected.460,484
bleeding risk.
9.5.3 Labile international normalized ratio and adequate
In AF patients who suffer a stroke, non-vitamin K antagonist oral anticoagulant dosing
aspirin should be considered for TTR on VKA therapy is an important predictor of major haemor-
prevention of secondary stroke until IIa B 485
the initiation or resumption of oral rhage.432,441,494 Therefore, we recommend targeting the INR be-
anticoagulation. tween 2.0 and 3.0 in patients on VKAs, maintaining a high TTR
Systemic thrombolysis with rtPA is (e.g. ≥70%494), and to consider switching to a NOAC when a
not recommended if the INR is above III high TTR cannot be sustained.444 NOAC dosing should follow the
C 472, 474
1.7 (or, for patients on dabigatran, if (harm) dose-reduction criteria evaluated in the clinical trials, considering
aPTT is outside normal range). renal function, age, and weight. Patient information and empower-
NOACs are recommended in ment, best delivered through integrated AF management, seem
preference to VKAs or aspirin in AF I B 363,482
paramount to achieve this goal.
patients with a previous stroke.
After TIA or stroke, combination 9.5.4 Alcohol abuse
III
therapy of OAC and an antiplatelet is B 486 Alcohol excess is a risk factor for bleeding in anticoagulated pa-
(harm)
not recommended. tients,384 mediated by poor adherence, liver disease, variceal bleed-
After intracranial haemorrhage, oral ing, and risk of major trauma. Severe alcohol abuse and binge
anticoagulation in patients with AF drinking habits should be corrected in patients eligible for OAC.
may be reinitiated after 4–8 weeks 483, 484,
IIb B
provided the cause of bleeding or the 487 9.5.5 Falls and dementia
relevant risk factor has been treated
or controlled.
Falls and dementia are associated with increased mortality in AF pa-
tients,495 without evidence that these conditions markedly increase
the risk of intracranial haemorrhage.495,496 Hence, anticoagulation
AF ¼ atrial fibrillation; INR ¼ international normalized ratio; LMWH ¼ Low
Molecular Weight Heparin; NOAC ¼ non-vitamin K antagonist oral should only be withheld from patients with severe uncontrolled falls
anticoagulant; OAC ¼ oral anticoagulation; (e.g. epilepsy or advanced multisystem atrophy with backwards
TIA ¼ transient ischaemic attack; VKA ¼ vitamin K antagonist.
a falls), or in selected patients with dementia where compliance and
Class of recommendation.
b
Level of evidence. adherence cannot be ensured by a caregiver.
c
Reference(s) supporting recommendations.
9.5.6 Genetic testing
In addition to food and drug interactions, multiple genetic variations
affect the metabolism of VKAs.497 The systematic use of genetic in-
9.5 Strategies to minimize bleeding on formation for adjustment of VKA dosage has been evaluated in sev-
anticoagulant therapy eral controlled clinical studies.498 – 500 Genetic testing has little effect
In a meta-analysis of 47 studies, the overall incidence of major bleeding on TTR or bleeding risk on warfarin, and is not recommended for
with VKAs was 2.1 (range 0.9–3.4) per 100 patient-years in controlled clinical use at present.501
trials and 2.0 (range 0.2–7.6) per 100 patient-years for observational
9.5.7 Bridging periods off oral anticoagulation
data sets.488 Minimizing treatable bleeding risk factors (see Table 12)
Most cardiovascular interventions (e.g. percutaneous coronary
seems paramount to reduce the bleeding rate on anticoagulants.
intervention or pacemaker implantation) can be performed safely
9.5.1 Uncontrolled hypertension on continued OAC. When interruption of OAC is required,
Uncontrolled hypertension increases the risk of bleeding on bridging does not seem to be beneficial, except in patients with
OAC.53 Hence, keeping systolic blood pressure well controlled mechanical heart valves: In a randomized trial of 1884 patients
2924 ESC Guidelines

Patient with AF suffering from an intracranial bleed on OAC


If acute event: establish intensity of anticoagulation (see bleeding flow chart)

Contra-indication Consider further information to allow informed judgement


for OAC Factors supporting withholding of OAC: Factors supporting reinitiation of OAC:

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Bleeding occured on adequately dosed Bleeding occured on VKA or in setting of
NOAC or in setting of treatment interruption overdose
or underdosing Traumatic or treatable cause
Older age Younger age
Uncontrolled hypertension Well controlled hypertension
Cortical bleed Basal ganglia bleed
Severe intracranial bleed No or mild white matter lesions
Multiple microbleeds (e.g. >10) Surgical removal of subdural haematoma
Cause of bleed cannot be removed or treated Subarachnoid bleed: aneurysm clipped or
Chronic alcohol abuse coiled
Need for dual antiplatelet therapy after PCI High-risk of ischaemic stroke

Patient or next of kin choice informed


by multidisciplinary team advice

No stroke LAA Initiate or resume OAC, choosing


protection occlusion an agent with low intracranial bleeding risk,
(no evidence) (IIbC) after 4–8 weeks (IIbB)

VKA = vitamin K antagonist.

Figure 10 Initiation or resumption of anticoagulation in atrial fibrillation patients after an intracranial bleed. This approach is based on consensus
opinion and retrospective data. In all patients, evaluation by a multidisciplinary panel is required before treatment (stroke physician/neurologist,
cardiologist, neuroradiologist, and neurosurgeon).

with AF, interruption of anticoagulation was non-inferior to hep- time, activated partial thromboplastin time, and INR. Coagulation
arin bridging for the outcome of arterial thrombo-embolism (inci- tests do not provide much information in patients on NOACs, ex-
dence of 0.4% and 0.3%, respectively) and resulted in a lower risk cept for activated partial thromboplastin time in the case of dabiga-
of major bleeding (1.3% and 3.2%, respectively).502 OAC interrup- tran. More specific coagulation tests do exist, including diluted
tions should be minimized to prevent stroke. thrombin time (HEMOCLOT) for dabigatran and calibrated quanti-
tative anti-factor Xa assays for factor Xa inhibitors.503 However,
these tests are not always readily available and are often unneces-
9.6 Management of bleeding events in sary for bleeding management.504
anticoagulated patients with atrial We propose a simple scheme to manage bleeding events in patients
fibrillation on OAC (Figure 11). Minor bleeding events should be treated with
9.6.1 Management of minor, moderate, and severe bleeding supportive measures such as mechanical compression or minor sur-
General assessment of an anticoagulated patient with AF experien- gery to achieve haemostasis. In patients receiving VKAs, the next dose
cing a bleeding event should include the assessment of bleeding site, of VKA can be postponed. NOACs have a short plasma half-life of ap-
onset, and severity of the bleeding, the time-point of last intake of proximately 12 h, and improved haemostasis is expected within 12–
OAC and other antithrombotic drugs, and other factors influencing 24 h after a delayed or omitted dose. Treatment of moderate bleeding
bleeding risk such as CKD, alcohol abuse, and concurrent medica- events may require blood transfusions and fluid replacement. Specific
tions. Laboratory tests should include haemoglobin, haematocrit, diagnostic and treatment interventions directed against the cause of
platelet count, renal function, and, for VKA patients, prothrombin the bleeding (e.g. gastroscopy) should be performed promptly. If
ESC Guidelines 2925

Patient with active bleeding

Compress bleeding sites mechanically

Assess haemodynamic status, blood pressure, basic coagulation


parameters, blood count, and kidney function

Obtain anticoagulation history (last NOAC / VKA dose)

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VKA NOAC

Delay VKA until INR <2 Minor Delay NOAC for 1 dose or 1 day

Add symptomatic treatment: Add symptomatic treatment:


Fluid replacement Fluid replacement
Blood transfusion Blood transfusion
Treat bleeding cause Moderate - severe Treat bleeding cause
(e.g. gastroscopy) (e.g. gastroscopy)

Consider to add Consider to add oral charcoal


Vitamin K (1–10 mg) i.v. if recently ingested NOAC

Consider PCC and FFP Consider specific antidote, or


Consider replacement of platelets
Severe or PCC if no antidote available
where appropriate life-threatening Consider replacement of platelets
where appropriate

FFP = fresh frozen plasma; INR = international normalized ratio; i.v. = intravenous; NOAC = non-vitamin K antagonist oral anticoagulant; OAC = oral anticoagulation; PCC =
prothrombin complex concentrates; VKA = vitamin K antagonist.

Figure 11 Management of active bleeding in patients receiving anticoagulation. Institutions should have an agreed procedure in place.

the intake of NOAC was recent (,2–4 h), charcoal administration Several antidotes to NOACs are under development. Idarucizumab
and/or gastric lavage will reduce further exposure. Dialysis clears da- (approved in 2015 by the US Food and Drug Administration and the
bigatran but is less effective for the other NOACs. European Medicines Agency) is a clinically available humanized anti-
Immediate reversal of the antithrombotic effect is indicated in se- body fragment that binds dabigatran and rapidly and dose-dependently
vere or life-threatening bleeding events. An agreed institutional reverses its effects without over-correction or thrombin gener-
procedure for the management of life-threatening bleeds should be ation.475 Andexanet alpha, a modified recombinant human factor Xa
documented and accessible at all times to ensure adequate initial man- that lacks enzymatic activity, reverses the anticoagulant activity of fac-
agement. For VKAs, administration of fresh frozen plasma restores co- tor Xa antagonists in healthy subjects within minutes after administra-
agulation more rapidly than vitamin K, and prothrombin complex tion and for the duration of infusion, with a transient increase in
concentrates achieve even faster blood coagulation.505 Registry data markers of coagulation activity of uncertain clinical relevance.508 An-
suggest that the combination of plasma and prothrombin complex other agent under development is ciraparantag (PER977), an antidote
concentrates is associated with the lowest case fatality following intra- designed to reverse both direct thrombin and factor Xa inhibitors as
cranial haemorrhage on VKA treatment with an INR ≥1.3.506 In a mul- well as the indirect inhibitor enoxaparin.509 The clinical usefulness of
ticentre randomized trial of 188 patients, four-factor prothrombin these specific antidotes needs further evaluation.
complex concentrates achieved more rapid INR reversal and effective
haemostasis than plasma in patients undergoing urgent surgical or in- 9.6.2 Oral anticoagulation in atrial fibrillation patients at
vasive procedures.507 Administration of prothrombin complex con- risk of or having a bleeding event
centrates may also be considered for severe bleeding on NOAC While anticoagulation therapy should be paused to control active
treatment if specific antidotes are not available. bleeding, absolute contraindications to long-term OAC after a
2926 ESC Guidelines

bleeding episode are rare. When nuisance bleeds are the reason to lives. This scenario requires careful consideration of antithrombotic
stop OAC, a change from one anticoagulant to another seems rea- therapy, balancing bleeding risk, stroke risk, and risk of acute coron-
sonable. Many causes or triggers of major bleeding events can be ary syndromes (ACS).516 Co-prescription of OAC with antiplatelet
treated and/or eliminated, including uncontrolled hypertension, therapy, in particular triple therapy, increases the absolute risk of
gastrointestinal ulcers, and intracranial aneurysms. Reinitiation of an- major haemorrhage.445,517,518 A recent meta-analysis involving 30
ticoagulation after a bleeding event is often clinically justified.460,510 866 patients with a recent ACS evaluated the effects of adding
Difficult decisions, including the discontinuation and recommence- NOAC therapy to single (4135 patients) or dual (26 731 patients)
ment of OAC, should be taken by a multidisciplinary team, balancing antiplatelet therapy.519 The addition of a NOAC increased the
the estimated risk of recurrent stroke and bleeding, and considering bleeding risk by 79–134%, while reducing recurrent ischaemic events
the bleeding risk of different stroke prevention therapies. LAA ex- only marginally in patients without AF. OAC monotherapy, and not
clusion or occlusion might be an alternative in selected patients. combination therapy with antiplatelets, is recommended in AF pa-

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tients with stable CAD but without an ACS and/or coronary interven-
Recommendations for management of bleeding tion in the previous 12 months. In patients treated for ACS, and in
those receiving a coronary stent, short-term triple combination ther-
Recommendations Class a Levelb Ref C apy of OAC, clopidogrel, and aspirin seems warranted (Figure 12).

Blood pressure control in


anticoagulated patients with 9.7.1 Antithrombotic therapy after acute coronary
IIa B 511
hypertension should be considered syndromes and percutaneous coronary intervention in
to reduce the risk of bleeding patients requiring oral anticoagulation
When dabigatran is used, a reduced The optimal combination antithrombotic therapy or duration of
dose (110 mg twice daily) may be combination therapy for AF patients undergoing percutaneous cor-
IIb B 490
considered in patients >75 years to onary intervention is not known, but the continued bleeding risk
reduce the risk of bleeding.
suggests a short duration. Expert consensus,520 reviewed and re-
In patients at high-risk of considered by this Task Force, suggests the following principles:
gastrointestinal bleeding, a VKA or
321, 396, AF patients at risk for stroke, patients with mechanical valves, and
another NOAC preparation should
402, 405, patients with recent or recurrent deep vein thrombosis or pulmonary
be preferred over dabigatran IIa B
490, 492,
150 mg twice daily, rivaroxaban embolism should continue OAC during and after stenting. In general, a
493, 512
20 mg once daily, or edoxaban short period of triple therapy (OAC, aspirin, clopidogrel) is recom-
60 mg once daily.
mended, followed by a period of dual therapy (OAC plus a single anti-
Advice and treatment to avoid
platelet) (Figure 13). When a NOAC is used, the consensus
alcohol excess should be considered
IIa C recommendation is that the lowest dose effective for stroke preven-
in all AF patients considered for
OAC. tion in AF should be considered. Dose reduction beyond the approved
Genetic testing before the dosing tested in phase III trials (see Table 13) is not currently recom-
III
initiation of VKA therapy is not (no B 497 mended, and awaits assessment in ongoing controlled trials. The com-
recommended. benefit)
bination of aspirin, clopidogrel, and low-dose rivaroxaban (2.5 mg
Reinitiation of OAC after a bleeding twice daily) is not recommended for stroke prevention in AF.521
event should be considered in all The use of prasugrel or ticagrelor as part of triple therapy should
eligible patients by a
be avoided unless there is a clear need for these agents (e.g. stent
multidisciplinary AF team,
considering different anticoagulants IIa B 460 thrombosis on aspirin plus clopidogrel), given the lack of evidence
and stroke prevention interventions, and the greater risk of major bleeding compared with clopido-
improved management of factors grel.522,523 Ongoing trials will inform about such combination ther-
that contributed to bleeding, and
apies in the future.
stroke risk.
The omission of aspirin while maintaining clopidogrel and OAC
In AF patients with severe active
bleeding events, it is recommended
has been evaluated in the WOEST (What is the Optimal antiplatElet
I C and anticoagulant therapy in patients with oral anticoagulation and
to interrupt OAC therapy until the
cause of bleeding is resolved. coronary StenTing) trial, in which 573 anticoagulated patients
undergoing percutaneous coronary intervention (70% with AF)
AF ¼ atrial fibrillation; NOAC ¼ non-vitamin K antagonist oral anticoagulant; were randomized to either dual therapy with OAC and clopidogrel
OAC ¼ oral anticoagulation; VKA ¼ vitamin K antagonist. (75 mg once daily) or to triple therapy with OAC, clopidogrel, and
a
Class of recommendation.
b
Level of evidence.
aspirin.524 Bleeding was lower in the dual vs. triple therapy arm, dri-
c
Reference(s) supporting recommendations. ven by fewer minor bleeding events. The rates of myocardial infarc-
tion, stroke, target vessel revascularization, and stent thrombosis
did not differ (albeit with low event numbers), but all-cause mortal-
9.7 Combination therapy with oral ity was lower in the dual therapy group at 1 year (2.5% vs. triple
anticoagulants and antiplatelets therapy 6.4%). Although the trial was too small to assess ischaemic
Approximately 15% of AF patients in contemporary trials513 and outcomes, dual therapy with OAC and clopidogrel may emerge in
registries514 – 516 have a history of myocardial infarction. Between the future as an alternative to triple therapy in patients with AF
5 – 15% of AF patients will require stenting at some point in their and ACS and/or coronary intervention.525
ESC Guidelines 2927

Recommendations for combination therapy with oral anticoagulants and antiplatelets

Recommendations Class a Levelb Ref C


After elective coronary stenting for stable coronary artery disease in AF patients at risk of stroke, combination triple
therapy with aspirin, clopidogrel and an oral anticoagulant should be considered for 1 month to prevent recurrent coronary IIa B 522, 524
and cerebral ischaemic events.
After an ACS with stent implantation in AF patients at risk of stroke, combination triple therapy with aspirin, clopidogrel and
IIa C 520
an oral anticoagulant should be considered for 1–6 months to prevent recurrent coronary and cerebral ischaemic events.
After an ACS without stent implantation in AF patients at risk of stroke, dual treatment with an oral anticoagulant and aspirin
IIa C
or clopidogrel should be considered for up to 12 months to prevent recurrent coronary and cerebral ischaemic events.
The duration of combination antithrombotic therapy, especially triple therapy, should be kept to a limited period, balancing

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IIa B 520
the estimated risk of recurrent coronary events and bleeding.
Dual therapy with any oral anticoagulant plus clopidogrel 75 mg/day may be considered as an alternative to initial triple
IIb C 524, 525
therapy in selected patients.

ACS ¼ acute coronary syndromes; AF ¼ atrial fibrillation; OAC ¼ oral anticoagulant.


a
Class of recommendation.
b
Level of evidence.
c
Reference(s) supporting recommendations.

AF patient in need of OAC after an ACS

Bleeding risk low Bleeding risk high


compared to risk for ACS compared to risk for ACS
or stent thrombosis or stent thrombosis

Time from ACS


0
Triple therapy a (IIaB)
1 month
Triple therapy a (IIaB)
3 months

Dual therapy b (IIaC)


6 months A or C
Dual therapy b (IIaC)
A or C
12 months
lifelong OAC monotherapy c (IB) OAC monotherapy c (IB)

OAC Aspirin 75–100 mg daily Clopidogrel 75 mg daily

PCI = percutaneous coronary intervention.


a
Dual therapy with OAC and aspirin or clopidogrel may be considered in selected patients, especially those not receiving a stent or patients at a longer time from the index event.
b
OAC plus single antiplatelet.
c
Dual therapy with OAC and an antiplatelet agent (aspirin or clopidogrel) may be considered in patients at high risk of coronary events.

Figure 12 Antithrombotic therapy after an acute coronary syndrome in atrial fibrillation patients requiring anticoagulation.
2928 ESC Guidelines

AF patient in need of OAC after elective PCI with stent

Bleeding risk low Bleeding risk high


compared to risk for ACS compared to risk for ACS
or stent thrombosis or stent thrombosis

Time from PCI


0
Triple therapy a (IIaB)

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1 month
3 months Dual therapyb (IIaC)
A or C
Dual therapyb (IIaC)
6 months A or C

12 months OAC monotherapy c (IB)


lifelong OAC monotherapy c (IB)

OAC Aspirin 75–100 mg daily Clopidogrel 75 mg daily

percutaneous coronary intervention.


a
Dual therapy with OAC and aspirin or clopidogrel may be considered in selected patients.
b
OAC plus single antiplatelet.
c
Dual therapy with OAC and an antiplatelet agent (aspirin or clopidogrel) may be considered in patients at high risk of coronary events.

Figure 13 Antithrombotic therapy after elective percutaneous intervention in atrial fibrillation patients requiring anticoagulation.

10. Rate control therapy in atrial diltiazem/verapamil are preferred over digoxin because of their
rapid onset of action and effectiveness at high sympathetic
fibrillation tone.528 – 532 The choice of drug (Table 15) and target heart
Rate control is an integral part of the management of AF patients, rate will depend on patient characteristics, symptoms, LVEF and
and is often sufficient to improve AF-related symptoms. Compared haemodynamics, but a lenient initial approach to heart rate seems
with stroke prevention and rhythm control, very little robust evi- acceptable. Combination therapy may be required (Figure 14). In
dence exists to inform the best type and intensity of rate control patients with HFrEF, beta-blockers, digitalis (digoxin or digitoxin),
treatment, with the majority of data derived from short-term cross- or their combination should be used,218,533 as diltiazem and
over trials and observational studies.41,526 – 528 Pharmacological rate verapamil can have negative inotropic effects in patients with
control can be achieved for acute or long-term rate control with LVEF ,40%.222,534,535 In critically ill patients and those with
beta-blockers, digoxin, the calcium channel blockers diltiazem and severely impaired LV systolic function, intravenous amiodarone
verapamil, or combination therapy (Table 15). A number of antiar- can be used where excess heart rate is leading to haemodynamic
rhythmic drugs also have rate-limiting properties (amiodarone, dro- instability.536 – 538 Urgent cardioversion should be considered in
nedarone, sotalol, and to some extent propafenone), but they unstable patients (see chapter 11.1).
should only be used in patients needing rhythm control therapy
(see Chapter 11). 10.2 Long-term pharmacological rate
control
10.1 Acute rate control 10.2.1 Beta-blockers
In the setting of acute new-onset AF, patients are often in need of Beta-adrenoreceptor blocker monotherapy is often the first-line
heart rate control. Physicians should evaluate underlying causes of rate-controlling agent,539 largely based on observations of better
elevated heart rate, such as infection, endocrine imbalance, anaemia, acute heart rate control than digoxin. Interestingly, the prognostic
and pulmonary embolism. For acute rate control, beta-blockers and benefit of beta-blockers seen in HFrEF patients with sinus rhythm
ESC Guidelines 2929

Table 15 Rate control therapy in atrial fibrillation

Therapy Acute intravenous rate Long-term oral rate Side effect profile Comments
control control
Beta-blockersa
Bisoprolol Not available 1.25–20 mg once daily or split.Most common reported adverse Bronchospasm is rare – in cases
symptoms are lethargy, headache, of asthma, recommend beta-1
Carvedilol Not available 3.125–50 mg twice daily.
peripheral oedema, upper selective agents (avoid carvedilol).
Metoprolol 2.5–10 mg intravenous bolus 100–200 mg total daily dose respiratory tract symptoms, Contra-indicated in acute cardiac
(repeated as required). (according to preparation). gastrointestinal upset and failure and a history of severe
Nebivolol Not available 2.5–10 mg once daily or split. dizziness. Adverse effects include bronchospasm.
bradycardia, atrioventricular block

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Esmolol 0.5 mg/kg intravenous bolus over and hypotension.
1 min; then 0.05–0.25 mg/kg/min.
Calcium-channel blockers
Diltiazem 15–25 mg intravenous bolus 60 mg 3 times daily up to Most common reported adverse Use with caution in combination
(repeated as required). 360 mg total daily dose symptoms are dizziness, malaise, with beta-blockers. Reduce dose
(120–360 mg once daily lethargy, headache, hot flushes, with hepatic impairment and
modified release). gastrointestinal upset and start with smaller dose in renal
oedema. Adverse effects include impairment. Contra-indicated
Verapamil 2.5–10 mg intravenous bolus 40–120 mg 3 times daily
bradycardia, atrioventricular block in LV failure with pulmonary
(repeated as required). (120–480 mg once daily
and hypotension (prolonged congestion or LVEF <40%.
modified release).
hypotension possible with
verapamil).
Cardiac glycosides
Digoxin 0.5 mg intravenous bolus 0.0625–0.25 mg daily dose Most common reported adverse High plasma levels associated with
(0.75–1.5 mg over 24 hours in symptoms are gastrointestinal increased risk of death. Check
divided doses). upset, dizziness, blurred vision, renal function before starting and
headache and rash. In toxic adapt dose in patients with CKD.
states (serum levels >2 ng/ Contra-indicated in patients with
mL), digoxin is proarrhythmic accessory pathways, ventricular
and can aggravate heart failure, tachycardia and hypertrophic
particularly with cardiomyopathy with outflow
Digitoxin 0.4–0.6 mg intravenous bolus. 0.05–0.3 mg daily dose. co-existent hypokalaemia. tract obstruction.

Specific indications
Amiodarone 300 mg intravenously diluted in 200 mg daily Hypotension, bradycardia, nausea, Suggested as adjunctive therapy
250 mL 5% dextrose over 30–60 QT prolongation, pulmonary in patients where heart rate
minutes (preferably via central toxicity, skin discolouration, control cannot be achieved using
venous cannula).b thyroid dysfunction, corneal combination therapy.
deposits and cutaneous reaction
with extravasation.

AF ¼ atrial fibrillation; CKD ¼ chronic kidney disease; i.v. ¼ intravenous; LV ¼ left ventricular; LVEF ¼ left ventricular ejection fraction.
a
A number of other beta-blockers are also available, but are not recommended as specific rate control therapy in AF. These include atenolol (25 – 100 mg once daily with a short
biological half-life), propranolol [non-selective, 1 mg over 1 min and repeat up to 3 mg at 2-min intervals (acute) or 10 –40 mg three times daily (long-term)], or labetalol
[non-selective, 1– 2 mg/min (acute)].
b
If ongoing requirement for amiodarone, follow with 900 mg i.v. over 24 h diluted in 500– 1000 mL via a central venous cannula.

is lost in those with AF. In an individual patient-level meta-analysis of patients, based on the potential for symptomatic and functional im-
RCTs, beta-blockers did not reduce all-cause mortality compared provement as a result of rate control, the lack of harm from pub-
to placebo in those with AF at baseline (HR 0.97; 95% CI 0.83 – lished studies, and the good tolerability profile across all ages in
1.14; P ¼ 0.73), whereas there was a clear benefit in patients with sinus rhythm and in AF.23,540
sinus rhythm (HR 0.73; 95% CI 0.67 – 0.80; P , 0.001).23 The ana-
lysis, which included 3066 participants with HFrEF and AF, showed 10.2.2 Non-dihydropyridine calcium channel blockers
consistency across all subgroups and outcomes, with no heterogen- Verapamil or diltiazem provide reasonable rate control in AF pa-
eity between the 10 RCTs included (I2 ¼ 0%). Despite this lack of tients.541 They should be avoided in patients with HFrEF because
prognostic benefit in HFrEF, this Task Force still considers beta- of their negative inotropic effects.222,534,535 Verapamil or diltiazem
blockers as a useful first-line rate control agent across all AF can improve arrhythmia-related symptoms,526 in comparison with
2930 ESC Guidelines

Acute heart rate control of AF

LVEF <40% or signs of


LVEF ≥40%
congestive heart failure

Smallest dose of beta-blocker to Beta-blocker or diltiazem or

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achieve rate control verapamil

Amiodarone is an option in patients with


Check previous drug history to avoid
haemodynamic instability or severely
concomitant administration
reduced LVEF
Initial resting heart rate target <110 bpm
Initial resting heart rate target <110 bpm

Add digoxin Add digoxin

Initial resting heart rate target <110 bpm Initial resting heart rate target <110 bpm

Avoid bradycardia
Perform echocardiogram to
determine further management/
choice of maintenance therapy
Consider need for anticoagulation

See Table 15 for medication dosage. Digitoxin is a suitable alternative to digoxin, where available.

Figure 14 Acute heart rate control in patients with atrial fibrillation.

beta-blockers, which reduced exercise capacity and increased higher B-type natriuretic peptide levels, combination carvedilol/
B-type natriuretic peptide in one small trial of low-risk patients digoxin improved LVEF, and digoxin withdrawal reduced LVEF.554
with preserved LVEF.542 Comparisons with other rate control therapies are based on small,
short-duration studies that identify no or marginal differences
10.2.3 Digitalis in exercise capacity, quality of life, or LVEF compared to
Cardiac glycosides such as digoxin and digitoxin have been in use for digoxin.526,554 – 558 Lower doses of digoxin (≤250 mg once daily),
over two centuries, although prescriptions have been declining corresponding to serum digoxin levels of 0.5 – 0.9 ng/mL, may be
steadily over the past 15 years.543 In the randomized Digitalis Inves- associated with better prognosis.225
tigation Group (DIG) trial, digoxin had no effect on mortality com-
pared to placebo in HFrEF patients in sinus rhythm (RR 0.99; 95% CI 10.2.4 Amiodarone
0.91 – 1.07), but reduced hospital admissions (RR 0.72; 95% CI Amiodarone can be useful for rate control as a last resort. The wide
0.66 – 0.79).544,545 There have been no head-to-head RCTs of di- array of extracardiac adverse effects associated with amiodarone
goxin in AF patients.546 Observational studies have associated di- renders it a reserve agent in patients whose heart rate cannot be
goxin use with excess mortality in AF patients,547 – 549 but this controlled with combination therapy (e.g. beta-blocker or verap-
association is likely due to selection and prescription biases rather amil/diltiazem combined with digoxin).
than harm caused by digoxin,550 – 553 particularly as digoxin is com-
monly prescribed to sicker patients.225 In a crossover mechanistic In summary, there is equipoise for the use of different rate control
trial of 47 patients with HFrEF and AF, there were no differences agents in AF. The choice of beta-blocker, diltiazem/verapamil, di-
in heart rate, blood pressure, walking distance, or LVEF between goxin, or combination therapy should be made on an individual ba-
carvedilol and digoxin, although beta-blockers did result in sis, after consideration of patient characteristics and patient
ESC Guidelines 2931

Long-term heart rate control of AF

Perform echocardiogram (IC)


Choose initial rate control therapy (IB) and combination therapy if required (IIaC)
Target initial resting heart rate <110 bpm (IIaB), avoiding bradycardia

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LVEF <40% LVEF ≥40%

Diltiazem/ Digoxin
Beta-blocker Digoxin Beta-blocker
verapamil

Consider early low-dose Add therapy to achieve target heart rate or


combination therapy if ongoing symptoms

Add diltiazem,
Add
Add digoxin Add digoxin Add digoxin verapamil or
beta-blocker
beta-blocker

See Table 15 for medication dosage. Digitoxin is a suitable alternative to digoxin, where available.

Figure 15 Long-term heart rate control in patients with atrial fibrillation.

preference. All available therapies have the potential for adverse ef- control is an acceptable initial approach, regardless of heart failure
fects and patients should initially be treated with a low dose and up- status, unless symptoms call for stricter rate control.
titrated to achieve symptom improvement. In practice, achieving a
heart rate ,110 b.p.m. will often require combination therapy
(Figure 15). The benefit of different rate control strategies on symp-
10.4 Atrioventricular node ablation and
toms, quality of life, and other intermediate outcomes is under pacing
investigation.559 Ablation of the atrioventricular node/His bundle and implantation of
a VVI pacemaker can control ventricular rate when medications fail
to control rate and symptoms. It is a relatively simple procedure with
10.3 Heart rate targets in atrial a low complication rate and low long-term mortality risk,563,564 es-
fibrillation pecially when the pacemaker is implanted a few weeks before the AV
The optimal heart rate target in AF patients is unclear. The RACE nodal ablation and the initial pacing rate after ablation is set at 70–90
(Rate Control Efficacy in Permanent Atrial Fibrillation) II study ran- b.p.m.565,566 The procedure does not worsen LV function567 and
domized 614 patients with permanent AF to either a target heart may even improve LVEF in selected patients.568 – 570 In selected
rate ,80 b.p.m. at rest and ,110 b.p.m. during moderate exercise, HFrEF patients treated with biventricular pacing (cardiac resynchro-
or to a lenient heart rate target of ,110 b.p.m. There was no differ- nization therapy), AF can terminate,571 although such a ‘rhythm con-
ence in a composite of clinical events (14.9% in the strict rate con- trol’ effect of cardiac resynchronization therapy is likely to be small
trol group, 12.9% in the lenient group),560 NYHA class, or and clearly needs confirmation.572 AV nodal ablation renders pa-
hospitalizations.560,561 Similar results were found in a pooled ana- tients pacemaker-dependent for the rest of their lives, limiting AV
lysis of the AFFIRM (Atrial Fibrillation Follow-up Investigation of nodal ablation and pacing to patients whose symptoms cannot be
Rhythm Management) and RACE trials (1091 participants), albeit managed by rate-controlling medication or by reasonable rhythm
with smaller heart rate differences and without randomization.562 control interventions (see AF Heart Team, chapter 11.6). The
It is worthwhile to note that many ‘adequately rate-controlled’ pa- choice of pacing therapy (right ventricular or biventricular pacing
tients (resting heart rate 60–100 b.p.m.) are severely symptomatic, with or without an implantable defibrillator) will depend on individ-
calling for additional management.194 Nonetheless, lenient rate ual patient characteristics, including LVEF.573,574
2932 ESC Guidelines

management involving catheter ablation, combination therapy, and


Recommendations for rate control early therapy leads to a reduction in major cardiovascular events is
currently under investigation, e.g. in the EAST – AFNET 4 (Early
Recommendations Classa Levelb Ref C treatment of Atrial fibrillation for Stroke prevention Trial)40 and
Beta-blockers, digoxin, diltiazem, 225, 526, CABANA (Catheter Ablation vs. Anti-arrhythmic Drug Therapy
or verapamil are recommended to
I B
528, 531, for Atrial Fibrillation Trial)594 trials. For now, rhythm control therapy
control heart rate in AF patients with 532, 541,
is indicated to improve symptoms in AF patients who remain symp-
LVEF ≥40%. 555, 575
tomatic on adequate rate control therapy.
23, 225,
Beta-blockers and/or digoxin are
526, 533,
recommended to control heart rate I B 11.1 Acute restoration of sinus rhythm
554, 575,
in AF patients with LVEF <40%.
576 11.1.1 Antiarrhythmic drugs for acute restoration of sinus

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Combination therapy comprising rhythm (‘pharmacological cardioversion’)
different rate controlling agents Antiarrhythmic drugs can restore sinus rhythm in patients with
23, 554,
should be considered if a single agent IIa C
577 AF (pharmacological cardioversion) as shown in small controlled
does not achieve the necessary heart
rate target. trials, meta-analyses, 41,584,595,596 and in a few larger controlled
trials.597 – 605 Outside of Europe, dofetilide is available and can con-
In patients with haemodynamic
instability or severely depressed vert recent-onset AF.606 Pharmacological cardioversion restores si-
Ilb B 536–538
LVEF, amiodarone may be considered nus rhythm in approximately 50% of patients with recent-onset AF
for acute control of heart rate. (Table 16).607 – 609 In the short-term, electrical cardioversion
In patients with permanent AF (i.e. restores sinus rhythm quicker and more effectively than pharmaco-
where no attempt to restore sinus logical cardioversion and is associated with shorter hospitaliza-
III 41, 578,
rhythm is planned), antiarrhythmic A
(harm) 579 tion.609 – 613 Pharmacological cardioversion, conversely, does not
drugs should not routinely be used
for rate control. require sedation or fasting (Figure 16).
A resting heart rate of <110 bpm
Flecainide and propafenone are effective for pharmacological cardi-
(i.e. lenient rate control) should be oversion,595,602 – 605,614,615 but their use is restricted to patients with-
IIa B 560
considered as the initial heart rate out structural heart disease. Ibutilide is an alternative where available,
target for rate control therapy. but carries a risk of torsades de pointes.615 Vernakalant602 – 605 can
Rhythm rather than rate control be given to patients with mild heart failure (NYHA Class I or II), includ-
strategies should be considered as ing those with ischaemic heart disease, provided they do not present
IIa C
the preferred management in pre-
excited AF and AF during pregnancy. with hypotension or severe aortic stenosis.616 – 618 Amiodarone can
be used in patients with heart failure and in patients with ischaemic
Atrioventricular node ablation
should be considered to control heart disease (although patients with severe heart failure were ex-
heart rate in patients unresponsive cluded from most of the AF cardioversion trials).596 Amiodarone
184, 564,
or intolerant to intensive rate and IIa B also slows heart rate by 10–12 b.p.m. after 8–12 h when given intra-
569
rhythm control therapy, accepting venously.596 Both amiodarone and flecainide appear more effective
that these patients will become
pacemaker dependent. than sotalol in restoring sinus rhythm.600,601,619

11.1.2 ‘Pill in the pocket’ cardioversion performed by


AF ¼ atrial fibrillation; bpm ¼ beats per minute; LVEF ¼ left ventricular ejection
fraction. patients
Digitoxin is a suitable alternative to digoxin, where available. In patients with heart In selected patients with infrequent symptomatic episodes of parox-
failure with reduced ejection fraction (LVEF ,40%), recommended beta-blockers ysmal AF, a single bolus of oral flecainide (200–300 mg) or propafe-
are bisoprolol, carvedilol, long-acting metoprolol, and nebivolol.
a
Class of recommendation. none (450–600 mg) can be self-administered by the patient at home
b
Level of evidence. (‘pill in the pocket’ therapy) to restore sinus rhythm, after safety has
c
Reference(s) supporting recommendations. been established in the hospital setting.620 This approach seems mar-
ginally less effective than hospital-based cardioversion,621 but is prac-
tical and provides control and reassurance to selected patients.
11. Rhythm control therapy in
11.1.3 Electrical cardioversion
atrial fibrillation Synchronized direct current electrical cardioversion quickly and ef-
Restoring and maintaining sinus rhythm is an integral part of AF fectively converts AF to sinus rhythm, and is the method of choice
management. Antiarrhythmic drugs approximately double the rate in severely haemodynamically compromised patients with new-onset
of sinus rhythm compared with placebo.580 – 584 Catheter ablation or AF (Figure 16).626 – 628 Electrical cardioversion can be performed safe-
combination therapy is often effective when antiarrhythmic drugs ly in sedated patients treated with intravenous midazolam and/or pro-
fail.226,585 – 587 Although many clinicians believe that maintaining sinus pofol. Continuous monitoring of blood pressure and oximetry during
rhythm can improve outcomes in AF patients,588 all trials that have the procedure is important.629 Skin burns may occasionally be ob-
compared rhythm control and rate control to rate control alone served. Intravenous atropine or isoproterenol, or temporary transcu-
(with appropriate anticoagulation) have resulted in neutral out- taneous pacing, should be available to mitigate post-cardioversion
comes.41,578,579,582,589 – 593 Whether modern rhythm control bradycardia. Biphasic defibrillators are more effective than
ESC Guidelines 2933

Table 16 Antiarrhythmic drugs for pharmacological cardioversion

Drug Route 1st dose Follow-up dose Risks Reference


Flecainide Oral 200–300 mg N/A Hypotension, atrial flutter with 1:1 conduction, QT prolongation. 595, 598
Avoid in patients with IHD and/or significant structural heart disease.
IV 1.5–2 mg/kg
over 10 min
Amiodarone IV a 5–7 mg/kg 50 mg/hour to a maximum Phlebitis, hypotension, bradycardia/AV block. Will slow ventricular rate. 596–601
over 1–2 hours of 1.0 g over 24 hours Delayed conversion to sinus rhythm (8–12 hours).
Propafenone IV 1.5–2 mg/kg Hypotension, atrial flutter with 1:1 conduction, QRS prolongation 622, 625
over 10 min (mild).

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Avoid in patients with IHD and/or significant structural heart disease.
Oral 450–600 mg
b
Ibutilide IV 1 mg over 1 mg over 10 min after QT prolongation, polymorphic ventricular tachycardia/torsades de 614, 615
10 min waiting for 10 min pointes (3–4% of patients). Will slow ventricular rate.
Avoid in patients with QT prolongation, hypokalemia, severe LVH or
low ejection fraction.
Vernakalant IV 3 mg/kg over 2 mg/kg over 10 min after Hypotension, non-sustained ventricular arrhythmias, QT and QRS 602–605,
10 min waiting for 15 min prolongation. 618
Avoid in patients with SBP <100 mmHg, recent (<30 days) ACS,
NYHA Class III and IV heart failure, QT interval prolongation
(uncorrected QT >440 ms) and severe aortic stenosis.

ACS ¼ acute coronary syndromes; AV ¼ atrio-ventricular; IHD ¼ ischaemic heart disease; i.v. ¼ intravenous; LVH ¼ left ventricular hypertrophy; NYHA ¼ New York Heart
Association; SBP ¼ systolic blood pressure.
a
Use a large peripheral vessel and change to oral amiodarone within 24 h of i.v. (central line) administration.
b
Ibutilide is only available in selected European countries.

monophasic waveforms, and have become the industry stand- 11.2 Long-term antiarrhythmic drug
ard.626,628 Anterior–posterior electrode positions generate a stron- therapy
ger shock field in the left atrium than anterolaterally positioned
The aim of antiarrhythmic drug therapy is improvement in
electrodes, and restore sinus rhythm more effectively.626,627,630
AF-related symptoms.41,580 Hence, the decision to initiate long-
Pre-treatment with amiodarone (requiring a few weeks of ther-
term antiarrhythmic drug therapy needs to balance symptom bur-
apy),631,632 sotalol,631 ibutilide,633 or vernakalant634 can improve
den, possible adverse drug reactions, and patient preferences. The
the efficacy of electrical cardioversion, and similar effects are likely
principles of antiarrhythmic drug therapy outlined in the 2010
for flecainide584 and propafenone.635 Beta-blockers,636 verapamil,
ESC AF guidelines369 are still relevant and should be observed:
diltiazem,637 – 639 and digoxin640,641 do not reliably terminate AF
or facilitate electrical cardioversion. When antiarrhythmic drug
(1) Treatment is aimed at reducing AF-related symptoms;
therapy is planned to maintain sinus rhythm after cardioversion, it
(2) Efficacy of antiarrhythmic drugs to maintain sinus rhythm is modest;
seems prudent to start therapy 1 – 3 days before cardioversion
(3) Clinically successful antiarrhythmic drug therapy may reduce ra-
(amiodarone: a few weeks) to promote pharmacological conversion
ther than eliminate the recurrence of AF;
and to achieve effective drug levels.584,601
(4) If one antiarrhythmic drug ‘fails’, a clinically acceptable response
may be achieved with another agent;
11.1.4 Anticoagulation in patients undergoing (5) Drug-induced pro-arrhythmia or extracardiac side-effects are
cardioversion frequent;
Cardioversion carries an inherent risk of stroke in non-anticoagulated (6) Safety rather than efficacy considerations should primarily guide
patients,642 which is reduced substantially by the administration of an- the choice of antiarrhythmic drug.
ticoagulation.643 Immediate initiation of anticoagulation is important
in all patients scheduled for cardioversion.644 – 646 Patients who Antiarrhythmic drug therapy approximately doubles sinus rhythm
have been in AF for longer than 48 h should start OAC at least 3 maintenance compared with no therapy.580 There is no appreciable
weeks before cardioversion and continue it for 4 weeks afterwards effect on mortality or cardiovascular complications, but rhythm
(in patients without a need for long-term anticoagulation). OAC control therapy can slightly increase the risk of hospitalizations (of-
should be continued indefinitely in patients at risk of stroke. This prac- ten for AF).41,578,579,582,589 – 593 To reduce the risk of side-
tice has never been evaluated in controlled trials, but seemed safe in a effects,201,580 a shorter duration of antiarrhythmic drug therapy
large observational data set from Finland.647 When early cardiover- seems desirable. As an example, short-term treatment (4 weeks)
sion is desired, TOE can exclude the majority of left atrial thrombi, with flecainide for 4 weeks after cardioversion of AF was well-
allowing immediate cardioversion.648,649 Ongoing studies will inform tolerated and prevented most (80%) AF recurrences when com-
about the safety and efficacy of newly initiated anticoagulation using pared with long-term treatment.584 Short-term antiarrhythmic
NOACs in patients scheduled for cardioversion. drug therapy is also used to avoid early AF recurrences after
2934 ESC Guidelines

Recent onset AF

Yes Haemodynamic No
instability?

Elective
Urgent

Patient choice

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Pharmacological
cardioversion

Coronary artery disease,


Severe HFrEF, No relevant
moderate HFrEF or
significant structural
HFmrEF/HFpEF,
aortic stenosis heart disease
abnormal LVH

Electrical Intravenous Intravenous Intravenous Pill in the pocket


cardioversion (IB) Amiodarone (IA) Vernakalant (IIbB) Flecainide (IA) Flecainide (IIaB)
Amiodarone (IA) Ibutilide (IIaB)a Propafenone (IIaB)
Propafenone (IA)
Vernakalant (IA)

fraction; LVH = left ventricular hypertrophy.


a
Ibutilide should not be used in patients with long QT interval.

Figure 16 Rhythm control management of recent onset atrial fibrillation.

catheter ablation,650 and may be reasonable in patients deemed at less suitable to episodic short-term therapy (unless after catheter
increased risk of antiarrhythmic drug side-effects or in those with ablation),655 probably because of its long biological half-life.
a low perceived risk of recurrent AF.
11.2.1.2 Dronedarone
In addition to antiarrhythmic drug therapy and catheter ablation
Dronedarone maintains sinus rhythm, reduces ventricular rate, and
(see Chapter 11.3), management of concomitant cardiovascular
prevents cardiovascularhospitalizations(mostly duetoAF) and cardio-
conditions can reduce symptom burden in AF and facilitate the
vascular death in patients with paroxysmal or persistent AF or flutter
maintenance of sinus rhythm.203,204,296,312 This includes weight re-
who had at least one relevant cardiovascular comorbidity.583,588,656
duction, blood pressure control, heart failure treatment, increasing
Dronedarone increases mortality in patients with recently decompen-
cardiorespiratory fitness, and other measures (see Chapter 7).
sated heartfailure (with orwithout AF),657 and inpatients with perman-
ent AF in whom sinus rhythm is not restored.658 Dronedarone
11.2.1 Selection of antiarrhythmic drugs for long-term moderately increases serum creatinine, reflecting a reduction in cre-
therapy: safety first! atinine excretion rather than a decline in kidney function.659
Usually, the safety of antiarrhythmic drug therapy determines the 11.2.1.3 Flecainide and propafenone
initial choice of antiarrhythmic drugs (Figure 17). The following ma- Flecainide and propafenone are effective in preventing recurrent
jor antiarrhythmic drugs are available to prevent AF: AF.581,584,620 They should only be used in patients without significant
11.2.1.1 Amiodarone ischaemic heart disease or heart failure to avoid the risk of life-
Amiodarone is an effective multichannel blocker, reduces ven- threatening ventricular arrhythmias.660 High ventricular rates result-
tricular rate, and is safe in patients with heart failure.582,651 Torsades ing from the conversion of AF into atrial flutter with 1:1 conduction
de pointes pro-arrhythmia can occur, and QT interval and TU waves by flecainide or propafenone can be prevented by pre-administering
should be monitored on therapy (see Table 17).652 Amiodarone of- a beta-blocker, verapamil, or diltiazem.
ten causes extracardiac side-effects, especially on long-term ther- 11.2.1.4 Quinidine and disopyramide
apy,653,654 rendering it a second-line treatment in patients who Quinidine and disopyramide have been associated with an increase in
are suitable for other antiarrhythmic drugs. Amiodarone appears all-cause mortality (OR 2.39; 95% CI 1.03– 5.59; number needed to
ESC Guidelines 2935

Initiation of long term rhythm control therapy to improve symptoms in AF

Coronary artery disease,


No or minimal signs
significant valvular heart Heart failure
for structural heart disease
disease, abnormal LVH

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Patient choice Patient choice Patient choice

Dronedarone (IA) Catheter Dronedarone (IA) Catheter Amiodarone Catheter


Flecainide (IA) ablation (IIaB)b Sotalol (IA)a ablation (IIaB)b (IA) ablation (IIaB)b,c
Propafenone (IA) Amiodarone (IA)d
Sotalol (IA)a

a
Sotalol requires careful evaluation of proarrhythmic risk.
b
Catheter ablation should isolate pulmonary veins and can be performed using radiofrequency or cryoballoon catheters.
c

d
Amiodarone is a second-choice therapy in many patients because of its extracardiac side-effects.

Figure 17 Initiation of long-term rhythm control therapy in symptomatic patients with atrial fibrillation.

harm 109; 95% CI 34–4985) at 1-year follow-up,580,661 likelydue toven- characteristics mentioned above, monitoring PR, QT, and QRS dura-
tricular arrhythmias (torsades de pointes).580,661 Although this tions during initiation of antiarrhythmic drug therapy can identify pa-
pro-arrhythmic effect is more common at higher doses, they are less tients at higher risk of drug-induced pro-arrhythmia on longer-term
commonly used for rhythm control in AF. Disopyramide may be useful treatment.669 – 671 In addition, the presence of ‘abnormal TU waves’ is
in ‘vagally mediated’ AF (e.g. AF occurring in athletes and/or during a sign of imminent torsades de pointes.652 Periodic ECG analysis for
sleep76), and has been shown to reduce LV outflow gradient and im- pro-arrhythmia signs has been used successfully in recent antiarrhyth-
prove symptoms in patients with hypertrophic cardiomyopathy.662 – 664 mic drug trials.118,584,672 Specifically, ECG monitoring was used system-
11.2.1.5 Sotalol atically on days 1–3 in patients receiving flecainide, propafenone, or
Sotalol has a relevant risk of torsades de pointes [1% in the Pre- sotalol to identify those at risk of pro-arrhythmia.118,584,601 Based on
vention of Atrial Fibrillation After Cardioversion (PAFAC) trial118]. this evaluated practice, we suggest to record an ECG in all patients
Its d-enantiomer is associated with increased mortality compared to before initiation of antiarrhythmic drugs. Scheduled ECGs during the
placebo in patients with LV dysfunction after a myocardial infarc- initiation period seem reasonable (Table 17).
tion,665 probably due to ventricular arrhythmias (OR 2.47; 95% CI
1.2 – 5.05; number needed to harm 166; 95% CI 61 – 1159).580,665
11.2.3 New antiarrhythmic drugs
On the other hand, d,l-sotalol has been used in AF patients without
Several compounds that inhibit the ultrarapid potassium current
safety signals in two controlled trials.581,601
(IKur) and other inhibitors of atypical ion channels are in clinical de-
11.2.1.6 Dofetilide velopment.673 – 675 They are not available for clinical use at present.
Dofetilide is another potassium channel blocker that is mainly The antianginal compound ranolazine inhibits potassium and sodium
available outside of Europe. Dofetilide restores and maintains sinus currents and increases glucose metabolism at the expense of free
rhythm in heart failure patients,666 and occasionally in patients re- fatty acid metabolism, thereby enhancing the efficient use of oxy-
fractory to other antiarrhythmic drugs.667 gen.676,677 Ranolazine was safe in patients with non – ST-segment
elevation myocardial infarction and unstable angina evaluated in
Overall, it seems prudent to limit the use of quinidine, disopyra-
the MERLIN (Metabolic Efficiency With Ranolazine for Less Ische-
mide, dofetilide, and sotalol to specific situations. Furthermore,
mia in Non ST-Elevation Acute Coronary Syndrome) trial.678 In a
combinations of QT-prolonging antiarrhythmic drugs should gener-
post hoc analysis of continuous ECG recordings obtained during
ally be avoided for rhythm control in AF (Table 17).
the first 7 days after randomization, patients assigned to ranolazine
11.2.2 The twelve-lead electrocardiogram as a tool to had a trend towards fewer episodes of AF than those on placebo [75
identify patients at risk of pro-arrhythmia (2.4%) vs. 55 (1.7%) patients; P ¼ 0.08].679 In the HARMONY
Identifying patients at risk of pro-arrhythmia can help to mitigate the (A Study to Evaluate the Effect of Ranolazine and Dronedarone
pro-arrhythmic risk of antiarrhythmic drugs.668 In addition to the clinical When Given Alone and in Combination in Patients With
2936 ESC Guidelines

Table 17 Oral antiarrhythmic drugs used for maintaining sinus rhythm after cardioversion

Drug Dose Main contra-indications and precautions Warning signs AV nodal Suggested ECG
warranting slowing monitoring
discontinuation during initiation
Amiodarone 600 mg in divided Caution when using concomitant therapy with QT prolongation 10–12 bpm Baseline, 1 week,
doses for QT-prolonging drugs and in patients with SAN or AV node >500 ms in AF 4 weeks
4 weeks, 400 mg and conduction disease.
for 4 weeks, The dose of VKAs and of digitalis should be reduced.
then 200 mg Increased risk of myopathy with statins.
once daily Caution in patients with pre-existing liver disease.
Dronedarone 400 mg Contra-indicated in NYHA Class III or IV or unstable heart QT prolongation 10–12 bpm Baseline, 1 week,

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twice daily failure, during concomitant therapy with QT-prolonging drugs, >500 ms in AF 4 weeks
or powerful CYP3A4 inhibitors (e.g. verapamil, diltiazem, azole
antifungal agents), and when CrCl <30 ml/min.
The dose of digitalis, beta-blockers, and of some statins should
be reduced.
Elevations in serum creatinine of 0.1–0.2 mg/dL are common
and do not reflect a decline in renal function.
Caution in patients with pre-existing liver disease.
Flecainide 100–150 mg Contra-indicated if CrCl <50 mg/mL, liver disease, IHD or QRS duration None Baseline, day 1,
twice daily reduced LV ejection fraction. increases >25% day 2–3
Caution in the presence of SAN or AV node or conduction above baseline
Flecainide slow 200 mg disease.
release once daily CYP2D6 inhibitors (e.g. fluoxetine or tricyclic
antidepressants) increase plasma concentration.
Propafenone 150–300 mg Contra-indicated in IHD or reduced LV ejection fraction. QRS duration Slight Baseline, day 1,
three times daily Caution in the presence of SAN or AV node and conduction increase >25% day 2–3
disease, renal or liver impairment, and asthma. above baseline
Propafenone 225–425 mg Increases concentration of digitalis and warfarin.
SR twice daily
d,l sotalol 80–160 mg Contra-indicated in the presence of significant LV QT interval Similar to Baseline, day 1,
twice daily hypertrophy, systolic heart failure, asthma, pre-existing QT >500 ms, QT high dose day 2–3
prolongation, hypokalaemia, CrCl<50 mg/mL. prolongation by blockers
Moderate renal dysfunction requires careful adaptation of >60 ms upon
dose. therapy initiation

AF ¼ atrial fibrillation; AV ¼ atrio-ventricular; bpm ¼ beats per minute; CrCl ¼ creatinine clearance; CYP2D6 ¼ cytochrome P450 2D6; CYP3A4 ¼ cytochrome P450 3A4;
ECG ¼ electrocardiogram; IHD ¼ ischaemic heart disease; LV ¼ left ventricular; LVEF ¼ left ventricular ejection fraction; NYHA ¼ New York Heart Association; SAN ¼ sino-
atrial node; VKA ¼ vitamin K antagonist.

Paroxysmal Atrial Fibrillation) trial, the highest tested dose of a com- Thus, ACE inhibitors or ARBs are unlikely to have a relevant direct
bination of ranolazine (750 mg twice daily) and dronedarone antiarrhythmic effect. However, it might be justified to consider adding
(225 mg twice daily) slightly reduced AF burden in 134 subjects ACE inhibitors or ARB therapy to antiarrhythmic drugs to reduce AF
with paroxysmal AF and dual-chamber pacemakers.680 Small, open- recurrences after cardioversion.248,249,687
label studies suggest that ranolazine might enhance the antiarrhythmic Compared with placebo, beta-blockers are associated with a re-
effect of amiodarone for cardioversion,681 – 683 whereas the results duced risk of new-onset AF in patients with HFrEF and sinus
from a controlled trial of ranolazine and the ranolazine–dronedarone rhythm.23 Beta-blockers have also been reported to reduce symp-
combination to prevent AHRE in pacemaker patients were ambigu- tomatic AF recurrences,580,636,688 but this finding may be driven
ous.684 At present, there is insufficient evidence to recommend rano- by the beneficial effect of rate control, which will render AF more
lazine as an antiarrhythmic drug, alone or in combination with other often asymptomatic.
antiarrhythmic drugs. Of note, the ‘funny channel blocker’ ivabradine, Peri-operative statin therapy appeared to reduce the risk of post-
which is used for angina and heart failure, increases the risk of AF.685 operative AF in a number of small RCTs689,690; however, an ad-
equately powered placebo-controlled trial has shown no effect of
11.2.4 Antiarrhythmic effects of non-antiarrhythmic drugs peri-operative rosuvastatin therapy on post-operative AF.691 Statin
ACE inhibitors or ARBs appear to prevent new-onset AF in patients treatment does not prevent AF in other settings.692,693 Similarly,
with LV dysfunction and in hypertensive patients with LV hyper- polyunsaturated fatty acids failed to show convincing bene-
trophy.219,236,237,239,246,250,686 Neprilysin inhibition needs to be fit.241,694 – 698 The role of aldosterone antagonists in the manage-
studied further, but does not seem to enhance this effect.224 A Danish ment of AF has not been extensively investigated in humans.
cohort study also suggested that initial treatment of uncomplicated Although preliminary evidence from trials of eplerenone is encour-
hypertension with ACE inhibitors or ARBs reduces incident AF com- aging for primary prevention,243 at present there is no robust evi-
pared with other hypertensive agents.245 ARB therapy did not reduce dence to make any recommendation for the use of aldosterone
the AF burden in patients with AF without structural heart disease.241 antagonists for secondary prevention of AF.699 – 701
ESC Guidelines 2937

Recommendations for rhythm control therapy

Recommendations Class a Level b Ref C


General recommendations
120, 586,
Rhythm control therapy is indicated for symptom improvement in patients with AF. I B
601
Management of cardiovascular risk factors and avoidance of AF triggers should be pursued in patients on rhythm control 203, 204,
IIa B
therapy to facilitate maintenance of sinus rhythm. 296, 312
With the exception of AF associated with haemodynamic instability, the choice between electrical and pharmacological
IIa C
cardioversion should be guided by patient and physician preferences.

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Cardioversion of AF
612,
Electrical cardioversion of AF is recommended in patients with acute haemodynamic instability to restore cardiac output. I B
702-704
584, 601,
Cardioversion of AF (either electrical or pharmacological) is recommended in symptomatic patients with persistent or
I B 627, 628,
long-standing persistent AF as part of rhythm control therapy.
648, 705
Pre-treatment with amiodarone, flecainide, ibutilide, or propafenone should be considered to enhance success of electrical 248, 584,
IIa B
cardioversion and prevent recurrent AF. 633
602–605,
In patients with no history of ischaemic or structural heart disease, flecainide, propafenone, or vernakalant are 614, 618,
I A
recommended for pharmacological cardioversion of new-onset AF. 622, 706,
707
In patients with no history of ischaemic or structural heart disease, ibutilide should be considered for pharmacological
IIa B
conversion of AF.
In selected patients with recent-onset AF and no significant structural or ischaemic heart disease, a single oral dose of
flecainide or propafenone (the ‘pill in the pocket’ approach) should be considered for patient-led cardioversion, following IIa B 620, 621
safety assessment.
In patients with ischaemic and/or structural heart disease, amiodarone is recommended for cardioversion of AF. I A 597–601
Vernakalant may be considered as an alternative to amiodarone for pharmacological conversion of AF in patients without 602–605,
IIb B
hypotension, severe heart failure or severe structural heart disease (especially aortic stenosis). 616, 618
Stroke prevention in patients designated for cardioversion of AF
Anticoagulation with heparin or a NOAC should be initiated as soon as possible before every cardioversion of AF or atrial
IIa B 708, 709
flutter.
For cardioversion of AF/atrial flutter, effective anticoagulation is recommended for a minimum of 3 weeks before
I B 648, 708
cardioversion.
Transoesophageal echocardiography (TOE) is recommended to exclude cardiac thrombus as an alternative to
I B 648, 708
preprocedural anticoagulation when early cardioversion is planned.
Early cardioversion can be performed without TOE in patients with a definite duration of AF <48 hours. IIa B 648
In patients at risk for stroke, anticoagulant therapy should be continued long-term after cardioversion according to the
long-term anticoagulation recommendations, irrespective of the method of cardioversion or the apparent maintenance I B 353, 710
of sinus rhythm. In patients without stroke risk factors, anticoagulation is recommended for 4 weeks after cardioversion.
In patients where thrombus is identified on TOE, effective anticoagulation is recommended for at least 3 weeks. I C
A repeat TOE to ensure thrombus resolution should be considered before cardioversion. IIa C
Anti-arrhythmic drugs for the long-term maintenance of sinus rhythm/prevention of recurrent AF
The choice of AAD needs to be carefully evaluated, taking into account the presence of comorbidities, cardiovascular risk
I A 41, 580
and potential for serious proarrhythmia, extracardiac toxic effects, patient preferences, and symptom burden.
581, 583,
Dronedarone, flecainide, propafenone, or sotalol are recommended for prevention of recurrent symptomatic AF in
I A 584, 588,
patients with normal left ventricular function and without pathological left ventricular hypertrophy.
601
Dronedarone is recommended for prevention of recurrent symptomatic AF in patients with stable coronary artery disease,
I A 583, 588
and without heart failure.
Amiodarone is recommended for prevention of recurrent symptomatic AF in patients with heart failure. I B 596–598
Amiodarone is more effective in preventing AF recurrences than other AAD, but extracardiac toxic effects are common
IIa C 596–598
and increase with time. For this reason, other AAD should be considered first.
583, 588,
Patients on AAD therapy should be periodically evaluated to confirm their eligibility for treatment. IIa C 657, 658,
660

Continued
2938 ESC Guidelines

Recommendations for rhythm control therapy (continued)

Recommendations Class a Level b Ref C


AAD for the long-term maintenance of sinus rhythm/prevention of recurrent AF (continued)
ECG recording during the initiation of AAD therapy should be considered to monitor heart rate, detect QRS and QT 582-584,
IIa B
interval prolongation, and the occurrence of AV block. 588, 601
AAD therapy is not recommended in patients with prolonged QT interval (>0.5 s) or those with significant sinoatrial III
C
node disease or AV node dysfunction who do not have a functioning permanent pacemaker. (harm)

Adding atrial-based bradycardia pacing to drug treatment that induces or exacerbates sinus node dysfunction should be
IIa B 711, 712
considered to allow continuation of AAD therapy in patients in whom AF ablation is declined or not indicated.

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Continuation of AAD therapy beyond the blanking period after AF ablation should be considered to maintain sinus rhythm
IIa B 713
when recurrences seem likely.
Antiarrhythmic effects of non-antiarrhythmic drugs
23, 219,
ACE-Is, ARBs and beta-blockers should be considered for prevention of new-onset AF in patients with heart failure and 236, 237,
IIa A
reduced ejection fraction. 239, 250,
714
ACE-Is and ARBs should be considered for prevention of new-onset AF in patients with hypertension, particularly with 238, 246,
IIa B
LV hypertrophy. 686, 714
Pre-treatment with ACE-Is or ARBs may be considered in patients with recurrent AF undergoing electrical cardioversion 236, 237,
IIb B
and receiving antiarrhythmic drug therapy. 248, 249

ACE-Is or ARBs are not recommended for the secondary prevention of paroxysmal AF in patients with little or no III
(no B 241, 697
underlying heart disease.

ACE ¼ angiotensin-converting enzyme; AF ¼ atrial fibrillation; ARB ¼ angiotensin receptor blocker; CHA2DS2-VASc ¼ Congestive Heart failure, hypertension, Age ≥75
(doubled), Diabetes, Stroke (doubled), Vascular disease, Age 65 –74, and Sex (female); ECG ¼ electrocardiogram; LV ¼ left ventricular; LVH ¼ left ventricular hypertrophy;
NOAC ¼ non-vitamin K antagonist oral anticoagulant; TOE ¼ transoesophageal echocardiography.
a
Class of recommendation.
b
Level of evidence.
c
Reference(s) supporting recommendations.

11.3 Catheter ablation performed in expert centres, justifying catheter ablation as first-line
Since the initial description of triggers in the pulmonary veins that therapy in selected patients with paroxysmal AF who ask for interven-
initiate paroxysmal AF,108 catheter ablation of AF has developed tional therapy. Fewer data are available reporting the effectiveness
from a specialized, experimental procedure into a common treat- and safety of catheter ablation in patients with persistent or long-
ment to prevent recurrent AF.587,715 This is primarily achieved standing persistent AF, but all point to lower recurrence rates after
through isolation of the pulmonary veins, probably requiring com- catheter ablation compared to antiarrhythmic drug therapy with or
plete isolation for full effectiveness,716 and additional ablation in without cardioversion (Web Figure 2).185,717,723 – 726,1039 In patients
the posterior left atrial wall. AF ablation, when performed in experi- who experience symptomatic recurrences of AF despite antiarrhyth-
enced centres by adequately trained teams, is more effective than mic drug therapy, all RCTs showed better sinus rhythm maintenance
antiarrhythmic drug therapy in maintaining sinus rhythm, and the with catheter ablation than on antiarrhythmic drugs.586,713,727,728
complication rate, though not negligible, is similar to the complica- There is no current indication for catheter ablation to prevent cardio-
tion rate for antiarrhythmic drugs.585,717 vascular outcomes (or desired withdrawal of anticoagulation), or to
reduce hospitalization.40,594

11.3.1 Indications 11.3.2 Techniques and technologies


Catheter ablation of AF is effective in restoring and maintaining sinus Complete pulmonary vein isolation (PVI) on an atrial level is the best
rhythm in patients with symptomatic paroxysmal, persistent, and documented target for catheter ablation,716,729 – 731 achievable by
probably long-standing persistent AF, in general as second-line treat- point-by-point radiofrequency ablation, linear lesions encircling
ment after failure of or intolerance to antiarrhythmic drug therapy. In the pulmonary veins, or cryoballoon ablation, with similar out-
such patients, catheter ablation is more effective than antiarrhythmic comes.732 – 734 Complete isolation of the pulmonary veins has better
drug therapy.185,586,713,717 – 720 As first-line treatment for paroxysmal rhythm outcomes than incomplete isolation.716 PVI was initially
AF, randomized trials showed only modestly improved rhythm out- tested in patients with paroxysmal AF, but appears to be non-
come with catheter ablation compared to antiarrhythmic drug ther- inferior to more extensive ablation in persistent AF as well.729,735
apy.585,721 – 723 Complication rates were similar, when ablation was More extensive ablations have been used in patients with persistent
ESC Guidelines 2939

AF, but there are insufficient data to guide the use of these at pre-
sent.117,718,719,735 – 737 Extended ablation procedures (beyond PVI) Table 18 Complications related to catheter ablation
consistently require longer procedures and more ionizing radiation, of atrial fibrillation
potentially creating risk for patients. Left atrial macro re-entrant
Complication Rate 727, 748,
tachycardia is relatively uncommon after PVI (≈5%). It also seems Complication type 750, 754-759
severity
rare after cryoballoon ablation,734 but may occur in up to 25% of pa-
Life-threatening Periprocedural death <0.2%
tients after left atrial substrate modification ablation, often due to in-
complications
complete ablation lines. Thus, for patients with persistent AF, ablation Oesophageal injury <0.5%
(perforation/fistula)a
of complex fractionated electrograms, ablation of rotors, or routine
deployment of linear lesions or other additional ablations does not Periprocedural stroke <1%
(including TIA/air embolism)
seem justified in the first procedure.735,738,739 However, additional
ablation on top of complete PVI716 may be considered in patients Cardiac tamponade 1–2%

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with recurrent AF after the initial ablation procedure.719,740,741 In pa- Severe complications Pulmonary vein stenosis <1%
tients with documented right atrial isthmus-dependent flutter under- Persistent phrenic nerve palsy 1–2%
going AF ablation, right atrial isthmus ablation is recommended. Vascular complications 2–4%
Adenosine testing to identify patients in need of additional ablation
Other severe complications ≈1%
remains controversial after evaluation in several reports.739,742 – 744
Other moderate or minor complications 1–2%
Ablation of so-called ‘rotors’, guided by body surface mapping or
endocardial mapping, is under evaluation and cannot be recom- Unknown significance Asymptomatic cerebral 5–20%
embolism (silent stroke)b
mended for routine clinical use at present.
Radiation exposure

11.3.3 Outcome and complications TIA ¼ transient ischaemic attack.


11.3.3.1 Outcome of catheter ablation for atrial fibrillation a
Oesophageal fistula should be suspected in patients presenting with the triad of
The rhythm outcome after catheter ablation of AF is difficult to unspecific signs of infection, chest pain, and stroke or TIA in the first weeks after an
ablation procedure. It requires immediate therapy.
predict in individual patients.173,227,713,728 Most patients require b
,10% for cryoablation or radiofrequency ablation, .20% for phased
more than one procedure to achieve symptom control.713,726,728 radiofrequency ablation.
In general, better rhythm outcome and lower procedure-related
complications can be expected in younger patients with a short his-
tory of AF and frequent, short AF episodes in the absence of signifi- oesophageal injury leading to atrio-oesophageal fistula weeks after
cant structural heart disease.745 Catheter ablation is more effective ablation (Table 18). ‘Silent strokes’ (i.e. white matter lesions detect-
than antiarrhythmic drug therapy in maintaining sinus rhythm (Web able by brain MRI) have been observed in around 10% of patients
Figure 2).746,1039 Sinus rhythm without severely symptomatic recur- treated with radiofrequency and cryoballoon ablation.752 The clinical
rences of AF is found in up to 70% of patients with paroxysmal AF, relevance of this observation is unclear.749 Post-procedural complica-
and around 50% in persistent AF.713,728,735 Very late recurrence of tions include stroke, with the highest risk within the first week,753 late
AF after years of sinus rhythm is not uncommon and may reflect dis- pericardial tamponade several days after catheter ablation,751 and oe-
ease progression, with important implications for continuation of AF sophageal fistulas, which usually become apparent 7–30 days after
therapies.728 Multiple variables have been identified as risk factors for ablation. Timely detection of atrio-oesophageal fistulas can be life-
recurrence after catheter ablation of AF, but their predictive power is saving and should be based on the typical triad of infection without
weak. The decision for catheter ablation, thus, should be based on a a clear focus, retrosternal pain, and stroke or TIA.748
shared decision-making process747 (see Chapter 8), following thor-
11.3.4 Anticoagulation: before, during, and after ablation
ough explanation of the potential benefits and risks, and of the alter-
Patients anticoagulated with VKAs should continue therapy during
natives such as antiarrhythmic drugs or acceptance of the current
ablation (with an INR of 2 – 3).760 Anticoagulation with NOACs is
symptoms without rhythm control therapy.175
an alternative to warfarin.478,761 – 765 There is no safety signal from
11.3.3.2 Complications of catheter ablation for atrial fibrillation observational cohorts treated with uninterrupted NOAC therapy
There is a clear need to systematically capture complications in undergoing catheter ablation in experienced centres.761,763,766,767
clinical practice to improve the quality of AF ablation procedures.175 The first controlled trial comparing continuous NOAC and VKA
The median length of hospital stay in AF patients undergoing their therapy in AF ablation patients, enrolling around 200 patients, has
first ablation as part of the EURObservational Research Programme recently been published,768 as well as several observational data
(EORP) was 3 days (interquartile range 2 – 4 days), based on data sets.761,769,770 Ongoing studies compare uninterrupted VKA with
from 1391 patients from hospitals performing at least 50 ablations NOAC therapy in AF patients undergoing ablation [e.g. AXAFA –
per year. Five to seven per cent of patients will suffer severe com- AFNET 5 (Anticoagulation using the direct factor Xa inhibitor
plications after catheter ablation of AF, and 2 – 3% will experience apixaban during Atrial Fibrillation catheter Ablation: Comparison
life-threatening but usually manageable complications.727,748 – 750 In- to vitamin K antagonist therapy; NCT02227550) and RE-CIRCUIT
traprocedural death has been reported, but is rare (,0.2%).751 The (Randomized Evaluation of dabigatran etexilate Compared to war-
most important severe complications are stroke/TIA (,1%), cardiac farin in pulmonaRy vein ablation: assessment of different peri-
tamponade (1 – 2%), pulmonary vein stenosis, and severe proCedUral anticoagulation sTrategies; NCT02348723)]. During
2940 ESC Guidelines

ablation, heparin should be given to maintain an activated clotting Thus, indications for catheter ablation in HFrEF patients should be
time .300 s. Anticoagulation should be maintained for at least 8 carefully balanced, and the procedures performed in experienced
weeks after ablation for all patients. The true incidence of thrombo- centres.
embolic events after catheter ablation has never been systematically
studied and the expected stroke risk has been adopted from non- 11.3.6 Follow-up after catheter ablation
ablation AF cohorts. Although observational studies suggest a rela- Patients and physicians involved in the follow-up after catheter abla-
tively low stroke rate in the first few years after catheter ablation of tion should know the signs and symptoms of late complications to al-
AF,737,771 – 776 the long-term risk of recurrent AF and the safety pro- low swift referral for treatment (Table 18). Patients should also be
file of anticoagulation in ablated patients need to be considered. In aware that symptomatic and asymptomatic AF recurrences are fre-
the absence of controlled trial data, OAC after catheter ablation quent after catheter ablation.119,781,782 In line with the primary goal
should follow general anticoagulation recommendations, regardless of rhythm control therapy, asymptomatic episodes should generally

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of the presumed rhythm outcome. not trigger further rhythm control therapy in routine care. Patients
should be seen at least once by a rhythm specialist in the first 12
11.3.5 Ablation of atrial fibrillation in heart failure patients months after ablation. Further rhythm control options should be con-
Catheter ablation, compared with amiodarone therapy, significantly sidered in patients with symptomatic recurrences, including discus-
reduces recurrent AF in AF patients with HFrEF.777 Selected sion in a Heart Team (Figure 17, Figure 19).
patients with HFrEF and AF can achieve recovery of LV systolic func-
tion after catheter ablation (probably reflecting tachycardiomyopa- 11.4 Atrial fibrillation surgery
thy). Several smaller trials suggest improved LV function after 11.4.1 Concomitant atrial fibrillation surgery
catheter ablation in HFrEF patients185,226 – 228,778,779 and reduced The Cox maze procedure was first performed 30 years ago as a
hospitalizations,720,777 especially in patients without a previous myo- ‘cut-and-sew’ technique, including isolation of the posterior left at-
cardial infarction.780 Larger trials are warranted to confirm these rium, a connection to the posterior mitral annulus, a cavotricuspid
findings. Catheter ablation can be demanding in these patients. connection, a cavocaval connection, and exclusion of the LAA

Figure 18 A: Surgical lesion sets for the biatrial Cox maze procedure. Surgeon’s view showing left atrial lesions (left panel) and right atrial le-
sions (middle and right panel). B: Left atrial lesions in a thoracoscopic minimally invasive surgical procedure (dashed lines), including left atrial
appendage exclusion (double line).
ESC Guidelines 2941

(Figure 18).783 Thereby, the Cox maze procedure creates an electrical and feasible, via a mini-thoracotomy.786,807,808 Thoracoscopic PVI
labyrinth (maze) of passages through which the sinoatrial node im- with bipolar radiofrequency prevents recurrence of paroxysmal
pulse finds a route to the atrioventricular node while preventing fibril- AF (69 – 91% freedom from arrhythmias at 1 year, see Figure 18B
latory conduction. The Cox maze procedure and other, often for lesion set),468,809,810 and seems effective in patients refractory
simpler, forms of AF surgery have mainly been used in patients under- to catheter ablation.811 The average length of hospital stay for thor-
going other open heart surgical procedures.461,466,784 – 798 In a system- acoscopic ablation varies from 3.6 to 6.0 days.468,812,813 The FAST
atic review commissioned for these guidelines, performing (Atrial Fibrillation Catheter Ablation vs. Surgical Ablation Treat-
concomitant AF surgery resulted in increased freedom from AF, atrial ment) trial,468 and another smaller trial,814 suggested that thoraco-
flutter, and atrial tachycardia compared to no concomitant AF sur- scopic AF surgery could be more effective than catheter ablation for
gery (RR 1.94; 95% CI 1.51–2.49; n ¼ 554 from seven RCTs) (Web the maintenance of sinus rhythm,468,814 while also causing more
Figure 3).1040 Patients undergoing the Cox maze procedure required complications (Table 19).815 To improve results,468,816 – 818 more
pacemaker implantation more often (RR 1.69; 95% CI 1.12–2.54; n ¼

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extensive lesion sets have been performed, including connecting
1631 from 17 RCTs), without a detectable difference in other out- lines between the PVI (“box lesion”) and lines towards the mitral an-
comes or complications. These findings are underpinned by an ana- nulus.812,819 – 822 To improve the generation of transmural le-
lysis of the Society of Thoracic Surgeons database comprising 67 sions,716 endo-epicardial ablation strategies have recently been
389 patients in AF undergoing open heart surgery: mortality or major proposed.812,823 – 825 Although preliminary experience with hybrid
morbidity was not affected by concomitant AF surgery (adjusted OR
1.00; 95% CI 0.83–1.20), but pacemaker implantation was more fre-
quent (adjusted OR 1.26; 95% CI 1.07–1.49).799 Predictors of AF re- Table 19 Complications of thoracoscopic atrial
currence after surgery include left atrial dilatation, older age, fibrillation surgery
.10-year history of AF, and non-paroxysmal AF.800 – 804 Regarding
AF type, surgical PVI seems effective in paroxysmal AF.805 Biatrial le- Complication Rate 468, 815, 822, 826
sion patterns may be more effective in persistent and long-standing
Conversion to sternotomy 0–1.6%
persistent AF.797,803,806 The suggested management of patients with
Pacemaker implantation 0–3.3%
AF-related symptoms undergoing cardiac surgery is displayed in Fig-
ure 19, with an important contribution of the AF Heart Team to ad- Drainage for pneumothorax 0–3.3%
vise and inform patient choice. Pericardial tamponade 0–6.0%
a
Transient ischaemic attack 0–3.0%
11.4.2 Stand-alone rhythm control surgery
Current technology (e.g. bipolar radiofrequency or cryothermy) a
The rate of asymptomatic cerebral embolism is unknown.
renders the Cox maze procedurec easier, and more reproducible

AF patient undergoing open heart surgery (e.g. CABG, valve surgery)

Rhythm control therapy


desirable to improve
AF-related symptoms
Yes No

Patient choice informed by AF Heart Team

AF surgery (IIaA)a No AF surgery

Consider to add surgical LAA exclusion in selected patients (IIbC)b

a
AF surgery may be PVI in paroxysmal AF and biatrial maze in persistent or long-standing persistent AF.
b
Oral anticoagulation should be continued in patients at risk of stroke irrespective of AF surgery or LAA exclusion.

Figure 19 Surgical rhythm control in patients with atrial fibrillation undergoing cardiac surgery.
2942 ESC Guidelines

simultaneous ablation shows promise, procedural time and rates of in patients who are in need of further rhythm control therapy after an
bleeding complications are higher.812,823 initial therapy failure.

11.5 Choice of rhythm control following


treatment failure 11.6 The Atrial Fibrillation Heart Team
There is insufficient evidence to underpin clear recommendations on In view of the complexity of the different treatment options in patients
how to treat patients with recurrent AF after catheter ablation. Early with failed rhythm control therapy who still require or demand further
recurrences of AF or atrial tachycardias after ablation (occurring with- rhythm control therapy, this Task Force proposes that decisions in-
in 8 weeks) may be treated with cardioversion. Many of the published volving AF surgery or extensive AF ablation should be based on advice
series of patients undergoing AF ablation included those who failed from an AF Heart Team. This will also apply to reversal to a rate con-
antiarrhythmic drug therapy. Thus, considering ablation therapy in pa- trol strategy in patients with severe (EHRA III or IV) AF symptoms. An

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tients who have symptomatic recurrences on antiarrhythmic drug AF Heart Team should consist of a cardiologist with expertise in anti-
therapy is often reasonable. Alternatively, trialling another antiar- arrhythmic drug therapy, an interventional electrophysiologist, and a
rhythmic drug can be considered. Combining an antiarrhythmic cardiac surgeon with expertise in appropriate patient selection, tech-
drug with ablation (‘hybrid therapy’, see Chapter 12) should be con- niques, and technologies for interventional or surgical AF ablation (Fig-
sidered based on the different and possibly synergistic effects of these ure 20). Such AF Heart Teams—and a collaborative infrastructure
drugs with AF ablation, possibly benefitting patients in whom either supporting a continued interaction between physicians delivering con-
treatment alone was previously ineffective. Rate control without tinued care, AF cardiologists, interventional electrophysiologists, and
rhythm control, surgical ablation, or repeat catheter ablation should AF surgeons—should be established to provide optimal advice, and ul-
be considered as well (Figure 20). Patient preferences and local access timately to improve rhythm outcomes for patients in need of advanced
to therapy are important considerations to inform the therapy choice and complex rhythm control interventions.

Selection of further rhythm control therapy after therapy failure to improve symptoms of AF

Failure of Failure of Failure of


dronedarone amiodarone catheter ablation
flecainide
propafenone
or sotalol

Patient choice Patient choice Patient choice

Amiodarone another Catheter ablation Hybrid therapy Repeat ablation another


(IA) AAD (IIa) (IA/IIaB) a (IIaC)c (IA/IIaB)a AAD (IIa)

Patient choice informed by AF Heart Team

AF surgery (IIaC)b Rate control (IB) Hybrid therapy (IIaC)c

a
catheter ablation should target PVI. IA for paroxysmal AF, IIaB for persistent and long-standing persistent AF.
b
AF surgery may be PVI (e.g. in paroxysmal AF) or maze surgery (e.g. in therapy-refractory or persistent and long-standing persistent AF).
c
Hybrid therapy involves combination of antiarrhythmic drugs, catheter ablation, and/or AF surgery.

Figure 20 Choice of rhythm control therapy following treatment failure.


ESC Guidelines 2943

Recommendations for catheter ablation of atrial fibrillation and atrial fibrillation surgery

Recommendations Class a Levelb Ref C


Catheter ablation of symptomatic paroxysmal AF is recommended to improve AF symptoms in patients who have
symptomatic recurrences of AF on antiarrhythmic drug therapy (amiodarone, dronedarone, flecainide, propafenone, 585–587,
I A
sotalol) and who prefer further rhythm control therapy, when performed by an electrophysiologist who has received 713, 727
appropriate training and is performing the procedure in an experienced centre.
Ablation of common atrial flutter should be considered to prevent recurrent flutter as part of an AF ablation procedure if
IIa B 827
documented or occurring during the AF ablation.
Catheter ablation of AF should be considered as first-line therapy to prevent recurrent AF and to improve symptoms in
selected patients with symptomatic paroxysmal AF as an alternative to antiarrhythmic drug therapy, considering patient IIa B 585

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choice, benefit, and risk.
All patients should receive oral anticoagulation for at least 8 weeks after catheter (IIaB) or surgical (IIaC) ablation. IIa B C 727
Anticoagulation for stroke prevention should be continued indefinitely after apparently successful catheter or surgical
IIa C
ablation of AF in patients at high-risk of stroke.
When catheter ablation of AF is planned, continuation of oral anticoagulation with a VKA (IIaB) or NOAC (IIaC) should be
IIa B C 760, 768
considered during the procedure, maintaining effective anticoagulation.
585, 715,
Catheter ablation should target isolation of the pulmonary veins using radiofrequency ablation or cryothermy balloon
IIa B 716, 734,
catheters.
735
185,
226–228,
AF ablation should be considered in symptomatic patients with AF and heart failure with reduced ejection fraction to
IIa C 720,
improve symptoms and cardiac function when tachycardiomyopathy is suspected.
777–779,
828
AF ablation should be considered as a strategy to avoid pacemaker implantation in patients with AF-related bradycardia. IIa C 829, 830
Catheter or surgical ablation should be considered in patients with symptomatic persistent or long-standing persistent AF 468, 735,
refractory to AAD therapy to improve symptoms, considering patient choice, benefit and risk, supported by an AF Heart IIa C 777, 831,
Team. 832, 1040
Minimally invasive surgery with epicardial pulmonary vein isolation should be considered in patients with symptomatic AF 468 812,
IIa B
when catheter ablation has failed. Decisions on such patients should be supported by an AF Heart Team. 819, 823
Maze surgery, possibly via a minimally invasive approach, performed by an adequately trained operator in an experienced
centre, should be considered by an AF Heart Team as a treatment option for patients with symptomatic refractory IIa C 808, 832
persistent AF or post-ablation AF to improve symptoms.
461, 466,
Maze surgery, preferably biatrial, should be considered in patients undergoing cardiac surgery to improve symptoms
IIa A 790, 791,
attributable to AF, balancing the added risk of the procedure and the benefit of rhythm control therapy.
796, 797
Concomitant biatrial maze or pulmonary vein isolation may be considered in asymptomatic AF patients undergoing cardiac 796, 797,
IIb C
surgery. 833

AF ¼ atrial fibrillation; NOAC ¼ non-vitamin K antagonist oral anticoagulant; VKA ¼ vitamin K antagonist.
a
Class of recommendation.
b
Level of evidence.
c
Reference(s) supporting recommendations.

12. Hybrid rhythm control therapy studies have not been done, but a meta-analysis of the available
(weak) evidence suggests slightly better prevention of recurrent AF
AF has many different drivers, which are only partially targeted by in patients treated with antiarrhythmic drugs after catheter ablation.713
antiarrhythmic drugs or catheter ablation.96 Hence, combination Many patients are treated with antiarrhythmic drug therapy after cath-
or ‘hybrid’ rhythm control therapy seems reasonable, although eter ablation (most often amiodarone or flecainide),587 and this seems
there is little evidence from controlled trials supporting its use. a reasonable option in patients with recurrent AF after ablation. It
seems common sense to consider antiarrhythmic drug therapy in pa-
tients who are in need of further rhythm control therapy after catheter
12.1 Combining antiarrhythmic drugs ablation, but controlled trials to confirm this are desirable.
and catheter ablation Combining cavotricuspid isthmus ablation and antiarrhythmic
Antiarrhythmic drug therapy is commonly given for 8 – 12 weeks drugs may lead to improved rhythm control without the need for
after ablation to reduce early recurrences of AF after catheter abla- left atrial ablation in patients who develop ‘drug-induced atrial flut-
tion, supported by a recent controlled trial where amiodarone ter’ on therapy with flecainide, propafenone, or amiodarone,834 – 836 al-
halved early AF recurrences compared with placebo.650 Prospective though recurrent AF is a concern in the long-term.837,838
2944 ESC Guidelines

12.2 Combining antiarrhythmic drugs options in AF, the available data support the use of available rate
and pacemakers and rhythm control interventions, including pacemakers and catheter
ablation, without justification to discriminate by age group. Individual
In selected patients with sick sinus syndrome and fast ventricular re-
patients at older age may present with multiple comorbidities including
sponse during AF paroxysms requiring rate control therapy, the add-
dementia, a tendency to falls, CKD, anaemia, hypertension, diabetes,
ition of a pacemaker not only optimizes rate control but may also help
and cognitive dysfunction. Such conditions may limit quality of life
to control rhythm.711,712 Moreover, when antiarrhythmic drug treat-
more than AF-related symptoms. Impairment of renal and hepatic
ment leads to sinus node dysfunction and bradycardia, pacing may per-
function and multiple simultaneous medications make drug interac-
mit uptitration of the antiarrhythmic drug dose. Such strategies have
tions and adverse drug reactions more likely. Integrated AF manage-
never been prospectively investigated and the existing populations
ment and careful adaptation of drug dosing seem reasonable to
studied are highly selected.839,840 Some patients with AF-induced
reduce the complications of AF therapy in such patients.843
bradycardia may benefit from catheter ablation of AF, obviating the

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need for antiarrhythmic drugs and pacemaker implantation.829,830
13.2 Inherited cardiomyopathies,
channelopathies, and accessory pathways
13. Specific situations Several inherited cardiac conditions are associated with early-onset
AF (Table 20). Treatment of the underlying cardiac condition is an
13.1 Frail and ‘elderly’ patients important contribution to AF management in these young patients
Many AF patients present at older age (e.g. .75 or .80 years). There (see also ESC guidelines on sudden cardiac death844 and hyper-
are no studies suggesting that cardiovascular risk reduction is less ef- trophic cardiomyopathy845).
fective in these ‘elderly’ AF patients than in younger patients. Rather,
age is one of the strongest predictors/risk factors for ischaemic stroke 13.2.1 Wolff –Parkinson –White syndrome
in AF.382 Good data are available to support the use of anticoagulants Patients with pre-excitation and AF are at risk of rapid conduction
in older patients from BAFTA (Birmingham Atrial Fibrillation Treat- across the accessory pathway, resulting in a fast ventricular rate,
ment of the Aged Study),362 the NOAC trials,39 and from analyses possible ventricular fibrillation, and sudden death. In AF patients
in elderly Americans (Medicare).396 Elderly AF patients are at higher with evidence of an antegrade accessory pathway, catheter ablation
risk of stroke and, thus, are more likely to benefit from OAC than of the pathway is recommended.869,870 This procedure is safe and
younger patients,841 and yet OAC is still underutilized in the elder- effective and may be considered as a prophylactic treatment strat-
ly.220,842 Although the evidence base is smaller for other treatment egy.871,872 In AF patients surviving a sudden death event with evidence

Table 20 Inherited cardiomyopathies, channelopathies, and pathways associated with atrial fibrillation

Syndrome Gene Functional alteration AF prevalence References

Long QT syndrome KCNQ1 IKs  5–10% 846–850


KCNH2 IKr 
SCN5A INa 
ANK2 INa,K 
Others Various effects
Brugada syndrome SCN5A INa  10–20% 851–855
GPDIL INa 
SCN1B INa 
CACNA1C ICa 
CACNB2b ICa 
Others Others
Short QT syndrome KCNQ1 IKs  Up to 70% 853, 856–858
KCNH2 IKr 
KCNJ2 IK1 
CACNA1C ICa 
CACNB2b ICa 
Catecholaminergic VT RYR2 Abnormal Ca2+ release from sarcoplasmic reticulum Variable but common 859–861
CASQ2
Hypertrophic Sarcomeric genes 5–15% 862–864
cardiomyopathy
Wolff-Parkinson-White PRKAG Variable 865
syndrome
Holt-Oram syndrome TBX5 Variable 866
Arrhythmogenic right Several desmosomal Reduced mechanical cell-cell contacts >40% in patients with 867, 868
ventricular cardiomyopathy genes, unknown gene loci VTs

AF ¼ atrial fibrillation; VT ¼ ventricular tachycardia.


ESC Guidelines 2945

of an accessory pathway, urgent catheter ablation of the pathway is effective to suppress symptomatic AF recurrences.880 – 884 Surgical
recommended.869 A documented short pre-excited RR interval treatment of AF may be appropriate in patients with hypertrophic car-
(,250 ms) during spontaneous or induced AF is one of the risk mar- diomyopathy undergoing surgery (e.g. for LV outflow tract obstruction
kers for sudden death in Wolff – Parkinson – White syndrome or mitral valve surgery), but experience is limited.
(WPW) syndrome, in addition to a history of symptomatic tachycar-
dia, the presence of multiple accessory pathways, and Ebstein’s anom- 13.2.3 Channelopathies and arrhythmogenic right
aly. Intravenous procainamide, propafenone, or ajmaline can be used ventricular cardiomyopathy
to acutely slow ventricular rate,873,874 whereas digoxin, verapamil, Many channelopathies and inherited cardiomyopathies are associated
and diltiazem are contraindicated.875 Intravenous amiodarone should with AF. AF prevalence ranges from 5–20% in patients with long QT
be used with caution, as there are case reports of accelerated ven- syndrome or Brugada syndrome, and is up to 70% in short QT syn-
tricular rhythms and ventricular fibrillation in patients with pre- drome (Table 20).853,856 – 858 Penetrance of disease phenotype includ-
excited AF receiving intravenous amiodarone infusion.876 ing AF is variable.61,852,885,886 Both shortening as well as prolongation

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of the atrial action potential have been demonstrated as likely me-
13.2.2 Hypertrophic cardiomyopathy chanisms underlying AF in these diseases. It seems reasonable to con-
AF is the most common arrhythmia in patients with hypertrophic car- sider antiarrhythmic drugs that reverse the suspected channel defect
diomyopathy, affecting approximately one-quarter of this popula- in AF patients with inherited cardiomyopathies (e.g. a sodium channel
tion.877 Observational data highlight a high stroke risk in hypertrophic blocker in LQT3852, or quinidine in Brugada syndrome887). More im-
cardiomyopathy patients with AF, confirming the need for OAC.878 portantly, new-onset AF in young, otherwise healthy individuals
While there is more experience with VKAs, there are no data to suggest should trigger a careful search for such inherited conditions, including
that NOACs cannot be used in these patients.845 Studies of rate or clinical history, family history, ECG phenotype, and echocardiography
rhythm control medications in patients with hypertrophic cardiomyop- and/or other cardiac imaging.
athy are relatively scarce. Beta-blockers and diltiazem or verapamil Monogenic defects only account for 3–5% of all patients with AF,
seem reasonable treatment options for rate control in these patients. even in younger populations.846,848,888 – 890 Furthermore, there is no
In the absence of significant LV outflow tract obstruction, digoxin can clear link between detected mutations and specific outcomes or
be used alone or in combination with beta-blockers.845 Amiodarone therapeutic needs. For these reasons, genetic testing is not recom-
seems a safe antiarrhythmic drug in AF patients with hypertrophic car- mended in the general AF population.77 Other guidelines have de-
diomyopathy,879 and expert opinion suggests that disopyramide may be scribed the indications for genetic testing in patients with
beneficial in those with outflow tract obstruction. AF ablation is inherited arrhythmogenic diseases.844,891

Recommendations for inherited cardiomyopathies

Recommendations Class a Level b Ref C

WPW syndrome
Catheter ablation of the accessory pathway in WPW patients with AF and rapid conduction over the accessory pathway
I B 892–894
is recommended to prevent sudden cardiac death.
Catheter ablation of the accessory pathway is recommended without delay in WPW patients who survive sudden cardiac
I C 869
death.
Asymptomatic patients with overt pre-excitation and AF should be considered for accessory pathway ablation after careful
IIa B 872, 892
counselling.
Hypertrophic cardiomyopathy
Lifelong oral anticoagulation to prevent stroke is recommended in HCM patients who develop AF. I B 878
Restoration of sinus rhythm by electrical or pharmacological cardioversion to improve symptoms is recommended in
I B 845
HCM patients with symptomatic new-onset AF.
In haemodynamically stable HCM patients with AF, ventricular rate control using beta-blockers and diltiazem/verapamil is
I C 845
recommended.
Treatment of LV outflow tract obstruction should be considered in AF patients with HCM to improve symptoms. IIa B 896
Amiodarone should be considered to achieve rhythm control and maintain sinus rhythm in HCM patients with recurrent
IIa C 845, 897
symptomatic AF.
Inherited cardiomyopathies and channelopathies
Targeted genetic testing should be considered in patients with AF and a suspicion of inherited cardiomyopathies or
IIa A 852
channelopathies based on clinical history, family history or electrocardiographic phenotype.

AF ¼ atrial fibrillation; HCM ¼ hypertrophic cardiomyopathy; LV ¼ left ventricular; WPW ¼ Wolff –Parkinson– White syndrome.
a
Class of recommendation.
b
Level of evidence.
c
Reference(s) supporting recommendations.
2946 ESC Guidelines

13.3 Sports and atrial fibrillation heart diseases will probably increase the incidence of AF during
Physical activity improves cardiovascular health, which translates pregnancy in the future.913 Pregnant women with AF should be
into a lower risk of AF.898 Therefore, physical activity is a corner- managed as high-risk pregnancies in close collaboration with cardi-
stone of preventing AF. Intensive sports practice, especially endur- ologists, obstetricians, and neonatologists.
ance sports (.1500 h of endurance sports practice),899 increases
the risk of AF later in life,900 – 902 probably mediated by altered auto- 13.4.1 Rate control
nomic tone, volume load during exercise, atrial hypertrophy, and Owing to a lack of specific data, beta-blockers, verapamil, diltiazem,
dilatation.903,904 This results in a U-shaped relationship of physical and digoxin all carry a US Food and Drug Administration pregnancy
activity and incident AF.214,898,902,905,906 Detraining can reduce AF safety category of C (benefits may outweigh risk), except for atenolol
in models904 and reduces ventricular arrhythmias in athletes,907 (category D: positive evidence of risk). Their use should be at the low-
but the role of detraining for AF in human athletes is unknown. est dose and for the shortest time required. None of the agents are
teratogenic, but they readily cross the placenta.914 Beta-blockers are

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The management of athletes with AF is similar to general AF man-
agement, but requires a few special considerations. Clinical risk fac- commonly used in pregnant women with cardiovascular conditions
tors will determine the need for anticoagulation. Sports with direct (e.g. for management of gestational hypertension and pre-eclampsia),
bodily contact or prone to trauma should be avoided in patients on but may be associated with intrauterine growth retardation,915 and
OAC. Beta-blockers are not well tolerated and at times prohibited, hence growth scans after 20 weeks’ gestation are recommended. Di-
and digoxin, verapamil, and diltiazem are often not potent enough to goxin is considered safe for maternal and foetal arrhythmias.916 There
slow heart rate during exertional AF. Catheter ablation for AF prob- are insufficient data to comment on verapamil or diltiazem, hence rate
ably has similar outcomes in athletes as in non-athletes,908,909 but control using beta-blockers and/or digoxin is recommended.917 With
further data are needed. Pill-in-the-pocket therapy has been used regards to breastfeeding, all rate control agents are present in breast
as well.620 After ingestion of flecainide or propafenone as milk, although levels of beta-blockers, digoxin, and verapamil are too
pill-in-the-pocket, patients should refrain from sports as long as low to be considered harmful. Diltiazem will be present at high levels
AF persists and until two half-lives of the antiarrhythmic drug and should be considered second-line treatment.918
have elapsed. Prophylactic ablation of the flutter circuit may be
considered in athletes treated with sodium channel blockers.910 13.4.2 Rhythm control
Rhythm control therapy in pregnant patients with AF has only been
Recommendations for physical activity in patients with reported in case studies. Amiodarone is associated with severe ad-
atrial fibrillation verse foetal side-effects and should only be considered for emer-
gency situations.919 Flecainide and sotalol can both be used for
conversion of foetal arrhythmias without major adverse effects,920
Recommendations Class a Levelb Ref C
and thus are likely to be safe to treat maternal symptomatic AF. Elec-
Moderate regular physical activity is trical cardioversion can be effective for restoration of sinus rhythm
recommended to prevent AF, while 214, 898,
athletes should be counselled that I A 900–902,
when tachyarrhythmia is causing haemodynamic instability, with low
long-lasting intense sports 905, 906 rates of adverse outcomes for both mother and foetus.921 However,
participation can promote AF. in view of the risk of foetal distress, electrical cardioversion should
AF ablation should be considered to only be carried out where facilities are available for foetal monitor-
IIa B 908, 909
prevent recurrent AF in athletes. ing and emergency caesarean section. As with other emergencies
The ventricular rate while exercising during pregnancy, patients should receive 100% oxygen, intravenous
with AF should be evaluated in access should be established early, and the mother should be posi-
every athlete (by symptoms and/ IIa C tioned in the left lateral position to improve venous return.922
or by monitoring), and titrated rate
control should be instituted.
After ingestion of pill-in-the-pocket
13.4.3 Anticoagulation
flecainide or propafenone, patients VKAs should be avoided in the first trimester because of teratogenic
should refrain from sports as long as IIa C 620 effects, and in the 2 – 4 weeks preceding delivery to avoid foetal
AF persists and until two half-lives of bleeding. Low-molecular-weight heparins are a safe substitute, as
the antiarrhythmic drug have elapsed.
they do not cross the placenta.923 In the third trimester, frequent
laboratory checks for adequate anticoagulation (e.g. every 10 – 14
AF ¼ atrial fibrillation.
a days) and corresponding dose adjustments are advised, given that
Class of recommendation.
b
Level of evidence. in some women high doses of both VKA and heparin may be needed
c
Reference(s) supporting recommendations. to maintain adequate anticoagulation. Pregnant patients with AF and
mechanical prosthetic valves who elect to stop VKA treatment in
consultation with their specialist team between 6–12 weeks of ges-
13.4 Pregnancy tation, should receive continuous, dose-adjusted unfractionated
AF in pregnant women is rare and is usually associated with pre- heparin or dose-adjusted subcutaneous low-molecular-weight hep-
existing heart disease. AF is associated with increased complications arin. As only limited data are available about teratogenesis for
for the mother and foetus.911,912 Better treatment of congenital NOACs, these drugs should be avoided during pregnancy.
ESC Guidelines 2947

AF and ischaemic stroke, compared with patients that remain in sinus


Recommendations during pregnancy rhythm after surgery.952 – 958 OAC at discharge has been associated
with a reduced long-term mortality in patients with post,operative
Recommendations Class a Levelb Ref C
AF,959 without evidence from controlled trials. Good quality data
Electrical cardioversion can be are needed to determine whether long-term anticoagulation can pre-
performed safely at all stages of
pregnancy, and is recommended in vent strokes in patients with post-operative AF at high stroke
patients who are haemodynamically I C risk,368,386 and to assess whether short episodes of post-operative
unstable due to AF, and whenever the
AF (e.g. ,48 h) carry a similar risk as longer episodes.960 The indica-
risk of ongoing AF is considered high
for the mother or the foetus. tion and timing of OAC in post-operative AF patients should take into
Anticoagulation is recommended consideration the risk of post-operative bleeding.
in pregnant patients with AF
at risk of stroke. To minimize 13.5.3 Rhythm control therapy in post-operative atrial

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teratogenic risk and intrauterine
bleeding, dose-adjusted heparin fibrillation
is recommended during the first I B 923 In haemodynamically unstable patients, cardioversion and consider-
trimester of pregnancy and in the ation of antiarrhythmic drugs is recommended. Amiodarone or ver-
2–4 weeks before delivery. Vitamin
K antagonists or heparin can be nakalant have been efficient in converting post-operative AF to sinus
used in the remaining parts of the rhythm.603,950,961 A recent medium-sized trial randomizing patients
pregnancy.
with post-operative AF to either rhythm control therapy with amio-
NOACs should be avoided in
III darone or to rate control did not find a difference in hospital admis-
pregnancy and in women planning a C
pregnancy.
(harm)
sions during a 60-day follow-up,962 underpinning that the aim of
rhythm control therapy should be to improve AF-related symptoms
NOAC ¼ non-vitamin K antagonist oral anticoagulants. in post-operative AF. In asymptomatic patients and in those with ac-
a
Class of recommendation. ceptable symptoms, rate control or deferred cardioversion pre-
b
Level of evidence.
c ceded by anticoagulation is a reasonable approach.
Reference(s) supporting recommendations.

Recommendations for preventing postoperative atrial


fibrillation
13.5 Post-operative atrial fibrillation
AF is common after cardiac surgery (occurring in 15 – 45% of pa- Recommendations Class a Levelb Ref C
tients),924 – 926 and is associated with increased length of hospital
Peri-operative oral beta-blocker
stay and higher rates of complications and mortality. 927 Post- therapy is recommended for the
I B 925, 928
operative AF is also not uncommon after other major surgery, prevention of post-operative AF after
cardiac surgery.
especially in elderly patients. The treatment of post-operative AF
Restoration of sinus rhythm
is mainly based on studies of patients undergoing cardiac surgery, by electrical cardioversion
with much less evidence in the non-cardiac surgery setting. or antiarrhythmic drugs is I C
recommended in postoperative AF
13.5.1 Prevention of post-operative atrial fibrillation with haemodynamic instability.
Beta-blockers reduce post-operative AF and supraventricular tachy- Long-term anticoagulation should be
cardias, albeit with high heterogeneity and moderate risk of bias in a considered in patients with AF after
cardiac surgery at risk for stroke, IIa B 368, 386
systematic review of published studies. The most commonly studied considering individual stroke and
drug was propranolol, with AF in 16.3% of the treatment group vs. bleeding risk.
31.7% in the control group.925 In the majority of these studies, beta- Antiarrhythmic drugs should
be considered for symptomatic
blockers were administered post-operatively, a regimen supported
postoperative AF after cardiac IIa C
in a recent meta-analysis.928 Amiodarone reduced the incidence of surgery in an attempt to restore
post-operative AF compared to beta-blocker therapy in several sinus rhythm.
meta-analyses, also reducing hospital stay.925,929 – 931 Peri-operative amiodarone should be
considered as prophylactic therapy IIa A 905
Despite initial reports from meta-analyses,689,932,933 pre-operative to prevent AF after cardiac surgery.
treatment with statins did not prevent post-operative AF in a prospect-
Asymptomatic postoperative AF
ive controlled trial.934 Other therapies have also been studied in small, should initially be managed with rate IIa B 962
hypothesis-generating trials, but have not demonstrated clear beneficial control and anticoagulation.
effects. These include magnesium,925,935,936 n-3 polyunsaturated fatty Intravenous vernakalant may be
considered for cardioversion of
acids,937 – 945 colchicine,946 corticosteroids,947,948 and posterior peri- postoperative AF in patients without
IIb B 603
cardectomy.949 Post-operative overdrive biatrial pacing has not gained severe heart failure, hypotension,
widespread use despite some suggestion of prophylactic effects.925,950 or severe structural heart disease
(especially aortic stenosis).
13.5.2 Anticoagulation
Post-operative AF is associated with an increased early stroke risk, in- AF ¼ atrial fibrillation.
a
creased morbidity, and 30-day mortality.927,951,952 In the long-term, b
Class of recommendation.
Level of evidence.
patients with an episode of post-operative AF have a two-fold increase c
Reference(s) supporting recommendations.
in cardiovascular mortality, and a substantially increased risk of future
2948 ESC Guidelines

13.6 Atrial arrhythmias in grown-up 13.6.2 Atrial tachyarrhythmias and atrial septal defects
patients with congenital heart disease Atrial flutter and fibrillation occur in 14–22% of adults with unoperated
atrial septal defects, especially in older patients,971 and can lead to heart
Atrial arrhythmias (AF, atrial flutter, atrial tachycardias) often occur
failure.972 Early repair can reduce but not eliminate the risk of AF.973
late after surgical repair of congenital heart defects, occurring in 15 –
Biatrial volume overload,974 pulmonary hypertension,975 and possibly
40% of grown-up patients with congenital heart disease (GUCH).
the arrhythmogenic effect of atrial patches can contribute to these ar-
They are associated with heart failure, syncope, thrombo-embolic
rhythmias.976 Anticoagulation should be decided upon based on stroke
events, and sudden death.963 – 967 The pathophysiological substrate
risk factors. In patients with a history of paroxysmal or persistent AF, AF
is complex, associated with hypertrophy, fibrosis, hypoxaemia,
surgery could be considered at the time of surgical closure, or catheter
chronic haemodynamic overload, and surgical scars and patches.
ablationatthetimeofinterventionalatrialseptaldefectclosure.Catheter
Additionally, related primary anomalies in the conduction pathways
ablation of late atrial arrhythmias has been shown to be effective in small
can lead to reentrant atrial and ventricular tachycardia, heart block,
cohorts of patients after surgical atrial septal defect.977

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and sinus node dysfunction.963 Macroreentrant atrial tachycardia or
atypical atrial flutter may be seen after nearly any surgical procedure 13.6.3 Atrial tachyarrhythmias after Fontan operation
involving atriotomy or atrial patches. Atrial arrhythmias occur in up to 40% of patients with a Fontan circu-
lation, and can manifest as atrial flutter, primary atrial tachycardia, AF,
13.6.1 General management of atrial arrhythmias in and accelerated junctional rhythm or junctional tachycardia978 with or
grown-up patients with congenital heart disease without sinoatrial node dysfunction.979 Patients with atriopulmonary
The conventional stroke risk factors should be used to inform deci- anastomoses (possibly due to higher atrial volume and pressure
sions on long-term anticoagulation in GUCH patients with AF. In load) and those with early post-operative atrial arrhythmias are
addition, anticoagulation should be considered in GUCH patients more likely to develop long-term atrial arrhythmias.980 Atrial arrhyth-
with atrial arrhythmias when they present with intracardiac repair, mias can also be the first manifestation of obstruction of the atriopul-
cyanosis, Fontan palliation, or systemic right ventricle.968 Beta- monary anastomosis, a complication that must be identified. Right atrial
blockers, verapamil, diltiazem, and digitalis can be used. Care should thrombus formation is common in Fontan patients with atrial arrhyth-
be taken to avoid bradycardia and hypotension. mias and requires oral anticoagulation.981 Operative conversion to to-
Sodium channel blockers suppress approximately half of atrial ar- tal cavopulmonary artery connection with concomitant arrhythmia
rhythmias in Fontan patients.969 Amiodarone is more effective, but surgery can, in some patients, improve heart failure symptoms and re-
long-term treatment with an antiarrhythmic drug carries a high risk duce recurrent arrhythmias,969,982 with low recurrence rates of clinic-
of extracardiac side-effects in this relatively young population. Intra- ally apparent atrial arrhythmias in the first few years after repeat
cardiac thrombi are common in GUCH patients undergoing cardio- surgery.983 – 985 Catheter ablation of atrial arrhythmia in Fontan patients
version for AF, but also in patients with atrial tachycardias or atrial has been successful in selected patients.986
flutter.970 Therefore, both a TOE and anticoagulation for a few 13.6.4 Atrial tachyarrhythmias after tetralogy of Fallot
weeks before the planned cardioversion should be considered.964 correction
Radiofrequency ablation may be a good option for symptomatic After repair of tetralogy of Fallot, approximately one-third of pa-
GUCH patients with atrial arrhythmias, especially in those with atrial tients develop atrial arrhythmias, including intra-atrial reentrant
flutter and other macro re-entrant tachycardias. Interventions tachycardia, focal atrial tachycardia, and AF.987 Circuits involving
should be performed in adequately qualified centres by specialized the cavotricuspid isthmus and areas of presumed surgical right atrial
teams. scarring have been described as responsible for atrial arrhythmias.

Recommendations in patients with grown-up congenital heart disease

Recommendations Classa Levelb Ref C


Atrial septal defect closure should be considered before the fourth decade of life to diminish the chance of atrial flutter and 971, 972,
IIa C
fibrillation. 974
In patients who need surgical closure of an atrial septal defect and who have a history of symptomatic atrial arrhythmia, AF 204, 988,
IIa C
ablation should be considered at the time of surgical closure. 989
Cox maze surgery should be considered in patients with symptomatic AF and an indication for corrective repair of
IIa C 988, 990
congenital heart defects. All such surgery should be done in experienced centres.
Oral anticoagulation should be considered in all adult patients with intracardiac repair, cyanosis, Fontan palliation or
systemic right ventricle and a history of AF, atrial flutter or intra- atrial reentrant tachycardia. In all other congenital heart IIa C 968
disease patients with AF, anticoagulation should be considered if CHA 2DS2VASC score is ≥1.
Catheter ablation of atrial arrhythmias associated with congenital heart defects may be considered when performed in
IIb C 991
experienced centres.
In patients with congenital heart disease, transoesophageal echocardiography may be considered together with 3-week 964, 970,
IIb C
anticoagulation therapy before cardioversion. 988, 990

AF ¼ atrial fibrillation; CHA2DS2-VASc ¼ Congestive Heart failure, hypertension, Age ≥75 (doubled), Diabetes, Stroke (doubled), Vascular disease, Age 65 –74, and Sex (female);
GUCH ¼ grown-up patients with congenital heart disease; OAC ¼ oral anticoagulation; TOE ¼ transoesophageal echocardiography.
a
Class of recommendation.
b
Level of evidence.
c
Reference(s) supporting recommendations.
ESC Guidelines 2949

13.7 Management of atrial flutter of chronic conditions such as AF will benefit from informed patients
The goals for the management of atrial flutter are similar to those for who are aware of their own responsibilities in the disease manage-
AF.992 Based on the available evidence, the stroke risk in patients with at- ment process.328 Shared decision-making747 and patient-centred
rial flutter is not much different from that in AF.827 Furthermore, many organization of care can help to ensure adherence to management
patients diagnosed with atrial flutter develop AF.993 – 995 Thus, anticoagu- and empower patients, and respect individual patient preferences,
lation should be used in patients with atrial flutter similar to that in pa- needs, and values (see Chapter 8.2).326,1008,1009 Patients in an active
tients with AF. Rate control in atrial flutter is achieved with the same role tend to have better health outcomes and care experiences, and
medicationsas inAF,but is often more difficultto achieve.Flecainide, pro- engagement itself can be considered as an intermediate
pafenone,dofetilide,andintravenousibutilideareusefulforcardioversion outcome.1010
of atrial flutter. They should be combined with a rate-controlling agent to
avoid 1:1 conduction of slowing flutter waves to the ventricles. Ibutilide is 14.2 Integrated patient education

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more effective for conversion of atrial flutter than AF, whereas vernaka- Education is a prerequisite for informed, involved patients
lant is less effective in converting typical atrial flutter.996,997 Electrical and patient-centred care. However, lack of AF-related knowledge
cardioversion of atrial flutter can be performed using lower energies in patients is common, even in those who have received verbal
(50–100 J) than for AF.998,999 Atrial overdrive pacing through pacemaker and written information,32,1011,1012 indicating the need to further
leads or endocardial or transesophageal catheters can convert atrial flut- develop structured patient education. Several patient information
ter to sinus rhythm.1000,1001 Anticoagulation and TOE around cardiover- tools have been developed, largely focusing on oral antico-
sion or overdrive pacing should be used similar to that in AF. agulation.1013 – 1016 This task force has developed a dedicated app
Ablation of the cavotricuspid isthmus for isthmus-dependent for AF patients to support patient information and education.Un-
right atrial flutter (either the common counter-clockwise atrial flut- derstanding patients’ perceptions and attitudes towards AF and its
ter or the less-common clockwise atrial flutter) restores and main- management can improve AF management and related out-
tains sinus rhythm with a success rate of 90 – 95%.1002 It may also comes.1017 This includes tailored patient education focusing on
reduce AF recurrences in selected patients,1003,1004 and help to pre- the disease, symptom recognition, therapy, modifiable risk factors
vent hospitalizations.1004,1005 Isthmus ablation is comparably safe for AF, and self-management activities.1018,1019
and more effective than antiarrhythmic drug therapy, and is recom-
mended for recurrent atrial flutter.585 – 587,713 Catheter ablation of
left atrial macroreentrant tachycardia is more complex, with lower
14.3 Self-management and shared
success rates and higher recurrence rates.1006,1007 decision-making
Self-management is primarily focused on tasks to manage the condi-
Recommendations for management of atrial flutter tion, such as adhering to a therapeutic regimen or modifying behav-
iour (e.g. resulting in smoking cessation or weight loss).1020 It
Recommendations Class a Level b Ref C requires understanding of the treatment modalities and goals.350
For patients with atrial flutter,
Within a multidisciplinary team, allied health professionals can guide
antithrombotic therapy is this interactive process in which communication, trust, and recipro-
I B 827
recommended according to the same cal respect foster patient engagement.1021 Shared decision-making
risk profile used for AF.
should be considered as a routine part of the decision-making pro-
Overdrive atrial pacing of atrial
flutter should be considered cess,747 supported by decision aids where applicable.1022 Models of
1000,
as an alternative to electrical IIa B care that integrate education, engagement, and shared decision
1001
cardioversion, depending on local
availability and experience. making are now available,1023 and may be of particular value in the
Management of typical atrial flutter management of AF.
with ablation of the cavotricuspid
isthmus is recommended for Recommendations for patient involvement,
I B 158
patients failing antiarrhythmic drug
therapy or as first-line treatment education, and self-management
considering patient preference.
If atrial flutter has been documented Recommendations Class a Level b Ref C
before AF ablation, ablation of the
cavotricuspid isthmus should be IIa C Tailored patient education is
considered as part of the AF ablation recommended in all phases of AF
1014,
procedure. management to support patients’ I C
1017
perception of AF and to improve
management.
AF ¼ atrial fibrillation. Patient involvement in the care
a
Class of recommendation. process should be considered to 328,
b IIa C
Level of evidence. encourage self-management and 1010
c
Reference(s) supporting recommendations. responsibility for lifestyle changes.
Shared decision making should be
considered to ensure that care is
based on the best available evidence IIa C 747
14. Patient involvement, and fits the needs, values and
preferences of the patient.
education, and self-management
AF ¼ atrial fibrillation.
14.1 Patient-centred care a
Class of recommendation.
b
Level of evidence.
Autonomous, informed patients are better placed to adhere to c
Reference(s) supporting recommendations.
long-term therapy, and it is very likely that long-term management
2950 ESC Guidelines

15. Gaps in evidence 15.6 Left atrial appendage occlusion for


There are some areas of AF management that are supported by ex-
stroke prevention
cellent evidence from multiple, adequately powered randomized The most common justification for LAA occlusion devices in clinical
trials (e.g. oral anticoagulation). Other areas, such as rhythm control practice is a perceived high bleeding risk and, less often, contraindica-
therapy, integrated AF management, and lifestyle modifications are tions for OAC.459 Unfortunately, LAA occluders have not been
clearly developing the required evidence, while areas such as rate tested in such populations. Furthermore, LAA occluders have not
control are in dire need of better studies to underpin future guide- been compared with NOAC therapy in patients at risk for bleeding,
lines. Here, we identify areas in need of further research. or with thoracoscopic LAA clipping. There is a clear need to conduct
adequately designed and powered trials to define the clinical role of
15.1 Major health modifiers causing atrial LAA occluders compared with NOAC therapy in patients with rela-
tive or absolute contraindications for anticoagulation, and/or in those
fibrillation

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suffering from an ischaemic stroke on anticoagulant therapy.
Atrial fibrillation has different causes in different patients. More re-
search is needed into the major causes (and electrophysiological
mechanisms) of AF in different patient groups.176,1024 Such research
15.7 Anticoagulation in atrial fibrillation
should consider the major comorbidities associated with AF, and patients after a bleeding or stroke event
characterize the response to AF therapy in patients with different, At least 2% of anticoagulated patients with AF will experience a ser-
pathophysiologically distinct types of AF. ious bleeding event per year. Observational data suggest that OAC
can be reinitiated even after an intracerebral bleeding event.460,484
15.2 How much atrial fibrillation Controlled studies evaluating different anticoagulation and stroke
constitutes a mandate for therapy? prevention interventions are urgently needed to provide evidence
on the best management of patients who have suffered a bleeding
Technological advances allow screening for an irregular pulse using
event that would usually lead to withholding OAC. Some studies
patient-operated ECG devices, smartphones, and a variety of other
(e.g. APACHE-AF [Apixaban versus Antiplatelet drugs or no antith-
technologies. These may be very useful to detect silent, undiagnosed
rombotic drugs after anticoagulation-associated intraCerebral HaEm-
AF.157 Adequately powered studies evaluating the diagnostic accuracy
orrhage in patients with Atrial Fibrillation]1025) are ongoing, but
of such technologies, the diagnostic yield in different populations, the
adequately powered trials are needed. Similarly, prospectively col-
shortest duration and pattern of atrial arrhythmias conveying a stroke
lected data are needed on the stroke prevention and bleeding risk fol-
risk, and the effect of ECG screening on outcomes are needed.
lowing (re-)initiation of OAC after stroke or intracranial bleeding.
15.3 Atrial high-rate episodes (AHRE)
and need for anticoagulation 15.8 Anticoagulation and optimal timing
All of the information on the benefit of OAC has been generated in
of non-acute cardioversion
patients with AF diagnosed by ECG. Technological advances allow Based on retrospective data, previous recommendations on the safe
ready detection of AHRE in patients with implanted devices and time-window in which a cardioversion can be performed in new-
an atrial lead. Such patients are at increased stroke risk, but it is un- onset AF used ≤48 h as the ‘gold standard’ for non-protected
clear whether they benefit from OAC. Controlled trials evaluating cardioversion. However, new evidence has emerged that
OAC in AHRE patients are ongoing and will provide evidence on the initiating pre-cardioversion anticoagulation in patients with AF epi-
best antithrombotic therapy in these patients. sodes of ,24 h or even ,12 h would provide even better
safety.642,647,1026 – 1028 Further research is needed to establish a clear
15.4 Stroke risk in specific populations safety margin in this clinical situation.
Several specific AF groups should be studied to better characterize
their risk for AF, stroke, and other AF-related complications (e.g. 15.9 Competing causes of stroke or
patients with one stroke risk factor, and non-Caucasian patients). transient ischaemic attack in atrial
Confounding factors (e.g. different therapy of concomitant cardio- fibrillation patients
vascular diseases) may help to explain the variability in the reported Prospective RCTs have demonstrated the superiority of carotid
rates of incident AF, prevalent AF, and AF complications. This also endarterectomy compared to stenting in patients with symptomatic
applies to the effect of gender in AF patients.47 high-degree stenosis of the internal carotid artery.1029 As endartect-
omy minimizes the need for combination therapy with OAC and
15.5 Anticoagulation in patients with antiplatelets,1030 this approach has appeal in patients with AF to re-
severe chronic kidney disease duce bleeding risk. However, few of these studies included patients
The use of NOACs has not been tested in patients with creatinine with AF. In a large observational study, the composite of in-hospital
clearance ,30 mL/min, and there is very little evidence on the mortality, post-procedural stroke, and cardiac complications was
effects of OAC in patients on haemodialysis or on other forms of higher in AF patients undergoing carotid stenting (457/7668; 6.0%)
renal replacement therapy. Studies evaluating OAC in patients compared with endarterectomy (4438/51 320; 8.6%; P ,
with severe CKD are needed to inform the best management in 0.0001).1031 Despite adjustment for baseline risk, this may just re-
this patient group at high risk for stroke and bleeding. flect the type of patients referred for each procedure, and further
ESC Guidelines 2951

randomized studies are needed to confirm the optimal treatment and such interventions often follow local or operator-specific proto-
strategy in AF patients with carotid disease. cols without clear evidence to support the choice of ablation target
or intervention. There is a clear clinical need to define the best ap-
15.10 Anticoagulation in patients with proach in patients who are in need of a second ablation procedure.
biological heart valves (including
transcatheter aortic valve implantation) 15.15 Combination therapy for
and specific forms of valvular heart disease maintenance of sinus rhythm
The optimal antithrombotic therapy in the first months after bio- In the follow-up after initially successful catheter ablation, even
logical valve replacement (including after catheter-based valve re- when done in experienced centres, many patients will experience
placement) is not known. VKAs remain the mainstay during the symptomatic recurrences of AF. These patients are often managed
initial post-operative period; NOACs probably deliver the same with antiarrhythmic drugs. There is a surprising paucity of data

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protection. In patients without AF, many centres use platelet inhibi- evaluating different rhythm control interventions in patients with re-
tors only. NOACs appear to be equally effective as VKAs in patients current AF after catheter ablation. Such studies seem reasonable
with moderate aortic stenosis, based on a subanalysis from the and feasible.
ROCKET-AF trial,1032 as well as the Loire Valley AF project.1033 Fur-
ther data would be helpful to confirm these observations.1034 The
15.16 Can rhythm control therapy convey
safety and efficacy of NOACs in patients with rheumatic mitral valve a prognostic benefit in atrial fibrillation
disease has not been evaluated and should be studied. patients?
The progress in rhythm control therapy (catheter ablation, new antiar-
15.11 Anticoagulation after ‘successful’ rhythmic drugs) and observational long-term analyses suggest that
catheter ablation rhythm control therapy may have a prognostic benefit in anticoagulated
In view of the long-term recurrence rates of AF, this Task Force re- AF patients. Ongoing trials such as CABANA and EAST – AFNET 4
commends that OAC is continued in AF patients after ‘successful’ will provide initial answers to this important question, but more data
catheter ablation. Nonetheless, observational data suggest that are needed, including trials of surgical ablation techniques.
the stroke risk may be lower after catheter ablation of AF compared
with other AF patients. The ongoing EAST – AFNET 4 trial will in- 15.17 Thoracoscopic ‘stand-alone’ atrial
form, in a more general way, whether rhythm control therapy can fibrillation surgery
reduce stroke rates in anticoagulated AF patients. In addition, there Minimally invasive epicardial ablation surgery for the treatment of
seems to be a place for a controlled trial evaluating the termination stand-alone AF was reported a decade ago.1035 The procedure has
of OAC therapy at an interval after ‘successful’ catheter ablation. since evolved towards a totally thoracoscopic procedure,1036 and le-
sion sets were extended to a complete left atrial maze.822 Rando-
15.12 Comparison of rate control agents mized trials using a standardized procedure are urgently needed to
Although the use of rate control therapy is very common in AF pa- clearly define the benefits and risks of thoracoscopic AF ablation,
tients, robust data comparing rate control therapies are scant, with and to further support decisions of the AF Heart Team.
the majority of studies being small uncontrolled trials over short
periods of follow-up. Some studies are ongoing [e.g. RATE-AF 15.18 Surgical exclusion of the left atrial
(Rate Control Therapy Evaluation in Permanent Atrial Fibrilla- appendage
tion)559] and will investigate the potential benefits of different rate- Exclusion of the LAA has been performed by cardiothoracic surgeons
controlling agents, characteristics, or biomarkers that can help to for decades, but prospective randomized studies comparing the rate
personalize the use of rate control, and the adverse event profile of ischaemic stroke with or without left appendage exclusion are pres-
of specific drugs in defined groups of patients. ently lacking. The LAAOS (Left Atrial Appendage Occlusion Study) III
is currently randomizing cardiac surgery patients with AF to undergo
15.13 Catheter ablation in persistent and concomitant occlusion or no occlusion of the appendage.467 More
long-standing persistent atrial fibrillation data are also needed to confirm the safety and efficacy of thoraco-
While a few recent randomized studies support the use of catheter scopic exclusion, following early positive observational data.1037
or surgical ablation in patients with persistent AF and long-standing
persistent AF,1042 there is a clear need for more data evaluating this 15.19 Concomitant atrial fibrillation
intervention in adequately powered randomized trials. surgery
Adequately powered randomized trials are needed, employing sys-
15.14 Optimal technique for repeat tematic follow-up with uniform lesion sets and energy sources, to
catheter ablation evaluate the benefits and risks of concomitant AF surgery in symp-
PVI emerges as the most important target for catheter ablation of AF. tomatic AF patients. An RCT on non-uniform lesion sets with long-
Although a plethora of different additional ablation techniques have term follow-up is due to publish shortly.1038 Such trials will assist the
been published, their added value is questionable in patients undergo- AF Heart Team to decide on optimal therapy for individual patients,
ing a first catheter ablation, including those with persistent AF.735,1042 including the full repertoire of medical and surgical options for the
Many patients are in need of multiple catheter ablation procedures, treatment of AF.
2952 ESC Guidelines

16. To do and not to do messages from the Guidelines

Recommendations Class a Level b


Recommendations for diagnosis and screening of AF
ECG documentation is required to establish the diagnosis of AF. I B
Opportunistic screening for AF is recommended by pulse taking or ECG rhythm strip in patients >65 years of age. I B
In patients with TIA or ischaemic stroke, screening for AF is recommended by short-term ECG recording followed by continuous
I B
ECG monitoring for at least 72 hours.
It is recommended to interrogate pacemakers and ICDs on a regular basis for atrial high rate episodes (AHRE). Patients with AHRE

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I B
should undergo further ECG monitoring to document AF before initiating AF therapy.
Recommendations for general management of AF
Tailored patient education is recommended in all phases of AF management to support patients’ perception of AF and to improve
I C
management.
A full cardiovascular evaluation, including an accurate history, careful clinical examination, and assessment of concomitant conditions,
I C
is recommended in all AF patients.
Use of the modified EHRA symptom scale is recommended in clinical practice and research studies to quantify AF-related symptoms. I C
Transthoracic echocardiography is recommended in all AF patients to guide management. I C
The assessment of kidney function by serum creatinine or creatinine clearance is recommended in all AF patients to detect kidney
I A
disease and to support correct dosing of AF therapy.
Recommendations for stroke prevention in AF
The CHA 2DS2 -VASc score is recommended for stroke risk prediction in patients with AF. I A
Oral anticoagulation therapy to prevent thromboembolism is recommended for all male AF patients with a CHA 2DS2 -VASc score of
I A
2 or more.
Oral anticoagulation therapy to prevent thromboembolism is recommended in all female AF patients with a CHA2DS2 -VASc score of
I A
3 or more.
When oral anticoagulation is initiated in a patient with AF who is eligible for a non vitamin-K-antagonist oral anticoagulant (apixaban,
I A
dabigatran, edoxaban, or rivaroxaban), a NOAC is recommended in preference to a vitamin K antagonist.
Vitamin K antagonist therapy (INR 2.0–3.0 or higher) is recommended for stroke prevention in AF patients with moderate-to-
I B
severe mitral stenosis or mechanical heart valves.
NOACs (apixaban, dabigatran, edoxaban, and rivaroxaban) are not recommended in patients with mechanical heart valves (Level of III
B C
evidence B) or moderate-to-severe mitral stenosis (Level of evidence C). (harm)

When patients are treated with a vitamin K antagonist, time in therapeutic range (TTR) should be kept as high as possible and
I A
closely monitored.
Combinations of oral anticoagulants and platelet inhibitors increase bleeding risk and should be avoided in AF patients without III
B
another indication for platelet inhibition. (harm)

In male or female AF patients without additional stroke risk factors, anticoagulant or antiplatelet therapy is not recommended for III
B
stroke prevention. (harm)

III
Antiplatelet monotherapy is not recommended for stroke prevention in AF patients, regardless of stroke risk. A
(harm)

After surgical occlusion or exclusion of the left atrial appendage, it is recommended to continue anticoagulation in at-risk patients
I B
with AF for stroke prevention.
III
Genetic testing before the initiation of vitamin K antagonist therapy is not recommended. B
(no benefit)

In AF patients with severe active bleeding events, it is recommended to interrupt oral anticoagulation therapy until the underlying
I C
cause is resolved.
III
NOACs should be avoided in pregnancy and in women planning a pregnancy. C
(harm)

For patients with atrial flutter, antithrombotic therapy is recommended according to the same risk profile used for AF. I B
Management of typical atrial flutter with ablation of the cavotricuspid isthmus is recommended for patients failing antiarrhythmic
I B
drug therapy or as first-line treatment considering patient preference.
Lifelong oral anticoagulation to prevent stroke is recommended in hypertrophic cardiomyopathy patients who develop AF. I B
III
Anticoagulation with heparin or low-molecular-weight heparin immediately after ischaemic stroke is not recommended in AF patients. A
(harm)

Systemic thrombolysis with a recombinant tissue plasminogen activator is not recommended if the INR is above 1.7 (or, for patients III
C
on dabigatran, if activated partial thromboplastin time is outside the normal range). (harm)

III
After TIA or stroke, combination therapy of OAC and an antiplatelet is not recommended. B
(harm)

continued
ESC Guidelines 2953

Recommendations Class a Level b


Recommendations for rate control of AF
Beta-blockers, digoxin, diltiazem, or verapamil are recommended to control heart rate in AF patients with LVEF ≥40%. I B
Beta-blockers and/or digoxin are recommended to control heart rate in AF patients with LVEF <40%. I B
In patients with permanent AF (i.e. where no attempt to restore sinus rhythm is planned), antiarrhythmic drugs should not routinely III
A
be used for rate control. (harm)

Recommendations for rhythm control of AF


Rhythm control therapy is indicated for symptom improvement in patients with AF. I B

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Cardioversion of AF (either electrical or pharmacological) is recommended in symptomatic patients with persistent or long-standing
I B
persistent AF as part of rhythm control therapy.
In patients with no history of ischaemic or structural heart disease, flecainide, propafenone, or vernakalant are recommended for
I A
pharmacological cardioversion of new-onset AF.
In patients with ischaemic and/or structural heart disease, amiodarone is recommended for cardioversion of AF. I A
For cardioversion of AF/atrial flutter, effective anticoagulation is recommended for a minimum of 3 weeks before cardioversion. I B
Transoesophageal echocardiography (TOE) is recommended to exclude cardiac thrombus as an alternative to preprocedural
I B
anticoagulation when early cardioversion is planned.
The choice of antiarrhythmic drug needs to be carefully evaluated, taking into account the presence of comorbidities, cardiovascular
I A
risk and potential for serious proarrhythmia, extracardiac toxic effects, patient preferences, and symptom burden.
Dronedarone, flecainide, propafenone, or sotalol are recommended for prevention of recurrent symptomatic AF in patients with
I A
normal left ventricular function and without pathological left ventricular hypertrophy.
Dronedarone is recommended for prevention of recurrent symptomatic AF in patients with stable coronary artery disease, and
I A
without heart failure.
Amiodarone is recommended for prevention of recurrent symptomatic AF in patients with heart failure. I B
Antiarrhythmic drug therapy is not recommended in patients with prolonged QT interval (> 0.5 s) or with significant sinoatrial node III
C
disease or atrioventricular node dysfunction who do not have a functioning permanent pacemaker. (harm)

Catheter ablation of symptomatic paroxysmal AF is recommended to improve AF symptoms in patients who have symptomatic
recurrences of AF on antiarrhythmic drug therapy (amiodarone, dronedarone, flecainide, propafenone, sotalol) and who prefer
I A
further rhythm control therapy, when performed by an electrophysiologist who has received appropriate training and is performing
the procedure in an experienced centre.
ACE-Is or ARBs are not recommended for the secondary prevention of paroxysmal AF in patients with little or no underlying heart III
B
disease. (no benefit)

Moderate regular physical activity is recommended to prevent AF, while athletes should be counselled that long-lasting, more intense
I A
sports participation can promote AF.

ACE ¼ angiotensin-converting enzyme; AF ¼ atrial fibrillation; AHRE ¼ atrial high rate episodes; ARB ¼ angiotensin receptor blocker; CHA2DS2-VASc ¼ Congestive Heart
failure, hypertension, Age ≥75 (doubled), Diabetes, Stroke (doubled), Vascular disease, Age 65 –74, and Sex (female); ECG ¼ electrocardiogram; EHRA ¼ European Heart
Rhythm Association; ICD ¼ implantable cardioverter defibrillator; INR ¼ international normalized ratio; LV ¼ left ventricular; LVEF ¼ left ventricular ejection fraction; LVH ¼ left
ventricular hypertrophy; NOAC ¼ non-vitamin K antagonist oral anticoagulant; OAC ¼ oral anticoagulation; TIA ¼ transient ischaemic attack; TOE ¼ transoesophageal
echocardiography; TTR ¼ time in therapeutic range; VKA ¼ vitamin K antagonist.
2954 ESC Guidelines

(Germany), Jeroen J. Bax (The Netherlands), Héctor Bueno (Spain),


17. A short summary of the management of atrial
fibrillation patients Scipione Carerj (Italy), Veronica Dean (France), Çetin Erol (Turkey),
Donna Fitzsimons (UK), Oliver Gaemperli (Switzerland), Paulus
Here, we provide 17 simple rules to guide the diagnosis and management Kirchhof (UK/Germany), Philippe Kolh (Belgium), Patrizio Lancellot-
of AF patients according to the 2016 ESC Guidelines for the management ti (Belgium), Gregory Y. H. Lip (UK), Petros Nihoyannopoulos (UK),
of atrial fibrillation developed in cooperation with EACTS.
Massimo F. Piepoli (Italy), Piotr Ponikowski (Poland), Marco Roffi
(1) Use ECG screening in at-risk populations for AF, especially stroke (Switzerland), Adam Torbicki (Poland), António Vaz Carneiro
survivors and the elderly. (Portugal), Stephan Windecker (Switzerland).
(2) Document AF by ECG before starting treatment.
ESC National Cardiac Societies actively involved in the
(3) Evaluate all AF patients by clinical evaluation, ECG, and
echocardiogram for underlying cardiovascular conditions such as review process of the 2016 ESC Guidelines for the management
hypertension, heart failure, valvular heart disease, and others. of atrial fibrillation developed in collaboration with EACTS:
(4) Provide tailored information and education to AF patients to

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Armenia: Armenian Cardiologists Association, Hamlet
empower them to support AF management. G. Hayrapetyan; Austria: Austrian Society of Cardiology, Franz
(5) Propose lifestyle changes to all suitable AF patients to make their
Xaver Roithinger; Azerbaijan: Azerbaijan Society of Cardiology,
management more effective.
(6) Treat underlying cardiovascular conditions adequately, e.g. valve Farid Aliyev; Belarus: Belorussian Scientific Society of Cardiolo-
repair or replacement in AF patients with significant valvular heart gists, Alexandr Chasnoits; Belgium: Belgian Society of Cardiology,
disease, treatment of heart failure, or management of Georges H. Mairesse; Bosnia and Herzegovina: Association of
hypertension, among others. Cardiologists of Bosnia and Herzegovina, Daniela Loncar Matičević;
(7) Use oral anticoagulation in all AF patients unless they are at low
Bulgaria: Bulgarian Society of Cardiology, Tchavdar Shalganov;
risk for stroke based on the CHA2DS2VASc score or have true
contraindications for anticoagulant therapy. Croatia: Croatian Cardiac Society, Boško Skorić; Cyprus: Cyprus
(8) Anticoagulate patients with atrial flutter similar to AF. Offer Society of Cardiology, Loizos Antoniades; Czech Republic: Czech
isthmus ablation to symptomatic flutter patients. Society of Cardiology, Milos Taborsky; Denmark: Danish Society
(9) Reduce all modifiable bleeding risk factors in all AF patients on of Cardiology, Steen Pehrson; Egypt: Egyptian Society of Cardi-
oral anticoagulation, e.g. by treating hypertension, minimizing
ology, Said Khaled; Estonia: Estonian Society of Cardiology, Priit
the duration and intensity of concomitant antiplatelet and
non-steroidal anti-inflammatory drug therapy, treating anaemia Kampus; Finland: Finnish Cardiac Society, Antti Hedman;
and eliminating causes for blood loss, maintaining stable INR The Former Yugoslav Republic of Macedonia: Macedonian
values in patients on VKAs, and moderating alcohol intake. Society of Cardiology, Lidija Poposka; France: French Society of
(10) Check ventricular rate in all AF patients and use rate control Cardiology, Jean-Yves Le Heuzey; Georgia: Georgian Society of
medications to achieve lenient rate control.
Cardiology, Kakhaber Estadashvili; Germany: German Cardiac So-
(11) Evaluate AF-related symptoms in all AF patients using the
modified EHRA symptoms scale. Whenever patients have ciety, Dietmar Bänsch; Hungary: Hungarian Society of Cardiology,
AF-related symptoms, aim to improve symptoms by adjustment Zoltán Csanádi; Ireland: Irish Cardiac Society, David Keane; Israel:
of rate control therapy and by offering antiarrhythmic drugs, Israel Heart Society, Roy Beinart; Italy: Italian Federation of Cardi-
cardioversion, or catheter or surgical ablation. ology, Francesco Romeo; Kazakhstan: Association of Cardiolo-
(12) Select antiarrhythmic drugs based on their safety profile and
gists of Kazakhstan, Kulzida Koshumbayeva; Kosovo: Kosovo
consider catheter or surgical ablation when antiarrhythmic
drugs fail. Society of Cardiology, Gani Bajraktari; Kyrgyzstan: Kyrgyz Society
(13) Do not offer routine genetic testing in AF patients unless there is of Cardiology, Aibek Mirrakhimov, Latvia: Latvian Society of Car-
suspicion of an inherited cardiac condition. diology, Oskars Kalejs; Lebanon: Lebanese Society of Cardiology,
(14) Do not use antiplatelet therapy for stroke prevention in AF. Samer Nasr; Lithuania: Lithuanian Society of Cardiology, Germa-
(15) Do not permanently discontinue oral anticoagulation in AF
nas Marinskis; Luxembourg: Luxembourg Society of Cardiology,
patients at increased risk of stroke unless such a decision is taken
by a multidisciplinary team. Carlo Dimmer; Malta: Maltese Cardiac Society, Mark Sammut;
(16) Do not use rhythm control therapy in asymptomatic AF patients, Moldova: Moldavian Society of Cardiology, Aurel Grosu;
nor in patients with permanent AF. Morocco: Moroccan Society of Cardiology, Salima Abdelali;
(17) Do not perform cardioversion or catheter ablation without The Netherlands: Netherlands Society of Cardiology, Martin
anticoagulation, unless an atrial thrombus has been ruled out
E. W. Hemels; Norway: Norwegian Society of Cardiology, Ole-
transoesophageal echocardiogram.
Gunnar Anfinsen; Poland: Polish Cardiac Society, Beata Średniawa;
Portugal: Portuguese Society of Cardiology, Pedro Adragao;
Romania: Romanian Society of Cardiology, Gheorghe-Andrei
18. Web addenda Dan; Russian Federation: Russian Society of Cardiology, Evgeny
Three additional Web figures and two additional Web tables can be N. Mikhaylov; San Marino: San Marino Society of Cardiology, Mar-
accessed in the Web addenda to the 2016 ESC AF Guidelines, avail- co Zavatta; Serbia: Cardiology Society of Serbia, Tatjana Potpara;
able at European Heart Journal online and also via the ESC Website Slovakia: Slovak Society of Cardiology, Peter Hlivak Slovenia: Slo-
(www.escardio.org/guidelines). venian Society of Cardiology, Igor Zupan; Spain: Spanish Society of
Cardiology, Angel Arenal; Sweden: Swedish Society of Cardiology,
Frieder Braunschweig; Switzerland: Swiss Society of Cardiology,
19. Appendix Dipen Shah; Tunisia: Tunisian Society of Cardiology and Cardio-
ESC Committee for Practice Guidelines (CPG): Jose Luis Vascular Surgery, Ag Sana Ouali; Turkey: Turkish Society of Cardi-
Zamorano (Chairperson) (Spain), Victor Aboyans (France), Stephan ology, Mesut Demir; Ukraine: Ukrainian Association of Cardiology,
Achenbach (Germany), Stefan Agewall (Norway), Lina Badimon Oleg Sychov; United Kingdom: British Cardiovascular Society, Ed
(Spain), Gonzalo Barón-Esquivias (Spain), Helmut Baumgartner Duncan.
European Heart Journal (2016) 37, 2129–2200 ESC GUIDELINES
doi:10.1093/eurheartj/ehw128

2016 ESC Guidelines for the diagnosis and


treatment of acute and chronic heart failure
The Task Force for the diagnosis and treatment of acute and chronic
heart failure of the European Society of Cardiology (ESC)

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Developed with the special contribution of the Heart Failure
Association (HFA) of the ESC
Authors/Task Force Members: Piotr Ponikowski* (Chairperson) (Poland),
Adriaan A. Voors* (Co-Chairperson) (The Netherlands), Stefan D. Anker (Germany),
Héctor Bueno (Spain), John G. F. Cleland (UK), Andrew J. S. Coats (UK),
Volkmar Falk (Germany), José Ramón González-Juanatey (Spain), Veli-Pekka Harjola
(Finland), Ewa A. Jankowska (Poland), Mariell Jessup (USA), Cecilia Linde (Sweden),
Petros Nihoyannopoulos (UK), John T. Parissis (Greece), Burkert Pieske (Germany),
Jillian P. Riley (UK), Giuseppe M. C. Rosano (UK/Italy), Luis M. Ruilope (Spain),
Frank Ruschitzka (Switzerland), Frans H. Rutten (The Netherlands),
Peter van der Meer (The Netherlands)
Document Reviewers: Gerasimos Filippatos (CPG Review Coordinator) (Greece), John J. V. McMurray (CPG Review
Coordinator) (UK), Victor Aboyans (France), Stephan Achenbach (Germany), Stefan Agewall (Norway),
Nawwar Al-Attar (UK), John James Atherton (Australia), Johann Bauersachs (Germany), A. John Camm (UK),
Scipione Carerj (Italy), Claudio Ceconi (Italy), Antonio Coca (Spain), Perry Elliott (UK), Çetin Erol (Turkey),
Justin Ezekowitz (Canada), Covadonga Fernández-Golfı́n (Spain), Donna Fitzsimons (UK), Marco Guazzi (Italy),

* Corresponding authors: Piotr Ponikowski, Department of Heart Diseases, Wroclaw Medical University, Centre for Heart Diseases, Military Hospital, ul. Weigla 5, 50-981 Wroclaw,
Poland, Tel: +48 261 660 279, Tel/Fax: +48 261 660 237, E-mail: piotrponikowski@4wsk.pl.
Adriaan Voors, Cardiology, University of Groningen, University Medical Center Groningen, Hanzeplein 1, PO Box 30.001, 9700 RB Groningen, The Netherlands, Tel: +31 50 3612355,
Fax: +31 50 3614391, E-mail: a.a.voors@umcg.nl.
ESC Committee for Practice Guidelines (CPG) and National Cardiac Societies document reviewers: listed in the Appendix.
ESC entities having participated in the development of this document:
Associations: Acute Cardiovascular Care Association (ACCA), European Association for Cardiovascular Prevention and Rehabilitation (EACPR), European Association of
Cardiovascular Imaging (EACVI), European Heart Rhythm Association (EHRA), Heart Failure Association (HFA).
Councils: Council on Cardiovascular Nursing and Allied Professions, Council for Cardiology Practice, Council on Cardiovascular Primary Care, Council on Hypertension.
Working Groups: Cardiovascular Pharmacotherapy, Cardiovascular Surgery, Myocardial and Pericardial Diseases, Myocardial Function, Pulmonary Circulation and Right Ventricular
Function, Valvular Heart Disease.
The content of these European Society of Cardiology (ESC) Guidelines has been published for personal and educational use only. No commercial use is authorized. No part of the ESC
Guidelines may be translated or reproduced in any form without written permission from the ESC. Permission can be obtained upon submission of a written request to Oxford
University Press, the publisher of the European Heart Journal and the party authorized to handle such permissions on behalf of the ESC (journals.permissions@oup.com).
Disclaimer. The ESC Guidelines represent the views of the ESC and were produced after careful consideration of the scientific and medical knowledge and the evidence available at
the time of their publication. The ESC is not responsible in the event of any contradiction, discrepancy and/or ambiguity between the ESC Guidelines and any other official recom-
mendations or guidelines issued by the relevant public health authorities, in particular in relation to good use of healthcare or therapeutic strategies. Health professionals are encour-
aged to take the ESC Guidelines fully into account when exercising their clinical judgment, as well as in the determination and the implementation of preventive, diagnostic or
therapeutic medical strategies; however, the ESC Guidelines do not override, in any way whatsoever, the individual responsibility of health professionals to make appropriate and
accurate decisions in consideration of each patient’s health condition and in consultation with that patient and, where appropriate and/or necessary, the patient’s caregiver. Nor
do the ESC Guidelines exempt health professionals from taking into full and careful consideration the relevant official updated recommendations or guidelines issued by the competent
public health authorities, in order to manage each patient’s case in light of the scientifically accepted data pursuant to their respective ethical and professional obligations. It is also the
health professional’s responsibility to verify the applicable rules and regulations relating to drugs and medical devices at the time of prescription.
The article has been co-published with permission in European Heart Journal and European Journal of Heart Failure. All rights reserved in respect of European Heart Journal.
& European Society of Cardiology 2016. All rights reserved. For permissions please email: journals.permissions@oup.com.
2130 ESC Guidelines

Maxime Guenoun (France), Gerd Hasenfuss (Germany), Gerhard Hindricks (Germany), Arno W. Hoes
(The Netherlands), Bernard Iung (France), Tiny Jaarsma (Sweden), Paulus Kirchhof (UK/Germany), Juhani Knuuti
(Finland), Philippe Kolh (Belgium), Stavros Konstantinides (Germany/Greece), Mitja Lainscak (Slovenia),
Patrizio Lancellotti (Belgium), Gregory Y. H. Lip (UK), Francesco Maisano (Switzerland), Christian Mueller
(Switzerland), Mark C. Petrie (UK), Massimo F. Piepoli (Italy), Silvia G. Priori (Italy), Adam Torbicki (Poland),
Hiroyuki Tsutsui (Japan), Dirk J. van Veldhuisen (The Netherlands), Stephan Windecker (Switzerland), Clyde Yancy
(USA), Jose Luis Zamorano (Spain)

The disclosure forms of all experts involved in the development of these guidelines are available on the ESC website
http://www.escardio.org/guidelines.
Online publish-ahead-of-print 20 May 2016

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- - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - -- - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - -
Keywords Guidelines † Heart failure † Natriuretic peptides † Ejection fraction † Diagnosis † Pharmacotherapy †
Neuro-hormonal antagonists † Cardiac resynchronization therapy † Mechanical circulatory support †
Transplantation † Arrhythmias † Co-morbidities † Hospitalization † Multidisciplinary management

Table of Contents
Abbreviations and acronyms . . . . . . . . . . . . . . . . . . . . . . . .2131 5.9 Cardiac computed tomography . . . . . . . . . . . . . . . . .2144
1. Preamble . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .2134 5.10 Other diagnostic tests . . . . . . . . . . . . . . . . . . . . . .2145
2. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .2136 5.10.1 Genetic testing in heart failure . . . . . . . . . . . . . .2145
3. Definition, epidemiology and prognosis . . . . . . . . . . . . . . .2136 6. Delaying or preventing the development of overt heart
3.1 Definition of heart failure . . . . . . . . . . . . . . . . . . . . .2136 failure or preventing death before the onset of symptoms . . . . .2146
3.2 Terminology . . . . . . . . . . . . . . . . . . . . . . . . . . . . .2137 7. Pharmacological treatment of heart failure with reduced
3.2.1 Heart failure with preserved, mid-range and reduced ejection fraction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .2147
ejection fraction . . . . . . . . . . . . . . . . . . . . . . . . . . . .2137 7.1 Objectives in the management of heart failure . . . . . . .2147
3.2.2 Terminology related to the time course of heart 7.2 Treatments recommended in all symptomatic patients
failure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .2137 with heart failure with reduced ejection fraction . . . . . . . . .2148
3.2.3 Terminology related to the symptomatic severity 7.2.1 Angiotensin-converting enzyme inhibitors . . . . . . .2148
of heart failure . . . . . . . . . . . . . . . . . . . . . . . . . . . . .2138 7.2.2 Beta-blockers . . . . . . . . . . . . . . . . . . . . . . . . . .2148
3.3 Epidemiology, aetiology and natural history of heart failure 2138 7.2.3 Mineralocorticoid/aldosterone receptor antagonists .2148
3.4 Prognosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .2138 7.3 Other treatments recommended in selected symptomatic
4. Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .2138 patients with heart failure with reduced ejection fraction . . .2148
4.1 Symptoms and signs . . . . . . . . . . . . . . . . . . . . . . . .2138 7.3.1 Diuretics . . . . . . . . . . . . . . . . . . . . . . . . . . . . .2148
4.2 Essential initial investigations: natriuretic peptides, 7.3.2 Angiotensin receptor neprilysin inhibitor . . . . . . . .2151
electrocardiogram, and echocardiography . . . . . . . . . . . . .2139 7.3.3 If - channel inhibitor . . . . . . . . . . . . . . . . . . . . . .2152
4.3 Algorithm for the diagnosis of heart failure . . . . . . . . .2140 7.3.4 Angiotensin II type I receptor blockers . . . . . . . . .2152
4.3.1 Algorithm for the diagnosis of heart failure in the 7.3.5 Combination of hydralazine and isosorbide
non-acute setting . . . . . . . . . . . . . . . . . . . . . . . . . . .2140 dinitrate . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .2152
4.3.2 Diagnosis of heart failure with preserved ejection 7.4 Other treatments with less certain benefits in
fraction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .2140 symptomatic patients with heart failure with reduced ejection
5. Cardiac imaging and other diagnostic tests . . . . . . . . . . . . .2142 fraction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .2152
5.1 Chest X-ray . . . . . . . . . . . . . . . . . . . . . . . . . . . . .2142 7.4.1 Digoxin and other digitalis glycosides . . . . . . . . . .2152
5.2 Transthoracic echocardiography . . . . . . . . . . . . . . . .2142 7.4.2 n-3 polyunsaturated fatty acids . . . . . . . . . . . . . .2153
5.2.1 Assessment of left ventricular systolic function . . . .2142 7.5 Treatments not recommended (unproven benefit) in
5.2.2 Assessment of left ventricular diastolic function . . .2143 symptomatic patients with heart failure with reduced ejection
5.2.3 Assessment of right ventricular function and fraction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .2153
pulmonary arterial pressure . . . . . . . . . . . . . . . . . . . .2143 7.5.1 3-Hydroxy-3-methylglutaryl-coenzyme A reductase
5.3 Transoesophageal echocardiography . . . . . . . . . . . . .2143 inhibitors (‘statins’) . . . . . . . . . . . . . . . . . . . . . . . . . .2153
5.4 Stress echocardiography . . . . . . . . . . . . . . . . . . . . .2143 7.5.2 Oral anticoagulants and antiplatelet therapy . . . . . .2153
5.5 Cardiac magnetic resonance . . . . . . . . . . . . . . . . . . .2143 7.5.3 Renin inhibitors . . . . . . . . . . . . . . . . . . . . . . . .2153
5.6 Single-photon emission computed tomography and 7.6 Treatments not recommended (believed to cause harm)
radionuclide ventriculography . . . . . . . . . . . . . . . . . . . . .2143 in symptomatic patients with heart failure with reduced
5.7 Positron emission tomography . . . . . . . . . . . . . . . . .2143 ejection fraction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .2154
5.8 Coronary angiography . . . . . . . . . . . . . . . . . . . . . . .2144 7.6.1 Calcium-channel blockers . . . . . . . . . . . . . . . . . .2154
ESC Guidelines 2131

8. Non-surgical device treatment of heart failure with reduced 12. Acute heart failure . . . . . . . . . . . . . . . . . . . . . . . . . . . .2171
ejection fraction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .2154 12.1 Definition and classification . . . . . . . . . . . . . . . . . . .2171
8.1 Implantable cardioverter-defibrillator . . . . . . . . . . . . .2154 12.2 Diagnosis and initial prognostic evaluation . . . . . . . . .2172
8.1.1 Secondary prevention of sudden cardiac death . . . .2154 12.3 Management . . . . . . . . . . . . . . . . . . . . . . . . . . . .2176
8.1.2 Primary prevention of sudden cardiac death . . . . . .2155 12.3.1 Identification of precipitants/causes leading to
8.2 Cardiac resynchronization therapy . . . . . . . . . . . . . . .2156 decompensation that needs urgent management . . . . . . .2176
8.3 Other implantable electrical devices . . . . . . . . . . . . . .2157 12.3.2 Criteria for hospitalization in ward vs intensive
9. Treatment of heart failure with preserved ejection fraction . .2157 care/coronary care unit . . . . . . . . . . . . . . . . . . . . . . .2177
9.1 Effect of treatment on symptoms in heart failure with 12.3.3 Management of the early phase . . . . . . . . . . . . .2177
preserved ejection fraction . . . . . . . . . . . . . . . . . . . . . . .2158 12.3.4 Management of patients with cardiogenic shock . .2182
9.2 Effect of treatment on hospitalization for heart failure in 12.4 Management of evidence-based oral therapies . . . . . .2182

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heart failure with preserved ejection fraction . . . . . . . . . . .2158 12.5 Monitoring of clinical status of patients hospitalized due
9.3 Effect of treatment on mortality in heart failure with to acute heart failure . . . . . . . . . . . . . . . . . . . . . . . . . .2183
preserved ejection fraction . . . . . . . . . . . . . . . . . . . . . . .2158 12.6 Criteria for discharge from hospital and follow-up in
9.4 Other considerations . . . . . . . . . . . . . . . . . . . . . . .2158 high-risk period . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .2183
10. Arrhythmias and conductance disturbances . . . . . . . . . . . .2158 12.7 Goals of treatment during the different stages of
10.1 Atrial fibrillation . . . . . . . . . . . . . . . . . . . . . . . . . .2159 management of acute heart failure . . . . . . . . . . . . . . . . . .2183
10.1.1 Prevention of atrial fibrillation in patients with heart 13. Mechanical circulatory support and heart transplantation . . .2184
failure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .2159 13.1 Mechanical circulatory support . . . . . . . . . . . . . . . .2184
10.1.2 Management of new-onset, rapid atrial fibrillation in 13.1.1 Mechanical circulatory support in acute heart
patients with heart failure . . . . . . . . . . . . . . . . . . . . . .2159 failure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .2184
10.1.3 Rate control . . . . . . . . . . . . . . . . . . . . . . . . .2159 13.1.2 Mechanical circulatory support in end-stage chronic
10.1.4 Rhythm control . . . . . . . . . . . . . . . . . . . . . . .2160 heart failure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .2184
10.1.5 Thromboembolism prophylaxis . . . . . . . . . . . . .2161 13.2 Heart transplantation . . . . . . . . . . . . . . . . . . . . . . .2186
10.2 Ventricular arrhythmias . . . . . . . . . . . . . . . . . . . . .2161 14. Multidisciplinary team management . . . . . . . . . . . . . . . . .2187
10.3 Symptomatic bradycardia, pauses and 14.1 Organization of care . . . . . . . . . . . . . . . . . . . . . . .2187
atrio-ventricular block . . . . . . . . . . . . . . . . . . . . . . . . . .2162 14.2 Discharge planning . . . . . . . . . . . . . . . . . . . . . . . .2189
11. Co-morbidities . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .2163 14.3 Lifestyle advice . . . . . . . . . . . . . . . . . . . . . . . . . . .2189
11.1 Heart failure and co-morbidities . . . . . . . . . . . . . . .2163 14.4 Exercise training . . . . . . . . . . . . . . . . . . . . . . . . . .2189
11.2 Angina and coronary artery disease . . . . . . . . . . . . .2163 14.5 Follow-up and monitoring . . . . . . . . . . . . . . . . . . . .2189
11.2.1 Pharmacological management . . . . . . . . . . . . . .2163 14.6 The older adult, frailty and cognitive impairment . . . . .2190
11.2.2 Myocardial revascularization . . . . . . . . . . . . . . .2163 14.7 Palliative and end-of-life care . . . . . . . . . . . . . . . . . .2190
11.3 Cachexia and sarcopenia (for frailty, please refer to 15. Gaps in evidence . . . . . . . . . . . . . . . . . . . . . . . . . . . . .2191
Section 14) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .2164 16. To do and not to messages from the Guidelines . . . . . . . . .2192
11.4 Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .2164 17. Web Addenda . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .2193
11.5 Central nervous system (including depression, stroke and 18. Appendix . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .2194
autonomic dysfunction) . . . . . . . . . . . . . . . . . . . . . . . . .2165 19. References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .2194
11.6 Diabetes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .2165
11.7 Erectile dysfunction . . . . . . . . . . . . . . . . . . . . . . . .2166
11.8 Gout and arthritis . . . . . . . . . . . . . . . . . . . . . . . . .2166 Abbreviations and acronyms
11.9 Hypokalaemia and hyperkalaemia . . . . . . . . . . . . . . .2166
11.10 Hyperlipidaemia . . . . . . . . . . . . . . . . . . . . . . . . .2166 ACC/AHA American College of Cardiology/American
11.11 Hypertension . . . . . . . . . . . . . . . . . . . . . . . . . . .2166 Heart Association
11.12 Iron deficiency and anaemia . . . . . . . . . . . . . . . . . .2167 ACCF/AHA American College of Cardiology Foundation/
11.13 Kidney dysfunction (including chronic kidney disease, American Heart Association
acute kidney injury, cardio-renal syndrome, and prostatic ACE angiotensin-converting enzyme
obstruction) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .2168 ACEI angiotensin-converting enzyme inhibitor
11.14 Lung disease (including asthma and chronic obstructive ACS acute coronary syndrome
pulmonary disease) . . . . . . . . . . . . . . . . . . . . . . . . . . . .2169 AF atrial fibrillation
11.15 Obesity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .2169 AHF acute heart failure
11.16 Sleep disturbance and sleep-disordered AHI apnoea/hypopnoea index
breathing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .2169 AIDS acquired immunodeficiency syndrome
11.17 Valvular heart disease . . . . . . . . . . . . . . . . . . . . . .2170 AKI acute kidney injury
11.17.1 Aortic stenosis . . . . . . . . . . . . . . . . . . . . . . .2170 Aldo-DHF aldosterone receptor blockade in diastolic
11.17.2 Aortic regurgitation . . . . . . . . . . . . . . . . . . . .2170 heart failure
11.17.3 Mitral regurgitation . . . . . . . . . . . . . . . . . . . .2170 AL amyloid light chain
11.17.4 Tricuspid regurgitation . . . . . . . . . . . . . . . . . .2170 ALT alanine aminotransferase
2132 ESC Guidelines

AMI acute myocardial infarction CHARM-Preserved Candesartan Cilexetil in Heart Failure Assess-
AMICA Atrial fibrillation Management In Congestive ment of Reduction in Mortality and Morbidity
heart failure with Ablation CI cardiac index
ANP A-type natriuretic peptide CI-AKI contrast-induced acute kidney injury
ANS autonomic nervous system CIBIS II Cardiac Insufficiency Bisoprolol Study II
ARB angiotensin receptor blocker CK creatine kinase
ARNI angiotensin receptor neprilysin inhibitor CKD chronic kidney disease
ARVC arrhythmogenic right ventricular CK-MB creatine kinase MB
cardiomyopathy CMP cardiomyopathy
AST aspartate aminotransferase CMR cardiac magnetic resonance
ASV assisted servo-ventilation COMPANION Comparison of Medical Therapy, Pacing, and

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ATLAS Assessment of Treatment with Lisinopril And Defibrillation in Heart Failure
Survival CONFIRM-HF Ferric CarboxymaltOse evaluatioN on per-
ATTR transthyretin-mediated amyloidosis Formance in patients with IRon deficiency
AV atrio-ventricular in coMbination with chronic Heart Failure
AVP arginine vasopressin CONSENSUS Cooperative North Scandinavian Enalapril
b.i.d. bis in die (twice daily) Survival Study
BioPACE Biventricular Pacing for Atrio-ventricular COPD chronic obstructive pulmonary disease
Block to Prevent Cardiac Desynchronization COPERNICUS Carvedilol Prospective Randomized Cumula-
BiPAP bilevel positive airway pressure tive Survival
BiVAD biventricular assist device COX-2 inhibitor cyclooxygenase-2 inhibitor
BLOCK-HF Biventricular versus Right Ventricular Pacing in CPAP continuous positive airway pressure
Heart Failure Patients with Atrio-ventricular CPG Committee for Practice Guidelines
Block CRT cardiac resynchronization therapy
BMI body mass index CRT-D defibrillator with cardiac resynchronization
BNP B-type natriuretic peptide therapy
BP blood pressure CRT-P pacemaker with cardiac resynchronization
bpm beats per minute therapy
BSA body surface area CSA central sleep apnoea
BTB bridge to bridge CSR Cheyne-Stokes respiration
BTC bridge to candidacy CT computed tomography
BTD bridge to decision CYP3A4 cytochrome P450 3A4
BTR bridge to recovery DCM dilated cardiomyopathy
BTT bridge to transplantation DES desmin
BUN blood urea nitrogen DHA docosahexaenoic acid
CABANA Catheter ABlation versus ANtiarrhythmic DIG-PEF ancillary Digitalis Investigation Group trial
drug therapy for Atrial fibrillation DNA deoxyribonucleic acid
CABG coronary artery bypass graft/grafting DOSE Diuretic Optimization Strategies Evaluation
CAD coronary artery disease DPD 3,3-diphosphono-1,2-propanodicarboxylic
CARE-HF CArdiac REsynchronization in Heart Failure acid
CASTLE-AF Catheter Ablation versus Standard conven- DPP4i dipeptidyl peptidase-4 inhibitor
tional Treatment in patients with LEft ven- DT destination therapy
tricular dysfunction and Atrial Fibrillation e′ early diastolic tissue velocity
CCB calcium-channel blocker ECG electrocardiogram
CCM cardiac contractility modulation Echo-CRT Echocardiography Guided Cardiac Resyn-
CCS Canadian Cardiovascular Society chronization Therapy
CCU coronary care unit ECLS extracorporeal life support
CHA2DS2-VASc Congestive heart failure or left ventricular dys- ECMO extracorporeal membrane oxygenation
function, Hypertension, Age ≥75 (doubled), ED emergency department
Diabetes, Stroke (doubled)-Vascular disease, EF ejection fraction
Age 65–74, Sex category (female) eGFR estimated glomerular filtration rate
CHARM-Alternative Candesartan in heart failure assessment of EHRA European Heart Rhythm Association
reduction in mortality and morbidity EMA European Medicines Agency
CHARM-Added Candesartan Cilexetil in Heart Failure Assess- EMB endomyocardial biopsy
ment of Reduction in Mortality and Morbidity EMF endomyocardial fibrosis
ESC Guidelines 2133

EMPHASIS-HF Eplerenone in Mild Patients Hospitalization IVRT isovolumetric relaxation time


and Survival Study in Heart Failure KCCQ Kansas City Cardiomyopathy Questionnaire
EPA eicosapentaenoic acid LA left atrial/atrium
EPHESUS Eplerenone Post-Acute Myocardial Infarction LAE left atrial enlargement
Heart Failure Efficacy and Survival Study LAVI left atrial volume index
ESC European Society of Cardiology LBBB left bundle branch block
EU European Union LGE late gadolinium enhancement
EULAR European League Against Rheumatism LMNA lamin A/C
Ex-DHF Exercise training in Diastolic Heart Failure LMWH low-molecular-weight heparin
FACIT-Pal Functional Assessment of Chronic Illness LV left ventricular/left ventricle
Therapy - Palliative Care LVAD left ventricular assist device

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FAIR-HF Ferinject Assessment in Patients with Iron LVEDP left ventricular end diastolic pressure
Deficiency and Chronic Heart Failure LVEDV left ventricular end diastolic volume
FCM ferric carboxymaltose LVEF left ventricular ejection fraction
FiO2 fraction of inspired oxygen LVESV left ventricular end systolic volume
GFR glomerular filtration rate LVID left ventricular internal dimension
GGTP gamma-glutamyl transpeptidase LVMI left ventricular mass index
GH growth hormone LVSD left ventricular systolic dysfunction
GLS global longitudinal strain MADIT-CRT Multicenter Automatic Defibrillator Implant-
GLP-1 glucagon-like peptide 1 ation Trial with Cardiac Resynchronization
HAS-BLED Hypertension, Abnormal renal/liver function Therapy
(1 point each), Stroke, Bleeding history or MCS mechanical circulatory support
predisposition, Labile international normal- MERIT-HF Metoprolol CR/XL Randomised Intervention
ized ratio, Elderly (.65 years), Drugs/alcohol Trial in Congestive Heart Failure
concomitantly (1 point each) MR mineralocorticoid receptor/magnetic
HbA1c glycated haemoglobin resonance
HCM hypertrophic cardiomyopathy MRA mineralocorticoid receptor antagonist
HES hypereosinophilic syndrome MR-proANP mid-regional pro A-type natriuretic peptide
HF heart failure MV mitral valve
HFA Heart Failure Association MV A-Wave mitral valve late diastolic flow
HFmrEF heart failure with mid-range ejection fraction MV E-Wave mitral valve early diastolic flow
HFpEF heart failure with preserved ejection fraction MYBPC3 cardiac myosin binding protein C
HFrEF heart failure with reduced ejection fraction MYH7 cardiac b-myosin heavy chain
H-ISDN hydralazine and isosorbide dinitrate n-3 PUFA n-3 polyunsaturated fatty acid
HIV/AIDS human immunodeficiency virus/acquired NEP neprilysin
immune deficiency syndrome NOAC non-vitamin K antagonist oral anticoagulant
HR heart rate NP natriuretic peptide
Hs troponin high sensitivity troponin NPPV non-invasive positive pressure ventilation
IABP intra-aortic balloon pump NSAID non-steroidal anti-inflammatory drug
IABP-SHOCK IntraAortic Balloon Pump in Cardiogenic Shock NSTE-ACS non-ST elevation acute coronary syndrome
IABP-SHOCK II IntraAortic Balloon Pump in Cardiogenic NT-proBNP N-terminal pro-B type natriuretic peptide
Shock II NYHA New York Heart Association
ICD implantable cardioverter-defibrillator o.d. omne in die (once daily)
ICU intensive care unit OMT optimal medical therapy
IHD ischaemic heart disease OSA obstructive sleep apnoea
IL interleukin PaCO2 partial pressure of carbon dioxide in arterial
INH Interdisciplinary Network for Heart Failure blood
INTERMACS Interagency Registry for Mechanically PAH pulmonary arterial hypertension
Assisted Circulatory Support PaO2 partial pressure of oxygen in arterial blood
IN-TIME Implant-based multiparameter telemonitor- PARADIGM-HF Prospective Comparison of ARNI with ACEI
ing of patients with heart failure to Determine Impact on Global Mortality and
IPD individual patient data Morbidity in Heart Failure Trial
I-PRESERVE Irbesartan in Heart Failure with Preserved PARAMOUNT LCZ696 Compared to Valsartan in Patients
Ejection Fraction Study With Chronic Heart Failure and Preserved
i.v. intravenous Left-ventricular Ejection Fraction
IVC inferior vena cava PCI percutaneous coronary intervention
2134 ESC Guidelines

PCWP pulmonary capillary wedge pressure SpO2 transcutaneous oxygen saturation


PDE5I phosphodiesterase 5 inhibitor SPPB Short Physical Performance Battery
Peak VO2 peak oxygen uptake SPRINT Systolic Blood Pressure Intervention
PEP-CHF Perindopril in Elderly People with Chronic Trial
Heart Failure STEMI ST segment elevation myocardial
PET positron emission tomography infarction
PLN phospholamban STICH Surgical Treatment for Ischemic Heart
PPV positive pressure ventilation Failure
PRISMA 7 seven-item, self-completion questionnaire to STS structured telephone support
identify older adults with moderate to severe TAPSE tricuspid annular plane systolic excursion
disabilities TAVI transaortic valve implantation

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PROTECT II Prospective, Multi-center, Randomized TDI tissue Doppler imaging
Controlled Trial of the IMPELLA RECOVER TECOS Trial Evaluating Cardiovascular Outcomes
LP 2.5 System Versus Intra Aortic Balloon with Sitagliptin
Pump (IABP) in Patients Undergoing Non TEHAF Telemonitoring in Patients with Heart
Emergent High Risk PCI Failure
PS-PEEP pressure-support positive end-expiratory Tele-HF Telemonitoring to Improve Heart
pressure Failure Outcomes
PV pulmonary vein TIA transient ischaemic attack
PVR pulmonary vascular resistance TIBC total iron-binding capacity
QALY quality-adjusted life year t.i.d. ter in die (three times a day)
QRS Q, R, and S waves (combination of three of TIM-HF Telemedical Interventional Monitoring in
the graphical deflections) Heart Failure
RA right atrium/atrial TOE transoesophageal echocardiography
RAAS renin –angiotensin– aldosterone system TOPCAT Treatment of Preserved Cardiac Function
RAFT Resynchronization-Defibrillation for Ambu- Heart Failure with an Aldosterone
latory Heart Failure Trial Antagonist
RALES Randomized Aldactone Evaluation Study TR tricuspid regurgitation
RCT randomized controlled trial TRV tricuspid regurgitation velocity
RELAX Phosphodiesterase-5 Inhibition to Improve TSAT transferrin saturation
Clinical Status and Exercise Capacity in TSH thyroid-stimulating hormone
Diastolic Heart Failure TTE transthoracic echocardiography
REVERSE REsynchronization reVErses Remodeling in TTN titin
Systolic left vEntricular dysfunction ULT urate lowering therapy
RV right ventricular/ventricle VAD ventricular assist device
RVAD right ventricular assist device Val-HeFT Valsartan Heart Failure Trial
SADHART Sertraline Antidepressant Heart Attack VE-VCO2 ventilatory equivalent ratio for carbon
Randomized Trial dioxide
SAVE Survival After Veno-arterial ECMO VT ventricular tachycardia
SBP systolic blood pressure VV interval interventricular pacing interval
SCD-HeFT Sudden Cardiac Death in Heart Failure Trial WBC white blood cells
SDB sleep-disordered breathing WISH Weight Monitoring in Patients with Severe
SENIORS Study of the Effects of Nebivolol Intervention Heart Failure
on Outcomes and Rehospitalisations in WRF worsening renal function
Seniors with Heart Failure
SERVE-HF Treatment of sleep-disordered breathing 1. Preamble
with predominant central sleep apnoea with
adaptive Servo-ventilation in patients with Guidelines summarize and evaluate all available evidence on a par-
chronic heart failure ticular issue at the time of the writing process, with the aim of assist-
SHIFT Systolic Heart failure treatment with the If ing health professionals in selecting the best management strategies
inhibitor ivabradine Trial for an individual patient with a given condition, taking into account
SIGNIFY Study Assessing the Morbidity – Mortality the impact on outcome, as well as the riskbenefit ratio of particular
Benefits of the I f Inhibitor Ivabradine in diagnostic or therapeutic means. Guidelines and recommendations
Patients with Coronary Artery Disease should help health professionals to make decisions in their daily
SOLVD Studies of Left Ventricular Dysfunction practice. However, the final decisions concerning an individual pa-
SPECT single-photon emission computed tient must be made by the responsible health professional(s) in con-
tomography sultation with the patient and caregiver as appropriate.
ESC Guidelines 2135

A great number of Guidelines have been issued in recent years by panels. The Committee is also responsible for the endorsement pro-
the European Society of Cardiology (ESC) as well as by other soci- cess of these Guidelines. The ESC Guidelines undergo extensive re-
eties and organisations. Because of the impact on clinical practice, view by the CPG and external experts. After appropriate revisions
quality criteria for the development of guidelines have been estab- the Guidelines are approved by all the experts involved in the Task
lished in order to make all decisions transparent to the user. The re- Force. The finalized document is approved by the CPG for publica-
commendations for formulating and issuing ESC Guidelines can be tion in the European Heart Journal. The Guidelines were developed
found on the ESC website (http://www.escardio.org/Guidelines- after careful consideration of the scientific and medical knowledge
&-Education/Clinical-Practice-Guidelines/Guidelines-development/ and the evidence available at the time of their dating.
Writing-ESC-Guidelines). ESC Guidelines represent the official pos- The task of developing ESC Guidelines covers not only integration
ition of the ESC on a given topic and are regularly updated. of the most recent research, but also the creation of educational tools
Members of this Task Force were selected by the ESC to re- and implementation programmes for the recommendations. To im-

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present professionals involved with the medical care of patients plement the guidelines, condensed pocket guidelines versions, sum-
with this pathology. Selected experts in the field undertook a com- mary slides, booklets with essential messages, summary cards for
prehensive review of the published evidence for management (in- non-specialists, and an electronic version for digital applications
cluding diagnosis, treatment, prevention and rehabilitation) of a (smartphones, etc.) are produced. These versions are abridged and
given condition according to ESC Committee for Practice Guide- thus, if needed, one should always refer to the full text version, which
lines (CPG) policy. A critical evaluation of diagnostic and therapeutic is freely available on the ESC website. The National Cardiac Societies
procedures was performed, including assessment of the risk-benefit of the ESC are encouraged to endorse, translate and implement all
ratio. Estimates of expected health outcomes for larger populations ESC Guidelines. Implementation programmes are needed because
were included, where data exist. The level of evidence and the
strength of the recommendation of particular management options
were weighed and graded according to predefined scales, as out-
Table 1.2 Level of evidence
lined in Tables 1.1 and 1.2.
The experts of the writing and reviewing panels provided declara-
tions of interest forms for all relationships that might be perceived as
real or potential sources of conflicts of interest. These forms were
compiled into one file and can be found on the ESC website (http://
www.escardio.org/guidelines). Any changes in declarations of interest
that arise during the writing period must be notified to the ESC and
updated. The Task Force received its entire financial support from the
ESC without any involvement from the healthcare industry.
The ESC CPG supervises and coordinates the preparation of new
Guidelines produced by task forces, expert groups or consensus

Table 1.1 Classes of recommendations


2136 ESC Guidelines

it has been shown that the outcome of disease may be favourably in- (viii) a new algorithm for a combined diagnosis and treatment ap-
fluenced by the thorough application of clinical recommendations. proach of acute HF based on the presence/absence of conges-
Surveys and registries are needed to verify that real-life daily prac- tion/hypoperfusion.
tice is in keeping with what is recommended in the guidelines, thus
We followed the format of the previous ESC 2012 HF Guidelines.
completing the loop between clinical research, writing of guidelines,
Therapeutic recommendations state the treatment effect supported
disseminating them and implementing them into clinical practice.
by the class and level of recommendation in tabular format; in the
Health professionals are encouraged to take the ESC Guidelines
case of chronic HF due to left ventricular systolic dysfunction
fully into account when exercising their clinical judgment, as well as
(LVSD) the recommendations focus on mortality and morbidity
in the determination and the implementation of preventive, diagnos-
outcomes. Detailed summaries of the key evidence supporting gen-
tic or therapeutic medical strategies. However, the ESC Guidelines
erally recommended treatments have been provided. For diagnostic
do not override in any way whatsoever the individual responsibility
recommendations a level of evidence C has been typically decided

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of health professionals to make appropriate and accurate decisions
upon, because for the majority of diagnostic tests there are no data
in consideration of each patient’s health condition and in consult-
from randomized controlled trials (RCTs) showing that they will
ation with that patient and the patient’s caregiver where appropriate
lead to reductions in morbidity and/or mortality. Practical guidance
and/or necessary. It is also the health professional’s responsibility to
is provided for the use of the important disease-modifying drugs and
verify the rules and regulations applicable to drugs and devices at the
diuretics. When possible, other relevant guidelines, consensus
time of prescription.
statements and position papers have been cited to avoid unduly
lengthy text. All tables should be read in conjunction with their ac-
companying text and not read in isolation.
This document is the result of extensive interactions between the
2. Introduction Task Force, the review team and the ESC Committee for Practice
The aim of all the ESC Guidelines is to help health professionals to Guidelines. It represents a consensus of opinion of all of the experts
make decisions in their everyday life based on the best available evi- involved in its development. Concurrently to the development of
dence. We will soon be celebrating the 30th anniversary of clinical the 2016 ESC Guidelines on HF, the group writing the “2016
trials that for the first time incontrovertibly demonstrated that the ACC/AHA/HFSA Focused Update on New Pharmacological Ther-
miserable outcome of patients with heart failure (HF) can be mark- apy for Heart Failure” independently developed its recommenda-
edly improved.2 Since then, in the area of HF management we have tions on new pharmacotherapy for Heart Failure. Both working
witnessed and celebrated numerous highs, which have definitely groups/Task Force independently surveyed the evidence, arrived
outnumbered several lows, all of which have allowed us to unravel at similar conclusions, and constructed similar, but not identical, re-
the pathophysiology of this clinical syndrome, but more importantly commendations. Given the concordance, the respective organiza-
has led to better care of our patients.3 In the year 2016, no one tions simultaneously issued aligned recommendations on the use
would any longer dispute that, by applying all evidence-based dis- of these new treatments to minimize confusion and improve the
coveries, HF is now becoming a preventable and treatable disease. care of patients with HF.
The aim of this document is to provide practical, evidence-based
guidelines for the diagnosis and treatment of HF. The principal
changes from the 2012 guidelines relate to: 3. Definition, epidemiology and
(i) a new term for patients with HF and a left ventricular ejection prognosis
fraction (LVEF) that ranges from 40 to 49% — ‘HF with mid-
range EF (HFmrEF)’; we believe that identifying HFmrEF as a 3.1 Definition of heart failure
separate group will stimulate research into the underlying char- HF is a clinical syndrome characterized by typical symptoms
acteristics, pathophysiology and treatment of this population; (e.g. breathlessness, ankle swelling and fatigue) that may be accom-
(ii) clear recommendations on the diagnostic criteria for HF with re- panied by signs (e.g. elevated jugular venous pressure, pulmonary
duced EF (HFrEF), HFmrEF and HF with preserved EF (HFpEF); crackles and peripheral oedema) caused by a structural and/or func-
(iii) a new algorithm for the diagnosis of HF in the non-acute set- tional cardiac abnormality, resulting in a reduced cardiac output and/
ting based on the evaluation of HF probability; or elevated intracardiac pressures at rest or during stress.
(iv) recommendations aimed at prevention or delay of the devel- The current definition of HF restricts itself to stages at which clinical
opment of overt HF or the prevention of death before the on- symptoms are apparent. Before clinical symptoms become apparent,
set of symptoms; patients can present with asymptomatic structural or functional cardiac
(v) indications for the use of the new compound sacubitril/ abnormalities [systolic or diastolic left ventricular (LV) dysfunction],
valsartan, the first in the class of angiotensin receptor neprily- which are precursors of HF. Recognition of these precursors is import-
sin inhibitors (ARNIs); ant because they are related to poor outcomes, and starting treatment
(vi) modified indications for cardiac resynchronization therapy at the precursor stage may reduce mortality in patients with asymp-
(CRT); tomatic systolic LV dysfunction4,5 (for details see Section 6).
(vii) the concept of an early initiation of appropriate therapy going Demonstration of an underlying cardiac cause is central to the
along with relevant investigations in acute HF that follows the diagnosis of HF. This is usually a myocardial abnormality causing sys-
‘time to therapy’ approach already well established in acute tolic and/or diastolic ventricular dysfunction. However, abnormal-
coronary syndrome (ACS); ities of the valves, pericardium, endocardium, heart rhythm and
ESC Guidelines 2137

conduction can also cause HF (and more than one abnormality is of- characteristics, pathophysiology and treatment of this group of pa-
ten present). Identification of the underlying cardiac problem is cru- tients. Patients with HFmrEF most probably have primarily mild sys-
cial for therapeutic reasons, as the precise pathology determines the tolic dysfunction, but with features of diastolic dysfunction
specific treatment used (e.g. valve repair or replacement for valvular (Table 3.1).
disease, specific pharmacological therapy for HF with reduced EF, Patients without detectable LV myocardial disease may have
reduction of heart rate in tachycardiomyopathy, etc). other cardiovascular causes for HF (e.g. pulmonary hypertension,
valvular heart disease, etc.). Patients with non-cardiovascular path-
ologies (e.g. anaemia, pulmonary, renal or hepatic disease) may have
3.2 Terminology
symptoms similar or identical to those of HF and each may compli-
3.2.1 Heart failure with preserved, mid-range and reduced
cate or exacerbate the HF syndrome.
ejection fraction
The main terminology used to describe HF is historical and is based

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on measurement of the LVEF. HF comprises a wide range of pa- 3.2.2 Terminology related to the time course of heart
tients, from those with normal LVEF [typically considered as failure
≥50%; HF with preserved EF (HFpEF)] to those with reduced In these guidelines, the term HF is used to describe the symptomatic
LVEF [typically considered as ,40%; HF with reduced EF (HFrEF)] syndrome, graded according to the New York Heart Association
(Table 3.1). Patients with an LVEF in the range of 40 –49% represent (NYHA) functional classification (see Section 3.2.3 and Web
a ‘grey area’, which we now define as HFmrEF (Table 3.1). Differen- Table 3.2), although a patient can be rendered asymptomatic by
tiation of patients with HF based on LVEF is important due to treatment. In these guidelines, a patient who has never exhibited
different underlying aetiologies, demographics, co-morbidities and the typical symptoms and/or signs of HF and with a reduced LVEF
response to therapies.6 Most clinical trials published after 1990 se- is described as having asymptomatic LV systolic dysfunction. Patients
lected patients based on LVEF [usually measured using echocardiog- who have had HF for some time are often said to have ‘chronic HF’.
raphy, a radionuclide technique or cardiac magnetic resonance A treated patient with symptoms and signs that have remained gen-
(CMR)], and it is only in patients with HFrEF that therapies have erally unchanged for at least 1 month is said to be ‘stable’. If chronic
been shown to reduce both morbidity and mortality. stable HF deteriorates, the patient may be described as ‘decompen-
The diagnosis of HFpEF is more challenging than the diagnosis of sated’ and this may happen suddenly or slowly, often leading to hos-
HFrEF. Patients with HFpEF generally do not have a dilated LV, but pital admission, an event of considerable prognostic importance.
instead often have an increase in LV wall thickness and/or increased New-onset (‘de novo’) HF may also present acutely, for example,
left atrial (LA) size as a sign of increased filling pressures. Most have as a consequence of acute myocardial infarction (AMI), or in a sub-
additional ‘evidence’ of impaired LV filling or suction capacity, also acute (gradual) fashion, for example, in patients with a dilated cardio-
classified as diastolic dysfunction, which is generally accepted as myopathy (DCM), who often have symptoms for weeks or months
the likely cause of HF in these patients (hence the term ‘diastolic before the diagnosis becomes clear. Although symptoms and signs
HF’). However, most patients with HFrEF (previously referred to of HF may resolve, the underlying cardiac dysfunction may not, and
as ‘systolic HF’) also have diastolic dysfunction, and subtle abnormal- patients remain at the risk of recurrent ‘decompensation’.
ities of systolic function have been shown in patients with HFpEF. Occasionally, however, a patient may have HF due to a problem
Hence the preference for stating preserved or reduced LVEF over that resolves completely (e.g. acute viral myocarditis, takotsubo car-
preserved or reduced ‘systolic function’. diomyopathy or tachycardiomyopathy). Other patients, particularly
In previous guidelines it was acknowledged that a grey area exists those with ‘idiopathic’ DCM, may also show substantial or even
between HFrEF and HFpEF.7 These patients have an LVEF that complete recovery of LV systolic function with modern disease-
ranges from 40 to 49%, hence the term HFmrEF. Identifying HFmrEF modifying therapy [including angiotensin-converting enzyme inhibi-
as a separate group will stimulate research into the underlying tor (ACEI), beta-blocker, mineralocorticoid receptor antagonist

Table 3.1 Definition of heart failure with preserved (HFpEF), mid-range (HFmrEF) and reduced ejection fraction
(HFrEF)

BNP ¼ B-type natriuretic peptide; HF ¼ heart failure; HFmrEF ¼ heart failure with mid-range ejection fraction; HFpEF ¼ heart failure with preserved ejection fraction; HFrEF ¼
heart failure with reduced ejection fraction; LAE ¼ left atrial enlargement; LVEF ¼ left ventricular ejection fraction; LVH ¼ left ventricular hypertrophy; NT-proBNP ¼ N-terminal
pro-B type natriuretic peptide.
a
Signs may not be present in the early stages of HF (especially in HFpEF) and in patients treated with diuretics.
b
BNP.35 pg/ml and/or NT-proBNP.125 pg/mL.
2138 ESC Guidelines

(MRA), ivabradine and/or CRT]. ‘Congestive HF’ is a term that is In clinical practice, a clear distinction between acquired and inher-
sometimes used, and may describe acute or chronic HF with evi- ited cardiomyopathies remains challenging. In most patients with a
dence of volume overload. Many or all of these terms may be accur- definite clinical diagnosis of HF, there is no confirmatory role for
ately applied to the same patient at different times, depending upon routine genetic testing, but genetic counselling is recommended in
their stage of illness. patients with hypertrophic cardiomyopathy (HCM), ‘idiopathic’
DCM or arrhythmogenic right ventricular cardiomyopathy
3.2.3 Terminology related to the symptomatic severity (ARVC) (see Section 5.10.1), since the outcomes of these tests
of heart failure may have clinical implications.
The NYHA functional classification (Web Table 3.2) has been used Over the last 30 years, improvements in treatments and their im-
to describe the severity of symptoms and exercise intolerance. plementation have improved survival and reduced the hospitalization
However, symptom severity correlates poorly with many measures rate in patients with HFrEF, although the outcome often remains un-

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of LV function; although there is a clear relationship between the se- satisfactory. The most recent European data (ESC-HF pilot study)
verity of symptoms and survival, patients with mild symptoms may demonstrate that 12-month all-cause mortality rates for hospitalized
still have an increased risk of hospitalization and death.8 – 10 and stable/ambulatory HF patients were 17% and 7%, respectively,
Sometimes the term ‘advanced HF’ is used to characterize pa- and the 12-month hospitalization rates were 44% and 32%, respect-
tients with severe symptoms, recurrent decompensation and severe ively.35 In patients with HF (both hospitalized and ambulatory), most
cardiac dysfunction.11 The American College of Cardiology Founda- deaths are due to cardiovascular causes, mainly sudden death and
tion/American Heart Association (ACCF/AHA) classification de- worsening HF. All-cause mortality is generally higher in HFrEF than
scribes stages of HF development based on structural changes and HFpEF.35,36 Hospitalizations are often due to non-cardiovascular
symptoms (Web Table 3.3).12 The Killip classification may be used to causes, particularly in patients with HFpEF. Hospitalization for cardio-
describe the severity of the patient’s condition in the acute setting vascular causes did not change from 2000 to 2010, whereas those
after myocardial infarction (see Section 12).13 with non-cardiovascular causes increased.31

3.4 Prognosis
3.3 Epidemiology, aetiology and natural Estimation of prognosis for morbidity, disability and death helps pa-
history of heart failure tients, their families and clinicians decide on the appropriate type
and timing of therapies (in particular, decisions about a rapid transi-
The prevalence of HF depends on the definition applied, but is ap-
tion to advanced therapies) and assists with planning of health and
proximately 1–2% of the adult population in developed countries,
social services and resources.
rising to ≥10% among people .70 years of age.14 – 17 Among peo-
Numerous prognostic markers of death and/or HF hospitalization
ple .65 years of age presenting to primary care with breathlessness
have been identified in patients with HF (Web Table 3.5). However,
on exertion, one in six will have unrecognized HF (mainly
their clinical applicability is limited and precise risk stratification in
HFpEF).18,19 The lifetime risk of HF at age 55 years is 33% for
HF remains challenging.
men and 28% for women.16 The proportion of patients with HFpEF
In recent decades, several multivariable prognostic risk scores
ranges from 22 to 73%, depending on the definition applied, the clin-
have been developed for different populations of patients with
ical setting (primary care, hospital clinic, hospital admission), age and
HF,36 – 41 and some are available as interactive online applications.
sex of the studied population, previous myocardial infarction and
Multivariable risk scores may help predict death in patients with
the year of publication.17,18,20 – 30
HF, but remain less useful for the prediction of subsequent HF hos-
Data on temporal trends based on hospitalized patients suggest
pitalizations.37,38 A systematic review examining 64 prognostic
that the incidence of HF may be decreasing, more for HFrEF than
models37 along with a meta-analysis and meta-regression study of
for HFpEF.31,32 HFpEF and HFrEF seem to have different epidemio-
117 prognostic models38 revealed only a moderate accuracy of
logical and aetiological profiles. Compared with HFrEF, patients
models predicting mortality, whereas models designed to predict
with HFpEF are older, more often women and more commonly
the combined endpoint of death or hospitalization, or only hospital-
have a history of hypertension and atrial fibrillation (AF), while a his-
ization, had an even poorer discriminative ability.
tory of myocardial infarction is less common.32,33 The characteristics
of patients with HFmrEF are between those with HFrEF and HFpEF,34
but further studies are needed to better characterize this population. 4. Diagnosis
The aetiology of HF is diverse within and among world regions.
There is no agreed single classification system for the causes of 4.1 Symptoms and signs
HF, with much overlap between potential categories (Table 3.4). Symptoms are often non-specific and do not, therefore, help discrim-
Many patients will have several different pathologies—cardiovascu- inate between HF and other problems (Table 4.1).42 – 46 Symptoms and
lar and non-cardiovascular—that conspire to cause HF. Identifica- signs of HF due to fluid retention may resolve quickly with diuretic
tion of these diverse pathologies should be part of the diagnostic therapy. Signs, such as elevated jugular venous pressure and displace-
workup, as they may offer specific therapeutic opportunities. ment of the apical impulse, may be more specific, but are harder to
Many patients with HF and ischaemic heart disease (IHD) have a detect and have poor reproducibility.18,46,47 Symptoms and signs
history of myocardial infarction or revascularization. However, a may be particularly difficult to identify and interpret in obese indivi-
normal coronary angiogram does not exclude myocardial scar duals, in the elderly and in patients with chronic lung disease.48 – 50
(e.g. by CMR imaging) or impaired coronary microcirculation as al- Younger patients with HF often have a different aetiology, clinical pres-
ternative evidence for IHD. entation and outcome compared with older patients.51,52
ESC Guidelines 2139

Table 3.4 Aetiologies of heart failure

DISEASED MYOCARDIUM
Ischaemic heart Myocardial scar
disease
Myocardial stunning/hibernation
Epicardial coronary artery disease
Abnormal coronary microcirculation
Endothelial dysfunction
Toxic damage Recreational substance abuse Alcohol, cocaine, amphetamine, anabolic steroids.
Heavy metals Copper, iron, lead, cobalt.

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Medications Cytostatic drugs (e.g. anthracyclines), immunomodulating drugs (e.g. interferons monoclonal
antibodies such as trastuzumab, cetuximab), antidepressant drugs, antiarrhythmics, non-steroidal

Radiation
Immune-mediated Related to infection Bacteria, spirochaetes, fungi, protozoa, parasites (Chagas disease), rickettsiae, viruses (HIV/AIDS).
Not related to infection Lymphocytic/giant cell myocarditis, autoimmune diseases (e.g. Graves’ disease, rheumatoid
damage
arthritis, connective tissue disorders, mainly systemic lupus erythematosus), hypersensitivity and
eosinophilic myocarditis (Churg–Strauss).
Related to malignancy
Not related to malignancy Amyloidosis, sarcoidosis, haemochromatosis (iron), glycogen storage diseases (e.g. Pompe disease),
lysosomal storage diseases (e.g. Fabry disease).
Metabolic Hormonal
derangements disease, Addison disease, diabetes, metabolic syndrome, phaeochromocytoma, pathologies related
to pregnancy and peripartum.
Nutritional
(e.g. malignancy, AIDS, anorexia nervosa), obesity.
Genetic abnormalities Diverse forms HCM, DCM, LV non-compaction, ARVC, restrictive cardiomyopathy (for details see respective
expert documents), muscular dystrophies and laminopathies.
ABNORMAL LOADING CONDITIONS
Hypertension
Valve and Acquired Mitral, aortic, tricuspid and pulmonary valve diseases.
myocardium
Congenital Atrial and ventricular septum defects and others (for details see a respective expert document).
structural defects
Pericardial and Pericardial Constrictive pericarditis
endomyocardial Pericardial effusion
pathologies
Endomyocardial
High output states
Volume overload
ARRHYTHMIAS
Tachyarrhythmias Atrial, ventricular arrhythmias.
Bradyarrhythmias Sinus node dysfunctions, conduction disorders.

ARVC ¼ arrhythmogenic right ventricular cardiomyopathy; DCM ¼ dilated cardiomyopathy; EMF ¼ endomyocardial fibrosis; GH ¼ growth hormone; HCM ¼ hypertrophic
cardiomyopathy; HES ¼ hypereosinophilic syndrome; HIV/AIDS ¼ human immunodeficiency virus/acquired immune deficiency syndrome; LV ¼ left ventricular.

A detailed history should always be obtained. HF is unusual in an 4.2 Essential initial investigations:
individual with no relevant medical history (e.g. a potential cause of natriuretic peptides, electrocardiogram
cardiac damage), whereas certain features, particularly previous
myocardial infarction, greatly increase the likelihood of HF in a pa-
and echocardiography
tient with appropriate symptoms and signs.42 – 45 The plasma concentration of natriuretic peptides (NPs) can be used
At each visit, symptoms and signs of HF need to be assessed, with as an initial diagnostic test, especially in the non-acute setting when
particular attention to evidence of congestion. Symptoms and signs echocardiography is not immediately available. Elevated NPs help
are important in monitoring a patient’s response to treatment and establish an initial working diagnosis, identifying those who require
stability over time. Persistence of symptoms despite treatment usu- further cardiac investigation; patients with values below the cut-
ally indicates the need for additional therapy, and worsening of point for the exclusion of important cardiac dysfunction do not
symptoms is a serious development (placing the patient at risk of ur- require echocardiography (see also Section 4.3 and Section 12).
gent hospital admission and death) and merits prompt medical Patients with normal plasma NP concentrations are unlikely to
attention. have HF. The upper limit of normal in the non-acute setting for
2140 ESC Guidelines

Echocardiography is the most useful, widely available test in pa-


Table 4.1 Symptoms and signs typical of heart failure tients with suspected HF to establish the diagnosis. It provides im-
mediate information on chamber volumes, ventricular systolic and
Symptoms Signs
diastolic function, wall thickness, valve function and pulmonary
Typical hypertension.65 – 74 This information is crucial in establishing the
Breathlessness Elevated jugular venous pressure diagnosis and in determining appropriate treatment (see Sections
Orthopnoea 5.2 –5.4 for details on echocardiography).
Paroxysmal nocturnal dyspnoea Third heart sound (gallop rhythm)
The information provided by careful clinical evaluation and the
Reduced exercise tolerance Laterally displaced apical impulse
Fatigue, tiredness, increased time above mentioned tests will permit an initial working diagnosis and
to recover after exercise treatment plan in most patients. Other tests are generally required
Ankle swelling only if the diagnosis remains uncertain (e.g. if echocardiographic

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Less typical images are suboptimal or an unusual cause of HF is suspected)
Nocturnal cough Weight gain (>2 kg/week) (for details see Sections 5.5 –5.10).
Wheezing Weight loss (in advanced HF)
Bloated feeling Tissue wasting (cachexia)
Loss of appetite Cardiac murmur
Confusion (especially in the Peripheral oedema (ankle, sacral, 4.3 Algorithm for the diagnosis of heart
elderly) scrotal) failure
Depression Pulmonary crepitations 4.3.1 Algorithm for the diagnosis of heart failure in the
Palpitations Reduced air entry and dullness to
Dizziness percussion at lung bases (pleural
non-acute setting
Syncope effusion) An algorithm for the diagnosis of HF in the non-acute setting is
Bendopnea53 Tachycardia shown in Figure 4.1. The diagnosis of HF in the acute setting is
Irregular pulse discussed in Section 12.
Tachypnoea
Cheyne Stokes respiration
For patients presenting with symptoms or signs for the first time,
Hepatomegaly non-urgently in primary care or in a hospital outpatient clinic
Ascites (Table 4.1), the probability of HF should first be evaluated based
Cold extremities on the patient’s prior clinical history [e.g. coronary artery disease
Oliguria
Narrow pulse pressure
(CAD), arterial hypertension, diuretic use], presenting symptoms
(e.g. orthopnoea), physical examination (e.g. bilateral oedema, in-
creased jugular venous pressure, displaced apical beat) and resting
HF ¼ heart failure.
ECG. If all elements are normal, HF is highly unlikely and other diag-
noses need to be considered. If at least one element is abnormal,
B-type natriuretic peptide (BNP) is 35 pg/mL and for N-terminal plasma NPs should be measured, if available, to identify those
pro-BNP (NT-proBNP) it is 125 pg/mL; in the acute setting, higher who need echocardiography (an echocardiogram is indicated if
values should be used [BNP , 100 pg/mL, NT-proBNP , 300 pg/ the NP level is above the exclusion threshold or if circulating NP
mL and mid-regional pro A-type natriuretic peptide (MR-proANP) levels cannot be assessed).55 – 60,75 – 78
, 120 pmol/L]. Diagnostic values apply similarly to HFrEF and
HFpEF; on average, values are lower for HFpEF than for HFrEF.54,55
At the mentioned exclusionary cut-points, the negative predictive 4.3.2 Diagnosis of heart failure with preserved ejection
fraction
values are very similar and high (0.94 –0.98) in both the non-acute
The diagnosis of HFpEF remains challenging. LVEF is normal and
and acute setting, but the positive predictive values are lower
signs and symptoms for HF (Table 4.1) are often non-specific and
both in the non-acute setting (0.44 – 0.57) and in the acute setting
do not discriminate well between HF and other clinical conditions.
(0.66 – 0.67).54,56 – 61 Therefore, the use of NPs is recommended
This section summarizes practical recommendations necessary for
for ruling-out HF, but not to establish the diagnosis.
proper diagnosis of this clinical entity in clinical practice.
There are numerous cardiovascular and non-cardiovascular
The diagnosis of chronic HFpEF, especially in the typical elderly
causes of elevated NPs that may weaken their diagnostic utility in
patient with co-morbidities and no obvious signs of central fluid
HF. Among them, AF, age and renal failure are the most important
overload, is cumbersome and a validated gold standard is missing.
factors impeding the interpretation of NP measurements.55 On the
To improve the specificity of diagnosing HFpEF, the clinical diagnosis
other hand, NP levels may be disproportionally low in obese pa-
needs to be supported by objective measures of cardiac dysfunction
tients62 (see also Section 12.2 and Table 12.3).
at rest or during exercise. The diagnosis of HFpEF requires the fol-
An abnormal electrocardiogram (ECG) increases the likelihood
lowing conditions to be fulfilled (see Table 3.1):
of the diagnosis of HF, but has low specificity.18,46,63,64 Some abnor-
malities on the ECG provide information on aetiology (e.g. myocar- † The presence of symptoms and/or signs of HF (see Table 4.1)
dial infarction), and findings on the ECG might provide indications † A ‘preserved’ EF (defined as LVEF ≥50% or 40 – 49% for
for therapy (e.g. anticoagulation for AF, pacing for bradycardia, HFmrEF)
CRT if broadened QRS complex) (see Sections 8 and 10). HF is un- † Elevated levels of NPs (BNP .35 pg/mL and/or NT-proBNP
likely in patients presenting with a completely normal ECG (sensitiv- .125 pg/mL)
ity 89%).43 Therefore, the routine use of an ECG is mainly † Objective evidence of other cardiac functional and structural al-
recommended to rule out HF. terations underlying HF (for details, see below)
ESC Guidelines 2141

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Figure 4.1 Diagnostic algorithm for a diagnosis of heart failure of non-acute onset
BNP ¼ B-type natriuretic peptide; CAD ¼ coronary artery disease; HF ¼ heart failure; MI ¼ myocardial infarction; NT-proBNP ¼ N-terminal
pro-B type natriuretic peptide.
a
Patient reporting symptoms typical of HF (see Table 4.1).
b
Normal ventricular and atrial volumes and function.
c
Consider other causes of elevated natriuretic peptides (Table 12.3).
2142 ESC Guidelines

† In case of uncertainty, a stress test or invasively measured ele- Patients with HFpEF are a heterogeneous group with various
vated LV filling pressure may be needed to confirm the diagnosis underlying aetiologies and pathophysiological abnormalities. Based
(for details, see below). on specific suspected causes, additional tests can be performed
(Web Table 4.4).71,88 – 94 However, they can only be recommended
The initial assessment consists of a clinical diagnosis compatible with if the results might affect management.
the algorithm presented above and the assessment of LVEF by echo-
cardiography. The cut-off of 50% for a diagnosis of HFpEF is arbi-
trary; patients with an LVEF between 40 and 49% are often 5. Cardiac imaging and other
classified as HFpEF in clinical trials.79 However, in the present guide- diagnostic tests
lines, we define HFpEF as an LVEF ≥50% and consider patients with
an LVEF between 40 and 49% as a grey area, which could be indi- Cardiac imaging plays a central role in the diagnosis of HF and in guiding
treatment. Of several imaging modalities available, echocardiography is

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cated as HFmrEF. Clinical signs and symptoms are similar for pa-
tients with HFrEF, HFmrEF and HFpEF. Typical demographics and the method of choice in patients with suspected HF, for reasons of ac-
co-morbidities are provided in Web Table 4.2. The resting ECG curacy, availability (including portability), safety and cost.68,69,72 Echocar-
may reveal abnormalities such as AF, LV hypertrophy and repolari- diography may be complemented by other modalities, chosen
sation abnormalities. A normal ECG and/or plasma concentrations according to their ability to answer specific clinical questions and taking
of BNP ,35 pg/mL and/or NT-proBNP ,125 pg/mL make a diag- account of contraindications to and risks of specific tests.71,73
nosis of HFpEF, HFmrEF or HFrEF unlikely. In general, imaging tests should only be performed when they
The next step comprises an advanced workup in case of initial evi- have a meaningful clinical consequence. The reliability of the out-
dence of HFpEF/HFmrEF and consists of objective demonstration of comes is highly dependent on the imaging modality, the operator
structural and/or functional alterations of the heart as the underlying and centre experience and imaging quality. Normal values may
cause for the clinical presentation. Key structural alterations are a vary with age, sex and imaging modality.
left atrial volume index (LAVI) .34 mL/m2 or a left ventricular
mass index (LVMI) ≥115 g/m 2 for males and ≥95 g/m 2 for fe- 5.1 Chest X-ray
males.65,67,72 Key functional alterations are an E/e′ ≥13 and a A chest X-ray is of limited use in the diagnostic work-up of patients
mean e’ septal and lateral wall ,9 cm/s.65,67,70,72,80 – 84 Other (indir- with suspected HF. It is probably most useful in identifying an alter-
ect) echocardiographically derived measurements are longitudinal native, pulmonary explanation for a patient’s symptoms and signs,
strain or tricuspid regurgitation velocity (TRV).72,82 An overview i.e. pulmonary malignancy and interstitial pulmonary disease, al-
of normal and abnormal values for echocardiographic parameters though computed tomography (CT) of the chest is currently the
related to diastolic function is presented in Web Table 4.3. Not all standard of care. For the diagnosis of asthma or chronic obstructive
of the recommended values are identical to those published in pre- pulmonary disease (COPD), pulmonary function testing with spir-
vious guidelines, because of the inclusion of new data published in ometry is needed. The chest X-ray may, however, show pulmonary
recent reports, in particular by Cabarello et al. 70 venous congestion or oedema in a patient with HF, and is more
A diastolic stress test can be performed with echocardiography, helpful in the acute setting than in the non-acute setting.49,64 It is im-
typically using a semi-supine bicycle ergometer exercise protocol portant to note that significant LV dysfunction may be present with-
with assessment of LV (E/e′ ) and pulmonary artery pressures out cardiomegaly on the chest X-ray.49,64
(TRV), systolic dysfunction (longitudinal strain), stroke volume and
cardiac output changes with exercise.85,86 Different dynamic exercise 5.2 Transthoracic echocardiography
protocols are available, with semi-supine bicycle ergometry and echo- Echocardiography is a term used here to refer to all cardiac ultra-
cardiography at rest and submaximal exercise being used most of- sound imaging techniques, including two-dimensional/three-
ten.85 Exercise-induced increases in E/e′ beyond diagnostic cut-offs dimensional echocardiography, pulsed and continuous wave Dop-
(i.e. .13), but also other indirect measures of systolic and diastolic pler, colour flow Doppler, tissue Doppler imaging (TDI) contrast
function, such as longitudinal strain or TRV, are used. Alternatively, in- echocardiography and deformation imaging (strain and strain rate).
vasive haemodynamics at rest with assessment of filling pressures Transthoracic echocardiography (TTE) is the method of choice
[pulmonary capillary wedge pressure (PCWP) ≥15 mmHg or left for assessment of myocardial systolic and diastolic function of
ventricular end diastolic pressure (LVEDP) ≥16 mmHg] followed both left and right ventricles.
by exercise haemodynamics if below these thresholds, with assess-
ment of changes in filling pressures, pulmonary artery systolic pres- 5.2.1 Assessment of left ventricular systolic function
sure, stroke volume and cardiac output, can be performed.87 For measurement of LVEF, the modified biplane Simpson’s rule is re-
The diagnosis of HFpEF in patients with AF is difficult. Since AF is commended. LV end diastolic volume (LVEDV) and LV end systolic
associated with higher NP levels, the use of NT-proBNP or BNP for volume (LVESV) are obtained from apical four- and two-chamber
diagnosing HFpEF probably needs to be stratified by the presence of views. This method relies on accurate tracing of endocardial bor-
sinus rhythm (with lower cut-offs) vs. AF (higher cut-offs). LAVI is ders. In case of poor image quality, contrast agents should be
increased by AF, and functional parameters of diastolic dysfunction used to improve endocardial delineation.72 Measurement of region-
are less well established in AF, and other cut-off values probably ap- al wall motion abnormalities might be particularly relevant for pa-
ply. On the other hand, AF might be a sign of the presence of HFpEF, tients suspected of CAD or myocarditis.
and patients with AF and HFpEF often have similar patient character- The Teichholz and Quinones methods of calculating LVEF from
istics. In addition, patients with HFpEF and AF might have more ad- linear dimensions, as well as a measurement of fractional shortening,
vanced HF compared with patients with HFpEF and sinus rhythm. are not recommended, as they may result in inaccuracies,
ESC Guidelines 2143

particularly in patients with regional LV dysfunction and/or LV re- 5.4 Stress echocardiography
modelling. Three-dimensional echocardiography of adequate quality Exercise or pharmacological stress echocardiography may be used
improves the quantification of LV volumes and LVEF and has the for the assessment of inducible ischaemia and/or myocardium viabil-
best accuracy compared with values obtained through CMR.95 ity99 and in some clinical scenarios of patients with valve disease (e.g.
Doppler techniques allow the calculation of haemodynamic vari- dynamic mitral regurgitation, low-flow – low-gradient aortic sten-
ables, such as stroke volume index and cardiac output, based on the osis).99,100 There are also suggestions that stress echocardiography
velocity time integral at the LV outflow tract area. may allow the detection of diastolic dysfunction related to exercise
In recent years, tissue Doppler parameters (S wave) and deform- exposure in patients with exertional dyspnoea, preserved LVEF and
ation imaging techniques (strain and strain rate) have been shown to inconclusive diastolic parameters at rest.85,86
be reproducible and feasible for clinical use, especially in detecting sub-
tle abnormalities in systolic function in the preclinical stage; however, 5.5 Cardiac magnetic resonance
measurements may vary among vendors and software versions.74

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CMR is acknowledged as the gold standard for the measurements of
volumes, mass and EF of both the left and right ventricles. It is the
5.2.2 Assessment of left ventricular diastolic function best alternative cardiac imaging modality for patients with non-
LV diastolic dysfunction is thought to be the underlying pathophysio- diagnostic echocardiographic studies (particularly for imaging of
logical abnormality in patients with HFpEF and perhaps HFmrEF, and the right heart) and is the method of choice in patients with complex
thus its assessment plays an important role in diagnosis. Although congenital heart diseases.91,101,102
echocardiography is at present the only imaging technique that can CMR is the preferred imaging method to assess myocardial fibrosis
allow for the diagnosis of diastolic dysfunction, no single echocardiog- using late gadolinium enhancement (LGE) along with T1 mapping and
raphy variable is sufficiently accurate to be used in isolation to make a can be useful for establishing HF aetiology.91,103 For example, CMR
diagnosis of LV diastolic dysfunction. Therefore, a comprehensive with LGE allows differentiation between ischaemic and non-ischaemic
echocardiography examination incorporating all relevant two- origins of HF and myocardial fibrosis/scars can be visualized. In addition,
dimensional and Doppler data is recommended (see Section 4.3.2). CMR allows the characterization of myocardial tissue of myocarditis,
amyloidosis, sarcoidosis, Chagas disease, Fabry disease non-compaction
5.2.3 Assessment of right ventricular function and cardiomyopathy and haemochromatosis.91,101,103,104
pulmonary arterial pressure CMR may also be used for the assessment of myocardial ischae-
An obligatory element of echocardiography examination is the as- mia and viability in patients with HF and CAD (considered suitable
sessment of right ventricle (RV) structure and function, including for coronary revascularization). However, limited evidence from
RV and right atrial (RA) dimensions, an estimation of RV systolic RCTs has failed to show that viability assessed by CMR or other
function and pulmonary arterial pressure. Among parameters re- means identified patients who obtained clinical benefit from revas-
flecting RV systolic function, the following measures are of particular cularization.105 – 107
importance: tricuspid annular plane systolic excursion (TAPSE; ab- Clinical limitations of CMR include local expertise, lower availability
normal TAPSE ,17 mm indicates RV systolic dysfunction) and and higher costs compared with echocardiography, uncertainty about
tissue Doppler-derived tricuspid lateral annular systolic velocity safety in patients with metallic implants (including cardiac devices) and
(s′ ) (s′ velocity ,9.5 cm/s indicates RV systolic dysfunction).72,96 less reliable measurements in patients with tachyarrhythmias. Claus-
Systolic pulmonary artery pressure is derived from an optimal trophobia is an important limitation for CMR. Linear gadolinium-
recording of maximal tricuspid regurgitant jet and the tricuspid based contrast agents are contraindicated in individuals with a glom-
systolic gradient, together with an estimate of RA pressure on the erular filtration rate (GFR) ,30 mL/min/1.73m2, because they may
basis of inferior vena cava (IVC) size and its breathing-related col- trigger nephrogenic systemic fibrosis (this may be less of a concern
lapse.97 RV size should be routinely assessed by conventional two- with newer cyclic gadolinium-based contrast agents).108
dimensional echocardiography using multiple acoustic windows, and
the report should include both qualitative and quantitative para- 5.6 Single-photon emission computed
meters. In laboratories with experience in three-dimensional echo- tomography and radionuclide
cardiography, when knowledge of RV volumes may be clinically
ventriculography
important, three-dimensional measurement of RV volumes is re-
Single-photon emission CT (SPECT) may be useful in assessing is-
commended.95 Three-dimensional speckle tracking echocardio-
chaemia and myocardial viability.109 Gated SPECT can also yield in-
graphy may be an additional quantitative method to assess RV
formation on ventricular volumes and function, but exposes the
function in specialised centres.98
patient to ionizing radiation. 3,3-diphosphono-1,2-propanodicar-
boxylic acid (DPD) scintigraphy may be useful for the detection of
5.3 Transoesophageal echocardiography transthyretin cardiac amyloidosis.110
Transoesophageal echocardiography (TOE) is not needed in the
routine diagnostic assessment of HF; however, it may be valuable 5.7 Positron emission tomography
in some clinical scenarios of patients with valve disease, suspected Positron emission tomography (PET) (alone or with CT) may be
aortic dissection, suspected endocarditis or congenital heart disease used to assess ischaemia and viability, but the flow tracers (N-13
and for ruling out intracavitary thrombi in AF patients requiring car- ammonia or O-15 water) require an on-site cyclotron.92,111 Rubid-
dioversion. When the severity of mitral or aortic valve disease does ium is an alternative tracer for ischaemia testing with PET, which can
not match the patient’s symptoms using TTE alone, a TOE examin- be produced locally at relatively low cost. Limited availability, radi-
ation should be performed. ation exposure and cost are the main limitations.
2144 ESC Guidelines

5.8 Coronary angiography 5.9 Cardiac computed tomography


Indications for coronary angiography in patients with HF are in con- The main use of cardiac CT in patients with HF is as a non-invasive
cordance with the recommendations of other relevant ESC guide- means to visualize the coronary anatomy in patients with HF with
lines.112 – 114 Coronary angiography is recommended in patients low intermediate pre-test probability of CAD or those with equivo-
with HF who suffer from angina pectoris recalcitrant to medical cal non-invasive stress tests in order to exclude the diagnosis of
therapy,115 provided the patient is otherwise suitable for coronary CAD, in the absence of relative contraindications. However, the
revascularization. Coronary angiography is also recommended in test is only required when its results might affect a therapeutic
patients with a history of symptomatic ventricular arrhythmia or decision.
aborted cardiac arrest. Coronary angiography should be considered The most important clinical indications for the applicability of cer-
in patients with HF and intermediate to high pre-test probability of tain imaging methods in patients with suspected or confirmed HF
CAD and the presence of ischaemia in non-invasive stress tests in are shown in the recommendations table.

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order to establish the ischaemic aetiology and CAD severity.

Recommendations for cardiac imaging in patients with suspected or established heart failure

Recommendations Class a Level b Ref c

TTE is recommended for the assessment of myocardial structure and function in subjects with suspected HF in order to establish
I C
a diagnosis of either HFrEF, HFmrEF or HFpEF.

TTE is recommended to assess LVEF in order to identify patients with HF who would be suitable for evidence-based
I C
pharmacological and device (ICD, CRT) treatment recommended for HFrEF.

TTE is recommended for the assessment of valve disease, right ventricular function and pulmonary arterial pressure in patients with
I C
an already established diagnosis of either HFrEF, HFmrEF or HFpEF in order to identify those suitable for correction of valve disease.

TTE is recommended for the assessment of myocardial structure and function in subjects to be exposed to treatment which
I C
potentially can damage myocardium (e.g. chemotherapy).

Other techniques (including systolic tissue Doppler velocities and deformation indices, i.e. strain and strain rate), should be
IIa C
considered in a TTE protocol in subjects at risk of developing HF in order to identify myocardial dysfunction at the preclinical stage.

CMR is recommended for the assessment of myocardial structure and function (including right heart) in subjects with poor
I C
acoustic window and patients with complex congenital heart diseases (taking account of cautions/contra-indications to CMR).

CMR with LGE should be considered in patients with dilated cardiomyopathy in order to distinguish between ischaemic and non-
IIa C
ischaemic myocardial damage in case of equivocal clinical and other imaging data (taking account of cautions/contra-indications to CMR).

CMR is recommended for the characterization of myocardial tissue in case of suspected myocarditis, amyloidosis, sarcoidosis,
Chagas disease, Fabry disease non-compaction cardiomyopathy, and haemochromatosis (taking account of cautions/contra- I C
indications to CMR).

Non-invasive stress imaging (CMR, stress echocardiography, SPECT, PET) may be considered for the assessment of myocardial
ischaemia and viability in patients with HF and CAD (considered suitable for coronary revascularization) before the decision on IIb B 116–118
revascularization.

Invasive coronary angiography is recommended in patients with HF and angina pectoris recalcitrant to pharmacological
therapy or symptomatic ventricular arrhythmias or aborted cardiac arrest (who are considered suitable for potential coronary I C
revascularization) in order to establish the diagnosis of CAD and its severity.

Invasive coronary angiography should be considered in patients with HF and intermediate to high pre-test probability of CAD and
the presence of ischaemia in non-invasive stress tests (who are considered suitable for potential coronary revascularization) in IIa C
order to establish the diagnosis of CAD and its severity.

Cardiac CT may be considered in patients with HF and low to intermediate pre-test probability of CAD or those with equivocal
IIb C
non-invasive stress tests in order to rule out coronary artery stenosis.

Reassessment of myocardial structure and function is recommended using non-invasive imaging:


- in patients presenting with worsening HF symptoms (including episodes of AHF) or experiencing any other
important cardiovascular event;
I C
- in patients with HF who have received evidence-based pharmacotherapy in maximal tolerated doses, before the decision on
device implantation (ICD, CRT);
- in patients exposed to therapies which may damage the myocardium (e.g. chemotherapy) (serial assessments).

AHF ¼ acute heart failure; CAD ¼ coronary artery disease; CMR ¼ cardiac magnetic resonance; CRT ¼ cardiac resynchronization therapy; CT ¼ computed tomography; HF ¼
heart failure; HFpEF ¼ heart failure with preserved ejection fraction; HFmrEF ¼ heart failure with mid-range ejection fraction; HFrEF ¼ heart failure with reduced ejection fraction;
ICD ¼ implantable cardioverter-defibrillator; LGE ¼ late gadolinium enhancement; LVEF ¼ left ventricular ejection fraction; PET ¼ positron emission tomography; SPECT ¼
single-photon emission computed tomography; TTE ¼ transthoracic echocardiography.
a
Class of recommendation.
b
Level of evidence.
c
Reference(s) supporting recommendations.
ESC Guidelines 2145

5.10 Other diagnostic tests sessments and endomyocardial biopsy. The major typical indications
Comprehensive assessment of patients with HF comprises, besides are summarized in the recommendations table for diagnostic tests in
medical history and physical examination, including adequate imaging patients with HF. Although there is extensive research on biomarkers
techniques, a set of additional diagnostic tests, i.e. laboratory vari- in HF (e.g. ST2, galectin 3, copeptin, adrenomedullin), there is no def-
ables, ECG, chest X-ray, exercise testing, invasive haemodynamic as- inite evidence to recommend them for clinical practice.

Recommendations for diagnostic tests in patients with heart failure

Recommendations Class a Level b Ref c

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The following diagnostic tests are recommended/should be considered for initial assessment of a patient with newly diagnosed
HF in order to evaluate the patient’s suitability for particular therapies, to detect reversible/treatable causes of HF and co-
morbidities interfering with HF:
- haemoglobin and WBC
- sodium, potassium, urea, creatinine (with estimated GFR)
- liver function tests (bilirubin, AST, ALT, GGTP)
- glucose, HbA1c I C

- TSH
- ferritin, TSAT = TIBC
- natriuretic peptides IIa C

Additional diagnostic tests aiming to identify other HF aetiologies and comorbidities should be considered in individual
IIa C
patients with HF when there is a clinical suspicion of a particular pathology (see Table 3.4 on HF aetiologies).

A 12-lead ECG is recommended in all patients with HF in order to determine heart rhythm, heart rate, QRS morphology, and
I C
QRS duration, and to detect other relevant abnormalities. This information is needed to plan and monitor treatment.

Exercise testing in patients with HF:


- is recommended as a part of the evaluation for heart transplantation and/or mechanical circulatory support
I C 119, 120
(cardiopulmonary exercise testing);
- should be considered to optimize prescription of exercise training (preferably cardiopulmonary exercise testing); IIa C
- should be considered to identify the cause of unexplained dyspnoea (cardiopulmonary exercise testing). IIa C
- may be considered to detect reversible myocardial ischaemia. IIb C

Chest radiography (X-ray) is recommended in patients with HF to detect/exclude alternative pulmonary or other diseases,
which may contribute to dyspnoea. It may also identify pulmonary congestion/oedema and is more useful in patients with I C
suspected HF in the acute setting.

Right heart catheterization with a pulmonary artery catheter:


- is recommended in patients with severe HF being evaluated for heart transplantation or mechanical circulatory support; I C
IIa C
pulmonary hypertension and its reversibility before the correction of valve/structural heart disease;
- may be considered in order to adjust therapy in patients with HF who remain severely symptomatic despite initial
IIb C
standard therapies and whose haemodynamic status is unclear.

EMB should be considered in patients with rapidly progressive HF despite standard therapy when there is a probability of a
IIa C 93

IIb C 121

Ultrasound measurement of inferior vena cava diameter may be considered for the assessment of volaemia status in patients with HF. IIb C

AHF ¼ acute heart failure; ALT ¼ alanine aminotransferase; AST ¼ aspartate aminotransferase; BNP ¼ B-type natriuretic peptide; ECG ¼ electrocardiogram; eGFR ¼ estimated
glomerular filtration rate; EMB ¼ endomyocardial biopsy; GFR ¼ glomerular filtration rate; GGTP ¼ gamma-glutamyl transpeptidase; HbA1c ¼ glycated haemoglobin; HF ¼
heart failure; HFrEF ¼ heart failure with reduced ejection fraction; QRS ¼ Q, R, and S waves (combination of three of the graphical deflections); TIBC ¼ total iron-binding capacity;
TSAT ¼ transferrin saturation; TSH ¼ thyroid-stimulating hormone; WBC ¼ white blood cell.
a
Class of recommendation.
b
Level of evidence.
c
Reference(s) supporting recommendations.

5.10.1 Genetic testing in heart failure sufficiently high and consistent to justify routine targeted genetic
Molecular genetic analysis in patients with cardiomyopathies is re- screening. Recommendations for genetic testing in patients with
commended when the prevalence of detectable mutations is HF are based on the position statement of the European Society
2146 ESC Guidelines

of Cardiology Working Group on Myocardial and Pericardial Dis- hypertensive patients reduces the risk of cardiovascular disease,
eases.94 In most patients with a definite clinical diagnosis of HF, there death and hospitalization for HF.129
is no confirmatory role for routine genetic testing to establish the Recently, empaglifozin (an inhibitor of sodium-glucose cotran-
diagnosis. Genetic counselling is recommended in patients with sporter 2), has been shown to improve outcomes (including the re-
HCM, idiopathic DCM and ARVC. Restrictive cardiomyopathy duction of mortality and HF hospitalizations) in patients with type 2
and isolated non-compaction cardiomyopathies are of a possible diabetes.130 Other hypoglycaemic agents have not been shown con-
genetic origin and should also be considered for genetic testing. vincingly to reduce the risk of cardiovascular events and may in-
HCM is mostly inherited as an autosomal dominant disease with crease the risk of HF. Intensification of hypoglycaemic therapy to
variable expressivity and age-related penetrance. Currently, more drive down glycated haemoglobin (HbA1c) with agents other than
than 20 genes and 1400 mutations have been identified, most of which empagliflozin does not reduce the risk of developing HF (for details
are located in the sarcomere genes encoding cardiac b-myosin heavy see Section 11.6 on diabetes).
chain (MYH7) and cardiac myosin binding protein C (MYBPC3).88,122

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Although smoking cessation has not been shown to reduce the
DCM is idiopathic in 50% of cases, about one-third of which are her- risk of developing HF, the epidemiological associations with the de-
editary. There are already more than 50 genes identified that are asso- velopment of cardiovascular disease131 suggest that such advice, if
ciated with DCM. Many genes are related to the cytoskeleton. The most followed, would be beneficial.
frequent ones are titin (TTN), lamin (LMNA) and desmin (DES).88,123 The association between alcohol intake and the risk of developing
ARVC is hereditary in most cases and is caused by gene mutations de novo HF is U-shaped, with the lowest risk with modest alcohol
that encode elements of the desmosome. Desmosomal gene muta- consumption (up to 7 drinks/week).132 – 134 Greater alcohol intake
tions explain 50% of cases and 10 genes are currently associated may trigger the development of toxic cardiomyopathy, and when
with the disease.124 present, complete abstention from alcohol is recommended.
Counselling should be performed by someone with sufficient An inverse relationship between physical activity and the risk of
knowledge of the specific psychological, social and medical implica- HF has been reported. A recent meta-analysis found that doses
tions of a diagnosis. Determination of the genotype is important, of physical activity in excess of the guideline recommended
since some forms [e.g. mutations in LMNA and phospholamban minimal levels may be required for more substantial reductions in
(PLN)] are related to a poorer prognosis. DNA analysis could also HF risk.135
be of help to establish the diagnosis of rare forms, such as mitochon- It has been shown that among subjects ≥40 years of age with ei-
drial cardiomyopathies. Screening of first-degree relatives for early ther cardiovascular risk factors or cardiovascular disease (but nei-
detection is recommended from early adolescence onwards, al- ther asymptomatic LV dysfunction nor overt HF), BNP-driven
though earlier screening may be considered depending on the age collaborative care between the primary care physician and the spe-
of disease onset in other family members. cialist cardiovascular centre may reduce the combined rates of LV
Recently, the MOGE(S) classification of inherited cardiomyopathies systolic dysfunction and overt HF.136
has been proposed, which includes the morphofunctional phenotype Statins reduce the rate of cardiovascular events and mortality;
(M), organ(s) involvement (O), genetic inheritance pattern (G), aetio- there is also reasonable evidence that they prevent or delay the on-
logical annotation (E), including genetic defect or underlying disease/ set of HF.137 – 140 Neither aspirin nor other antiplatelet agents, nor
substrate, and the functional status (S) of the disease.125 revascularization, have been shown to reduce the risk of developing
HF or mortality in patients with stable CAD. Obesity is also a risk
factor for HF,141 but the impact of treatments of obesity on the de-
6. Delaying or preventing the velopment of HF is unknown.
In patients with CAD, without LV systolic dysfunction or HF, ACEIs
development of overt heart failure prevent or delay the onset of HF and reduce cardiovascular and all-
or preventing death before the cause mortality, although the benefit may be small in the
contemporary setting, especially in patients receiving aspirin.142
onset of symptoms Up-titration of renin–angiotensin system antagonists and beta-blockers
There is considerable evidence that the onset of HF may be delayed to maximum tolerated dosages may improve outcomes, including HF, in
or prevented through interventions aimed at modifying risk factors patients with increased plasma concentrations of NPs.136,143
for HF or treating asymptomatic LV systolic dysfunction (see recom- A primary percutaneous coronary intervention (PCI) at the earli-
mendations table). Many trials show that control of hypertension est phase of an ST segment elevation myocardial infarction (STEMI)
will delay the onset of HF and some also show that it will prolong to reduce infarct size decreases the risk of developing a substantial
life.126 – 129 Different antihypertensive drugs [diuretics, ACEIs, angio- reduction in LVEF and subsequent development of HFrEF.112 Initi-
tensin receptor blockers (ARBs), beta-blockers] have been shown ation of an ACEI, a beta-blocker and an MRA immediately after a
to be effective, especially in older people, both in patients with myocardial infarction, especially when it is associated with LV
and without a history of myocardial infarction.126 – 128 Along with systolic dysfunction, reduces the rate of hospitalization for HF and
the ongoing discussion on optimal target blood pressure values in mortality,144 – 148 as do statins.137 – 139
hypertensive non-diabetic subjects, the recent SPRINT study has In asymptomatic patients with chronically reduced LVEF, regard-
already demonstrated that treating hypertension to a lower goal less of its aetiology, an ACEI can reduce the risk of HF requiring hos-
[systolic blood pressure (SBP) ,120 mmHg vs. ,140 mmHg] in pitalization.5,144,145 This has not yet been shown for beta-blockers
older hypertensive subjects (≥75 years of age) or high-risk or MRAs.
ESC Guidelines 2147

In patients with asymptomatic LV systolic dysfunction (LVEF plantable cardioverter-defibrillator (ICD) is recommended to
,30%) of ischaemic origin who are ≥40 days after an AMI, an im- prolong life.149

Recommendations to prevent or delay the development of overt heart failure or prevent death before the onset of
symptoms

Recommendations Class a Level b Ref c

126, 129,
Treatment of hypertension is recommended to prevent or delay the onset of HF and prolong life. I A
150, 151

Treatment with statins is recommended in patients with or at high-risk of CAD whether or not they have LV systolic 137–140,
I A

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dysfunction, in order to prevent or delay the onset of HF and prolong life. 152

Counselling and treatment for smoking cessation and alcohol intake reduction is recommended for people who smoke or who
I C 131–134
consume excess alcohol in order to prevent or delay the onset of HF.

130, 141,
Treating other risk factors of HF (e.g. obesity, dysglycaemia) should be considered in order to prevent or delay the onset of HF. IIa C
153–155

IIa B 130

ACE-I is recommended in patients with asymptomatic LV systolic dysfunction and a history of myocardial infarction in order to 5, 144,
I A
prevent or delay the onset of HF and prolong life. 145

ACE-I is recommended in patients with asymptomatic LV systolic dysfunction without a history of myocardial infarction, in order
I B 5
to prevent or delay the onset of HF.

ACE-I should be considered in patients with stable CAD even if they do not have LV systolic dysfunction, in order to prevent
IIa A 142
or delay the onset of HF.

Beta-blocker is recommended in patients with asymptomatic LV systolic dysfunction and a history of myocardial infarction, in
I B 146
order to prevent or delay the onset of HF or prolong life.

ICD is recommended in patients:


a) with asymptomatic LV systolic dysfunction (LVEF ≤30%) of ischaemic origin, who are at least 40 days after acute
myocardial infarction, 149,
I B
b) with asymptomatic non-ischaemic dilated cardiomyopathy (LVEF ≤30%), who receive OMT therapy, 156–158

in order to prevent sudden death and prolong life.

ACEI ¼ angiotensin-converting enzyme inhibitor; CAD ¼ coronary artery disease; HF ¼ heart failure; ICD ¼ implantable cardioverter-defibrillator; LV ¼ left ventricular;
LVEF ¼ left ventricular ejection fraction; OMT ¼ optimal medical therapy
a
Class of recommendation.
b
Level of evidence.
c
Reference(s) supporting recommendations.

7. Pharmacological treatment of Figure 7.1 shows a treatment strategy for the use of drugs (and de-
vices) in patients with HFrEF. The recommendations for each treat-
heart failure with reduced ejection ment are summarized below.
fraction Neuro-hormonal antagonists (ACEIs, MRAs and beta-blockers)
have been shown to improve survival in patients with HFrEF and
7.1 Objectives in the management of are recommended for the treatment of every patient with HFrEF,
heart failure unless contraindicated or not tolerated. A new compound
(LCZ696) that combines the moieties of an ARB (valsartan) and a
The goals of treatment in patients with HF are to improve their clin-
neprilysin (NEP) inhibitor (sacubitril) has recently been shown to
ical status, functional capacity and quality of life, prevent hospital ad-
be superior to an ACEI (enalapril) in reducing the risk of death
mission and reduce mortality. The fact that several drugs for HF
and of hospitalization for HF in a single trial with strict inclusion/ex-
have shown detrimental effects on long-term outcomes, despite
clusion criteria.162 Sacubitril/valsartan is therefore recommended to
showing beneficial effects on shorter-term surrogate markers, has
replace ACEIs in ambulatory HFrEF patients who remain symptom-
led regulatory bodies and clinical practice guidelines to seek mortal-
atic despite optimal therapy and who fit these trial criteria. ARBs
ity/morbidity data for approving/recommending therapeutic inter-
have not been consistently proven to reduce mortality in patients
ventions for HF. However, it is now recognized that preventing
with HFrEF and their use should be restricted to patients intolerant
HF hospitalization and improving functional capacity are important
of an ACEI or those who take an ACEI but are unable to tolerate an
benefits to be considered if a mortality excess is ruled out.159 – 161
2148 ESC Guidelines

MRA. Ivabradine reduces the elevated heart rate often seen in Practical guidance on how to use ACE inhibitors is given in Web
HFrEF and has also been shown to improve outcomes, and should Table 7.4.
be considered when appropriate.
The above medications should be used in conjunction with diure- 7.2.2 Beta-blockers
tics in patients with symptoms and/or signs of congestion. The use of Beta-blockers reduce mortality and morbidity in symptomatic
diuretics should be modulated according to the patient’s clinical patients with HFrEF, despite treatment with an ACEI and, in
status. most cases, a diuretic,167,168,170,172,173 but have not been tested
The key evidence supporting the recommendations in this in congested or decompensated patients. There is consensus
section is given in Web Table 7.1. The recommended doses of these that beta-blockers and ACEIs are complementary, and can be
disease-modifying medications are given in Table 7.2. The started together as soon as the diagnosis of HFrEF is made.
recommendations given in Sections 7.5 and 7.6 summarize drugs There is no evidence favouring the initiation of treatment

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that should be avoided or used with caution in patients with HFrEF. with a beta-blocker before an ACEI has been started.176 Beta-
blockers should be initiated in clinically stable patients at a low
7.2 Treatments recommended in dose and gradually up-titrated to the maximum tolerated dose.
all symptomatic patients with heart In patients admitted due to acute HF (AHF) beta-blockers
failure with reduced ejection should be cautiously initiated in hospital, once the patient is
stabilized.
fraction
An individual patient data meta-analysis of all the major beta-
7.2.1 Angiotensin-converting enzyme inhibitors
blocker trials in HFrEF has shown no benefit on hospital admis-
ACEIs have been shown to reduce mortality and morbidity in pa-
sions and mortality in the subgroup of patients with HFrEF who
tients with HFrEF2,5,163 – 165 and are recommended unless contrain-
are in AF.177 However, since this is a retrospective subgroup
dicated or not tolerated in all symptomatic patients. ACEIs should
analysis, and because beta-blockers did not increase the risk,
be up-titrated to the maximum tolerated dose in order to achieve
the guideline committee decided not to make a separate recom-
adequate inhibition of the renin – angiotensin – aldosterone system
mendation according to heart rhythm. Beta-blockers should be
(RAAS). There is evidence that in clinical practice the majority of pa-
considered for rate control in patients with HFrEF and AF, es-
tients receive suboptimal doses of ACEI.166 ACEIs are also recom-
pecially in those with high heart rate (see Section 10.1 for
mended in patients with asymptomatic LV systolic dysfunction to
details).
reduce the risk of HF development, HF hospitalization and death
Beta-blockers are recommended in patients with a history of
(see Section 6).
myocardial infarction and asymptomatic LV systolic dysfunction to
reduce the risk of death (see Section 6).
Pharmacological treatments indicated in patients with Practical guidance on how to use beta-blockers is given in Web
symptomatic (NYHA Class II-IV) heart failure with Table 7.5.
reduced ejection fraction
7.2.3 Mineralocorticoid/aldosterone receptor antagonists
Recommendations Class a Level b Ref c MRAs (spironolactone and eplerenone) block receptors that
An ACE-Id is recommended, bind aldosterone and, with different degrees of affinity, other ster-
in addition to a beta-blocker, 2, oid hormone (e.g. corticosteroids, androgens) receptors. Spirono-
for symptomatic patients with I A 163 lactone or eplerenone are recommended in all symptomatic
HFrEF to reduce the risk of HF –165
patients (despite treatment with an ACEI and a beta-blocker)
hospitalization and death.
with HFrEF and LVEF ≤35%, to reduce mortality and HF
A beta-blocker is recommended,
hospitalization.174,175
in addition an ACE-Id, for
167– Caution should be exercised when MRAs are used in patients
patients with stable, symptomatic I A
173
HFrEF to reduce the risk of HF with impaired renal function and in those with serum potassium
hospitalization and death. levels .5.0 mmol/L. Regular checks of serum potassium levels
An MRA is recommended for and renal function should be performed according to clinical
patients with HFrEF, who remain status.
symptomatic despite treatment
with an ACE-Id and a
I A 174, 175 Practical guidance on how to use MRAs is given in Web
beta-blocker, to reduce the risk of Table 7.6.
HF hospitalization and death.

ACEI ¼ angiotensin-converting enzyme inhibitor; HF ¼ heart failure; HFrEF ¼ 7.3 Other treatments recommended in
heart failure with reduced ejection fraction; MRA ¼ mineralocorticoid receptor
antagonist; NYHA ¼ New York Heart Association.
selected symptomatic patients with heart
a
Class of recommendation. failure with reduced ejection fraction
b
Level of evidence. 7.3.1 Diuretics
c
Reference(s) supporting recommendations.
d
Or ARB if ACEI is not tolerated/contraindicated Diuretics are recommended to reduce the signs and symptoms
of congestion in patients with HFrEF, but their effects on
ESC Guidelines 2149

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Figure 7.1 Therapeutic algorithm for a patient with symptomatic heart failure with reduced ejection fraction. Green indicates a class I recom-
mendation; yellow indicates a class IIa recommendation. ACEI ¼ angiotensin-converting enzyme inhibitor; ARB ¼ angiotensin receptor blocker;
ARNI ¼ angiotensin receptor neprilysin inhibitor; BNP ¼ B-type natriuretic peptide; CRT ¼ cardiac resynchronization therapy; HF ¼ heart fail-
ure; HFrEF ¼ heart failure with reduced ejection fraction; H-ISDN ¼ hydralazine and isosorbide dinitrate; HR ¼ heart rate; ICD ¼ implantable
cardioverter defibrillator; LBBB ¼ left bundle branch block; LVAD ¼ left ventricular assist device; LVEF ¼ left ventricular ejection fraction; MR ¼
mineralocorticoid receptor; NT-proBNP ¼ N-terminal pro-B type natriuretic peptide; NYHA ¼ New York Heart Association; OMT ¼ optimal
medical therapy; VF ¼ ventricular fibrillation; VT ¼ ventricular tachycardia. aSymptomatic ¼ NYHA Class II-IV. bHFrEF ¼ LVEF ,40%. cIf ACE
inhibitor not tolerated/contra-indicated, use ARB. dIf MR antagonist not tolerated/contra-indicated, use ARB. eWith a hospital admission for
HF within the last 6 months or with elevated natriuretic peptides (BNP . 250 pg/ml or NTproBNP . 500 pg/ml in men and 750 pg/ml in women).
f
With an elevated plasma natriuretic peptide level (BNP ≥ 150 pg/mL or plasma NT-proBNP ≥ 600 pg/mL, or if HF hospitalization within recent
12 months plasma BNP ≥ 100 pg/mL or plasma NT-proBNP ≥ 400 pg/mL). gIn doses equivalent to enalapril 10 mg b.i.d. hWith a hospital admis-
sion for HF within the previous year. iCRT is recommended if QRS ≥ 130 msec and LBBB (in sinus rhythm). jCRT should/may be considered if
QRS ≥ 130 msec with non-LBBB (in a sinus rhythm) or for patients in AF provided a strategy to ensure bi-ventricular capture in place (individua-
lized decision). For further details, see Sections 7 and 8 and corresponding web pages.
2150 ESC Guidelines

mortality and morbidity have not been studied in RCTs. A Co- Loop diuretics produce a more intense and shorter diuresis
chrane meta-analysis has shown that in patients with chronic HF, than thiazides, although they act synergistically and the combin-
loop and thiazide diuretics appear to reduce the risk of death ation may be used to treat resistant oedema. However, adverse
and worsening HF compared with placebo, and compared effects are more likely and these combinations should only be
with an active control, diuretics appear to improve exercise used with care. The aim of diuretic therapy is to achieve and main-
capacity.178,179 tain euvolaemia with the lowest achievable dose. The dose of the
diuretic must be adjusted according to the individual needs over
time. In selected asymptomatic euvolaemic/hypovolaemic patients,
the use of a diuretic drug might be (temporarily) discontinued. Pa-
tients can be trained to self-adjust their diuretic dose based on
Table 7.2 Evidence-based doses of disease-modifying monitoring of symptoms/signs of congestion and daily weight

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drugs in key randomized trials in heart failure with measurements.
reduced ejection fraction (or after myocardial Doses of diuretics commonly used to treat HF are provided in
infarction) Table 7.3. Practical guidance on how to use diuretics is given in
Web Table 7.7.
Starting dose (mg) Target dose (mg)
ACE-I
Captoprila 6.25 t.i.d. 50 t.i.d.
Enalapril 2.5 b.i.d. 10–20 b.i.d.
Lisinoprilb 2.5–5.0 o.d. 20–35 o.d.
Ramipril 2.5 o.d. 10 o.d.
Trandolaprila 0.5 o.d. 4 o.d.
Table 7.3 Doses of diuretics commonly used in
Beta-blockers
patients with heart failure
Bisoprolol 1.25 o.d. 10 o.d.
Carvedilol 3.125 b.i.d. 25 b.i.d.d Diuretics Initial dose (mg) Usual daily dose
Metoprolol succinate (CR/XL) 12.5–25 o.d. 200 o.d. (mg)

Nebivololc 1.25 o.d. 10 o.d. Loop diuretics a

ARBs Furosemide 20–40 40–240

Candesartan 4–8 o.d. 32 o.d. Bumetanide 0.5–1.0 1–5

Valsartan 40 b.i.d. 160 b.i.d. Torasemide 5–10 10–20

Losartanb,c 50 o.d. 150 o.d. Thiazides b

MRAs 2.5 2.5–10

Eplerenone 25 o.d. 50 o.d. Hydrochlorothiazide 25 12.5–100

Spironolactone 25 o.d. 50 o.d. Metolazone 2.5 2.5–10


c
ARNI lndapamide 2.5 2.5–5

Sacubitril/valsartan 49/51 b.i.d. 97/103 b.i.d. Potassium-sparing diureticsd

If -channel blocker +ACE-I/ -ACE-I/ +ACE-I/ -ACE-I/


ARB ARB ARB ARB
Ivabradine 5 b.i.d. 7.5 b.i.d.
Spironolactone/ 12.5–25 50 50 100–
eplerenone 200
ACE ¼ angiotensin-converting enzyme; ARB ¼ angiotensin receptor blocker;
ARNI ¼ angiotensin receptor neprilysin inhibitor; b.i.d. ¼ bis in die (twice daily);
Amiloride 2.5 5 5–10 10–20
MRA ¼ mineralocorticoid receptor antagonist; o.d. ¼ omne in die (once daily); Triamterene 25 50 100 200
t.i.d. ¼ ter in die (three times a day).
a
Indicates an ACE-I where the dosing target is derived from post-myocardial
infarction trials. ACE-I ¼ angiontensin-converting enzyme inhibitor, ARB ¼ angiotensin receptor
b
Indicates drugs where a higher dose has been shown to reduce morbidity/ blocker.
a
mortality compared with a lower dose of the same drug, but there is no substantive Oral or intravenous; dose might need to be adjusted according to volume status/
randomized, placebo-controlled trial and the optimum dose is uncertain. weight; excessive doses may cause renal impairment and ototoxicity.
b
c
Indicates a treatment not shown to reduce cardiovascular or all-cause mortality in Do not use thiazides if estimated glomerular filtration rate ,30 mL/min/1.73 m2 ,
patients with heart failure (or shown to be non-inferior to a treatment that does). except when prescribed synergistically with loop diuretics.
d c
A maximum dose of 50 mg twice daily can be administered to patients weighing lndapamide is a non-thiazide sulfonamide.
d
over 85 kg. A mineralocorticoid antagonist (MRA) i.e. spironolactone/eplerenone is always
preferred. Amiloride and triamterene should not be combined with an MRA.
ESC Guidelines 2151

Other pharmacological treatments recommended in selected patients with symptomatic (NYHA Class II-IV) heart
failure with reduced ejection fraction

Recommendations Class a Level b Ref c


Diuretics
Diuretics are recommended in order to improve symptoms and exercise capacity in patients with signs and/or symptoms of congestion. I B 178, 179
Diuretics should be considered to reduce the risk of HF hospitalization in patients with signs and/or symptoms of congestion. IIa B 178, 179
Angiotensin receptor neprilysin inhibitor
Sacubitril/valsartan is recommended as a replacement for an ACE-I to further reduce the risk of HF hospitalization and death in
I B 162
ambulatory patients with HFrEF who remain symptomatic despite optimal treatment with an ACE-I, a beta-blocker and an MRAd

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I f -channel inhibitor
Ivabradine should be considered to reduce the risk of HF hospitalization or cardiovascular death in symptomatic patients
with LVEF ≤35%, in sinus rhythm and a resting heart rate ≥70 bpm despite treatment with an evidence-based dose of beta- IIa B 180
blocker (or maximum tolerated dose below that), ACE-I (or ARB), and an MRA (or ARB).
Ivabradine should be considered to reduce the risk of HF hospitalization and cardiovascular death in symptomatic patients with
LVEF ≤35%, in sinus rhythm and a resting heart rate ≥70 bpm who are unable to tolerate or have contra-indications for a IIa C 181
beta-blocker. Patients should also receive an ACE-I (or ARB) and an MRA (or ARB).
ARB
An ARB is recommended to reduce the risk of HF hospitalization and cardiovascular death in symptomatic patients unable to
I B 182
tolerate an ACE-I (patients should also receive a beta-blocker and an MRA).
An ARB may be considered to reduce the risk of HF hospitalization and death in patients who are symptomatic despite treatment
IIb C -
with a beta-blocker who are unable to tolerate an MRA.
Hydralazine and isosorbide dinitrate
≤35% or with an
LVEF <45% combined with a dilated LV in NYHA Class III–IV despite treatment with an ACE-I a beta-blocker and an MRA IIa B 183
to reduce the risk of HF hospitalization and death.
Hydralazine and isosorbide dinitrate may be considered in symptomatic patients with HFrEF who can tolerate neither an ACE-I
IIb B 184
nor an ARB (or they are contra-indicated) to reduce the risk of death.

Digoxin
Digoxin may be considered in symptomatic patients in sinus rhythm despite treatment with an ACE-I (or ARB), a beta-blocker
IIb B 185
and an MRA, to reduce the risk of hospitalization (both all-cause and HF-hospitalizations).
N-3 PUFA
An n-3 PUFAe preparation may be considered in symptomatic HF patients to reduce the risk of cardiovascular hospitalization
IIb B 186
and cardiovascular death.

ACEI ¼ angiotensin-converting enzyme inhibitor; ARB ¼ angiotensin receptor blocker; BNP ¼ B-type natriuretic peptide; bpm ¼ beats per minute; HF ¼ heart failure; HFrEF ¼
heart failure with reduced ejection fraction; LVEF ¼ left ventricular ejection fraction; MRA ¼ mineralocorticoid receptor antagonist; NT-proBNP ¼ N-terminal pro-B type
natriuretic peptide; NYHA ¼ New York Heart Association; PUFA ¼ polyunsaturated fatty acid. OMT ¼ optimal medical therapy (for HFrEF this mostly comprises an ACEI or
sacubitril/valsartan, a beta-blocker and an MRA).
a
Class of recommendation.
b
Level of evidence.
c
Reference(s) supporting recommendations.
d
Patient should have elevated natriuretic peptides (plasma BNP ≥150 pg/mL or plasma NT-proBNP ≥600 pg/mL, or if HF hospitalization within the last 12 months, plasma BNP
≥100 pg/mL or plasma NT-proBNP ≥400 pg/mL) and able to tolerate enalapril 10 mg b.i.d.
e
Applies only to preparation studied in cited trial.

7.3.2 Angiotensin receptor neprilysin inhibitor physiologic effects through binding to NP receptors and the aug-
A new therapeutic class of agents acting on the RAAS and the neu- mented generation of cGMP, thereby enhancing diuresis, natriuresis
tral endopeptidase system has been developed [angiotensin recep- and myocardial relaxation and anti-remodelling. ANP and BNP also
tor neprilysin inhibitor (ARNI)]. The first in class is LCZ696, which is inhibit renin and aldosterone secretion. Selective AT1-receptor
a molecule that combines the moieties of valsartan and sacubitril blockade reduces vasoconstriction, sodium and water retention
(neprilysin inhibitor) in a single substance. By inhibiting neprilysin, and myocardial hypertrophy.187,188
the degradation of NPs, bradykinin and other peptides is slowed. A recent trial investigated the long-term effects of sacubi-
High circulating A-type natriuretic peptide (ANP) and BNP exert tril/valsartan compared with an ACEI (enalapril) on morbidity
2152 ESC Guidelines

and mortality in patients with ambulatory, symptomatic HFrEF Practical guidance on how to use ivabradine is given in Web
with LVEF ≤40% (this was changed to ≤35% during the Table 7.8.
study), elevated plasma NP levels (BNP ≥150 pg/mL or
NT-proBNP ≥600 pg/mL or, if they had been hospitalized 7.3.4 Angiotensin II type I receptor blockers
for HF within the previous 12 months, BNP ≥100 pg/mL or ARBs are recommended only as an alternative in patients intolerant
NT-proBNP ≥400 pg/mL), and an estimated GFR (eGFR) of an ACEI.182 Candesartan has been shown to reduce cardiovascu-
≥30 mL/min/1.73 m 2 of body surface area, who were able lar mortality.182 Valsartan showed an effect on hospitalization for HF
to tolerate separate treatments periods with enalapril (but not on all-cause hospitalizations) in patients with HFrEF receiv-
(10 mg b.i.d.) and sacubitril/valsartan (97/103 mg b.i.d.) during ing background ACEIs.194
a run-in period.162 In this population, sacubitril/valsartan (97/ The combination of ACEI/ARB for HFrEF was reviewed by the
103 mg b.i.d.) was superior to ACEI (enalapril 10 mg b.i.d.) in EMA, which suggested that benefits are thought to outweigh risks
only in a select group of patients with HFrEF in whom other treat-

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reducing hospitalizations for worsening HF, cardiovascular
mortality and overall mortality.162 Sacubitril/valsartan is there- ments are unsuitable. Therefore, ARBs are indicated for the treat-
fore recommended in patients with HFrEF who fit this profile. ment of HFrEF only in patients who cannot tolerate an ACEI
Despite the superiority of sacubitril/valsartan over enalapril in because of serious side effects. The combination of ACEI/ARB
the PARADIGM-HF trial, some relevant safety issues remain should be restricted to symptomatic HFrEF patients receiving a
when initiating therapy with this drug in clinical practice. Symp- beta-blocker who are unable to tolerate an MRA, and must be
tomatic hypotension was more often present in the sacubitril/ used under strict supervision.
valsartan group (in those ≥75 years of age, it affected 18% in
the sacubitril/valsartan group vs. 12% in the enalapril group), al- 7.3.5 Combination of hydralazine and isosorbide dinitrate
though there was no increase in the rate of discontinuation.162 There is no clear evidence to suggest the use of this fixed-dose
The risk of angioedema in the trial was reduced by recruiting combination therapy in all patients with HFrEF. Evidence on the
only those who tolerated therapy with enalapril 10 mg b.i.d. clinical utility of this combination is scanty and comes from one
and an sacubitril/valsartan during an active run-in phase of 5 – 9 relatively small RCT conducted exclusively in men and before
weeks (it resulted in a 0.4% rate of angioedema in sacubitril/val- ACEIs or beta-blockers were used to treat HF.184 A subsequent
sartan group vs. 0.2% in an enalapril group). Also, the number of RCT conducted in self-identified black patients (defined as being
African American patients, who are at a higher risk of angioede- of African descent) showed that addition of the combination of hy-
ma, was relatively small in this study. To minimize the risk of an- dralazine and isosorbide dinitrate to conventional therapy (ACEI,
gioedema caused by overlapping ACE and neprilysin inhibition, beta-blocker and MRA) reduced mortality and HF hospitalizations
the ACEI should be withheld for at least 36 h before initiating in patients with HFrEF and NYHA Classes III – IV.183 The results of
sacubitril/valsartan. Combined treatment with an ACEI (or this study are difficult to translate to patients of other racial or eth-
ARB) and sacubitril/valsartan is contraindicated. There are add- nic origins.
itional concerns about its effects on the degradation of Additionally, a combination of hydralazine and isosorbide dini-
beta-amyloid peptide in the brain, which could theoretically ac- trate may be considered in symptomatic patients with HFrEF who
celerate amyloid deposition.189 – 191 However, a recent small can tolerate neither ACEI nor ARB (or they are contraindicated)
14-day study with healthy subjects showed elevation of the to reduce mortality. However, this recommendation is based on
beta-amyloid protein in the soluble rather than the aggregable the results of the Veterans Administration Cooperative Study,
form, which if confirmed over longer time periods in patients which recruited symptomatic HFrEF patients who received only di-
with HFrEF may indicate the cerebral safety of sacubitril/valsar- goxin and diuretics.184
tan.192 Long-term safety needs to be addressed.
7.4 Other treatments with less certain
7.3.3 If-channel inhibitor benefits in symptomatic patients with
Ivabradine slows the heart rate through inhibition of the I f heart failure with reduced ejection
channel in the sinus node and therefore should only be used fraction
for patients in sinus rhythm. Ivabradine reduced the combined This section describes treatments that have shown benefits in
endpoint of mortality or hospitalization for HF in patients with terms of symptomatic improvement, reduction in HF hospitaliza-
symptomatic HFrEF or LVEF ≤35%, in sinus rhythm and with a tions or both, and are useful additional treatments in patients
heart rate ≥70 beats per minute (bpm) who had been hospi- with HFrEF.
talized for HF within the previous 12 months, receiving treat-
ment with an evidence-based dose of beta-blocker (or 7.4.1 Digoxin and other digitalis glycosides
maximum tolerated dose), an ACEI (or ARB) and an MRA.180 Digoxin may be considered in patients in sinus rhythm with symp-
The European Medicines Agency (EMA) approved ivabradine tomatic HFrEF to reduce the risk of hospitalization (both all-cause
for use in Europe in patients with HFrEF with LVEF ≤35% and HF hospitalizations),185 although its effect on top of beta-
and in sinus rhythm with a resting heart rate ≥75 bpm, because blockers has never been tested. The effects of digoxin in patients
in this group ivabradine conferred a survival benefit193 based with HFrEF and AF have not been studied in RCTs, and recent stud-
on a retrospective subgroup analysis requested by the EMA. ies have suggested potentially higher risk of events (mortality and HF
ESC Guidelines 2153

hospitalization) in patients with AF receiving digoxin.195,196 How- underlying CAD or/and hyperlipidaemia, a continuation of this
ever, this remains controversial, as another recent meta-analysis therapy should be considered.
concluded on the basis of non-RCTs that digoxin has no deleterious
effect on mortality in patients with AF and concomitant HF, most of
whom had HFrEF.197 7.5.2 Oral anticoagulants and antiplatelet therapy
In patients with symptomatic HF and AF, digoxin may be use- Other than in patients with AF (both HFrEF and HFpEF), there is no
ful to slow a rapid ventricular rate, but it is only recommended evidence that an oral anticoagulant reduces mortality/morbidity
for the treatment of patients with HFrEF and AF with rapid ven- compared with placebo or aspirin.206,207 Studies testing the non-
tricular rate when other therapeutic options cannot be pur- vitamin K antagonist oral anticoagulants (NOACs) in patients with
sued. 196,198 – 201 Of note, the optimal ventricular rate for HFrEF are currently ongoing. Patients with HFrEF receiving oral an-
patients with HF and AF has not been well established, but ticoagulation because of concurrent AF or risk of venous thrombo-
embolism should continue anticoagulation. Detailed information is

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the prevailing evidence suggests that strict rate control might
be deleterious. A resting ventricular rate in the range of 70 – provided in Section 10.1.
90 bpm is recommended based on current opinion, although Similarly, there is no evidence on the benefits of antiplatelet
one trial suggested that a resting ventricular rate of up to 110 drugs (including acetylsalicylic acid) in patients with HF without ac-
bpm might still be acceptable.202 This should be tested and re- companying CAD, whereas there is a substantial risk of gastro-
fined by further research. intestinal bleeding, particularly in elderly subjects, related with
Digitalis should always be prescribed under specialist supervi- this treatment.
sion. Given its distribution and clearance, caution should be ex-
erted in females, in the elderly and in patients with reduced
renal function. In the latter patients, digitoxin should be 7.5.3 Renin inhibitors
preferred. Aliskiren (direct renin inhibitor) failed to improve outcomes for pa-
tients hospitalized for HF at 6 months or 12 months in one study208
and is not presently recommended as an alternative to an ACEI or
7.4.2 n-3 polyunsaturated fatty acids ARB.
n-3 polyunsaturated fatty acids (n-3 PUFAs) have shown a small
treatment effect in a large RCT.186 n-3 PUFA preparations dif-
Treatments (or combinations of treatments) that may
fer in composition and dose. Only preparations with eicosa-
cause harm in patients with symptomatic (NYHA Class
pentaenoic acid (EPA) and docosahexaenoic acid (DHA) as
II– IV) heart failure with reduced ejection fraction
ethyl esters of at least 85% (850 mg/g) have shown an effect
on the cumulative endpoint of cardiovascular death and hospi-
Recommendations Class a Level b Ref c
talization. No effect of n-3 PUFA preparations containing
,850 mg/g has been shown in either HFrEF or post-myocardial Thiazolidinediones (glitazones) are
infarction.203 n-3 PUFA preparations containing 850 – 882 mg of not recommended in patients with
III A 209, 210
HF, as they increase the risk of HF
EPA and DHA as ethyl esters in the average ratio of 1 : 1.2 may worsening and HF hospitalization.
be considered as an adjunctive therapy in patients with symp-
NSAIDs or COX-2 inhibitors are
tomatic HFrEF who are already receiving optimized recom- not recommended in patients with 211–
mended therapy with an ACEI (or ARB), a beta-blocker and III B
HF, as they increase the risk of HF 213
an MRA. worsening and HF hospitalization.
Diltiazem or verapamil are not
recommended in patients with
HFrEF, as they increase the III C 214
7.5 Treatments not recommended risk of HF worsening and HF
(unproven benefit) in symptomatic hospitalization.
patients with heart failure with reduced The addition of an ARB (or renin
inhibitor) to the combination
ejection fraction of an ACE-I and an MRA is not
7.5.1 3-Hydroxy-3-methylglutaryl-coenzyme A reductase recommended in patients with III C
inhibitors (‘statins’) HF, because of the increased
Although statins reduce mortality and morbidity in patients with risk of renal dysfunction and
hyperkalaemia.
atherosclerotic disease, statins are not effective in improving the
prognosis in patients with HFrEF. Most statin trials excluded pa-
tients with HF (because it was uncertain that they would bene- ACEI ¼ angiotensin-converting enzyme inhibitor; ARB ¼ angiotensin receptor
blocker; COX-2 inhibitor ¼ cyclooxygenase-2 inhibitor; HF ¼ heart failure;
fit).204 The two major trials that studied the effect of statin HFrEF ¼ heart failure with reduced ejection fraction; MRA ¼ mineralocorticoid
treatment in patients with chronic HF did not demonstrate any receptor antagonist; NSAIDs ¼ non-steroidal anti-inflammatory drugs.
a
evidence of benefit.205 Therefore, evidence does not support b
Class of recommendation.
Level of evidence.
the initiation of statins in most patients with chronic HF. How- c
Reference(s) supporting recommendations
ever, in patients who already receive a statin because of
2154 ESC Guidelines

7.6 Treatments not recommended specific guideline recommendations for other therapeutic technolo-
(believed to cause harm) in symptomatic gies, including baroreflex activation therapy,217 vagal stimulation,218
diaphragmatic pacing219,220 and cardiac contractility modula-
patients with heart failure with reduced tion;221,222 further research is required. Implantable devices to
ejection fraction monitor arrhythmias or haemodynamics are discussed elsewhere
7.6.1 Calcium-channel blockers in these guidelines.
Non-dihydropyridine calcium-channel blockers (CCBs) are not in-
dicated for the treatment of patients with HFrEF. Diltiazem and ver-
apamil have been shown to be unsafe in patients with HFrEF.214 8.1 Implantable cardioverter-defibrillator
There is a variety of dihydropyridine CCBs; some are known to A high proportion of deaths among patients with HF, especially
increase sympathetic tone and they may have a negative safety pro- those with milder symptoms, occur suddenly and unexpectedly.
file in HFrEF. There is only evidence on safety for amlodipine215 and Many of these are due to electrical disturbances, including ven-

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felodipine216 in patients with HFrEF, and they can be used only if tricular arrhythmias, bradycardia and asystole, although some are
there is a compelling indication in patients with HFrEF. due to coronary, cerebral or aortic vascular events. Treatments
that improve or delay the progression of cardiovascular disease
will reduce the annual rate of sudden death, but they may have lit-
8. Non-surgical device treatment tle effect on lifetime risk and will not treat arrhythmic events when
of heart failure with reduced they occur. ICDs are effective in preventing bradycardia and cor-
recting potentially lethal ventricular arrhythmias. Some antiar-
ejection fraction rhythmic drugs might reduce the rate of tachyarrhythmias and
This section provides recommendations on the use of ICDs and sudden death, but they do not reduce overall mortality and may
CRT. Currently, the evidence is considered insufficient to support increase it.

Recommendations for implantable cardioverter-defibrillator in patients with heart failure

Recommendations Class a Level b Ref c


Secondary prevention
An ICD is recommended to reduce the risk of sudden death and all-cause mortality in patients who have recovered from a I A 223–226
ventricular arrhythmia causing haemodynamic instability, and who are expected to survive for >1 year with good functional status.
Primary prevention
An ICD is recommended to reduce the risk of sudden death and all-cause mortality in patients with symptomatic HF (NYHA
Class II–III), and an LVEF ≤35% despite ≥3 months of OMT, provided they are expected to survive substantially longer than one
year with good functional status, and they have:
149, 156,
• IHD (unless they have had an MI in the prior 40 days – see below). I A
227
156, 157,
• DCM. I B
227
ICD implantation is not recommended within 40 days of an MI as implantation at this time does not improve prognosis. III A 158, 228
ICD therapy is not recommended in patients in NYHA Class IV with severe symptoms refractory to pharmacological therapy
III C 229–233
unless they are candidates for CRT, a ventricular assist device, or cardiac transplantation.
Patients should be carefully evaluated by an experienced cardiologist before generator replacement, because management goals
IIa B 234–238
and the patient’s needs and clinical status may have changed.
A wearable ICD may be considered for patients with HF who are at risk of sudden cardiac death for a limited period or as a
IIb C 239–241
bridge to an implanted device.

CAD ¼ coronary artery disease; CRT ¼ cardiac resynchronization therapy; DCM ¼ dilated cardiomyopathy; HF ¼ heart failure; ICD ¼ implantable cardioverter-defibrillator;
IHD ¼ ischaemic heart disease; LVEF ¼ left ventricular ejection fraction; MI ¼ myocardial infarction; NYHA ¼ New York Heart Association, OMT ¼ optimal medical therapy.
a
Class of recommendation.
b
Level of evidence.
c
Reference(s) supporting recommendations.

8.1.1 Secondary prevention of sudden cardiac death survival; the decision to implant should take into account the
Compared with amiodarone treatment, ICDs reduce mortality patient’s view and their quality of life, the LVEF (survival bene-
in survivors of cardiac arrest and in patients who have experi- fit is uncertain when the LVEF is .35%) and the absence of
enced sustained symptomatic ventricular arrhythmias. An ICD other diseases likely to cause death within the following
is recommended in such patients when the intent is to increase year.223 – 225
ESC Guidelines 2155

8.1.2 Primary prevention of sudden cardiac death ICD therapy is not recommended in patients in NYHA Class IV
Although amiodarone may have reduced mortality in older trials of with severe symptoms refractory to pharmacological therapy who
HF,242,243 contemporary studies conducted since the widespread are not candidates for CRT, a ventricular assist device or cardiac
introduction of beta-blockers suggest that it does not reduce mor- transplantation, because such patients have a very limited life ex-
tality in patients with HFrEF.227,244,245 Dronedarone246,247 and class pectancy and are likely to die from pump failure.
I antiarrhythmic agents246,248 should not be used for prevention of Patients with serious co-morbidities who are unlikely to survive
arrhythmias in this population. substantially more than 1 year are unlikely to obtain substantial
Some guideline-recommended therapies, including beta- benefit from an ICD.229 – 233
blockers, MRAs, sacubitril/valsartan and pacemakers with CRT Patients should be counselled as to the purpose of an ICD, com-
(CRT-Ps), reduce the risk of sudden death (see Section 7). plications related to implantation and device activation (predomin-
An ICD reduces the rate of sudden arrhythmic death in patients antly inappropriate shocks) and under what circumstances it might
with HFrEF.249,250 In patients with moderate or severe HF, a reduc-

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be deactivated (terminal disease) or explanted (infection, recovery
tion in sudden death may be partially or wholly offset by an increase of LV function).255
in death due to worsening HF.227 In patients with mild HF (NYHA II), If HF deteriorates, deactivation of a patient’s ICD may be consid-
an ICD will prevent about two deaths per year for every 100 devices ered after appropriate discussion with the patient and caregiver(s).
implanted.227 On average, patients with IHD are at greater risk of If the ICD generator reaches its end of life or requires explant-
sudden death than patients with DCM and therefore, although the ation, it should not automatically be replaced.234 – 238 Patients should
relative benefits are similar, the absolute benefit is greater in pa- be carefully evaluated by an experienced cardiologist before gener-
tients with IHD.249 Patients with longer QRS durations may also re- ator replacement. Treatment goals may have changed and the risk of
ceive greater benefit from an ICD, but these patients should often fatal arrhythmia may be lower or the risk of non-arrhythmic death
receive a CRT device.227,251 higher. It is a matter of some controversy whether patients whose
Two RCTs showed no benefit in patients who had an ICD im- LVEF has greatly improved and who have not required device ther-
planted within 40 days after a myocardial infarction. 158,228 Al- apy during the lifetime of the ICD should have another device im-
though sudden arrhythmic deaths were reduced, this was planted.234 – 238
balanced by an increase in non-arrhythmic deaths. Accordingly, Subcutaneous defibrillators may be as effective as conventional
an ICD is contraindicated in this time period. A wearable defibril- ICDs with a lower risk from the implantation procedure.256,257
lator may be considered if the patient is deemed to be at high risk They may be the preferred option for patients with difficult access
of ventricular fibrillation, although evidence from randomized or who require ICD explantation due to infection. Patients must be
trials is lacking.239 – 241 carefully selected, as they have limited capacity to treat serious bra-
ICD implantation is recommended only after a sufficient trial dyarrhythmia and can deliver neither antitachycardia pacing nor
(minimum 3 months) of optimal medical therapy (OMT) has failed CRT. Substantial RCTs with these devices and more data on safety
to increase the LVEF to .35%. However, one of the two landmark and efficacy are awaited.258,259
papers on which these recommendations are based included pa- A wearable ICD (an external defibrillator with leads and elec-
tients with an LVEF .30%. Fewer than 400 patients with an LVEF trode pads attached to a wearable vest) that is able to recognize
of 30 – 35% were included in the landmark studies, and although and interrupt VT/ventricular fibrillation may be considered for a lim-
there was no statistical interaction between treatment effect and ited period of time in selected patients with HF who are at high risk
LVEF, the evidence of benefit is less robust in this group of patients. for sudden death but otherwise are not suitable for ICD implant-
Conservative programming with long delays252 between detec- ation (e.g. those with poor LVEF after acute myocardial damage until
tion and the ICD delivering therapy dramatically reduces the risk LV function recovers, patients scheduled for heart transplant-
of both inappropriate (due to artefacts or AF) and appropriate ation).239 – 241,260 However, no prospective RCTs evaluating this de-
but unnecessary [due to self-terminating ventricular tachycardia vice have been reported.
(VT)] shocks.252 – 254 For detailed recommendations on the use/indications of ICD we
Patients with a QRS duration ≥130 ms should be considered for refer the reader to the ESC/European Heart Rhythm Association
a defibrillator with CRT (CRT-D) rather than ICD. See the guideline (EHRA) guidelines on ventricular tachyarrhythmias and sudden car-
on CRT for further details (Section 8.2). diac death.260
2156 ESC Guidelines

8.2 Cardiac resynchronization therapy

Recommendations for cardiac resynchronization therapy implantation in patients with heart failure

Recommendations Class a Level b Ref c


CRT is recommended for symptomatic patients with HF in sinus rhythm with a QRS duration ≥150 msec and LBBB QRS
I A 261–272
morphology and with LVEF ≤35% despite OMT in order to improve symptoms and reduce morbidity and mortality.
CRT should be considered for symptomatic patients with HF in sinus rhythm with a QRS duration ≥150 msec and non-LBBB
IIa B 261–272
QRS morphology and with LVEF ≤35% despite OMT in order to improve symptoms and reduce morbidity and mortality.
CRT is recommended for symptomatic patients with HF in sinus rhythm with a QRS duration of 130–149 msec and LBBB QRS
I B 266, 273
morphology and with LVEF ≤35% despite OMT in order to improve symptoms and reduce morbidity and mortality.

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CRT may be considered for symptomatic patients with HF in sinus rhythm with a QRS duration of 130–149 msec and non-LBBB
IIb B 266, 273
QRS morphology and with LVEF ≤35% despite OMT in order to improve symptoms and reduce morbidity and mortality.
CRT rather than RV pacing is recommended for patients with HFrEF regardless of NYHA class who have an indication for ventricular
I A 274–277
pacing and high degree AV block in order to reduce morbidity.This includes patients with AF (see Section 10.1).
CRT should be considered for patients with LVEF ≤35% in NYHA Class III–IVd despite OMT in order to improve symptoms and
275,
reduce morbidity and mortality, if they are in AF and have a QRS duration ≥130 msec provided a strategy to ensure bi-ventricular IIa B
278–281
capture is in place or the patient is expected to return to sinus rhythm.
Patients with HFrEF who have received a conventional pacemaker or an ICD and subsequently develop worsening HF despite OMT
IIb B 282
and who have a high proportion of RV pacing may be considered for upgrade to CRT.This does not apply to patients with stable HF.
266,
CRT is contra-indicated in patients with a QRS duration < 130 msec. III A
283–285

AF ¼ atrial fibrillation; AV ¼ atrio-ventricular; CRT ¼ cardiac resynchronization therapy; HF ¼ heart failure; HFrEF ¼ heart failure with reduced ejection fraction; ICD ¼
implantable cardioverter-defibrillator; LBBB ¼ left bundle branch block; LVEF ¼ left ventricular ejection fraction; NYHA ¼ New York Heart Association; OMT ¼ optimal medical
therapy; QRS ¼ Q, R and S waves (combination of three of the graphical deflections); RV ¼ right ventricular.
a
Class of recommendation.
b
Level of evidence.
c
Reference(s) supporting recommendations.
d
Use judgement for patients with end-stage HF who might be managed conservatively rather than with treatments to improve symptoms or prognosis.

CRT improves cardiac performance in appropriately selected pa- CRT response and was the inclusion criterion in all randomized
tients and improves symptoms286 and well-being286 and reduces trials. But QRS morphology has also been related to a beneficial re-
morbidity and mortality.266 Of the improvement in quality-adjusted sponse to CRT. Several studies have shown that patients with left
life-years (QALYs) with CRT among patients with moderate to se- bundle branch block (LBBB) morphology are more likely to respond
vere HF, two-thirds may be attributed to improved quality of life and favourably to CRT, whereas there is less certainty about patients
one-third to increased longevity.287 with non-LBBB morphology. However, patients with LBBB morph-
Only the COMPANION265 and CARE-HF trials262,263 compared ology often have wider QRS duration, and there is a current debate
the effect of CRT to guideline-advised medical therapy. Most other about whether QRS duration or QRS morphology is the main pre-
trials have compared CRT-D to ICD, and a few have compared dictor of a beneficial response to CRT. Evidence from two IPD
CRT-P to backup pacing. The prevention of lethal bradycardia might meta-analyses indicates that after accounting for QRS duration,
be an important mechanism of benefit shared by all pacing devices. there is little evidence to suggest that QRS morphology or aetiology
In CARE-HF, at baseline, 25% of patients had a resting heart rate of of disease influence the effect of CRT on morbidity or mortal-
≤60 bpm.262 – 264 If prevention of bradycardia is important, the ef- ity.266,273 In addition, none of the landmark trials selected patients
fect of CRT will appear greater in trials where there is no device for inclusion according to QRS morphology, sex or ischaemic aeti-
in the control group. ology, nor were they powered for subgroup analyses.
Most studies of CRT have specified that the LVEF should be ,35%, The Echo-CRT283,284 trial and an IPD meta-analysis266 suggest
but RAFT267 and MADIT-CRT268,269 specified an LVEF ,30%, while possible harm from CRT when QRS duration is ,130 ms, thus im-
REVERSE270 – 272 specified ,40% and BLOCK-HF274 ,50%. Rela- plantation of CRT is not recommended if QRS duration is ,130
tively few patients with an LVEF of 35–40% have been randomized, ms.266,283,284
but an individual participant data (IPD) meta-analysis suggests no If a patient is scheduled to receive an ICD and is in sinus rhythm
diminution of the effect of CRT in this group.266 with a QRS duration ≥130 ms, CRT-D should be considered if
Not all patients respond favourably to CRT.286 Several character- QRS is between 130 and 149 ms and is recommended if QRS is
istics predict improvement in morbidity and mortality, and the ex- ≥150 ms. However, if the primary reason for implanting a CRT
tent of reverse remodelling is one of the most important is for the relief of symptoms, then the clinician should choose
mechanisms of action of CRT. Patients with ischaemic aetiology CRT-P or CRT-D, whichever they consider appropriate. Clinical
will have less improvement in LV function due to myocardial scar tis- practice varies widely among countries. The only randomized trial
sue, which is less likely to undergo favourable remodelling.288 Con- to compare CRT-P and CRT-D265 failed to demonstrate a differ-
versely, women may be more likely to respond than men, possibly ence in morbidity or mortality between these technologies.288 If
due to smaller body and heart size.273,285,289 QRS width predicts the primary reason for implanting CRT is to improve prognosis,
ESC Guidelines 2157

then the majority of evidence lies with CRT-D for patients in enhance contractile performance without activating extra systolic
NYHA Class II and with CRT-P for patients in NYHA Classes contractions. CCM has been evaluated in patients with HFrEF in
III – IV. It is unclear whether CRT reduces the need for an ICD NYHA Classes II – III with normal QRS duration (,120 ms).221,222
(by reducing the arrhythmia burden) or increases the benefit An individual patient data meta-analysis demonstrated an improve-
from an ICD (by reducing mortality rates from worsening HF, lead- ment in exercise tolerance (peak VO2) and quality of life (Minnesota
ing to longer exposure to the risk of arrhythmia). Living with Heart Failure questionnaire). Thus CCM may be consid-
When LVEF is reduced, RV pacing may exacerbate cardiac dyssyn- ered in selected patients with HF. The effect of CCM on HF morbid-
chrony. This can be prevented by CRT, which might improve patient ity and mortality remains to be established.
outcomes.274,275,277,290 However, a difference in outcome was not Most other devices under evaluation involve some modification
observed between CRT and RV pacing in a subgroup analysis of of the activity of the autonomic nervous system (ANS) by targeted
RAFT267 or in patients without HFrEF in BioPACE.291 On balance, electrical stimulation.298,299 These include vagal nerve stimulation,

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CRT rather than RV pacing is recommended for patients with HFrEF spinal cord stimulation, carotid body ablation and renal denervation,
regardless of NYHA class who have an indication for ventricular pa- but so far none of the devices has improved symptoms or outcomes
cing in order to reduce morbidity, although no clear effect on mor- in RCTs.
tality was observed. Patients with HFrEF who have received a Devices for remote monitoring are discussed in Section 14.
conventional pacemaker or an ICD and subsequently develop wor-
sening HF with a high proportion of RV pacing, despite OMT, may be
considered for upgrading to CRT. 9. Treatment of heart failure with
Only two small trials have compared pharmacological therapy
alone vs. CRT in patients with AF, with conflicting results. Several
preserved ejection fraction
studies have indicated that CRT is superior to RV pacing in patients While there is clear agreement that the diagnosis of HFrEF requires
undergoing atrio-ventricular (AV) node ablation.275,277,290 How- an LVEF ,40%, the exact definition of HFpEF is less clear. Accord-
ever, CRT is not an indication to carry out AV node ablation except ing to the definition provided in this document (see Section 3), the
in rare cases when ventricular rate remains persistently high (.110 diagnosis of HFpEF requires an LVEF ≥50%, whereas patients with
bpm) despite attempts at pharmacological rate control. A subgroup LVEF between 40 and 49% are considered to have HFmrEF (for de-
analysis of patients with AF from the RAFT study found no benefit tails, please refer to Section 3). Patients with HFmrEF have generally
from CRT-D compared with ICD, although less than half of patients been included in trials of HFpEF. Accordingly, the guidance in this
had .90% biventricular capture.276 Observational studies report section applies to patients with both HFmrEF and HFpEF. As new
that when biventricular capture is ,98%, the prognosis of patients data and analyses become available, it might be possible to make re-
with CRT declines.277 Whether this association reflects a loss of re- commendations for each phenotype separately.
synchronization (which might be remedied by device programming), In clinical practice and clinical trials, compared with HFrEF patients,
poor placing of the LV lead (which might be avoided at implantation) only slightly fewer patients with HFpEF and HFmrEF currently appear
or greater difficulty in pacing severely diseased myocardium (which to receive diuretics, beta-blockers, MRAs and ACEIs or ARBs.166,300 –
302
might not be amenable to the above) is uncertain. This observation This may reflect treatment of cardiovascular co-morbidities, such
has not been confirmed in a randomized trial. as hypertension, CAD and AF, or extrapolation of results from trials
Imaging tests for dyssynchrony have not yet been shown to be of conducted for these conditions showing a reduction in new-onset
value in selecting patients for CRT.292 Patients with extensive myo- HF,127 or failure to distinguish between guideline recommendations
cardial scar will have less improvement in LV function with CRT, but for HFrEF and HFmrEF/HFpEF or a belief that existing clinical trials
this is true of any treatment for HFrEF and does not reliably predict provide some evidence of benefit with these agents.
less clinical benefit.293 Pacing thresholds are higher in scarred myo- A summary of phase II and III clinical trials of patients with HFpEF
cardium and, if possible, lead placement should avoid such re- and HFmrEF is presented in Web Table 9.1.
gions.294,295 Although patients with extensive scarring have an The pathophysiology underlying HFpEF and HFmrEF is heteroge-
intrinsically worse prognosis, there is little evidence that they obtain neous, and they are associated with different phenotypes including
less prognostic benefit from CRT.266 diverse concomitant cardiovascular diseases (e.g. AF, arterial hyper-
The reader is directed to guidelines on pacing and CRT for re- tension, CAD, pulmonary hypertension) and non-cardiovascular
commendations on device implantation procedures. The value of diseases [diabetes, chronic kidney disease (CKD), anaemia, iron de-
trying to optimize AV or VV intervals after implantation using ficiency, COPD and obesity].303,304 Compared with HFrEF patients,
echo- or electrocardiographic criteria or blood pressure response hospitalizations and deaths in patients with HFmrEF/HFpEF are
is uncertain, but may be considered for patients who have had a dis- more likely to be non-cardiovascular.305,306 Therefore patients
appointing response to CRT.296,297 should be screened for cardiovascular and non-cardiovascular co-
morbidities, which if present should be managed with interventions
8.3 Other implantable electrical devices that have been shown to improve symptoms, well-being or out-
For patients with HFrEF who remain symptomatic despite OMTand do come related to that co-morbidity and not to exacerbate HF (see
not have an indication for CRT, new device therapies have been pro- Section 11).
posed and in some cases are approved for clinical use in several Euro- No treatment has yet been shown, convincingly, to reduce mor-
pean Union (EU) countries but remain under trial evaluation. bidity or mortality in patients with HFpEF or HFmrEF. However,
Cardiac contractility modulation (CCM) is similar in its mode of since these patients are often elderly and highly symptomatic, and
insertion to CRT, but it involves non-excitatory electrical stimula- often have a poor quality of life,307 an important aim of therapy
tion of the ventricle during the absolute refractory period to may be to alleviate symptoms and improve well-being.308
2158 ESC Guidelines

9.1 Effect of treatment on symptoms and in cardiovascular mortality.130 However, aggressive manage-
in heart failure with preserved ejection ment of dysglycaemia may be harmful.153,320
Myocardial ischaemia may contribute to symptoms, morbidity
fraction and mortality and should be considered when assessing patients.
Diuretics will usually improve congestion, if present, thereby im- However, there is only anecdotal evidence that revascularization
proving symptoms and signs of HF. The evidence that diuretics improves symptoms or outcome. Patients with angina should follow
improve symptoms is similar across the spectrum of LVEF.178,179 the same management route as patients with HFrEF.112
Evidence that beta-blockers and MRAs improve symptoms in Patients with HFpEF and HFmrEF have impaired exercise toler-
these patients is lacking. There is inconsistent evidence for an im- ance, commonly accompanied by an augmented blood pressure re-
provement in symptoms in those treated with ARBs (only for can- sponse to exercise and chronotropic incompetence. Combined
desartan was there an improvement in NYHA class)309,310 and endurance/resistance training appears safe for patients with HFpEF
ACEIs.311

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and HFmrEF and improves exercise capacity (as reflected by an in-
crease in peak oxygen consumption), physical functioning score and
9.2 Effect of treatment on hospitalization diastolic function.307,321
for heart failure in heart failure with
Recommendations for treatment of patients with heart
preserved ejection fraction failure with preserved ejection fraction and heart failure
For patients in sinus rhythm, there is some evidence that nebivo- with mid-range ejection fraction
lol,173,312,313 digoxin, 314 spironolactone301 and candesartan310
might reduce HF hospitalizations. For patients in AF, beta-blockers Recommendations Class a Level b Ref c
do not appear to be effective and digoxin has not been studied. The
it is recommended to screen
evidence in support of either ARBs315 or ACEIs311 is inconclusive.
patients with HFpEF or HFmrEF
for both cardiovascular and non-
cardiovascular comorbidities, which,
9.3 Effect of treatment on mortality in if present, should be treated provided
I C
heart failure with preserved ejection safe and effective interventions exist
fraction to improve symptoms, well-being
and/or prognosis.
Trials of ACEIs, ARBs, beta-blockers and MRAs have all failed to re-
Diuretics are recommended in
duce mortality in patients with HFpEF or HFmrEF. However, in old- congested patients with HFpEF
er patients with HFrEF, HFpEF or HFmrEF, nebivolol reduced the I B 178, 179
or HFmrEF in order to alleviate
combined endpoint of death or cardiovascular hospitalization,173,312 symptoms and signs.
with no significant interaction between treatment effect and base-
line LVEF.313 HFmrEF ¼ heart failure with mid-range ejection fraction; HFpEF ¼ heart failure
with preserved ejection fraction.
a
Class of recommendation.
9.4 Other considerations b
c
Level of evidence.
Reference(s) supporting recommendations.
Patients in AF should receive an anticoagulant to reduce the risk of
thromboembolic events (for details, see the ESC guidelines of
AF316]. Antiplatelet agents are ineffective for this purpose. Renal
dysfunction, which is common in this population, may contraindicate 10. Arrhythmias and conductance
or increase the risk of haemorrhage with NOACs.
The optimal ventricular rate in patients with HFmrEF/HFpEF and
disturbances
AF is uncertain, and aggressive rate control might be deleterious. Ambulatory electrocardiographic monitoring can be used to investi-
Whether digoxin, beta-blockers or rate-limiting CCBs, or a combin- gate symptoms that may be due to arrhythmias,322 – 324 but evidence
ation of these, should be preferred is unknown. Verapamil or diltia- is lacking to support routine, systematic monitoring for all patients
zem should not be combined with a beta-blocker. There are with HF to identify tachy- and bradyarrhythmias. There is no evidence
insufficient data to recommend ablation strategies (either pulmon- that clinical decisions based on routine ambulatory electrocardio-
ary venous or AV node) for HFpEF and HFmrEF. graphic monitoring improve outcomes for patients with HF.
Circumstantial evidence suggests that treating hypertension, of- Ambulatory electrocardiographic recording detects premature
ten predominantly systolic, is important in HFmrEF/HFpEF.127,317 ventricular complexes in virtually all patients with HF. Episodes of
Diuretics, ACEIs, ARBs and MRAs all appear appropriate agents, asymptomatic, non-sustained VT are common, increasing in fre-
but beta-blockers may be less effective in reducing SBP. A recent quency with the severity of HF and ventricular dysfunction and indi-
study suggests that patients with hypertension and HFpEF or cating a poor prognosis in patients with HF, but provide little
HFmrEF should not receive an ARB (olmesartan) if they are receiv- discrimination between sudden death or death due to progressive
ing ACEIs and beta-blockers.318 HF.316,325 Bradycardia and pauses are also commonly observed, es-
The first-line oral hypoglycaemic drug for patients with HFpEF pecially at night when sympathetic activity is often lower and para-
and HFmrEF should be metformin319 (see also Section 11.6). Re- sympathetic activity higher; sleep apnoea may be a trigger.326 – 328
cently, a trial of empagliflozin showed a reduction in blood pressure Pauses are associated with a poor prognosis in patients with CAD
and body weight, probably by inducing glycosuria and osmotic diur- and left ventricular dysfunction.329 Bradyarrhythmias may make an
esis. Its use was associated with a reduction in hospitalization for HF important contribution to sudden death in HF.330
ESC Guidelines 2159

10.1 Atrial fibrillation must not be given. Longer-term infusion of amiodarone should be
AF is the most common arrhythmia in HF irrespective of concomi- given only by central or long-line venous access to avoid peripheral
tant LVEF; it increases the risk of thromboembolic complications vein phlebitis. In patients with haemodynamic collapse, emergency
(particularly stroke) and may impair cardiac function, leading to electrical cardioversion is recommended (see also Section 12).
worsening symptoms of HF.316 Incident HF precipitated by AF is as-
sociated with a more benign prognosis,331 but new-onset AF in a pa- Recommendations for initial management of a
tient with established HF is associated with a worse outcome, rapid ventricular rate in patients with heart failure and
probably because it is both a marker of a sicker patient and because atrial fibrillation in the acute or chronic setting
it impairs cardiac function.332,333 Patients with chronic HF and per-
manent AF have a worse outcome than those in sinus rhythm, al- Recommendations Class a Level b Ref c
though this is largely explained by more advanced age and HF Urgent electrical cardioversion is

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severity.332,333 Persistent ventricular rates .150 bpm may cause recommended if AF is thought to
HFrEF that resolves with rate control or rhythm correction (‘tachy- be contributing to the patient’s
I C
haemodynamic compromise in
cardiomyopathy’).334,335 AF should be classified and managed ac-
order to improve the patient clinical
cording to the current AF guidelines (i.e. first diagnosed episode, condition.
paroxysmal, persistent, long-standing persistent or permanent), rec- For patients in NYHA Class IV, in
ognizing the uncertainty about the actual duration of the episode addition to treatment for AHF, an
and about previous undetected episodes.316 intravenous bolus of amiodarone
The following issues need to be considered in patients with HF or, in digoxin-naïve patients, an IIa B 348, 349
intravenous bolus of digoxin should
presenting with AF, irrespective of LVEF, especially with a first diag- be considered to reduce the
nosed episode of AF or paroxysmal AF:316 ventricular rate.
† identification of potentially correctable causes (e.g. hypothyroid- For patients in NYHA Class I–III, a
ism or hyperthyroidism, electrolyte disorders, uncontrolled beta-blocker, usually given orally, is
safe and therefore is recommended
hypertension, mitral valve disease) and precipitating factors I A 177
(e.g. recent surgery, chest infection or exacerbation of COPD/ ventricular rate, provided the patient
asthma, acute myocardial ischaemia, alcohol binge), as this may is euvolaemic.
determine management strategy; For patients in NYHA Class I–III,
† assessment of stroke risk and need for anticoagulation; digoxin, should be considered
when ventricular rate remains highd
† assessment of ventricular rate and need for rate control; IIa B 197
despite beta-blockers or when
† evaluation of symptoms of HF and AF. beta-blockers are not tolerated or
contra-indicated.
For details, the reader should refer to the 2016 ESC guidelines on
AF.316 AV node catheter ablation may be
considered to control heart rate
10.1.1 Prevention of atrial fibrillation in patients with heart and relieve symptoms in patients
failure unresponsive or intolerant to
IIb B 290
intensive pharmacological rate and
Many treatments for HF, including ACEIs,336 ARBs,337 beta-
rhythm control therapy, accepting
blockers177,338 and MRAs,339,340 will reduce the incidence of AF, that these patients will become
but ivabradine may increase it.341 CRT has little effect on the inci- pacemaker dependent.
dence of AF.342 Treatment with dronedarone to
Amiodarone will reduce the incidence of AF, induce pharmaco- improve ventricular rate control
III A 347
logical cardioversion, maintain more patients in sinus rhythm after is not recommended due to safety
concerns.
cardioversion and may be used to control symptoms in patients
with paroxysmal AF if beta-blockers fail to do so.343 – 346 Amiodar-
one should generally be restricted to short-term (,6 months) use AF ¼ atrial fibrillation; AHF ¼ acute heart failure; AV ¼ atrio-ventricular; bpm ¼
beats per minute; HF ¼ heart failure; NYHA ¼ New York Heart Association.
in patients with paroxysmal or persistent AF to help attain sinus a
Class of recommendation.
b
rhythm and to reduce the high rate of recurrent AF immediately Level of evidence.
c
after cardioversion. Dronedarone is contraindicated in patients Reference(s) supporting recommendations.
d
The optimal ventricular rate for patients with HF and AF has not been established,
with HF and AF.246,247,347 but the prevailing evidence suggests that strict rate control might be deleterious. A
resting ventricular rate in the range of 60 –100 bpm may be considered based on
10.1.2 Management of new-onset, rapid atrial fibrillation in the current opinion of this Task Force,350,351 although one trial suggested that a
patients with heart failure resting ventricular rate of up to 110 bpm might still be acceptable, and this is
If the patient has no distressing symptoms of HF, then treatment currently recommended by the ESC guidelines on AF.198,316 This should be tested
and refined by further research.
with oral beta-blockers may be initiated to provide ventricular
rate control. For patients with marked congestion who nonetheless
have few symptoms at rest, initial treatment with oral or intravenous 10.1.3 Rate control
(i.v.) digoxin is preferred. For patients in haemodynamic instability, Assessment of ventricular rate control from the radial pulse is not
an i.v. bolus of digoxin or amiodarone348,349 should be administered ideal, especially in patients with HF, as ventricular activation may
into a peripheral vein with extreme care to avoid extravasation into not always generate a palpable pulse. Rate control should be docu-
tissues; where uncertainty exists about venous access, amiodarone mented electrocardiographically. A wearable device enables
2160 ESC Guidelines

ventricular rate to be assessed during rest, exercise and sleep, but cardioversion.343 – 346 When used, the need for continued administra-
the value of routine monitoring has not yet been established. Im- tion of amiodarone should be regularly reviewed and justified.
planted devices such as pacemakers, CRT or ICDs can also be The safety and efficacy of catheter ablation in the atria and pul-
used to measure ventricular rate. monary veins (PV) as a rhythm control strategy in HF is at present
The optimal resting ventricular rate in patients with AF and HF is uncertain except for tachycardia induced cardiomyopathy.316 One
uncertain but may be between 60 – 100 bpm.350,352 – 354 One trial small study suggested that AF ablation was superior to AV node ab-
suggested that a resting ventricular rate of up to 110 bpm might still lation and CRT.360 Another study, including 203 patients with per-
be acceptable,198,202 and 2016 ESC AF guidelines recommend this sistent AF, HF and an ICD or CRT device, showed that AF ablation
threshold as the target for rate control therapy.316 However, this was superior to amiodarone in correcting AF, and this was asso-
Task Force believes that a lower rate for patients with HF may be ciated with fewer hospitalizations for HF and lower mortality.
preferable (60 – 100 bpm). Ventricular rates ,70 bpm are asso- Two small studies of AF ablation compared with rate control met
ciated with a worse outcome.351 This may explain why beta-

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with mixed success in terms of procedural complications and suc-
blockers titrated to guideline-target doses failed to reduce morbid- cess in improving symptoms.278,279 The most recent evidence
ity or mortality in patients with HFrEF and AF,177 and might also ex- from a meta-analysis that included 914 patients suggests an encour-
plain the association between digoxin and adverse outcomes aging success rate of PV ablation of AF in patients with LV dysfunc-
reported in some observational studies of AF.355 – 357 The optimal tion, with improvements in LVEF and functional capacity.361 These
ventricular rate during exercise is also uncertain, but may be results need to be confirmed in ongoing RCTs such as CASTLE
,110 bpm during light exercise.354 Beta-blockers, digoxin and their AF,362 AMICA and CABANA.
combination may be used to control ventricular rate.358 It is uncer-
tain which approach is optimal, but beta-blockers appear safe as the
first-line agent even if it is not clear that they reduce morbidity and Recommendations for a rhythm control management
mortality in patients with AF. Beta-blockers reduce ventricular rate strategy in patients with atrial fibrillation, symptomatic
during periods of activity, while digoxin exerts a greater effect at heart failure (NYHA Class II– IV) and left ventricular
night.358 Persistently high ventricular rates may indicate thyrotoxi- systolic dysfunction and no evidence of acute
cosis or excessive sympathetic activity due to congestion, which decompensation
might respond to diuresis. Although amiodarone and non-
dihydropyridine CCBs can reduce ventricular rate, they have Recommendations Class a Level b Ref c
more adverse effects and should generally be avoided in patients Electrical cardioversion or
with HFrEF and, with less certainty, in patients with HFpEF and pharmacological cardioversion with
amiodarone may be considered in
HFmrEF. Rarely, ventricular rate cannot be reduced below 100 –
patients with persisting symptoms
110 bpm by pharmacological means alone and AV node ablation IIb B 344
and/or signs of HF, despite OMT and
with ventricular pacing may be considered; in this situation, for pa- adequate control of ventricular rate,
tients with HFrEF, CRT should be considered instead of convention- to improve clinical/symptomatic
status.
al RV pacing. There is little evidence, other than from registries, to
support a strategy of AV node ablation and CRT compared with AF ablation may be considered in
order to restore sinus rhythm to
pharmacological therapy alone in patients with AF and a resting ven-
improve symptoms in patients with
tricular rate ,100 –110 bpm (see Section 8.2).281 However, in pa- persisting symptoms and/or signs IIb B 279, 363
tients with a fast ventricular rate and intractable symptoms, AV node of HF, despite OMT and adequate
ablation may be considered. Also, if the patient is indicated for an control of ventricular rate, to
improve clinical/symptomatic status.
ICD, AV node ablation with implantation of CRT-D may be a pre-
ferred option, especially if the patient has moderate to severe Amiodarone may be considered
prior to (and following) successful
symptoms. IIb B 342, 360
electrical cardioversion to maintain
10.1.4 Rhythm control sinus rhythm.
In patients with chronic HF, a rhythm control strategy (including Dronedarone is not recommended
because of an increased risk
pharmacological or electrical cardioversion) has not been shown to
of hospital admissions for
be superior to a rate control strategy in reducing mortality or morbid- III A 247, 347
cardiovascular causes and an
ity.359 Urgent cardioversion is indicated only if the AF is life threaten- increased risk of premature death in
ing, otherwise both HF and ventricular rate should be controlled NYHA Class III–IV patients.
prior to cardioversion. A rhythm control strategy is probably best re- Class I antiarrhythmic agents are
248, 364,
served for patients with a reversible secondary cause of AF (e.g. not recommended because of an III A
365
increased risk of premature death.
hyperthyroidism) or an obvious precipitant (e.g. recent pneumonia)
and in patients with troublesome symptoms due to AF after optimiza-
tion of rate control and HF therapy. The use of class I antiarrhythmic AF ¼ atrial fibrillation; HF ¼ heart failure; NYHA ¼ New York Heart Association,
OMT ¼ optimal medical therapy.
agents and dronedarone increases morbidity and mortality in patients Patients should generally be anticoagulated for 6 weeks prior to electrical
with HF and AF and should be avoided.246,247,347 Amiodarone will cardioversion.
a
cause some patients with chronic AF to revert to sinus rhythm, Class of recommendation.
b
Level of evidence.
may reduce symptomatic paroxysms of AF and will help maintain c
Reference(s) supporting recommendations.
patients in sinus rhythm after spontaneous or electrical
ESC Guidelines 2161

10.1.5 Thromboembolism prophylaxis HF and AF who have mechanical heart valves or at least moderate mi-
Patients with HF and AF should generally be anticoagulated and the tral stenosis, only oral vitamin K antagonists should be used for pre-
balance of benefit and risk of bleeding (using CHA2DS2-VASc and vention of thromboembolic stroke.370
HAS-BLED scores; for details, please see Web Tables 10.1 and The dabigatran dose should be reduced to 110 mg b.i.d. when cre-
10.2.) should be evaluated as recommended in the ESC guidelines atinine clearance is 30 –49 mL/min, rivaroxaban to 15 mg daily and
for AF.316 A substantial proportion of patients with HF will have edoxaban to 30 mg daily when creatinine clearance is 30 – 50 mL/
both benefit and risk scores ≥3, indicating that careful consider- min and apixaban to 2.5 mg twice daily if a patient has two or
ation should be given before prescribing an oral anticoagulant and more of the following: age ≥80 years, serum creatinine ≥1.5 mg/
that regular review is subsequently needed (and correctable risk dL or body weight ≤60 kg.370 – 375 The summary of the recommen-
factors for bleeding addressed) if an oral anticoagulant is given. dations for the prevention of thromboembolism in patients with
NOACs are preferred for patients with HF with non-valvular AF, as symptomatic HF and paroxysmal or persistent/permanent AF is

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NOACs compared with vitamin K antagonists seem to be at least presented in the recommendations table. For further details, please
similarly effective and even safer (less intracranial haemorrhage) in refer to the recent ESC guidelines on AF.316
patients with HF than in subjects without HF,316,366,367 although con- A left atrial occlusion device could be considered in a patient with
cerns exist about their safety in older patients with HF and poor renal AF as an alternative to an oral anticoagulant who is at high-risk both
function368,369 [for a detailed description of the interaction between of thromboembolism and of bleeding in order to avoid the risk of
NOAC and renal function, see Heidbuchel et al. 370]. In patients with haemorrhage due to anticoagulation risk.381,382

Recommendations for the prevention of thrombo-embolism in patients with symptomatic heart failure (NYHA Class II –
IV) and paroxysmal or persistent/permanent atrial fibrillation

Recommendations Class a Level b Ref c


The CHA2DS2-VASc and HAS-BLED scores are recommended tools in patients with HF for the estimation of the risk of
I B 376, 377
thromboembolism and the risk of bleeding associated with oral anticoagulation, respectively.
An oral anticoagulant is recommended to prevent thrombo-embolism for all patients with paroxysmal or persistent/permanent
372–375,
AF and a CHA2DS2-VASc score ≥2, without contra-indications, and irrespective of whether a rate or rhythm management strategy I A
378, 379
is used (including after successful cardioversion).
NOAC treatment is contra-indicated in patients with mechanical valves or at least moderate mitral stenosis. III B 380
In patients with AF of ≥48 h duration, or when the duration of AF is unknown, an oral anticoagulant is recommended at a
I B
therapeutic dose for ≥3 weeks prior to electrical or pharmacological cardioversion.
Intravenous heparin or LMWH and TOE quided strategy is recommended for patients who have not been treated with an
I C
anticoagulant dose for ≥3 weeks and require urgent electrical or pharmacological cardioversion for a life threatening arrhythmia.
Combination of an oral anticoagulant and an antiplatelet agent is not recommended in patients with chronic (>12 months
after an acute event) coronary or other arterial disease, because of a high-risk of serious bleeding. Single therapy with an oral III C
anticoagulant is preferred after 12 months.
For patients with HF and non-valvular AF eligible for anticoagulation based on a CHA2DS2-VASc score, NOACs rather than
warfarin should be considered for anticoagulation as NOACs are associated with a lower risk of stroke, intracranial haemorrhage IIa B 367
and mortality, which outweigh the increased risk of gastrointestinal haemorrhage.

AF ¼ atrial fibrillation; CHA2DS2-VASc ¼ Congestive heart failure or left ventricular dysfunction, Hypertension, Age ≥ 75 (doubled), Diabetes, Stroke (doubled)-Vascular disease,
Age 65 –74, Sex category (female); HAS-BLED ¼ Hypertension, Abnormal renal/liver function, Stroke, Bleeding history or predisposition, Labile international normalized ratio,
Elderly (.65 years), Drugs/alcohol concomitantly (1 point each); HF ¼ heart failure; LMWH ¼ low molecular weight heparin; NOAC ¼ non-vitamin K antagonist oral
anticoagulant; NYHA ¼ New York Heart Association; TOE ¼ transoesophageal echocardiography.
a
Class of recommendation.
b
Level of evidence.
c
Reference(s) supporting recommendations.

10.2 Ventricular arrhythmias revascularization for patients with HFrEF have not reduced overall
The initial management of asymptomatic ventricular arrhythmias mortality,107,385 even in subgroups of patients with angina or myo-
is correction of electrolyte abnormalities, particularly low serum cardial ischaemia,115,386 but further analysis did suggest a reduction
potassium and magnesium, withdrawal of agents that might in sudden deaths.387
provoke arrhythmias and, in patients with HFrEF, optimization Amiodarone (often in combination with a beta-blocker) may be
of pharmacological therapy with ACEIs, beta-blockers and used to suppress symptomatic ventricular arrhythmias, but it may
MRAs and sacubitril/valsartan, which all reduce the risk of sudden adversely affect prognosis, especially in patients with more severe
death.174,177,383,384 HF.227,244 Other antiarrhythmic drugs should be avoided.247 Trans-
The clinical relevance of myocardial ischaemia for the provoca- catheter radiofrequency modification of the arrhythmogenic sub-
tion of ventricular arrhythmias is uncertain, although anecdotal strate may reduce the number of appropriate ICD discharges
cases of ischaemia-induced arrhythmias exist. Randomized trials of and may be used to terminate arrhythmic storm in patients with
2162 ESC Guidelines

HF and frequent, recurrent ventricular tachyarrhythmias and amiodarone, digoxin and ivabradine. For patients in AF, a reduction
therefore should be considered in such patients. Seeking the in the dose of beta-blockers allowing the daytime resting ventricular
advice of the members of the HF Team with expertise in electro- rate to rise to 70– 90 bpm may be considered, since evidence that
physiology is recommended in patients with recalcitrant ventricu- beta-blockers improve outcome in patients with AF is lacking.177 For
lar arrhythmias. For further details we refer the reader to the ESC/ patients with pauses but in sinus rhythm, a reduction in the dose of
EHRA guidelines on ventricular arrhythmias and sudden cardiac beta-blockers should be avoided unless the pauses are symptomatic,
death.260 prolonged or frequent, in which case the relative merits of dose re-
duction, beta-blocker withdrawal and (biventricular) pacing may be
considered. However, evidence is lacking to support a strategy of
Recommendations for the management of ventricular
pacing solely to permit initiation or titration of beta-blocker therapy
tachyarrhythmias in heart failure
in the absence of a conventional pacing indication; this strategy is not

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recommended. For patients with HFrEF and high-degree AV block,
Recommendations Class a Level b Ref c
CRT is preferred over RV pacing (Section 8.2). When the cause of
Potential aggravating/precipitating bradycardia or pauses is sinus node disease with intact AV conduc-
factors (e.g. low serum potassium/
tion, then therapeutic strategies that avoid inducing ventricular dys-
magnesium, ongoing ischaemia) IIa C
should be sought and corrected in synchrony are preferred, although clinical trial evidence to support
patients with ventricular arrhythmias. this expert opinion for patients with HF is sparse. For other pacing
Treatment with beta-blocker, MRA indications, please consult the ESC Guidelines on Pacing and
and sacubitril/valsartan reduces CRT.389
the risk of sudden death and is 162,
I A
recommended for patients with 170–175
HFrEF and ventricular arrhythmias
(as for other patients)(see Section 7).
Recommendations for the management of
bradyarrhythmias in heart failure
Implantation of an ICD or CRT-D
223–226,
device is recommended for selected I A
388
patients with HFrEF (see Section 8). Recommendations Class a Level b Ref c
Several strategies should be When pauses >3 seconds are
considered to reduce
recurrent symptomatic arrhythmias bradycardia is symptomatic and the
in patients with an ICD resting ventricular rate is <50 bpm
(or in those who are not eligible IIa C in sinus rhythm or <60 bpm in AF,
for ICD), including attention to risk it should be considered whether IIa C
factors and optimal pharmacological there is need for any rate limiting
treatment of HF, amiodarone, medications prescribed; for patients
catheter ablation and CRT. in sinus rhythm beta-blockers should
Routine use of antiarrhythmic be reduced in dose or withdrawn
agents is not recommended in only as a last resort.
patients with HF and asymptomatic 247, 248, For patients with symptomatic,
III A
ventricular arrhythmias because 364, 365 prolonged or frequent pauses
of safety concerns (worsening HF, despite adjustment of rate limiting
proarrhythmia, and death). IIb C
medication, either beta-blocker
withdrawal or pacing may be
considered as the next step.
ACEI ¼ angiotensin-converting enzyme inhibitor; ARB ¼ angiotensin receptor
blocker; CRT ¼ cardiac resynchronization therapy; CRT-D ¼ defibrillator with Pacing solely to permit initiation or
cardiac resynchronization therapy; HF ¼ heart failure; HFrEF ¼ heart failure with titration of beta-blocker therapy in
reduced ejection fraction; ICD ¼ implantable cardioverter defibrillator; MRA ¼ III C
the absence of a conventional pacing
mineralocorticoid receptor antagonist. indication is not recommended.
a
Class of recommendation.
b
Level of evidence. In patients with HFrEF who require
c
Reference(s) supporting recommendations. pacing and who have high degree AV 274, 275,
I A
block, CRT rather than RV pacing is 290
recommended.
In patients with HFrEF who require
10.3 Symptomatic bradycardia, pauses pacing who do not have high degree
AV block, pacing modes that avoid IIa C
and atrio-ventricular block inducing or exacerbating ventricular
The ESC Guidelines on Pacing and CRT recommended intervention dyssynchrony should be considered.
when pauses exceed 6 s, even when this is not associated with symp-
toms.389 However, these recommendations were generated mainly AF ¼ atrial fibrillation; AV ¼ atrio-ventricular; bpm ¼ beats per minute; CRT ¼
for patients without obvious myocardial dysfunction, and shorter cardiac resynchronization therapy; ECG ¼ electrocardiogram; HFrEF ¼ heart
failure with reduced ejection fraction; RV ¼ right ventricular.
pauses might require intervention in patients with HFrEF.329 If a
Class of recommendation.
b
pauses .3 s are identified on electrocardiographic monitoring, Level of evidence.
c
medications should be reviewed and the following agents stopped Reference(s) supporting recommendations.

or reduced in dose, starting with rate-limiting CCBs then


ESC Guidelines 2163

11. Co-morbidities Table 11.1 Importance of co-morbidities in patients


with heart failure
11.1. Heart failure and co-morbidities
Co-morbidities are of great importance in HF (Table 11.1) and may 1. interfere with the diagnostic process of HF (e.g. COPD as a
affect the use of treatments for HF (e.g. it may not be possible to use potentially confounding cause of dyspnoea).390, 391
renin –angiotensin system inhibitors is some patients with severe re- 2. aggravate HF symptoms and further impair quality of life.391, 392
nal dysfunction) (see Section 7). The drugs used to treat co- 3. contribute to the burden of hospitalizations and mortality,393 as the
morbidities may cause worsening of HF (e.g. NSAIDs given for arth- main cause of readmissions at 1 and 3 months.394
ritis, some anti-cancer drugs) (see Section 7). Management of co- 4. may affect the use of treatments for HF (e.g. renin–angiotensin
morbidities is a key component of the holistic care of patients system inhibitors contra-indicated in some patients with severe renal
with HF (see Section 14). Many co-morbidities are actively managed dysfunction or beta-blockers relatively contra-indicated in asthma).395, 396

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by specialists in the field of the co-morbidity, and these physicians 5. evidence base for HF treatment is more limited as co-morbidities were
will follow their own specialist guidelines. The current guidelines
will identify where the presence of HF should change the way a co- is therefore often lacking in the presence of co-morbidities.
morbidity would normally be treated. This may be because either 6. drugs used to treat co-morbidities may cause worsening HF (e.g.
NSAIDs given for arthritis, some anti-cancer drugs).397
safety or efficacy may be different in the presence of HF (or may sim-
ply be unknown) or because of evidence of particular effects in an 7. interaction between drugs used to treat HF and those used to treat
HF population, either beneficial or detrimental. HFpEF has an even
occurrence of side effects (e.g. beta-blockers for HFrEF and beta-
higher prevalence of co-morbidities compared with HFrEF, and agonists for COPD and asthma).391, 395, 396
many of these may be instrumental in the progression of this
syndrome.398 HF ¼ heart failure; COPD ¼ chronic obstructive pulmonary disease; HFrEF ¼
heart failure with reduced ejection fraction; NSAIDs ¼ non-steroidal
anti-inflammatory drugs.
11.2 Angina and coronary artery disease
11.2.1 Pharmacological management
Beta-blockers, and in selected patients ivabradine,180 are effective
agents for angina control, as well as an essential component of
HFrEF therapy. In HFpEF patients, they may also be used for angina improve prognosis.112,113 However, one needs to be aware of a
relief, although this has never been formally tested.399 lack of studies including patients who have well-defined HF, there-
Trimetazidine has been shown to exert some beneficial effect as fore this recommendation is solely based on expert opinion. On
an add-on to beta-blockers in patients with HF and angina.400 – 406 the basis of the results of the STICH trial [which excluded patients
There are data suggesting that it may improve NYHA functional with left main disease and Canadian Cardiovascular Society (CCS)
capacity, exercise duration and LV function in patients with angina classes III – IV], CABG is also recommended in patients with
HFrEF.402 – 406 Certain other effective anti-anginal drugs have HFrEF, significant CAD (left anterior descending artery or multi-
been studied in sizeable numbers of HFrEF/LV dysfunction patients vessel disease) and LVEF ≤35% to reduce death and hospitaliza-
and shown to be safe [e.g. amlodipine,215,407 nicorandil408 and ni- tion for cardiovascular causes. 385 Patients with .10%
trates183,184,409]. The safety of other anti-anginal agents in HFrEF, dysfunctional but viable LV myocardium may be more likely to
such as ranolazine, is uncertain, while other drugs, specifically dil- benefit from myocardial revascularization (and those with ≤10%
tiazem and verapamil, are thought to be unsafe in patients with are less likely to benefit), although this approach to patient selec-
HFrEF (although they may be used in HFpEF).214 Dihydropyridine tion for revascularization is unproven. In the STICH trial, neither
CCBs may all increase sympathetic tone, and their safety in the presence of viability nor the severity of LV remodelling identi-
HFrEF [except amlodipine215 and felodipine216] and HFpEF is fied those who benefited from CABG in terms of a reduction in
uncertain. mortality.118 For the assessment of techniques to assess myocar-
dial viability, please refer to Section 5. Post hoc analyses from
11.2.2 Myocardial revascularization the STICH trial revealed that the presence of inducible myocardial
For indications for invasive coronary angiography in patients with ischaemia (either on radionuclide stress test or dobutamine stress
HF, please refer to Section 5.8. echocardiogram) or angina does not identify those with worse
Percutaneous and surgical revascularization are complementary prognosis and greater benefit from CABG over OMT.115,386 How-
approaches for symptomatic relief of angina in HFpEF, but whether ever, CABG does improve angina to a greater extent than medical
these interventions improve outcomes is not entirely clear. Recent therapy alone.
ESC guidelines on myocardial revascularization recommended The choice between CABG and PCI should be made by the Heart
coronary artery bypass grafting (CABG) for patients with signifi- Team after careful evaluation of the patient’s clinical status and cor-
cant left main stenosis and left main equivalent (proximal stenosis onary anatomy, expected completeness of revascularization, coex-
of both the left anterior descending and left circumflex arteries) to isting valvular disease and co-morbidities.
2164 ESC Guidelines

Recommendations for the treatment of stable angina pectoris with symptomatic (NYHA Class II-IV) heart failure with
reduced ejection fraction112,113

Recommendations Class a Level b Ref c


Step 1

I A 167–173

Step 2: on top of beta-blocker or if a beta-blocker is not tolerated


Ivabradine should be considered as an anti-anginal drug in suitable HFrEF patients (sinus rhythm and HR ≥70 bpm) as per 180, 410,
IIa B
recommended HFrEF management. 411

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Step 3: For additional angina symptom relief – except from any combination not recommended
183, 184,
A short-acting oral or transcutaneous nitrate should be considered (effective anti-anginal treatment, safe in HF). IIa A
409
A long acting oral or transcutaneous nitrate should be considered (effective anti-anginal treatment, not extensively studied in HF). IIa B 183, 184
Trimetazidine may be considered when angina persists despite treatment with a beta-blocker (or alternative) to relieve angina
IIb A 400–403
(effective anti-anginal treatment, safe in HF).
Amlodipine may be considered in patients unable to tolerate a beta-blocker to relieve angina (effective anti-anginal treatment, safe in HF). IIb B 215, 407
Nicorandil may be considered in patients unable to tolerate a beta-blocker to relieve angina (effective anti-anginal treatment,
IIb C
but safety in HF uncertain).
Ranolazine may be considered in patients unable to tolerate a beta-blocker to relieve angina (effective anti-anginal treatment, but
IIb C
safety in HF uncertain).
Step 4: Myocardial revascularization
385, 412,
Myocardial revascularization is recommended when angina persists despite treatment with anti-angina drugs. I A
413
Alternatives to myocardial revascularization: combination of ≥3 antianginal drugs (from those listed above) may be considered
when angina persists despite treatment with beta-blocker, ivabradine and an extra anti-angina drug (excluding the combinations IIb C
not recommended below).
The following are NOT recommended:
(1) Combination of any of ivabradine, ranolazine, and nicorandil because of unknown safety. III C
(2) Combination of nicorandil and a nitrate (because of lack of III C
Diltiazem and verapamil are not recommended because of their negative inotropic action and risk of worsening HF. III C 214

bpm ¼ beats per minute; HF ¼ heart failure; HFrEF ¼ heart failure with reduced ejection fraction; NYHA ¼ New York Heart Association.
a
Class of recommendation.
b
Level of evidence.
c
Reference(s) supporting recommendations.

11.3 Cachexia and sarcopenia (for frailty, resistance, reduced anabolic drive, prolonged immobilization and
please refer to Section 14) physical deconditioning, together characterized by catabolic/anabol-
ic imbalance.418 Skeletal muscle wasting, when associated with im-
Cachexia is a generalized wasting process affecting all body com-
paired mobility and symptoms (termed sarcopenia or myopenia),
partments [i.e. lean tissue (skeletal muscle), fat tissue (energy re-
occurs in 30 – 50% of patients with HFrEF.419 In its most severe
serves) and bone tissue (osteoporosis)]. It may occur in 5–15% of
form it is associated with frailty and poor morbidity and mortality.420
patients with HF, especially those with HFrEF, and more advanced
Potential treatments may include appetite stimulants, exercise
disease status.414 – 416 This serious complication is associated with
training120 and anabolic agents, including testosterone, in combin-
more severe symptoms and reduced functional capacity, more fre-
ation with the application of nutritional supplements and
quent hospitalization and decreased survival. Cachexia in HF can be
anti-catabolic interventions, although none is of proven benefit
diagnosed and defined as involuntary non-oedematous weight loss
and their safety is unknown.421
≥6% of total body weight within the previous 6–12 months.414 – 417
The causes are multifactorial, and in individual patients they are
difficult to determine. These may include pro-inflammatory immune 11.4 Cancer
activation, neurohormonal derangements, poor nutrition and mal- Certain chemotherapeutic agents can cause (or aggravate) LV sys-
absorption, impaired calorie and protein balance, anabolic hormone tolic dysfunction and HF. The best recognized of these are the
ESC Guidelines 2165

anthracyclines (e.g. doxorubicin), trastuzumab and tyrosine kinase in depressive symptoms or improvement in cardiovascular status
inhibitors.397,422 A recent Cochrane review found that dexrazoxane compared with placebo in HFrEF patients, but this trial was not
may confer some cardioprotection in patients receiving anthracy- powered enough to prove the latter. 435 Similarly, escitalopram
clines.423 Pre- and post-evaluation of LVEF, if available with myocar- had no effect on either depression or clinical outcomes during the
dial strain imaging, is essential in patients receiving cardiotoxic 24-month follow-up as compared with placebo in patients with
chemotherapy, as detailed elsewhere.397,422 A risk score for identi- HFrEF and depression. Importantly, tricyclic antidepressants should
fying women with breast cancer at risk of developing HF during tras- be avoided, because they may cause hypotension, worsening HF and
tuzumab therapy has been developed based on age, chemotherapy arrhythmias.429,435
details, baseline cardiovascular status and other co-morbidities, and
may be helpful. 424 Chemotherapy should be discontinued and 11.6 Diabetes
HFrEF therapy commenced in patients developing moderate to se- Dysglycaemia and diabetes are very common in HF, and diabetes is

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vere LV systolic dysfunction. If LV function improves, the risks and associated with poorer functional status and worse prognosis. In pa-
benefits of further chemotherapy need to be reconsid- tients with HFrEF, interventions that reduce morbidity and mortality
ered.397,425,426 Mediastinal irradiation can also lead to a variety of confer similar benefit in the presence or absence of diabetes.320 For
long-term cardiac complications. Cardiac biomarkers (NPs and tro- instance, beta-blockers improve outcome similarly, whether or not
ponins) can be used to identify patients at higher risk of cardiotoxi- the patient has diabetes, although different beta-blockers may vary
city and may be helpful in monitoring the use and dosing of in their effects on glycaemic indices.436
cardiotoxic cytotoxics.397,425,426 Whether strict glycaemic control alters the risk of cardiovascular
events in patients with HF is uncertain.437 Among patients with HF
who have not been treated for diabetes, higher HbA1c is associated
11.5 Central nervous system (including with greater risk of cardiovascular events,438,439 but this may not be
depression, stroke and autonomic the case once treatment for diabetes has been commenced.439
dysfunction) In patients with diabetes and HF, glycaemic control should be im-
Stroke and HF commonly coexist because of an overlap of shared plemented gradually and moderately, giving preference to those
risk factors. Both contribute to a worse prognosis. Stroke may drugs, such as metformin, that have been shown to be safe and ef-
make self-care more difficult for the HF patient. Management of fective. In contrast to what was previously believed, metformin is
high-risk stroke patients may require balancing the risk of anticoagu- safe to use in patients with HFrEF, and it should be the treatment
lant and antiplatelet therapies. of choice in patients with HF440,441 but is contraindicated in patients
Autonomic dysfunction is common in HFrEF, especially when se- with severe renal or hepatic impairment, because of the risk of lactic
vere.427 Combined with low blood pressure, it can make fainting and acidosis.
injuries more likely and can interfere with optimal dosing of beta- Insulin is required for patients with type 1 diabetes and to treat
blockers, ACEIs, ARBs and MRAs. Diuretic dosage may be reduced symptomatic hyperglycaemia in patients with type 2 diabetes and
to reduce the severity of postural hypotension. pancreatic islet b cell exhaustion. However, insulin is a powerful
Depression is common and is associated with worse clinical sta- sodium-retaining hormone, and when combined with a reduction
tus and a poor prognosis in HF.428 – 430 It may also contribute to in glycosuria, may exacerbate fluid retention, leading to HF wor-
poor adherence and social isolation. A high index of suspicion is sening. Sulphonylurea derivatives have also been associated with
needed to make the diagnosis, especially in the elderly. Routine an increased risk of worsening HF and should be used with
screening using a validated questionnaire is good practice. Until caution.
now, the Beck Depression Inventory (BDI) and Cardiac Depression Thiazolidinediones (glitazones) cause sodium and water
Scale have been formally validated as reliable tools for the assess- retention and increased risk of worsening HF and hospitalization
ment of depressive mood in patients with HF,431,432 but other ques- and are not recommended in patients with HF.209,210
tionnaires have been broadly used in this group of patients (e.g. Dipeptidylpeptidase-4 inhibitors (DPP4is; gliptins), which increase
Geriatric Depression Scale, Hamilton Depression Scale, Hospital incretin secretion, thereby stimulating insulin release, and long-
Anxiety and Depression Scale). acting glucagon-like peptide 1 (GLP-1) receptor agonists, which
Psychosocial intervention and pharmacological treatment are act as incretin mimetics, improve glycaemic indices but do not re-
helpful, as well as exercise training, in patients with HFrEF and duce and may increase the risk of cardiovascular events and wor-
depression. 433 Cognitive behavioural therapy delivered in pa- sening HF.320,442,443 Importantly, there are no data on the safety of
tients with HF and major depression beyond standard care gliptins and GLP-1 analogues in patients with HF.
and a structured education programme were able to reduce Recently, empagliflozin, an inhibitor of sodium-glucose co-
depression severity, anxiety and fatigue symptoms, as well as transporter 2, reduced hospitalization for HF and mortality, but
improve social functioning and mental and HF-related quality not myocardial infarction or stroke, in patients with diabetes at
of life.434 high cardiovascular risk, some of whom had HF.130 In the absence
Selective serotonin reuptake inhibitors are thought to be safe, al- of other studies with drugs from this group, the results obtained
though the Sertraline Antidepressant Heart Attack Randomized with empaglifozin cannot be considered as a proof of a class
Trial did not confirm that sertraline provides a greater reduction effect.
2166 ESC Guidelines

As glycaemic derangement progresses, the judgement on gly- The management of acute hyperkalaemia (.6.0 mmol/L) may re-
caemic control should be made according to cardiac conditions, quire a short-term cessation of potassium-retaining agents and
and if the new anti-diabetic drugs are to be prescribed, they have RAAS inhibitors, but this should be minimized and RAAS inhibitors
to be closely monitored by an HF team. should be carefully reintroduced as soon as possible while monitor-
ing potassium levels. A Cochrane review452 found no trial evidence
of major outcome benefits for any emergency therapy regimen for
11.7 Erectile dysfunction
hyperkalaemia. Two new potassium binders (patiromer and sodium
Erectile dysfunction is a common and important component of qual-
zirconium cyclosilicate) are currently under consideration for regu-
ity of life in men with HF.444,445 Its treatment should include optimal
latory approval.453,454 Initial results from patients with HF are avail-
therapies for underlying cardiovascular diseases and other interfer-
able and confirm the efficacy of these therapies in reducing serum
ing co-morbidities (e.g. diabetes) and amelioration of anxiety and
potassium455 and preventing recurrent hyperkalaemia in patients
depressive symptoms. Some drugs applied for HF therapy (e.g. thia-

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with HF and CKD in the context of treatment with RAAS
zide diuretics, spironolactone and beta-blockers) may augment
inhibitors.456
erectile dysfunction.444,445 Phosphodiesterase type 5 inhibitors
(PDE5Is) have been shown to have favourable haemodynamic and
anti-remodelling effects and to improve exercise capacity and qual- 11.10 Hyperlipidaemia
ity of life in patients with HFrEF,446,447 but they are contraindicated Elevated low-density lipoprotein cholesterol is uncommon in
in patients taking nitrates. HFrEF; patients with advanced HFrEF often have low concentrations
of low-density lipoprotein, which is associated with a worse progno-
11.8 Gout and arthritis sis. Rosuvastatin did not reduce the primary composite mortality/
Hyperuricaemia and gout are common in HF and may be caused or morbidity endpoints in two large RCTs in patients with HF with
aggravated by diuretic treatment. Hyperuricaemia is associated with or without IHD, but it also did not increase risk, and may have re-
a worse prognosis in HFrEF.448 The current European League duced, hospitalizations.205,457 Therefore there is no evidence to rec-
Against Rheumatism (EULAR) guideline for the management of ommend the initiation of statins in most patients with HF. However,
gout recommends that urate-lowering therapy (ULT) is indicated in patients who are already receiving a statin for CAD, a continu-
in patients with recurrent acute flares, arthropathy, tophi or radio- ation of this therapy may be considered.
graphic changes of gout, aiming to maintain a serum urate level be-
low the saturation point for monosodium urate [,357 mmol/L
11.11 Hypertension
(,6 mg/dL)].449
Hypertension is associated with an increased risk of developing HF;
Xanthine oxidase inhibitors (allopurinol, oxypurinol) may be used
antihypertensive therapy markedly reduces the incidence of HF
to prevent gout, although their safety in HFrEF is uncertain.450 Gout
(with an exception of a-adrenoceptor blockers, which are less ef-
attacks are better treated with colchicine rather than with NSAIDs
fective than other antihypertensives in preventing HF).458 A recent
(although colchicine should not be used in patients with very severe
prospective cohort study documented that in a population with in-
renal dysfunction and may cause diarrhoea). Intra-articular corticos-
cident HF, higher baseline systolic, diastolic and pulse pressure levels
teroids are an alternative for monoarticular gout, but systemic corti-
were associated with a higher rate of adverse events, which further
costeroids cause sodium and water retention.
supports the importance for optimized blood pressure control in
Arthritis is a common co-morbidity and is a common cause of
this population.459 Blood pressure control is an element of the hol-
both self-taken and prescribed drugs that can worsen renal function
istic management of patients with HF.
and HF, especially NSAIDs. Rheumatoid arthritis is associated with
Negatively inotropic CCBs (i.e. diltiazem and verapamil) should
an increased risk of HFpEF. The safety of disease-modifying drugs
not be used to treat hypertension in patients with HFrEF (but are
commonly given to patients with rheumatoid arthritis has not
believed to be safe in HFpEF), and moxonidine should also be
been established in HF.
avoided in patients with HFrEF, as it increased mortality in patients
in one RCT.460 If blood pressure is not controlled with an ACEI (or
11.9 Hypokalaemia and hyperkalaemia an ARB), a beta-blocker, an MRA and a diuretic, then hydralazine
Both hypokalaemia and hyperkalaemia are associated with HF and and amlodipine215 [or felodipine216] are additional blood pressure
with many drugs used for HF treatment.451 Both can aggravate ven- lowering agents that have been shown to be safe in systolic HF. The
tricular arrhythmias. blood pressure targets recommended in hypertension guide-
Loop and thiazide diuretics reduce serum potassium, while lines 317 are applicable to HF. Uncontrolled hypertension in
ACEIs, ARBs and MRAs can all increase serum potassium. Amiloride patients with HFrEF is very rare, provided they are optimally trea-
and triamterene are sometimes used as adjunct diuretics in resistant ted for HF. In contrast, treatment of hypertension is an important
oedema and to assist in preventing hypokalaemia. The treatment of issue in patients with HFpEF. In patients with AHF, i.v. nitrates (or
hypokalaemia can involve recommending high potassium foods or sodium nitroprusside) are recommended to lower blood pressure
prescribing potassium supplements. (see Section 12).
ESC Guidelines 2167

Recommendations for the treatment of hypertension in patients with symptomatic (NYHA Class II-IV) heart failure with
reduced ejection fraction

Recommendations Class a Level b Ref c


Step 1
2, 164,
165, 167,
168,
I A
171–174,
They are also safe in HFpEF.
182,
461–463

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Step 2
A thiazide diuretic (or if the patient is being treated with a thiazide diuretic, switching to a loop diuretic) is recommended to
reduce blood pressure when hypertension persists despite treatment with a combination of an ACE-I (or alternatively ARB but I C
NOT together withan ACE-I), a beta-blocker and an MRA.
Step 3
Amlodipine or hydralazine is recommended to reduce blood pressure when hypertension persists despite treatment with a 183, 184,
I A
combination of an ACE-I (or alternatively ARB but NOT together withan ACE-I), a beta-blocker, an MRA and a diuretic. 215, 409
Felodipine should be considered to reduce blood pressure when hypertension persists despite treatment with a combination of
IIa B 216
an ACE-I (or alternatively ARB but NOT together withan ACE-I), a beta-blocker, an MRA and a diuretic.
Moxonidine is not recommended to reduce blood pressure because of safety concerns in HFrEF patients (increased mortality). III B 460
Alpha-adrenoceptor antagonists are not recommended to reduce blood pressure because of safety concerns in HFrEF patients 458, 464,
III A
465
Diltiazem and verapamil are not recommended to reduce blood pressure in patients with HFrEF because of their negative
III C 214
inotropic action and risk of worsening HF.

ACE ¼ angiotensin-converting enzyme; ARB ¼ angiotensin receptor blocker; HF ¼ heart failure; HFmrEF ¼ heart failure with mid-range ejection fraction; HFpEF ¼ heart failure
with preserved ejection fraction; HFrEF ¼ heart failure with reduced ejection fraction; MRA ¼ mineralocorticoid receptor antagonist; NYHA ¼ New York Heart Association.
a
Class of recommendation.
b
Level of evidence.
c
Reference(s) supporting recommendations.

11.12 Iron deficiency and anaemia i.v. iron therapy in HFrEF patients with iron deficiency over up
Iron deficiency is common in HF, as it is with other chronic ill- to 52 weeks showed reduced hospitalization rates and improved
nesses, and it can lead to anaemia and/or skeletal muscle dysfunc- HF symptoms, exercise capacity and quality of life.472 Treatment
tion without anaemia.466 Within an HF population, iron deficiency with FCM may therefore result in sustainable improvement in func-
is associated with a worse prognosis.467,468 Intravenous iron has tional capacity, symptoms and quality of life. Treatment was also
been specifically studied in two RCTs in patients with HF and associated with a significant reduction in hospitalizations for wor-
iron deficiency (serum ferritin ,100 mg/L or ferritin between sening HF. The number of deaths and the incidence of adverse
100 and 299 mg/L and transferrin saturation ,20%)469,470 both events were similar. Neither i.v. iron trial was powered to test
with and without anaemia. Intravenous ferric carboxymaltose for an effect on major outcomes or to evaluate separately the ef-
(FCM) has been shown to improve self-reported patient global as- fects in anaemic and non-anaemic patients. The effect of treating
sessment, quality of life and NYHA class (over 6 months) in the iron deficiency in HFpEF/HFmrEF and the long-term safety of
FAIR-HF trial469 both in anaemic and non-anaemic patients with iron therapy in either HFrEF, HFmrEF or HFpEF is unknown. The
HF, 471 and in the CONFIRM-HF trial 470 , exercise capacity im- safety of i.v. iron is unknown in patients with HF and haemoglobin
proved over 24 weeks. In the analysis of secondary endpoints in .15 g/dL.469,470 Patients with iron deficiency need to be screened
the CONFIRM-HF trial, i.v. iron reduced the risk of HF hospitaliza- for any potentially treatable/reversible causes (e.g. gastrointestinal
tions in iron-deficient patients with HFrEF.470 A meta-analysis of sources of bleeding).
2168 ESC Guidelines

Recommendations for the treatment of other functional status, greater risk of HF hospitalization and reduced sur-
co-morbidities in patients with heart failure vival. A diagnostic workup to seek a cause for any finding of anaemia
is indicated (e.g. occult blood loss, iron deficiency, B12/folate defi-
Recommendations Class a Level b Ref c ciency, blood dyscrasias), although in many patients no specific
cause is found. The erythropoietin-stimulating agent darbepoetin
alfa did not improve clinical outcomes in HFrEF patients with mild
Intravenous FCM should be to moderate anaemia, but led to an excess of thromboembolic
considered in symptomatic patients
events and is therefore not recommended.475
(serum ferritin <100 µg/L, or
ferritin between 100–299 µg/L and IIa A 469, 470
transferrin saturation <20%) in
order to alleviate HF symptoms, 11.13 Kidney dysfunction (including

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and improve exercise capacity and chronic kidney disease, acute kidney
quality of life.
injury, cardio-renal syndrome and
Diabetes
prostatic obstruction)
Metformin should be considered as
HF and CKD frequently coexist, share many risk factors (diabetes,
IIa C 440 ,441
control in patients with diabetes hypertension, hyperlipidaemia) and interact to worsen progno-
and HF, unless contra-indicated. sis. 476,477 CKD is generally defined as an eGFR ,60 mL/min/
1.73 m 2 and/or the presence of albuminuria (high 30 – 300 or
FCM ¼ ferric carboxymaltose; HF ¼ heart failure; HFrEF ¼ heart failure with very high .300 mg albumin/1 g of urine creatinine). Patients
reduced ejection fraction.
a with severe renal dysfunction (eGFR ,30 mL/min/1.73m2) have
Class of recommendation.
b
Level of evidence. systematically been excluded from randomized clinical trials and
c
Reference(s) supporting recommendations. therefore there is lack of evidence-based therapies in these
Treatments not recommended for other co-morbidities in patients with heart failure
patients.
A further deterioration in renal function, termed worsening renal
function (WRF), is used to indicate an increase in serum creatinine,
Treatments not recommended of other co-morbidities usually by .26.5 mmol/L (0.3 mg/dL) and/or a 25% increase or a
in patients with heart failure 20% drop in GFR. The importance of these apparently small changes
is that they are frequent, they promote the development and pro-
Recommendations Class a Level b Ref c gression of CKD478 and, as a consequence, can worsen the progno-
Sleep apnoea sis of HF. Increases in creatinine during an AHF hospitalization are
Adaptive servo-ventilation is not always clinically relevant, especially when they are accompanied
not recommended in patients by appropriate decongestion, diuresis and haemoconcentration.479
with HFrEF and a predominant Large increases in serum creatinine, termed acute kidney injury
III B 473
central sleep apnoea because
(AKI), are relatively rare in HF and are probably associated with
of an increased all-cause and
cardiovascular mortality. the combination of diuretic therapy with other potentially nephro-
toxic drugs such as some antibiotics (gentamicin and trimethoprim),
Diabetes
contrast media, ACEIs, ARBs, NSAIDs, etc. Of relevance, some of
Thiazolidinediones (glitazones) are
these drugs may accumulate if they are renally excreted. In HF,
not recommended in patients with
III A 209, 210 WRF is relatively common, especially during initiation and up-
HF, as they increase the risk of HF
worsening and HF hospitalization. titration of RAAS inhibitor therapy. Despite the fact that RAAS
Arthritis blockers can frequently cause a decrease in GFR in patients with
NSAIDs or COX-2 inhibitors are HF, this reduction is usually small and should not lead to treatment
not recommended in patients with discontinuation unless there is a marked decrease, as the treatment
III B 211–213
HF, as they increase the risk of HF benefit in these patients is probably largely maintained.480 When
worsening and HF hospitalization. large increases in serum creatinine occur, care should be taken to
evaluate the patient thoroughly and should include assessment of
COX-2 ¼ cyclooxygenase 2; HF ¼ heart failure; HFrEF ¼ heart failure with a possible renal artery stenosis, excessive hyper- or hypovolaemia,
reduced ejection fraction; NSAID ¼ non-steroidal anti-inflammatory drug.
a
Class of recommendation.
concomitant medication and hyperkalaemia, which frequently
b
Level of evidence. coincides with WRF.
c
Reference(s) supporting recommendations. Diuretics, especially thiazides, but also loop diuretics, may be less ef-
fective in patients with a very low GFR, and if used, should be dosed ap-
Anaemia (defined as a haemoglobin concentration ,13.0 g/dL in propriately (higher doses to achieve similar effects). Renally excreted
men and ,12.0 g/dL in women) is common in HF, particularly in drugs (e.g. digoxin, insulin and low molecular weight heparin) may accu-
hospitalized patients. It is more common in women, the elderly mulate in patients with renal impairment and may need dose adjustment
and in patients with renal impairment and is associated with ad- if renal function deteriorates. Patients with HF and coronary or periph-
vanced myocardial remodelling, inflammation and volume over- eral vascular disease are at risk of acute renal dysfunction when they
load.474 Anaemia is associated with advanced symptoms, worse undergo contrast media enhanced angiography [contrast-induced acute
ESC Guidelines 2169

kidney injury (CI-AKI)]. Renal dysfunction and worsening renal function established that obesity is associated with lower mortality across a
is further discussed in the section about AHF (see Section 12). wide range of body mass indexes (BMIs) (see also cachexia in Section
Prostatic obstruction is common in older men and can interfere 11.3)—the so-called obesity paradox also seen in other chronic ill-
with renal function; it should therefore be ruled out in men with HF nesses.414,416 Obesity should be managed as recommended in the
with deteriorating renal function. a-adrenoceptor blockers cause ESC guidelines on cardiovascular disease prevention,483 if the aim is
hypotension and sodium and water retention, and may not be to prevent future development of HF. However, these guidelines do
safe in HFrEF.458,464,465 For these reasons, 5-a-reductase inhibitors not refer to the HF patient in whom higher BMI is not adverse, and, al-
are generally preferred in the medical treatment of prostatic though often recommended for symptom benefit and risk factor con-
obstruction in patients with HF. trol, weight loss as an intervention has never been prospectively shown
to be either beneficial or safe in HFrEF. When weight loss is occurring
11.14 Lung disease (including asthma and in HF, it is associated with high mortality and morbidity, worse symp-

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tom status and poor quality of life. In patients with HF with moderate
chronic obstructive pulmonary disease)
degrees of obesity (BMI ,35 kg/m2), weight loss cannot be recom-
The diagnosis of COPD and asthma may be difficult in patients with
mended. In more advanced obesity (BMI 35–45 kg/m2), weight loss
HF, due to overlap in symptoms and signs, but also problems in the
may be considered to manage symptoms and exercise capacity.
interpretation of spirometry, especially in HFpEF.48,49,391 COPD
(and asthma) in patients with HF may be overdiagnosed.481 Spirom- 11.16 Sleep disturbance and
etry should be performed when patients have been stable and euvo- sleep-disordered breathing
laemic for at least 3 months, to avoid the confounding effect of
Sleep-disordered breathing (SDB) occurs in more than one-third of
pulmonary congestion causing external obstruction of alveoli and
patients with HF,484 being even more prevalent in patients with
bronchioles.482 Both correctly and incorrectly labelled COPD are as-
AHF.485 The most common types are: central sleep apnoea (CSA,
sociated with worse functional status and a worse prognosis in HFrEF.
similar to Cheyne Stokes respiration, CSR), obstructive sleep ap-
Beta-blockers are only relatively contraindicated in asthma, but
noea (OSA), and a mixed pattern of the two. Other causes of sleep
not in COPD, although a more selective b1-adrenoceptor antagon-
disturbance include anxiety, depression, decubitus or paroxysmal
ist (i.e. bisoprolol, metoprolol succinate, or nebivolol) is pre-
pulmonary congestion (orthopnoea and paroxysmal nocturnal dys-
ferred.48,49,391 The contraindication to beta-blockers in asthma, as
pnoea) and diuretic therapy causing nocturnal diuresis. Reviewing
mentioned on pharmacy leaflets, is based on small case series pub-
sleep history (including asking a partner) is part of the holistic
lished in the 1980s and late 1990s with very high initial dosages in
care of patients with HF (see Section 14). CSA and OSA have
young patients with severe asthma. In clinical practice, starting with
been shown to be associated with a worse prognosis in HF.485,486
low doses of cardioselective beta-blockers combined with close
OSA is associated with an increased risk of incident HF in men.487
monitoring for signs of airway obstruction (wheezing, shortness of
CSA is the most common form of SDB in HFrEF, and HFrEF is
breath with lengthening of the expiration) may allow the use of pro-
the most common cause of CSA, so they are closely linked. Screen-
foundly effective beta-blockers in HFrEF, especially in older people
ing for, and the diagnosis and treatment of, sleep apnoea is discussed
where true severe asthma is uncommon. Therefore, according to
in detail elsewhere.484,488 Diagnosis used to require overnight poly-
the 2015 GINA global strategy report,395,396 asthma is not an absolute
somnography, although advanced home testing equipment which
contraindication, but these medications should only be used under
can distinguish the type of sleep apnoea has been developed.
close medical supervision by a specialist, with consideration of the
Nocturnal oxygen supplementation, continuous positive airway
risks for and against their use. The long-term safety of cardioactive in-
pressure (CPAP), bi-level positive airway pressure (BiPAP), and adap-
haled pulmonary drugs is uncertain and the need for their use should
tive servo-ventilation (ASV) may be considered to treat nocturnal
be reconsidered in patients with HFrEF, especially as their benefit in
hypoxaemia in OSA as recommended in other guidelines.489,490 An
asthma and COPD may be symptomatic only without a clear effect on
apnoea/hypopnoea index (AHI) of above 30 per hour can be treated
mortality. Oral corticosteroids can cause sodium and water reten-
using any of CPAP, BiPAP, ASV and nocturnal oxygen supplementa-
tion, potentially leading to worsening of HF, but this is not believed
tion, which have all been shown to be effective in this regard. It should
to be a problem with inhaled corticosteroids. Pulmonary hyperten-
be noted, however, that none of these interventions has been pro-
sion can complicate severe long-standing COPD, which, as a result,
spectively shown to be beneficial on major outcomes in HFrEF.
makes right-sided HF and congestion more likely. Non-invasive ven-
CPAP in HF related CSA has been shown to reduce the fre-
tilation, added to conventional therapy, improves the outcome of pa-
quency of episodes of apnoea and hypopnoea, and improve LVEF
tients with acute respiratory failure due to hypercapnic exacerbation
and 6 minute walk test distance, but did not improve prognosis or
of COPD or HF in situations of acute pulmonary oedema.
the rate of HF related hospitalizations.491
The recently published SERVE-HF473 trial has shown that ASV
11.15 Obesity used in patients with HFrEF and a predominantly CSA was neutral
Obesity is a risk factor for HF141 and complicates its diagnosis, because regarding the composite primary endpoint (all-cause death, lifesav-
it can cause dyspnoea, exercise intolerance and ankle swelling and may ing cardiovascular intervention, i.e. cardiac transplantation, implant-
result in poor-quality echocardiographic images. Obese individuals also ation of a ventricular assist device, resuscitation after sudden cardiac
have reduced NP levels.62 Obesity is more common in HFpEF than in arrest, or appropriate lifesaving shock, or unplanned hospitalization
HFrEF, although it is possible that misdiagnosis may explain at least for HF worsening), but more importantly led to an increase in both
some of this difference in prevalence. Although obesity is an independ- all-cause and cardiovascular mortality. Therefore ASV is not recom-
ent risk factor for developing HF, once HF is diagnosed, it is well mended in patients with HFrEF and predominantly CSA.
2170 ESC Guidelines

The safety and efficacy of alternative approaches to treating CSA Primary (organic) mitral regurgitation
in HFrEF patients, such as implantable phrenic nerve stimula- Surgery is indicated in symptomatic patients with severe organic
tion,219,220,492 are presently undergoing clinical investigation and mitral regurgitation with no contra-indications to surgery. The deci-
may require additional long term study. sion of whether to replace or repair depends mostly on valve anat-
omy, surgical expertise available, and the patient’s condition.
11.17. Valvular heart disease When the LVEF is , 30%, a durable surgical repair may improve
Valvular heart disease may cause or aggravate HF. This section brief- symptoms, although its effect on survival is unknown. In this situ-
ly addresses problems particularly relevant to HF, and the reader is ation, the decision to operate should take account of response to
referred to the recent guidelines on valvular disease for more medical therapy, co-morbidities, and the likelihood that the valve
information.493,494 can be repaired (rather than replaced).
Patients with HF and concomitant valvular heart disease constitute a
Secondary mitral regurgitation
high-risk population. Thus, the whole process of decision-making

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This occurs because LV enlargement and remodelling lead to
through a comprehensive evaluation of the risk–benefit ratio of differ-
reduced leaflet closing. Effective medical therapy (including CRT
ent treatment strategies should be made by a multidisciplinary ‘heart
in suitable patients) leading to reverse remodelling of the LV may
team’ with a particular expertise in valvular heart disease, including car-
reduce functional mitral regurgitation, and every effort should be
diologists with expertise in HF, cardiac surgeons, a structural valve
made to optimize medical treatment in these patients.
interventionist if a catheter-based therapy is being considered, imaging
Combined valve and coronary surgery should be considered in
specialists, anaesthetists and, if needed, general practitioners, geriatri-
symptomatic patients with LV systolic dysfunction (LVEF , 30%),
cians, or intensive care specialists. This may be particularly beneficial
coronary arteries suitable for revascularization, and evidence of via-
in patients with HF being considered for surgery, transcatheter aortic
bility. Surgery is also recommended in patients with severe mitral re-
valve implantation or transcatheter mitral valve intervention.
gurgitation undergoing CABG with LVEF . 30%.
All patients should receive OMT. In those with HFrEF pharmaco-
However, a recent study in patients with moderate, secondary is-
logical therapy should be planned according to a previously described
chaemic mitral regurgitation did not prove that the addition of mitral
algorithm (see Section 7 for details). Care must be taken using vaso-
valve repair to CABG would lead to a higher degree of LV reverse re-
dilators (ACEI, ARBs, CCBs, hydralazine, and nitrates) in patients with
modelling.501 Also, there is no evidence favouring mitral valve repair
severe aortic stenosis in order not to cause hypotension.
over replacement in the context of better outcomes and magnitude
11.17.1. Aortic stenosis of LV remodelling.502 In the presence of AF, atrial ablation and LA ap-
The main concern in patients with severe aortic stenosis and re- pendage closure may be considered at the time of mitral valve surgery.
duced LVEF is the entity of ‘low-flow, low-gradient’ aortic stenosis The role of isolated mitral valve surgery in patients with severe
(valve area , 1 cm2, LVEF , 40%, mean pressure gradient , 40 functional mitral regurgitation and severe LV systolic dysfunction
mmHg). In such individuals, low-dose dobutamine stress echocardi- (LVEF , 30%) who cannot be revascularized or have non-ischaemic
ography should be considered to differentiate between patients cardiomyopathy is questionable, and in most patients conventional
with moderate aortic stenosis, and those with severe stenosis and medical and device therapy are preferred. In selected cases, repair
low flow across the valve due to low stroke volume, and to evaluate may be considered in order to avoid or postpone transplantation.
for contractile or flow reserve. The decision should be based on comprehensive evaluation (includ-
If the mean gradient is . 40 mmHg, there is theoretically no low- ing strain echocardiography or magnetic resonance imaging499,503
er LVEF limit for aortic valve replacement in symptomatic patients and discussed within the ‘heart team’.
with severe aortic stenosis. In patients with HF with moderate-severe, secondary mitral re-
Transaortic valve implantation (TAVI) is recommended in pa- gurgitation who are judged inoperable or at high surgical risk, percu-
tients with severe aortic stenosis who are not suitable for surgery taneous mitral valve intervention (percutaneous edge-to-edge
as assessed by a ‘heart team’ and have predicted post-TAVI survival repair) may be considered in order to improve symptoms and qual-
. 1 year. TAVI should be also considered in high-risk patients with ity of life, although no RCT evidence of improvement has been pub-
severe aortic stenosis who may still be suitable for surgery, but in lished, only registry studies.504 – 506
whom TAVI is favoured by a ‘heart team’ based on the individual 11.17.4. Tricuspid regurgitation
risk profile and anatomic suitability.495,496 In a recent trial in patients Secondary (functional) tricuspid regurgitation (TR) frequently com-
with severe aortic stenosis, TAVI with a self-expanding transcath- plicates the natural course of HF, due to annular dilatation and in-
eter aortic valve bioprosthesis was associated with a significantly creased tricuspid leaflet tethering in relation to RV pressure and/
higher rate of survival at 1 year which was sustained at 2 years.497,498 or volume overload. Severe TR causes/deteriorates symptoms
11.17.2. Aortic regurgitation and signs of right HF, thus diuretics are used to reduce peripheral
In patients with severe aortic regurgitation, aortic valve repair or re- oedema. As hepatic congestion is often present in these patients
placement is recommended in all symptomatic patients and in (additionally contributing to hyperaldosteronism), an addition of
asymptomatic patients with resting LVEF ≤ 50%, who are otherwise an MRA (in higher natriuretic doses) may improve decongestion.507
fit for surgery.499,500 Management of HF which underlies secondary TR should be opti-
mized as TR may diminish, following the treatment of its cause. In-
11.17.3. Mitral regurgitation dications for surgical correction of secondary TR complicating HF
This section refers to chronic settings while acute settings are are not clearly established.493,494 The need for correction of TR is
discussed in Section 12. usually considered at the time of surgical correction of left-sided
ESC Guidelines 2171

Recommendations for treatment of valvular diseases in patients with heart failure

Recommendations Class a Level b Ref c


2
, LVEF <40%, mean
pressure gradient <40 mmHg), low-dose dobutamine stress echocardiography should be considered to identify those with severe IIa C
aortic stenosis suitable for valve replacement.
TAVI is recommended in patients with severe aortic stenosis who are not suitable for surgery as assessed by a ‘heart team’ 495, 496,
I B
and have predicted post-TAVI survival >1 year. 509
TAVI should be considered in high-risk patients with severe aortic stenosis who may still be suitable for surgery, but in whom TAVI is
IIa A 497, 498

In patients with severe aortic regurgitation, aortic valve repair or replacement is recommended in all symptomatic patients and

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I C 317
in asymptomatic patients with resting LVEF ≤

Evidence-based medical therapy in patients with HFrEF is recommended in order to reduce functional mitral regurgitation. I C

Combined surgery of secondary mitral regurgitation and coronary artery bypass grafting should be considered in symptomatic
IIa C
patients with LV systolic dysfunction (LVEF <30%), requiring coronary revascularization for angina recalcitrant to medical therapy.
Isolated surgery of non-ischaemic regurgitant mitral valve in patients with severe functional mitral regurgitation and severe LV systolic
IIb C
dysfunction (LVEF <30%) may be considered in selected patients in order to avoid or postpone transplantation.

HFrEF ¼ heart failure with reduced ejection fraction; LV ¼ left ventricular; LVEF ¼ left ventricular ejection fraction; TAVI ¼ transaortic valve implantation.
a
Class of recommendation.
b
Level of evidence.
c
Reference(s) supporting recommendations.

valve lesions.493,494 A recent first report indicated that catheter-


based interventions may be possible for TR.508 Table 12.1 Factors triggering acute heart failure

Acute coronary syndrome.


12. Acute heart failure
12.1 Definition and classification Excessive rise in blood pressure.

AHF refers to rapid onset or worsening of symptoms and/or signs Infection (e.g. pneumonia, infective endocarditis, sepsis).
of HF. It is a life-threatening medical condition requiring urgent
evaluation and treatment, typically leading to urgent hospital Bradyarrhythmia.
admission. Toxic substances (alcohol, recreational drugs).
AHF may present as a first occurrence (de novo) or, more fre-
Drugs (e.g. NSAIDs, corticosteroids, negative inotropic substances,
quently, as a consequence of acute decompensation of chronic cardiotoxic chemotherapeutics).
HF, and may be caused by primary cardiac dysfunction or precipi-
Exacerbation of chronic obstructive pulmonary disease.
tated by extrinsic factors, often in patients with chronic HF. Acute
Pulmonary embolism.
myocardial dysfunction (ischaemic, inflammatory or toxic), acute
valve insufficiency or pericardial tamponade are among the most Surgery and perioperative complications.
frequent acute primary cardiac causes of AHF. Decompensation Increased sympathetic drive, stress-related cardiomyopathy.
of chronic HF can occur without known precipitant factors, but Metabolic/hormonal derangements (e.g. thyroid dysfunction, diabetic
more often with one or more factors, such as infection, uncon- ketosis, adrenal dysfunction, pregnancy and peripartum related
trolled hypertension, rhythm disturbances or non-adherence with abnormalities).
drugs/diet (Table 12.1). Cerebrovascular insult.
A large number of overlapping classifications of AHF based on dif- Acute mechanical cause: myocardial rupture complicating ACS (free wall
ferent criteria have been proposed.510 – 513 In practice the most use- rupture, ventricular septal defect, acute mitral regurgitation), chest trauma
ful classifications are those based on clinical presentation at or cardiac intervention, acute native or prosthetic valve incompetence
secondary to endocarditis, aortic dissection or thrombosis.
admission, allowing clinicians to identify patients at high risk of com-
plications and to direct management at specific targets, which cre-
ACS ¼ acute coronary syndromes; NSAIDs ¼ non-steroidal anti-inflammatory
ates a pathway for personalized care in the AHF setting. In most drugs.
cases, patients with AHF present with either preserved (90 – 140
mmHg) or elevated (.140 mmHg; hypertensive AHF) systolic
blood pressure (SBP). Only 5 – 8% of all patients present with Another approach is to classify patients according to the presence
low SBP (i.e. ,90 mmHg; hypotensive AHF), which is associated of the following precipitants/causes leading to decompensation,
with poor prognosis, particularly when hypoperfusion is also which need to be treated/corrected urgently (see Section 12.3.1):
present.514,515 ACS, hypertensive emergency, rapid arrhythmias or severe
2172 ESC Guidelines

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Figure 12.1 Clinical profiles of patients with acute heart failure based on the presence/absence of congestion and/or hypoperfusion

bradycardia/conduction disturbance, acute mechanical cause under- rales and S3 gallop; class III, with frank acute pulmonary oedema;
lying AHF or acute pulmonary embolism. class IV, cardiogenic shock, hypotension (SBP ,90 mmHg) and evi-
Clinical classification can be based on bedside physical examination dence of peripheral vasoconstriction such as oliguria, cyanosis and
in order to detect the presence of clinical symptoms/signs of conges- diaphoresis.
tion (‘wet’ vs. ‘dry’ if present vs. absent) and/or peripheral hypoperfu- Definitions of the terms used in this section related to clinical
sion (‘cold’ vs. ‘warm’ if present vs. absent) (Figure 12.1).514,515 The presentation of patients with AHF are provided in Table 12.2.
combination of these options identifies four groups: warm and wet
(well perfused and congested) —most commonly present; cold and 12.2 Diagnosis and initial prognostic
wet (hypoperfused and congested); cold and dry (hypoperfused with- evaluation
out congestion); and warm and dry (compensated, well perfused with- The diagnostic workup needs to be started in the pre-hospital set-
out congestion). This classification may be helpful to guide therapy in ting and continued in the emergency department (ED) in order to
the initial phase and carries prognostic information.510,514,515 establish the diagnosis in a timely manner and initiate appropriate
Patients with HF complicating AMI can be classified according to management. The greater benefit of early treatment is well estab-
Killip and Kimball13 into class I, no clinical signs of HF; class II, HF with lished in ACS and now needs to be considered in the setting of
ESC Guidelines 2173

Table 12.2 Definitions of the terms used in Section 12 on acute heart failure

Term
Symptoms/signs of congestion (left-sided) Orthopnoea, paroxysmal nocturnal dyspnoea, pulmonary rales (bilateral), peripheral oedema (bilateral).
Symptoms/signs of congestion (right-sided)
symptoms of gut congestion.
Symptoms/signs of hypoperfusion Clinical: cold sweated extremities, oliguria, mental confusion, dizziness, narrow pulse pressure.
Laboratory measures: metabolic acidosis, elevated serum lactate, elevated serum creatinine.
Hypoperfusion is not synonymous with hypotension, but often hypoperfusion is accompanied by hypotension.
Hypotension Systolic BP <90 mmHg
Bradycardia Heart rate <40 bpm

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Tachycardia Heart rate >120 bpm
Abnormal respiratory effort Respiratory rate >25 breaths/min with use of accessory muscles for breathing, or respiratory rate
<8 breaths/min despite dyspnoea.
Low O2 saturation O2 saturation (SaO2) <90% in pulse oximetry
Normal SaO2 neither excludes hypoxaemia (low PaO2) nor tissue hypoxia.
Hypoxaemia O2 partial pressure (PaO2) in arterial blood <80 mmHg (<10,67 kPa) (blood gas analysis).
Hypoxaemic respiratory failure (type I) PaO2 <60 mmHg (<8 kPa)
Hypercapnia CO2 partial pressure (PaCO2) in arterial blood >45 mmHg (>6 kPa) (blood gas analysis).
Hypercapnic respiratory failure (type II) PaCO2 >50 mmHg (>6,65 kPa).
Acidosis pH <7.35
Elevated blood lactate >2 mmol/L
Oliguria Urine output <0.5 mL/kg/h

BP ¼ blood pressure; bpm ¼ beats per minute; PaCO2 ¼ partial pressure of carbon dioxide in arterial blood; PaO2 ¼ partial pressure of oxygen in arterial blood; SaO2 ¼ oxygen
saturation.

AHF.516,517 In parallel, coexisting life-threatening clinical conditions † Chest X-ray can be a useful test for the diagnosis of AHF. Pulmon-
and/or precipitants that require urgent treatment/correction need ary venous congestion, pleural effusion, interstitial or alveolar oe-
to be immediately identified and managed (Figure 12.2). Typically, dema and cardiomegaly are the most specific findings for AHF,
an initial step in the diagnostic workup of AHF is to rule out alter- although in up to 20% of patients with AHF, chest X-ray is nearly
native causes for the patient’s symptoms and signs (i.e. pulmonary normal.519 Supine chest radiographs are of limited value in AHF.
infection, severe anaemia, acute renal failure). Chest X-ray is also useful to identify alternative non-cardiac dis-
When AHF is confirmed clinical evaluation is mandatory to select eases that may cause or contribute to the patient’s symptoms
further management. (i.e. pneumonia, non-consolidative pulmonary infections).
It is recommended that initial diagnosis of AHF should be based † ECG is rarely normal in AHF (high negative predictive value).520 It
on a thorough history assessing symptoms, prior cardiovascular his- is also helpful in identifying underlying cardiac disease and poten-
tory and potential cardiac and non-cardiac precipitants, as well as on tial precipitants (rapid AF, acute myocardial ischaemia).
the assessment of signs/symptoms of congestion and/or hypoperfu- † Immediate echocardiography is mandatory only in patients with
sion by physical examination and further confirmed by appropriate haemodynamic instability (particularly in cardiogenic shock)
additional investigations such as ECG, chest X-ray, laboratory as- and in patients suspected of acute life-threatening structural or
sessment (with specific biomarkers) and echocardiography. functional cardiac abnormalities (mechanical complications,
In patients presenting with AHF, early initiation of appropriate acute valvular regurgitation, aortic dissection). Early echocardiog-
therapy (along with relevant investigations) is of key import- raphy should be considered in all patients with de novo AHF and in
ance.516 – 518 those with unknown cardiac function; however, the optimal tim-
Typically, symptoms and signs of AHF reflect fluid overload (pul- ing is unknown (preferably within 48 h from admission, if the ex-
monary congestion and/or peripheral oedema) or, less often, re- pertise is available). Pocket-size echocardiography may be used
duced cardiac output with peripheral hypoperfusion (Table 12.2). as an extension of the clinical examination in the first instance
Since the sensitivity and specificity of symptoms and signs are often where available. Repeated echocardiography is usually not
not satisfactory, careful clinical evaluation needs to be followed by needed unless there is relevant deterioration in clinical status.
these additional investigations: Bedside thoracic ultrasound for signs of interstitial oedema and
2174 ESC Guidelines

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Figure 12.2 Initial management of a patient with acute heart failure. aAcute mechanical cause: myocardial rupture complicating acute coronary
syndrome (free wall rupture, ventricular septal defect, acute mitral regurgitation), chest trauma or cardiac intervention, acute native or prosthetic
valve incompetence secondary to endocarditis, aortic dissection or thrombosis, see above.
ESC Guidelines 2175

stimulating hormone (TSH), glucose and complete blood


Table 12.3 Causes of elevated concentrations of count; D-dimer is indicated in patients with a suspicion of
natriuretic peptides522 – 524 acute pulmonary embolism.
W Routine arterial blood gas is not needed and should be re-
Cardiac Heart failure
Acute coronary syndromes stricted to patients in whom oxygenation cannot be readily
Pulmonary embolism assessed by pulse oximetry. However, arterial blood gas may
Myocarditis be useful when a precise measurement of O2 and CO2 par-
Left ventricular hypertrophy
tial pressures is needed. A venous sample might acceptably
Hypertrophic or restrictive cardiomyopathy
Valvular heart disease indicate pH and CO2.
Congenital heart disease W Of note, measurement of cardiac troponins is useful for de-
Atrial and ventricular tachyarrhythmias tection of ACS as the underlying cause of AHF. However,
Heart contusion

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elevated concentrations of circulating cardiac troponins
Cardioversion, ICD shock
Surgical procedures involving the heart are detected in the vast majority of patients with AHF, often
Pulmonary hypertension without obvious myocardial ischaemia or an acute coronary
Non-cardiac Advanced age event, suggesting ongoing myocyte injury or necrosis in
Ischaemic stroke these patients.525 Also in patients with acute pulmonary em-
Subarachnoid haemorrhage bolism as the underlying cause of acute decompensation,
Renal dysfunction
elevated troponins are useful for risk stratification and
Liver dysfunction (mainly liver cirrhosis with ascites)
Paraneoplastic syndrome decision-making.526
Chronic obstructive pulmonary disease W It is recommended to measure creatinine, BUN and electro-
Severe infections (including pneumonia and sepsis) lytes every 1 – 2 days while in the hospital and before dis-
Severe burns
charge from the hospital. Of note, more frequent testing
Anaemia
Severe metabolic and hormone abnormalities might be justified according to the severity of the case. Pre-
(e.g. thyrotoxicosis, diabetic ketosis) discharge assessment of NPs may be considered for prog-
nostic evaluation.
HFpEF ¼ heart failure with preserved ejection fraction; HFrEF ¼ heart failure with W Assessment of procalcitonin levels may be considered in pa-
reduced ejection fraction; ICD ¼ implantable cardioverter defibrillator. tients with AHF with suspected coexisting infection, particu-
larly for the differential diagnosis of pneumonia and to guide
antibiotic therapy,527 if considered.
W Liver function tests are often impaired in patients with AHF
due to haemodynamic derangements (both reduced output
pleural effusion may be useful in detecting AHF if the expertise is
and increased venous congestion). Abnormal liver function
available.
tests identify patients at risk of poor prognosis and may be
† Laboratory tests:
useful for optimal management.528 – 530
– Natriuretic peptides.
W Since both hypothyroidism and hyperthyroidism may precipi-
– Upon presentation to the ED or CCU/ICU, a plasma NP level
tate AHF, TSH should be assessed in newly diagnosed AHF.
(BNP, NT-proBNP or MR-proANP) should be measured in all
W Multiple other biomarkers, including those reflecting inflam-
patients with acute dyspnoea and suspected AHF to help in
mation, oxidative stress, neurohormonal disarray and myo-
the differentiation of AHF from non-cardiac causes of acute
cardial and matrix remodelling, have been investigated for
dyspnoea. NPs have high sensitivity, and normal levels in pa-
their diagnostic and prognostic value in AHF; however,
tients with suspected AHF makes the diagnosis unlikely
none has reached the stage of being recommended for rou-
(thresholds: BNP ,100 pg/mL, NT-proBNP ,300 pg/mL,
tine clinical use.
MR-proANP ,120 pg/mL).57 – 61,77,78,521 However, elevated
† Routine invasive haemodynamic evaluation with a pulmonary ar-
levels of NPs do not automatically confirm the diagnosis of
tery catheter is not indicated for the diagnosis of AHF. It may be
AHF, as they may also be associated with a wide variety of car-
helpful in selected cases of haemodynamically unstable patients
diac and non-cardiac causes (Table 12.3). Unexpectedly low
with an unknown mechanism of deterioration. Also, routine
levels of NPs can be detected in some patients with decom-
use of an arterial line or central venous line for diagnostic pur-
pensated end-stage HF, flash pulmonary oedema or right sided
poses is not indicated.
AHF.
Other laboratory tests at presentation.
– The following laboratory assessments should be performed at Numerous clinical and laboratory variables are independent pre-
admission on the blood of all patients with AHF: cardiac dictors of in-hospital complications and longer-term outcomes in
troponin, blood urea nitrogen (BUN) (or urea), creatinine, AHF syndromes, but their impact on management has not been ad-
electrolytes (sodium, potassium), liver function tests, thyroid- equately established.
2176 ESC Guidelines

Recommendations regarding applied diagnostic measurements

Recommendations Class a Level b Ref c


Upon presentation a measurement of plasma natriuretic peptide level (BNP, NT-proBNP or MR-proANP) is recommended in all
I A 531–534
patients with acute dyspnoea and suspected AHF to help in the differentiation of AHF from non-cardiac causes of acute dyspnoea.
At admission in all patients presenting with suspected AHF, the following diagnostic tests are recommended:
a. 12-lead ECG; I C
b. chest X-ray to assess signs of pulmonary congestion and detect other cardiac or non-cardiac diseases that may
I C
cause or contribute to the patient’s symptoms;
c. the following laboratory assessments in the blood: cardiac troponins, BUN (or urea), creatinine, electrolytes
I C
(sodium, potassium), glucose, complete blood count, liver function tests and TSH.

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Echocardiography is recommended immediately in haemodynamically unstable AHF patients and within 48 hours when
I C
cardiac structure and function are either not known or may have changed since previous studies.

AHF ¼ acute heart failure; BNP ¼ B-type natriuretic peptide; BUN ¼ blood urea nitrogen; ECG ¼ electrocardiogram; MR-proANP ¼ mid-regional pro A-type natriuretic
peptide; NT-proBNP ¼ N-terminal pro-B type natriuretic peptide; TSH ¼ thyroid-stimulating hormone
a
Class of recommendation.
b
Level of evidence.
c
Reference(s) supporting recommendations.

12.3 Management acute pulmonary oedema. A prompt reduction in blood pressure


AHF is a life-threatening medical condition, thus rapid transfer to the should be considered as a primary therapeutic target and initiated
nearest hospital should be pursued, preferably to a site with a cardiology as soon as possible. Aggressive blood pressure reduction (in the
department and/or a coronary care/intensive care unit (CCU/ICU). range of 25% during the first few hours and cautiously thereafter)
Early diagnosis is important in AHF. Therefore, all patients with with i.v. vasodilators in combination with loop diuretics is
suspected AHF should have a diagnostic workup and appropriate recommended.317,536,537
pharmacological and non-pharmacological treatment should be † Rapid arrhythmias or severe bradycardia/conduction dis-
started promptly and in parallel. turbance. Severe rhythm disturbances in patients with AHF and
Initial evaluation and continued non-invasive monitoring of the unstable conditions should be corrected urgently with medical
patient’s vital cardiorespiratory functions, including pulse oximetry, therapy, electrical cardioversion or temporary pacing260,316,389
blood pressure, respiratory rate and a continuous ECG instituted (see also Section 10.1 for AF management).
within minutes, is essential to evaluate whether ventilation, periph- Electrical cardioversion is recommended if an atrial or ven-
eral perfusion, oxygenation, heart rate and blood pressure are ad- tricular arrhythmia is thought to be contributing to the patient’s
equate. Urine output should also be monitored, although routine haemodynamic compromise in order to restore sinus rhythm and
urinary catheterization is not recommended. improve the patient’s clinical condition.
Patients with respiratory distress/failure or haemodynamic com- Patients with AHF and incessant ventricular arrhythmias pre-
promise should be triaged to a location where immediate respira- sent a challenging scenario, as arrhythmias and haemodynamic
tory and cardiovascular support can be provided (Figure 12.2). instability operate in a vicious circle, perpetuating each other. In
selected cases, immediate angiography (with resultant revascular-
ization, if needed) and electrophysiological testing with radiofre-
12.3.1 Identification of precipitants/causes leading to quency ablation may be considered.260
decompensation that needs urgent management † Acute mechanical cause underlying AHF. This may present
The next step should comprise the identification of major precipitants/ as a mechanical complication of ACS (free wall rupture, ventricu-
causes leading to decompensation, which should be managed urgently lar septal defect, acute mitral regurgitation), chest trauma or car-
to avoid further deterioration (Figure 12.2). These include the following: diac intervention, or as acute native or prosthetic valve
† Acute coronary syndrome. Patients presenting with ACS incompetence secondary to endocarditis, aortic dissection or
thrombosis and comprise rare causes of obstruction (e.g. cardiac
should be managed according to the ESC guidelines on non-ST
tumours). Echocardiography is essential for diagnosis, and treat-
elevation ACS (NSTE-ACS) and STEMI.114,535 Coexistence of
these two clinical conditions (ACS and AHF) always identifies a ment typically requires circulatory support with surgical or per-
cutaneous intervention.
very-high-risk group where an immediate (i.e. ,2 h from hospital
† Acute pulmonary embolism. When acute pulmonary em-
admission in patients with NSTEMI, analogous to STEMI manage-
ment) invasive strategy with intent to perform revascularization is bolism is confirmed as the cause of shock or hypotension, im-
mediate specific treatment is recommended with primary
recommended, irrespective of ECG or biomarker findings.114,535
reperfusion either with thrombolysis, catheter-based approach
See below for patients presenting with persistent haemodynamic
instability due to mechanical ACS complication. or surgical embolectomy.526 Patients presenting with acute pul-
monary embolism should be managed according to the appro-
† Hypertensive emergency. AHF precipitated by rapid and ex-
priate guidelines.526
cessive increase in arterial blood pressure typically manifests as
ESC Guidelines 2177

Identification of acute aetiologies/precipitants with subsequent – signs/symptoms of hypoperfusion


initiation of specific treatments should be done within the immedi- – oxygen saturation (SpO2) ,90% (despite supplemental oxygen)
ate phase of AHF management (initial 60– 120 min) (Figure 12.2). – use of accessory muscles for breathing, respiratory rate
.25/min
12.3.2 Criteria for hospitalization in ward vs. intensive
care/coronary care unit – heart rate ,40 or .130 bpm, SBP ,90 mmHg.540
† The remaining patients with AHF usually need hospitalization on
† Patients with persistent, significant dyspnoea or haemodynamic an ordinary ward. Only a few patients admitted to the ED with
instability should be triaged to a location where immediate resus- AHF (mainly as exacerbation of HF symptoms with subtle signs
citative support can be provided if needed. of congestion) after a small dose of diuretics and some adjust-
† For high-risk patients (i.e. with persistent, significant dyspnoea, ments of oral therapy can be discharged directly home from
haemodynamic instability, recurrent arrhythmias, AHF and associated the ED with advice to be clinically followed in an outpatient clinic.
† Step-down care from the ICU/CCU is dictated by clinical stabil-

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ACS), initial care should be provided in a high-dependency setting
(ICU/CCU). Clinical risk algorithms developed to predict in-hospital ization and resolution of morbid conditions. Further treatment
mortality of patients with AHF can assist in determining which patients will be continued with the involvement of a multidisciplinary
in the ED need the highest level of inpatient care.538,539 team and discharge planning.
† The criteria for ICU/CCU admission include any of the following: 12.3.3 Management of the early phase
– need for intubation (or already intubated) Oxygen therapy and/or ventilatory support

Recommendations for the management of patients with acute heart failure: oxygen therapy and ventilatory support

Recommendations Class a Level b Ref c


Monitoring of transcutaneous arterial oxygen saturation (SpO2) is recommended. I C
Measurement of blood pH and carbon dioxide tension (possibly including lactate) should be considered, especially in
patients with acute pulmonary oedema or previous history of COPD using venous blood. In patients with cardiogenic IIa C
shock arterial blood is preferable.
Oxygen therapy is recommended in patients with AHF and SpO2 <90% or PaO2 <60 mmHg (8.0 kPa) to correct hypoxaemia. I C
Non-invasive positive pressure ventilation (CPAP, BiPAP) should be considered in patients with respiratory distress
(respiratory rate >25 breaths/min, SpO 2 <90%) and started as soon as possible in order to decrease respiratory distress
and reduce the rate of mechanical endotracheal intubation. IIa B 541–545
Non-invasive positive pressure ventilation can reduce blood pressure and should be used with caution in hypotensive
patients. Blood pressure should be monitored regularly when this treatment is used.
Intubation is recommended, if respiratory failure, leading to hypoxaemia (PaO 2 <60 mmHg (8.0 kPa)), hypercapnia
I C
(PaCO2 >50 mmHg (6.65 kPa)) and acidosis (pH <7.35), cannot be managed non-invasively.

AHF ¼ acute heart failure; BiPAP ¼ bilevel positive airway pressure; COPD ¼ chronic obstructive pulmonary disease; CPAP ¼ continuous positive airway pressure; PaCO2 ¼
partial pressure of carbon dioxide in arterial blood; PaO2 ¼ partial pressure of oxygen in arterial blood; SpO2 ¼ transcutaneous oxygen saturation.
a
Class of recommendation.
b
Level of evidence.
c
Reference(s) supporting recommendations.

In AHF, oxygen should not be used routinely in non-hypoxaemic pa- mortality rates,543 although data regarding mortality are less
tients, as it causes vasoconstriction and a reduction in cardiac out- conclusive. CPAP is a feasible technique in the pre-hospital
put.546,547 In COPD, hyperoxygenation may increase ventilation – setting, because it is simpler than pressure support positive
perfusion mismatch, suppressing ventilation and leading to hyper- end-expiratory pressure (PS-PEEP) and requires minimal training
capnia. During oxygen therapy, acid –base balance and transcutane- and equipment. On hospital arrival, patients who still show signs
ous SpO2 should be monitored. of respiratory distress should continue with non-invasive ventila-
Non-invasive positive pressure ventilation includes both CPAP tion, preferably PS-PEEP, in case of acidosis and hypercapnia, par-
and bi-level positive pressure ventilation (PPV). Bi-level PPV also al- ticularly in those with a previous history of COPD or signs of
lows inspiratory pressure support that improves minute ventilation fatigue.540
and is especially useful in patients with hypercapnia, most typically Caution should be exercised with regard to side effects of anaes-
COPD patients. thetic drugs, among which propofol can induce hypotension and
Congestion affects lung function and increases intrapulmonary have cardiodepressive side effects. In contrast, midazolam may
shunting, resulting in hypoxaemia. The fraction of inspired oxygen have fewer cardiac side effects and thus is preferred in patients
(FiO2) should be increased up to 100% if necessary, according to with AHF or cardiogenic shock.
SpO2, unless contraindicated. Hyperoxia, however, should be A management algorithm for patients with AHF based on
avoided.546,547 Non-invasive positive pressure ventilation reduces the clinical profile during an early phase is presented in
respiratory distress541 – 545 and may decrease intubation and Figure 12.3.
2178 ESC Guidelines

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Figure 12.3 Management of patients with acute heart failure based on clinical profile during an early phase
a
Symptoms/signs of congestion: orthopnoea, paroxysmal nocturnal dyspnoea, breathlessness, bi-basilar rales, an abnormal blood pressure re-
sponse to the Valsalva maneuver (left-sided); symptoms of gut congestion, jugular venous distension, hepatojugular reflux, hepatomegaly, ascites,
and peripheral oedema (right-sided).
ESC Guidelines 2179

Pharmacological therapy

Recommendations for the management of patients with acute heart failure: pharmacotherapy

Recommendations Class a Level b Ref c


Diuretics

improve symptoms. It is recommended to regularly monitor symptoms, urine output, renal function and electrolytes during I C
use of i.v. diuretics.
In patients with new-onset AHF or those with chronic, decompensated HF not receiving oral diuretics the initial

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recommended dose should be 20–40 mg i.v. furosemide (or equivalent); for those on chronic diuretic therapy, initial i.v. I B 540, 548
dose should be at least equivalent to oral dose.
It is recommended to give diuretics either as intermittent boluses or as a continuous infusion, and the dose and duration
I B 548
should be adjusted according to patients’ symptoms and clinical status.
Combination of loop diuretic with either thiazide-type diuretic or spironolactone may be considered in patients with
IIb C 549

Vasodilators
i.v. vasodilators should be considered for symptomatic relief in AHF with SBP >90 mmHg (and without symptomatic
537,
hypotension). IIa B
550–555
Symptoms and blood pressure should be monitored frequently during administration of i.v. vasodilators.

In patients with hypertensive AHF, i.v. vasodilators should be considered as initial therapy to improve symptoms and reduce 537,
IIa B
congestion. 551–554

Inotropic agents – dobutamine, dopamine, levosimendan, phosphodiesterase III (PDE III) inhibitors
Short-term, i.v. infusion of inotropic agents may be considered in patients with hypotension (SBP <90 mmHg) and/or signs/
IIb C
peripheral perfusion and maintain end-organ function.
An intravenous infusion of levosimendan or a PDE III inhibitor may be considered to reverse the effect of beta-blockade
IIb C
if beta-blockade is thought to be contributing to hypotension with subsequent hypoperfusion.
Inotropic agents are not recommended unless the patient is symptomatically hypotensive or hypoperfused because of
III A 556, 557
safety concern.
Vasopressors
A vasopressor (norepinephrine preferably) may be considered in patients who have cardiogenic shock, despite treatment
IIb B 558
with another inotrope, to increase blood pressure and vital organ perfusion.
It is recommended to monitor ECG and blood pressure when using inotropic agents and vasopressors, as they can cause 540,
I C
arrhythmia, myocardial ischaemia, and in the case of levosimendan and PDE III inhibitors also hypotension. 559–563
In such cases intra-arterial blood pressure measurement may be considered. IIb C
Thrombo-embolism prophylaxis
Thrombo-embolism prophylaxis (e.g. with LMWH) is recommended in patients not already anticoagulated and with no
I B 564
contra-indication to anticoagulation, to reduce the risk of deep venous thrombosis and pulmonary embolism.
Other drugs

d
IIa C
b. amiodarone may be considered. IIb B 565–567
Opiates may be considered for cautious use to relieve dyspnoea and anxiety in patients with severe dyspnoea but nausea
IIb B 568, 569
and hypopnea may occur.

AHF ¼ acute heart failure; ECG ¼ electrocardiogram; HF ¼ heart failure; i.v. ¼ intravenous; LMWH ¼ low molecular weight heparin; SBP ¼ systolic blood pressure.
a
Class of recommendation.
b
Level of evidence.
c
Reference(s) supporting recommendations.
d
Beta-blockers should be used cautiously, if the patient is hypotensive.
2180 ESC Guidelines

Diuretics Use of an inotrope (Table 12.5) should be reserved for patients


Diuretics are a cornerstone in the treatment of patients with AHF with a severe reduction in cardiac output resulting in compromised
and signs of fluid overload and congestion. Diuretics increase renal vital organ perfusion, which occurs most often in hypotensive AHF.
salt and water excretion and have some vasodilatory effect. In pa- Inotropic agents are not recommended in cases of hypotensive AHF
tients with AHF and signs of hypoperfusion, diuretics should be where the underlying cause is hypovolaemia or other potentially
avoided before adequate perfusion is attained. correctable factors before elimination of these causes. Levosimen-
The initial approach to congestion management involves i.v. dan is preferable over dobutamine to reverse the effect of beta-
diuretics with the addition of vasodilators for dyspnoea relief if blockade if beta-blockade is thought to be contributing to hypoper-
blood pressure allows. To enhance diuresis or overcome diuretic fusion.572 However, levosimendan is a vasodilator, thus it is not suit-
resistance, options include dual nephron blockade by loop diuretics able for treatment of patients with hypotension (SBP ,85 mmHg)
(i.e. furosemide or torasemide) with thiazide diuretics or natriuretic or cardiogenic shock unless in combination with other inotropes or
doses of MRAs.570,571 However, this combination requires careful vasopressors.559,573,574 Inotropes, especially those with adrenergic

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monitoring to avoid hypokalaemia, renal dysfunction and mechanisms, can cause sinus tachycardia and may induce myocardial
hypovolaemia. ischaemia and arrhythmias, thus ECG monitoring is required. There
Data defining optimal dosing, timing and method of delivery are in- is long-standing concern that they may increase mortality, which
complete. In the ‘high-dose’ arm of the DOSE study, administration of
furosemide at 2.5 times the previous oral dose resulted in greater im-
provement in dyspnoea, larger weight change and fluid loss at the cost Table 12.5 Positive inotropes and/or vasopressors
of transient worsening in renal function.548 In AHF, i.v. furosemide is used to treat acute heart failure
the most commonly used first-line diuretic. The dose should be lim-
ited to the smallest amount to provide adequate clinical effect and Vasodilator Bolus Infusion rate
modified according to previous renal function and previous dose of
Dobutaminea No 2–20 µg/kg/min (beta+)
diuretics. The initial i.v. dose should be at least equal to the pre-
Dopamine No 3–5 µg/kg/min; inotropic (beta+)
existing oral dose used at home. Consequently, patients with new-
>5 µg/kg/min: (beta+),
onset AHF or those with chronic HF without a history of renal failure
vasopressor (alpha+)
and previous use of diuretics may respond to i.v. boluses of 20 –
Milrinonea,b 25–75 µg/kg 0.375–0.75 µg/kg/min
40 mg, whereas those with previous use of diuretics usually require over 10–20 min
higher doses. A bolus of 10–20 mg i.v. torasemide may be considered
Enoximonea 0.5–1.0 mg/kg 5–20 µg/kg/min
as an alternative. over 5–10 min
Levosimendana 12 µg/kg over 0.1 µg/kg/min, which can be
Vasodilators 10 min (optional) decreased to 0.05 or increased
c
Intravenous vasodilators (Table 12.4) are the second most often to 0.2 µg/kg/min
used agents in AHF for symptomatic relief; however, there is no ro- Norepinephrine No 0.2–1.0 µg/kg/min
bust evidence confirming their beneficial effects. Epinephrine Bolus: 1 mg 0.05–0.5 µg/kg/min
They have dual benefit by decreasing venous tone (to optimize can be given
i.v. during
preload) and arterial tone (decrease afterload). Consequently, resuscitation,
they may also increase stroke volume. Vasodilators are especially repeated every
useful in patients with hypertensive AHF, whereas in those with 3–5 min
SBP ,90 mmHg (or with symptomatic hypotension) they should
be avoided. Dosing should be carefully controlled to avoid excessive i.v. ¼ intravenous.
a
Also a vasodilator.
decreases in blood pressure, which is related to poor outcome. Va- b
Not recommended in acutely worsened ischaemic heart failure.
sodilators should be used with caution in patients with significant c
Bolus not recommended in hypotensive patients.
mitral or aortic stenosis.

Table 12.4 Intravenous vasodilators used to treat acute heart failure

Vasodilator Dosing Main side effects Other


Nitroglycerine Start with10–20 µg/min, increase up to 200 µg/min Hypotension, headache Tolerance on continuous use
Isosorbide dinitrate Start with 1 mg/h, increase up to 10 mg/h Hypotension, headache Tolerance on continuous use
Nitroprusside Start with 0.3 µg/kg/min and increase up to 5 µg/kg/min Hypotension, isocyanate toxicity Light sensitive
Nesiritidea Bolus 2 µg/kg + infusion 0.01 µg/kg/min Hypotension

a
Not available in many European countries.
ESC Guidelines 2181

derives from studies in which intermittent or continuous infusions Device therapy


of inotropes were given.559 – 563,575 In any case, inotropes have to
be used with caution starting from rather low doses and up-titrating Recommendations regarding renal replacement
with close monitoring. therapy in patients with acute heart failure

Vasopressors Recommendations Class a Level b Ref C


Drugs with prominent peripheral arterial vasoconstrictor action
such as norepinephrine or dopamine in higher doses (.5 mg/kg/ patients with refractory congestion,
IIb B 578–580
min) are given to patients with marked hypotension. These agents who failed to respond to diuretic-
based strategies.
are given to raise blood pressure and redistribute blood to the vital
organs. However, this is at the expense of an increase in LV Renal replacement therapy should
be considered in patients with

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afterload. IIa C
refractory volume overload and
Dopamine was compared with norepinephrine in the treatment acute kidney injury.
of various shock patients. A subgroup analysis suggested that nor-
epinephrine would have fewer side effects and lower mortality.558 a
Class of recommendation.
Epinephrine (adrenaline) should be restricted to patients with per- b
Level of evidence.
c
sistent hypotension despite adequate cardiac filling pressures and Reference(s) supporting recommendations.

the use of other vasoactive agents, as well as for resuscitation


protocols.576 Renal replacement therapy
Ultrafiltration involves the removal of plasma water across a
Thromboembolism prophylaxis semipermeable membrane in response to a transmembrane pres-
Thromboembolism prophylaxis with heparin or another anticoagu- sure gradient. There is no evidence favouring ultrafiltration over
lant is recommended unless contraindicated or unnecessary (be- loop diuretics as first-line therapy in patients with AHF.571,578 At
cause of existing treatment with oral anticoagulants). the present time, routine use of ultrafiltration is not recommended
and should be confined to patients who fail to respond to diuretic-
Digoxin based strategies.
Digoxin is mostly indicated in patients with AF and rapid ventricular The following criteria may indicate the need for initiation of renal
rate (.110 bpm) and given in boluses of 0.25–0.5 mg i.v. if not used replacement therapy in patients with refractory volume overload:
previously (0.0625–0.125 mg may be an adequate dose in patients oliguria unresponsive to fluid resuscitation measures, severe hyper-
with moderate to severe renal dysfunction). However, in patients kalaemia (K+ .6.5 mmol/L), severe acidaemia (pH ,7.2), serum
with co-morbidities or other factors affecting digoxin metabolism urea level .25 mmol/L (150 mg/dL) and serum creatinine .300
(including other drugs) and/or the elderly, the maintenance dose mmol/L (.3.4 mg/dL).
may be difficult to estimate theoretically, and in this situation it
should be established empirically, based on the measurements of di- Mechanical assist devices
goxin concentration in peripheral blood. Intra-aortic balloon pump
The conventional indications for an intra-aortic balloon pump
Vasopressin antagonists (IABP) are to support the circulation before surgical correction of
Vasopressin antagonists such as tolvaptan block the action of argin- specific acute mechanical problems (e.g. interventricular septal rup-
ine vasopressin (AVP) at the V2 receptor in renal tubules and pro- ture and acute mitral regurgitation), during severe acute myocarditis
mote aquaresis. Tolvaptan may be used to treat patients with and in selected patients with acute myocardial ischaemia or infarc-
volume overload and resistant hyponatraemia (thirst and dehydra- tion before, during and after percutaneous or surgical revasculariza-
tion are recognized adverse effects).577 tion. There is no good evidence that an IABP is of benefit in other
causes of cardiogenic shock (for details see below).
Opiates Ventricular assist devices
Opiates relieve dyspnoea and anxiety. In AHF, routine use of Ventricular assist devices and other forms of mechanical circulatory
opiates is not recommended and they may only be cautiously con- support (MCS) may be used as a ‘bridge to decision’ or longer term
sidered in patients with severe dyspnoea, mostly with pulmonary in selected patients (see Section 13).
oedema. Dose-dependent side effects include nausea, hypotension,
bradycardia and respiratory depression (potentially increasing the Other interventions
need for invasive ventilation). There are controversies regarding In patients with AHF and pleural effusion, pleurocentesis with fluid
the potentially elevated mortality risk in patients receiving evacuation may be considered if feasible in order to alleviate
morphine.568,569 dyspnoea.
In patients with ascites, ascitic paracentesis with fluid evacuation
Anxiolytics and sedatives may be considered in order to alleviate symptoms. This procedure,
Anxiolytics or sedatives may be needed in a patient with agitation or through reduction in intra-abdominal pressure, may also partially
delirium. Cautious use of benzodiazepines (diazepam or lorazepam) normalize the transrenal pressure gradient, thus improving renal
may be the safest approach. filtration.581
2182 ESC Guidelines

12.3.4 Management of patients with cardiogenic shock 12.4 Management of evidence-based oral
Cardiogenic shock is defined as hypotension (SBP ,90 mmHg) des- therapies
pite adequate filling status with signs of hypoperfusion (Table 12.2).
The pathogenetic scenarios of cardiogenic shock range from low- Recommendations regarding oral evidence-based
output advanced end-stage chronic HF to acute-onset de novo disease-modifying therapies in patients with acute heart
cardiogenic shock most often caused by STEMI, but also by various failure
aetiologies other than ACS. A patient in cardiogenic shock should
undergo immediate comprehensive assessment. ECG and echocar-
Recommendations Class a Level b
diography are required immediately in all patients with suspected
cardiogenic shock. In patients with cardiogenic shock complicating In case of worsening of chronic HFrEF, every
attempt should be made to continue evidence-
ACS, an immediate coronary angiography is recommended (within based, disease-modifying therapies, in the I C

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2 h from hospital admission) with an intent to perform coronary absence of haemodynamic instability or contra-
revascularization.114,535 Invasive monitoring with an arterial line indications.
should be also considered. In the case of de novo HFrEF, every attempt
There is no agreement on the optimal method of haemodynamic should be made to initiate these therapies after I C
monitoring in assessing and treating patients in cardiogenic shock, haemodynamic stabilization.
including pulmonary artery catheterization.
Pharmacologic therapy aims to improve organ perfusion by increas- AHF ¼ acute heart failure; HFrEF ¼ heart failure with reduced ejection
fraction.
ing cardiac output and blood pressure. After fluid challenge, pharmaco- a
Class of recommendation.
logic management consists of an inotropic agent and a vasopressor as b
Level of evidence.
needed. Treatment is guided by the continuous monitoring of organ
perfusion and haemodynamics. Pulmonary artery catheterization may
be considered. As a vasopressor, norepinephrine is recommended
when mean arterial pressure needs pharmacologic support. Dobuta- Oral disease-modifying HF therapy should be continued on ad-
mine is the most commonly used adrenergic inotrope. Levosimendan mission with AHF, except in the presence of haemodynamic in-
may also be used in combination with a vasopressor.582,583 Levosimen- stability (symptomatic hypotension, hypoperfusion, bradycardia),
dan infusion in cardiogenic shock following AMI on top of dobutamine hyperkalaemia or severely impaired renal function. In these cases,
and norepinephrine improved cardiovascular haemodynamics without the daily dosage of oral therapy may be reduced or stopped tem-
leading to hypotension.582,583 PDE3 inhibitors may be another option, porarily until the patient is stabilized. In particular, beta-blockers
especially in non-ischaemic patients.561,584 can be safely continued during AHF presentations except in car-
However, rather than combining several inotropes, device therapy has diogenic shock. A recent meta-analysis demonstrated that discon-
to be considered when there is an inadequate response. Recently the tinuation of beta-blockers in patients hospitalized with AHF was
IABP-SHOCK II trial showed that the use of an IABP did not improve associated with significantly increased in-hospital mortality, short-
outcomes in patients suffering from AMI and cardiogenic shock.585,586 term mortality and the combined endpoint of short-term rehos-
Therefore, routine use of an IABP cannot be recommended. pitalization or mortality.587

Recommendations regarding management of patients with cardiogenic shock

Recommendations Class a Level b Ref c


In all patients with suspected cardiogenic shock, immediate ECG and echocardiography are recommended. I C
All patients with cardiogenic shock should be rapidly transferred to a tertiary care center which has a 24/7 service of cardiac
I C
catheterization, and a dedicated ICU/CCU with availability of short-term mechanical circulatory support.
In patients with cardiogenic shock complicating ACS an immediate coronary angiography is recommended (within 2 hours
I C
from hospital admission) with an intent to perform coronary revascularization.
Continous ECG and blood pressure monitoring are recommended. I C
Invasive monitoring with an arterial line is recommended. I C

I C

Intravenous inotropic agents (dobutamine) may be considered to increase cardiac output. IIb C
Vasopressors (norepinephrine preferable over dopamine) may be considered if there is a need to maintain SBP in the
IIb B 558
presence of persistent hypoperfusion.
IABP is not routinely recommended in cardiogenic shock. III B 585, 586
Short-term mechanical circulatory support may be considered in refractory cardiogenic shock depending on patient age,
IIb C
comorbidities and neurological function.

ACS ¼ acute coronary syndrome; CCU ¼ coronary care unit; ECG ¼ electrocardiogram; IABP ¼ intra-aortic balloon pump; ICU ¼ intensive care unit; SBP ¼ systolic blood
pressure.
a
Class of recommendation.
b
Level of evidence.
c
Reference(s) supporting recommendations.
ESC Guidelines 2183

12.5 Monitoring of clinical status of † once provided with tailored education and advice about self-care.
patients hospitalized due to acute heart Patients should preferably be
failure † enrolled in a disease management programme; follow-up plans
must be in place prior to discharge and clearly communicated
Recommendations regarding monitoring of clinical to the primary care team;
status of patients hospitalized due to acute heart failure † reviewed by their general practitioner within 1 week of discharge;
† seen by the hospital cardiology team within 2 weeks of discharge
Recommendations Class a Level b if feasible.
Standard non-invasive monitoring of heart rate,
rhythm, respiratory rate, oxygen saturation and I C Patients with chronic HF should be followed up within a multipro-
blood pressure is recommended. fessional HF service. Pre- and post-discharge management should

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It is recommended that patients should be follow the standards of care of the HFA.540,591,592
I C
chart completed.
12.7 Goals of treatment during the
It is recommended to evaluate signs and
symptoms relevant to HF (e.g. dyspnoea, different stages of management of acute
I C
pulmonary rales, peripheral oedema, weight) heart failure
During the treatment of patients with AHF, one can distinguish
Frequent, often daily,measurement of subsequent stages that require different therapeutic approaches
renal function (blood urea, creatinine) and
electrolytes (potassium, sodium) during (described in the previous sections of this chapter). Importantly,
I C the goals of treatment during the different stages of management
i.v. therapy and when renin-angiotensin-
aldosterone system antagonists are initiated is of patients with AHF also differ, and are summarized in
recommended. Table 12.6.
Intra-arterial line should be considered in
patients with hypotension and persistent IIa C
symptoms despite treatment.
Pulmonary artery catheter may be considered
Table 12.6 Goals of treatment in acute heart failure
in patients who, despite pharmacological
treatment present refractory symptoms IIb C
(particularly with hypotension and Immediate (ED/ICU/CCU)
hypoperfusion). Improve haemodynamics and organ perfusion.
Restore oxygenation.
HF ¼ heart failure; i.v. ¼ intravenous.
a
Class of recommendation. Alleviate symptoms.
b
Level of evidence. Limit cardiac and renal damage.
Prevent thrombo-embolism.
Patients should be weighed daily and an accurate fluid balance chart Minimize ICU length of stay.
should be maintained. Renal function should preferably be moni-
Intermediate (in hospital)
tored with daily measurement of BUN/urea, creatinine and electro-
lytes. Routine use of a urinary catheter is not recommended. Identify aetiology and relevant co-morbidities.
Renal function is commonly impaired at admission, but may im- Titrate therapy to control symptoms and congestion and optimize blood
pressure.
prove or deteriorate with diuresis. Routine monitoring of pulse, re-
spiratory rate and blood pressure should continue. There is no Initiate and up-titrate disease-modifying pharmacological therapy.
study showing the usefulness of invasive haemodynamic monitoring Consider device therapy in appropriate patients.
in patients with AHF excluding those with cardiogenic shock. There Pre-discharge and long-term management
is evidence that measuring NPs during the hospital admission may Develop a careplan that provides:
help with discharge planning. Patients whose NP concentrations o A schedule for up-titration and monitoring of pharmacological therapy.
fall during admission have lower cardiovascular mortality and re- o Need and timing for review for device therapy.
admission rates at 6 months.588 – 590 o Who will see the patient for follow-up and when.
Enrol in disease management programme, educate, and initiate
12.6 Criteria for discharge from hospital appropriate lifestyle adjustments.
and follow-up in high-risk period Prevent early readmission.
552 Improve symptoms, quality of life, and survival.
Patients admitted with AHF are medically fit for discharge
† when haemodynamically stable, euvolaemic, established on
CCU ¼ coronary care unit; ED ¼ emergency department; ICU ¼ intensive care
evidence-based oral medication and with stable renal function unit.
for at least 24 hours before discharge;
2184 ESC Guidelines

13. Mechanical circulatory support for patients receiving ECMO for refractory cardiogenic shock
(online calculator at http://www.save-score.com).594
and heart transplantation In addition, MCS systems, particularly ECLS and ECMO, can be
used as a ‘bridge to decision’ (BTD) in patients with acute and rap-
13.1 Mechanical circulatory support idly deteriorating HF or cardiogenic shock to stabilize haemo-
For patients with either chronic or acute HF who cannot be stabi- dynamics, recover end-organ function and allow for a full clinical
lized with medical therapy, MCS systems can be used to unload the evaluation for the possibility of either heart transplant or a more
failing ventricle and maintain sufficient end-organ perfusion. Patients durable MCS device.595
in acute cardiogenic shock are initially treated with short-term as- Evidence regarding the benefits of temporary percutaneous MCS
sistance using extracorporeal, non-durable life support systems so in patients not responding to standard therapy, including inotropes,
that more definitive therapy may be planned. Patients with chronic, is limited. In a meta-analysis of three randomized clinical trials
refractory HF despite medical therapy can be treated with a per-

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comparing a percutaneous MCS vs. IABP in a total of 100 patients
manent implantable left ventricular assist device (LVAD). Table 13.1 in cardiogenic shock, percutaneous MCS appeared safe and demon-
lists the current indications for the use of mechanical circulatory as- strated better haemodynamics, but did not improve 30-day mortal-
sist devices.593 ity and was associated with more bleeding complications.596 In a
randomized trial on high-risk PCI in patients with impaired LV func-
tion (PROTECT II trial), the 30-day incidence of major adverse
13.1.1 Mechanical circulatory support in acute heart events was not different for patients with IABP or a haemodynamic
failure
support device.597 Based on these results, temporary percutaneous
To manage patients with AHF or cardiogenic shock (INTERMACS
MCS cannot be recommended as a proven or efficacious treatment
level 1), short-term mechanical support systems, including percu-
for acute cardiogenic shock. In selected patients it may serve as a
taneous cardiac support devices, extracorporeal life support
bridge to definite therapy. A difficult decision to withdraw MCS
(ECLS) and extracorporeal membrane oxygenation (ECMO) may
may need to be made when the patient has no potential for cardiac
be used to support patients with left or biventricular failure until
recovery and is not eligible for longer-term MCS support or heart
cardiac and other organ function have recovered. Typically the
transplant.
use of these devices is restricted to a few days to weeks. The Survival
After Veno-arterial ECMO (SAVE) score can help to predict survival
13.1.2 Mechanical circulatory support in end-stage chronic
heart failure
Heart transplantation has always been a limited therapeutic option
Table 13.1 Terms describing various indications for for patients with end-stage chronic HF. The increasing number of
mechanical circulatory support patients with refractory, chronic HF and the declining willingness
for organ donation have resulted in expanded waiting lists and pro-
Bridge to Use of short-term MCS (e.g. ECLS or ECMO) longed waiting times for patients listed for heart transplantation
decision (BTD)/ in patients with cardiogenic shock until
haemodynamics and end-organ perfusion are
(median 16 months in the region covered by Eurotransplant).598
Bridge to
bridge (BTB) stabilized, contra-indications for long-term MCS More than 60% of patients are transplanted in high-urgency status,
are excluded (brain damage after resuscitation) leaving little chance for patients listed for less urgent transplantation.
and additional therapeutic options including
Three times more patients are listed for heart transplantation annu-
long-term VAD therapy or heart transplant can
be evaluated. ally than are actually transplanted, and the mortality rate on the
Bridge to Use of MCS (usually LVAD) to improve end-organ Eurotransplant waiting list in 2013 was 21.7%.598
candidacy function in order to make an ineligible patient More recent data suggest that patients with ongoing LVAD sup-
(BTC) eligible for heart transplantation. port may have an improved survival on the transplant waiting
Bridge to Use of MCS (LVAD or BiVAD) to keep patient list.599 Accordingly, MCS devices, particularly continuous-flow
transplantation alive who is otherwise at high risk of death before LVADs, are increasingly seen as an alternative to heart transplant-
(BTT) transplantation until a donor organ becomes
available. ation. Initially LVADs were developed for use as a short-term BTT
Bridge to Use of MCS (typically LVAD) to keep patient approach (Table 13.1),600 but they are now being used for months
recovery (BTR) to years in patients who will either face a long-term wait on the
remove MCS. transplant list (currently only 10% of patients with an MCS device
Destination Long-term use of MCS (LVAD) as an alternative implanted with a BTT indication will receive an organ within 1
therapy (DT) to transplantation in patients with end-stage HF year of listing) or in patients who are not eligible for transplantation
ineligible for transplantation or long-term waiting
for heart transplantation. as permanent therapy or destination therapy. The number of pa-
tients with a permanent LVAD who are considered neither too
BiVAD ¼ biventricular assist device; BTB ¼ bridge to bridge; BTC ¼ bridge to
old nor ineligible for transplantation is constantly growing. For a ma-
candidacy; BTD ¼ bridge to decision; BTR ¼ bridge to recovery; BTT ¼ bridge to jority of these patients, lifelong LVAD therapy, despite eligibility for
transplantation; DT ¼ destination therapy; ECLS ¼ extracorporeal life support; transplantation, has become a clinical reality. Current 2–3-year sur-
ECMO ¼ extracorporeal membrane oxygenation; HF ¼ heart failure; LVAD ¼
left ventricular assist device; MCS ¼ mechanical circulatory support; VAD ¼
vival rates in carefully selected patients receiving the latest continu-
ventricular assist device. ous flow devices are excellent, and comparable to early survival
after heart transplantation.595 However, fewer data are available
ESC Guidelines 2185

Table 13.2 INTERMACS (Interagency Registry for Mechanically Assisted Circulatory Support) stages for classifying
patients with advanced heart failure

INTERMACS level NYHA Description Device 1y survival with


Class LVAD therapy
1. Cardiogenic shock IV Haemodynamic instability in spite of increasing doses of catecholamines ECLS, ECMO, 52.6±5.6%
“Crash and burn” and/or mechanical circulatory support with critical hypoperfusion of target percutaneous
organs (severe cardiogenic shock). support devices
2. Progressive decline IV Intravenous inotropic support with acceptable blood pressure but rapid ECLS, ECMO, 63.1±3.1%
despite inotropic deterioration of renal function, nutritional state, or signs of congestion. LVAD
support “Sliding on
inotropes”

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3. Stable but inotrope IV Haemodynamic stability with low or intermediate doses of inotropics, but LVAD 78.4±2.5%
dependent “Dependent necessary due to hypotension, worsening of symptoms, or progressive
stability” renal failure.
4. Resting symptoms IV Temporary cessation of inotropic treatment is possible, but patient presents LVAD 78.7±3.0%
ambulatory
5. Exertion intolerant IV Complete cessation of physical activity, stable at rest, but frequently with LVAD 93.0±3.9%a
“Housebound” ambulatory
6. Exertion limited III Minor limitation on physical activity and absence of congestion while at LVAD / Discuss -
“Walking wounded” rest. Easily fatigued by light activity. LVAD as option
7. “Placeholder” III Discuss LVAD -
as option

ECLS ¼ extracorporeal life support; ECMO ¼ extracorporeal membrane oxygenation; INTERMACS ¼ Interagency Registry for Mechanically Assisted Circulatory Support;
LVAD ¼ left ventricular assist device; NYHA ¼ New York Heart Association.
a
Kaplan-Meier estimates with standard error of the mean for 1 year survival with LVAD therapy. Patients were censored at time of last contact, recovery or heart transplantation.
Due to small numbers outcomes for INTERMACS levels 5, 6, 7 were combined610.

for longer-term outcomes. Among patients with continuous-flow INTERMACS class, although the majority of VAD implants are
LVADs, actuarial survival is 80% at 1 year and 70% at 2 years in pre- done at INTERMACS levels 1 – 3.604,610 Additionally, it needs to
dominantly non-transplant-eligible patients. Notably, survival of be remembered that no RCTs exist comparing medical therapy
85% at 2 years was recorded for patients up to 70 years of age with- vs. MCS devices in these transplant-eligible patients (Table 13.2).
out diabetes, renal impairment or cardiogenic shock.601,602 Patients Typically, patients with end-stage HF considered for MCS exhibit
receiving LVAD devices as BTT have a post-transplant survival rate many clinical hallmarks of declining cardiovascular function593 and
similar or better than those not requiring or receiving bridging.599 may already be on continuous inotropic support or manifest a de-
Despite technological improvements, bleeding, thromboembolism cline in end-organ function. Markers of liver and renal dysfunction,
(both of which can cause stroke), pump thrombosis, driveline infec- haematologic and coagulation abnormalities and lower serum albu-
tions and device failure remain significant problems and affect the min levels are associated with worse outcome.611,612
long-term outcome of patients on MCS. 599,603 – 606 It is recom- Evaluation of RV function is crucial since postoperative RV failure
mended that such devices should only be implanted and managed greatly increases perioperative mortality and reduces survival to,
at centres with appropriately trained specialist HF physicians and and after, transplantation. There are, however, multiple approaches
surgeons and an outpatient LVAD clinic with trained nursing staff.607 to assessment of the RV (see Section 5.2.3). If RV failure is expected
In some patients, LV reverse remodelling and functional improve- to be potentially reversible, temporary (days to weeks) extracor-
ment during MCS may permit removal of the LVAD [‘bridge to re- poreal right ventricular assist device (RVAD) support using a centri-
covery’ (BTR)]. This outcome is more likely in younger patients with fugal pump in addition to LVAD implantation may be considered.
an acute fulminant but reversible cause of HF, such as acute myocar- For patients with chronic biventricular failure or a high risk for per-
ditis or peripartum cardiomyopathy.608,609 LVADs may also be used sisting RV failure after LVAD implantation, implantation of a biven-
as a ‘bridge to candidacy’ (BTC) in order to permit recovery of tricular assist device (BiVAD) may be necessary. Patients requiring
end-organ dysfunction, improve RV function and relieve pulmonary long-term BiVAD support must be transplant-eligible, as BiVAD
hypertension, which may allow initially ineligible patients to become therapy is not suitable for destination therapy. The outcomes of Bi-
eligible for heart transplantation. VAD therapy are inferior to those for LVAD therapy and therefore
Earlier ventricular assist device (VAD) implantation in less severe- the indication for VAD therapy should be discussed before RV func-
ly ill patients, e.g. those not yet on inotropic support, was tested in a tion deteriorates. The implantation of a total artificial heart with re-
recent trial that revealed better outcomes than in those patients moval of the native heart should be restricted to selected patients
continuing on medical therapy.605 The INTERMACS registry like- who cannot be treated with an LVAD (unrepairable ventricular sep-
wise shows better outcomes in patients implanted with a higher tal defect, cardiac rupture).
2186 ESC Guidelines

Table 13.3 Patients potentially eligible for Table 13.4 Heart transplantation: indications and
implantation of a left ventricular assist device contra-indications

Patients with >2 months of severe symptoms despite optimal Patients to End-stage HF with severe symptoms, a poor prognosis,
medical and device therapy and more than one of the following: consider and no remaining alternative treatment options.
Motivated, well informed, and emotionally stable.
LVEF <25% and, if measured, peak VO2 <12 mL/kg/min.
Capable of complying with the intensive treatment
≥3 HF hospitalizations in previous 12 months without an obvious required postoperatively.
precipitating cause.
Contra- Active infection.
Dependence on i.v. inotropic therapy. indications Severe peripheral arterial or cerebrovascular disease.
Progressive end-organ dysfunction (worsening renal and/or hepatic Pharmacologically irreversible pulmonary hypertension
(LVAD should be considered with a subsequent re-

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pressure (PCWP ≥20 mmHg and SBP ≤80–90 mmHg or CI ≤2 L/min/m2). evaluation to establish candidacy).
Cancer (a collaboration with oncology specialists
Absence of severe right ventricular dysfunction together with severe should occur to stratify each patient as to their risk of
tricuspid regurgitation. tumour recurrence).
Irreversible renal dysfunction (e.g. creatinine clearance
<30 mL/min).
CI ¼ cardiac index; HF ¼ heart failure; i.v. ¼ intravenous; LVEF ¼ left ventricular
Systemic disease with multi-organ involvement.
ejection fraction; PCWP ¼ pulmonary capillary wedge pressure; SBP ¼ systolic
blood pressure; VO2 ¼ oxygen consumption.
Other serious co-morbidity with poor prognosis.
Pre-transplant BMI >35 kg/m2 (weight loss is
recommended to achieve a BMI <35 kg/m2).
Current alcohol or drug abuse.
Any patient for whom social supports are deemed
Patients with active infection, severe renal, pulmonary or hepatic
dysfunction or uncertain neurological status after cardiac arrest or setting.
due to cardiogenic shock are not usually candidates for BTT or
DT but may be candidates for BTC (Table 13.3). BMI ¼ body mass index; HF ¼ heart failure; LVAD ¼ left ventricular assist device.

Recommendations for implantation of mechanical


circulatory support in patients with refractory heart
failure 13.2 Heart transplantation
Heart transplantation is an accepted treatment for end-stage
Recommendations Class a
Level b
Ref c HF.614,615 Although controlled trials have never been conducted,
there is a consensus that transplantation—provided that proper se-
An LVAD should be considered in
patients who have end- stage HFrEF lection criteria are applied—significantly increases survival, exercise
despite optimal medical and device capacity, quality of life and return to work compared with conven-
therapy and who are eligible for tional treatment.
heart transplantation in order IIa C Apart from the shortage of donor hearts, the main challenges in
to improve symptoms, reduce the
risk of HF hospitalization and the transplantation are the consequences of the limited effectiveness
risk of premature death (Bridge to and complications of immunosuppressive therapy in the long term
transplant indication). (i.e. antibody-mediated rejection, infection, hypertension, renal fail-
An LVAD should be considered in ure, malignancy and coronary artery vasculopathy). The indications
patients who have end-stage HFrEF for and contraindications to heart transplantation have recently
despite optimal medical and device 605, 612, been updated and are summarized in Table 13.4.616 It needs to be
IIa B
therapy and who are not eligible for 613
heart transplantation to, reduce the considered that some contraindications are transient and treatable.
risk of premature death. While an active infection remains a relative contraindication to heart
transplantation, patients with HIV, hepatitis, Chagas disease and tu-
HF ¼ heart failure; HFrEF ¼ heart failure with reduced ejection fraction; LVAD ¼ berculosis can be considered as suitable candidates provided certain
left ventricular assist device. strict management principles are adhered to by the teams. In pa-
a
Class of recommendation.
b tients with cancer requiring heart transplantation, a close collabor-
Level of evidence.
c
Reference(s) supporting levels of evidence. ation with oncology specialists should occur to stratify each patient
as to their risk of tumour recurrence.616
ESC Guidelines 2187

Table 14.1 Characteristics and components of Recommendations for exercise, multidisciplinary


management programmes for patients with heart management and monitoring of patients with heart
failure failure

Characteristics Should employ a multidisciplinary approach Recommendations Class a Level b Ref c


(cardiologists, primary care physicians, nurses,
pharmacists, physiotherapists, dieticians, social It is recommended that regular
workers, surgeons, psychologists, etc.). aerobic exercise is encouraged 321,
I A
in patients with HF to improve 618–621
Should target high-risk symptomatic patients. functional capacity and symptoms.
Should include competent and professionally It is recommended that regular
educated staff.617 aerobic exercise is encouraged in
I A 618, 619

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Components Optimized medical and device management. stable patients with HFrEF to reduce
the risk of HF hospitalization.
Adequate patient education, with special emphasis
on adherence and self-care. It is recommended that patients with
HF are enrolled in a multidisciplinary
Patient involvement in symptom monitoring and care management programme to I A 622–625
reduce the risk of HF hospitalization
Follow-up after discharge (regular clinic and/or and mortality.
home-based visits; possibly telephone support or Referral to primary care for long-
remote monitoring). term follow-up may be considered
Increased access to healthcare (through in-person for stable HF patients who are on
IIb B 626, 627
follow-up and by telephone contact; possibly optimal therapy to monitor for
through remote monitoring). effectiveness of treatment, disease
progression and patient adherence.
Facilitated access to care during episodes of
decompensation. Monitoring of pulmonary artery
pressures using a wireless
Assessment of (and appropriate intervention in implantable haemodynamic
response to) an unexplained change in weight, monitoring system (CardioMems)
nutritional status, functional status, quality of life, may be considered in symptomatic IIb B 628, 629
patients with HF with previous
Access to advanced treatment options. HF hospitalization in order to
reduce the risk of recurrent HF
Provision of psychosocial support to patients and
hospitalization.
family and/or caregivers.
Multiparameter monitoring based
on ICD (IN-TIME approach) may be
considered in symptomatic patients IIb B 630
with HFrEF (LVEF ≤35%) in order to
improve clinical outcomes.

HF ¼ heart failure; HFrEF ¼ heart failure with reduced ejection fraction; ICD ¼
The use of mechanical circulatory support, particularly LVAD, implantable cardioverter-defibrillator; LVEF ¼ left ventricular ejection fraction,
should be considered for patients with potentially reversible or IN-TIME ¼ Implant-based multiparameter telemonitoring of patients with heart failure.
a
Class of recommendation.
treatable co-morbidities, such as cancer, obesity, renal failure, b
Level of evidence.
tobacco use and pharmacologically irreversible pulmonary c
Reference(s) supporting levels of evidence.
hypertension, with a subsequent re-evaluation to establish
candidacy.
14.1 Organization of care
The goal of management of HF is to provide a ‘seamless’ system of
14. Multidisciplinary team care that embraces both the community and hospital throughout
the health care journey. The standards of care that patients with HF
management should expect have been published by the ESC HFA.591 To achieve
Non-pharmacological non-device/surgical interventions used in the this goal, other services, such as cardiac rehabilitation and palliative
management of HF (both HFrEF and HFpEF) are summarized in care, must be integrated into the overall provision for patients with
Tables 14.1 and 14.2 and detailed practical recommendations on HF. Fundamental to the delivery of this complete package of care
their use have been published by the HFA of the ESC.591,592 There are multidisciplinary management programmes designed to improve
is no evidence that these on their own improve mortality, morbidity outcomes through structured follow-up with patient education, opti-
or quality of life. For this reason, these interventions have not been mization of medical treatment, psychosocial support and improved
given a recommendation with an evidence level. The exceptions are access to care (Table 14.1). Such strategies reduce HF hospitalization
implementation of care in a multidisciplinary framework, monitoring and mortality in patients discharged from the hospital.624,625
and exercise training (see recommendations table), all of which are Key to the success of these programmes is coordination of care
discussed below. along the continuum of HF and throughout the chain of care
2188 ESC Guidelines

Table 14.2 Key topics and self-care skills to include in patient education and the professional behaviours to optimize
learning and facilitate shared decision making

Education topic Patient skills Professional behaviours


• Understand the cause of HF, symptoms and disease • Provide oral and written information that takes account of educational
aetiology and trajectory. grade and health literacy.
trajectory of • Make realistic decisions including decisions about • Recognize HF disease barriers to communication and provide
HF (including treatment at end-of-life. information at regular time intervals.
prognosis). • Sensitively communicate information on prognosis at time of diagnosis,
during decision making about treatment options, when there is a
change in the clinical condition and whenever the patient requests.
Symptom • Monitor and recognize change in signs and symptoms. • Provide individualized information to support self-management such as:
monitoring and • Know how and when to contact a healthcare professional.  In the case of increasing dyspnoea or oedema or a sudden

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self-care. • In line with professional advice, know when to self- unexpected weight gain of >2 kg in 3 days, patients may increase
their diuretic dose and/or alert their healthcare team.

 Self-care support aids such as dosette box when appropriate.
Pharmacological • Understand the indications, dosing and side effects of drugs. • Provide written and oral information on dosing, effects and side
treatment. • Recognize the common side effects and know effects (see web tables 7.4–7.8 – practical guidance on use of
when to notify a healthcare professional. pharmacological agents).

Implanted devices • Understand the indications and aims of procedures/ •
and percutaneous/ implanted devices. • Provide written and oral information on regular control of device
surgical • Recognize the common complications and know when to functioning, along with documentation of regular check-up.
interventions. notify a healthcare professional.

implanted devices.
Immunization • • Advise on local guidance and immunization practice.
disease
Diet and alcohol • •
• weight and periods of high heat and humidity. Adjust advice during
 Increase intake during periods of high heat and periods of acute decompensation and consider altering these
humidity, nausea/vomiting restrictions towards end-of-life.
 Fluid restriction of 1.5–2 L/day may be considered in • Tailor alcohol advice to aetiology of HF; e.g. abstinence in
patients with severe HF to relieve symptoms and alcoholic cardiomyopathy.
congestion. • Normal alcohol guidelines apply (2 units per day in men or 1 unit per
• Monitor body weight and prevent malnutrition. day in women). 1 unit is 10 mL of pure alcohol (e.g. 1 glass of wine, 1/2
• Eat healthily, avoid excessive salt intake (>6 g/day) and pint of beer, 1 measure of spirit).
maintain a healthy body weight. • For management of obesity (see Section 11.15).
• Abstain from or avoid excessive alcohol intake, especially
for alcohol induced cardiomyopathy.
Smoking and • Stop smoking and taking recreational substances. • Refer for specialist advice for smoking cessation and drug withdrawal
recreational and replacement therapy.
substance use. • Consider referral for cognitive behavioural theory and psychological
support if patient wishes support to stop smoking.
Exercise • • Advice on exercise that recognizes physical and functional limitations,
moderate breathlessness. such as frailty, comorbidities.
• Referral to exercise programme when appropriate.
Travel and leisure • Prepare travel and leisure activities according to physical •
capacity. •

• Be aware of adverse reactions to sun exposure with


certain medication (such as amiodarone).
• Consider effect of high altitude on oxygenation.
• take medicine in cabin luggage in the plane, have a list with
you of treatments and the dosage with the generic name.
Sleep and • Recognize problems with sleeping, their relationship with • Provide advice such as timing of diuretics, environment for sleep, device
breathing (see HF and how to optimize sleep. support.
co-morbidities • In presence of sleep-disordered breathing provide advice on weight
Section 11.16). reduction/control.
Sexual activity (see • Be reassured about engaging in sex, provided sexual • Provide advice on eliminating factors predisposing to erectile
co-morbidities activity does not provoke undue symptoms. dysfunction and available pharmacological treatment of erectile
Section 11.7). • Recognize problems with sexual activity, their relationship dysfunction.
with HF and applied treatment and how to treat erectile • Refer to specialist for sexual counselling when necessary.
dysfunction.

continued
ESC Guidelines 2189

Table 14.2 Key topics and self-care skills to include in patient education and the professional behaviours to optimize
learning and facilitate shared decision making (continued)

Education topic Patient skills Professional behaviours


Psychosocial • Understand that depressive symptoms and cognitive • Regularly communicate information on disease, treatment options and
aspects dysfunction are found more frequently in people with HF, self-management.
and that they may affect adherence. • Involve family and carers in HF management and self-care.
• Recognize psychological problems which may occur • Refer to specialist for psychological support when necessary.
in the course of disease, in relation to changed lifestyle,
pharmacotherapy, implanted devices and other
procedures (including mechanical support and heart
transplantation).

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HF ¼ heart failure; ICD ¼ implantable cardioverter defibrillator.

delivered by the various services within the health care system. This exercise tolerance, health-related quality of life and HF hospitaliza-
necessitates close collaboration between HF practitioners (primar- tion rates in patients with HF. A single large RCT618 showed a modest
ily cardiologists, HF nurses and general practitioners) and other ex- and non-significant reduction in the primary composite outcome of
perts, including pharmacists, dieticians, physiotherapists, all-cause mortality or all-cause hospitalization. There was no reduc-
psychologists, palliative care providers and social workers. The con- tion in mortality and no safety concerns were raised.618,633 The
tent and structure of HF management programmes may vary in dif- most recent Cochrane review of exercise training619 included 33
ferent countries and health care settings. The components shown in trials with 4740 patients with HF (predominantly HFrEF). There
Table 14.1 are recommended. HF services should be easily access- was a trend towards a reduction in mortality with exercise in trials
ible to the patient and his/her family and care providers. A telephone with .1 year of follow-up. Compared with the control group, exer-
helpline may facilitate access to professional advice. cise training reduced the rate of overall and HF-specific hospitaliza-
The website http://ww.heartfailurematters.org is an option for tion and improved quality of life. Practical recommendations on
professional information for those patients and families with Inter- exercise training have been published by the HFA.120
net access. There is evidence that in patients with HFpEF, exercise training has
several benefits, including improvements in exercise capacity, as mea-
14.2 Discharge planning sured objectively using peak oxygen consumption, quality of life and
Early readmission after hospital discharge is common and may be ad- diastolic function, assessed by echocardiography.321,620,621,634
dressed through coordinated discharge planning. The standards of Patients with HF, regardless of LVEF, are recommended to perform
care that patients should expect have been published by the HFA properly designed exercise training (see the recommendations table).
and the Acute Cardiac Care Association.540,631 Discharge planning
should commence as soon as the patient’s condition is stable. During 14.5 Follow-up and monitoring
hospital admission, providing patients with information and education Patients with HF benefit from regular follow-up and monitoring of
for self-care improves outcome. Discharge should be arranged for biomedical parameters to ensure the safety and optimal dosing of
when the patient is euvolaemic and any precipitants of the admission medicines and detect the development of complications or disease
have been treated. Hospitals with early physician follow-up after dis- progression that may require a change in management (e.g. the onset
charge show reduced 30-day readmission, and those that initiated of AF or development of anaemia). Monitoring may be undertaken by
programmes to discharge patients with an outpatient follow-up ap- the patients themselves during home visits, in community or hospital
pointment already scheduled experienced a greater reduction in clinics, by remote monitoring with or without implanted devices or
readmissions than those not taking up this strategy.632 by structured telephone support (STS). The optimal method of mon-
itoring will depend on local organizations and resources and will vary
14.3 Lifestyle advice among patients. For example, more frequent monitoring will be re-
There is little evidence that specific lifestyle advice improves quality quired during periods of instability or optimization of medication.
of life or prognosis; however, providing this information has become Older adults may also benefit from more frequent monitoring.
a key component of education for self-care. Patients should be pro- Some patients will be keen and able to participate in self-monitoring.
vided with sufficient up-to-date information to make decisions on High circulating NPs predict unfavourable outcomes in patients
lifestyle adjustment and self-care. Ideally for those patients admitted with HF, and a decrease in NP levels during recovery from circula-
to the hospital, lifestyle advice should begin prior to discharge. Infor- tory decompensation is associated with a better prognosis.588 – 590
mation should be individually tailored to need and take into account Although it is plausible to monitor clinical status and tailor treatment
relevant co-morbidities that may influence retention of information based on changes in circulating NPs in patients with HF, published
(such as cognitive impairment and depression). Practical recommen- studies have provided differing results.635 – 638 This does not enable
dations have been published by the HFA.591 Key topics to include us to recommend a broad application of such an approach.
are recommended in Table 14.2. Telemedicine in HF, which is also termed remote patient manage-
ment, has variable clinical trial results.639 Several meta-analyses sug-
14.4 Exercise training gest clinical benefits, but numerous prospectively initiated clinical
Several systematic reviews and meta-analyses of small studies have trials including .3700 patients have not confirmed this. These clin-
shown that physical conditioning by exercise training improves ical trials include Tele-HF,640 TIM-HF,641 INH,642 WISH643 and
2190 ESC Guidelines

TEHAF.644 It is clear that there is not just one type of telemedicine,


and each approach needs to be assessed on its individual merit. Table 14.3 Specific recommendations regarding
Recently, two individual approaches were shown to be successful monitoring and follow-up of the older adult with heart
in improving clinical outcome when used in patients with HFpEF or failure
HFrEF. These approaches include the CardioMems system (tested
Monitor frailty and seek and address reversible causes (cardiovascular
in 550 patients with both HFrEF and HFpEF)628 and the IN-TIME
and non-cardiovascular) of deterioration in frailty score.
approach (tested in 664 HFrEF patients)630, which may be considered
Medication review: optimize doses of heart failure medication slowly and
for use in selected patients with HF (see the recommendations table).
with frequent monitoring of clinical status. Reduce polypharmacy; number,
doses and complexity of regime. Consider stopping medication without an
14.6 The older adult, frailty and cognitive immediate effect on symptom relief or quality of life (such as statin). Review
the timing and dose of diuretic therapy to reduce risk of incontinence.
impairment

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Consider need to refer to specialist care of the elderly team and to
HF management and self-care behaviour are complicated by ageing, general practitioner and social worker, etc. for follow-up and support for
co-morbid conditions, cognitive impairment, frailty and limited so- the patient and his/her family.
cial support. HF is also a leading cause of hospital admission in the
older adult, where it is associated with increased hospital length of
stay and risk of mortality.645
Frailty is common in older adults with HF, with a recent study sug-
Table 14.4 Patients with heart failure in whom end of
gesting it may be present in .70% of patients with HF and .80
life care should be considered
years of age.645 Frailty scoring systems provide an objective assess-
ment and identify the presence of or change in the level of frailty.
Progressive functional decline (physical and mental) and dependence in
Patients with a high frailty score will benefit from closer contact most activities of daily living.
with the HF specialist team, more frequent follow-up and monitor-
Severe heart failure symptoms with poor quality of life despite optimal
ing and individualized self-care support. pharmacological and non-pharmacological therapies.
Frailty scores include646 walking speed (gait speed test), timed
Frequent admissions to hospital or other serious episodes of
up-and-go test, PRISMA 7 questionnaire, Frail Score,647 Fried decompensation despite optimal treatment.
Score647,648 and Short Physical Performance Battery (SPPB). Heart transplantation and mechanical circulatory support ruled out.
Cognitive impairment and HF frequently coexist. Acute delirium
Cardiac cachexia.
is also associated with decompensated HF and may be present on
hospital admission. Cognitive function can be assessed using the Clinically judged to be close to end of life.
Mini-Mental State Examination649 or the Montreal cognitive assess-
ment.650 The presence of delirium and HF is found more commonly
in older adults and is associated with increased mortality and poorer
self-care ability and increases any hospital length of stay.651 There is Table 14.5 Key components of palliative care service
currently no clinical evidence that HF medication worsens or im- in patients with heart failure
proves cognitive function. However, its effect on HF outcome
suggests such medication should be used. Support from a multidis- Focus on improving or maintaining the quality of life of a patient and his/
ciplinary HF team in collaboration with specialist dementia support her family as well as possible until he/she dies.
teams, alongside medication compliance aids, tailored self-care Frequent assessment of symptoms (including dyspnoea and pain)
advice and involvement of family and caregivers, may improve resulting from advanced heart failure and other co-morbidities and focus
adherence with complex HF medication and self-care regimens on symptom relief.
(see Table 14.2 on patient education) (Table 14.3). Access for the patient and his/her family to psychological support and
spiritual care according to need.

14.7 Palliative and end-of-life care Advanced care planning, taking account of preferences for place of
death and resuscitation (which may include deactivating devices, such as
Palliative care approaches include a focus on symptom management,
emotional support and communication between the patient and his/
her family. Ideally this should be introduced early in the disease trajec-
tory and increased as the disease progresses. A decision to alter the
focus of care from modifying disease progression to optimising quality approach, is required in order to address and optimally coordinate
of life should be made in discussion with the patient, cardiologist, the patient’s care. Recent pilot studies have suggested an improve-
nurse and general practitioner. The patient’s family should be involved ment in symptom burden and quality of life,653,655 but these data are
in such discussions if requested by the patient652,653 (Table 14.4). too limited to provide a recommendation.
Key components of a palliative care service are recommended in Specific therapies and actions may provide palliation of symptoms
Table 14.5. Palliative care has been discussed in detail in a position and improve quality of life but have a limited evidence base:
paper from the ESC HFA.654
Liaison between the specialist palliative care services and the HF † Morphine (with an antiemetic when high doses are needed) can
team and/or the primary care physician, using a shared care be used to reduce breathlessness, pain and anxiety.656
ESC Guidelines 2191

† Increasing the inspired oxygen concentration may provide relief † Targeted therapies for specific aetiologies of HFrEF (e.g. myo-
of dyspnoea. carditis, peripartum cardiomyopathy)
† Diuretic management can be used to relieve severe congestion † Therapies directly improving cardiomyocyte function (e.g.
or optimize symptom control (congestion and thirst). acto-myosin cross-bridge activation, sarco/endoplasmic re-
† Reduce HF drugs that reduce blood pressure to maintain suffi- ticulum Ca2+-ATPase activation, ryanodine receptor stabiliza-
cient oxygenation and reduce the risk of falls. tion, energetic modulation) or targeting non-myocytic
compartment (e.g. anti-fibrosis/matrix remodelling)
Ideally these therapies should be delivered in the patient’s home. In the
† Therapies for HFmrEF/HFpEF (ARNIs, beta-blockers, soluble
majority of cases the whole family should receive social support.652
guanyl cyclase inhibitors, i.v. iron)
A management plan should be developed through discussion with
the patient and family. It should include 4. Devices and interventions
† A discussion about stopping medication that does not have an im-

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† Indications for ICDs in specific subgroups (e.g. ARVC and
mediate effect on symptom management or health-related quality HFmrEF/HFpEF) and optimal selection of ICD candidates
of life, such as agents to lower cholesterol or treat osteoporosis † QRS morphology or duration as a predictor of response to CRT
† Documentation of the patient’s decision regarding resuscitation † CRT in patients with AF
attempts † Efficacy of PV ablation as a rhythm-control strategy in patients
† Deactivation of an ICD at end-of-life (according to local legal with AF
regulations) † Interventional approach to recurrent, life-threatening ven-
† Preferred place for care and death tricular tachyarrhythmias
† Emotional support to the patient and family/caregiver with ap- † The role of remote monitoring strategies in HF
propriate referral for psychological or spiritual support † Non-surgical (percutaneous) correction of functional mitral
Clearly, symptoms and quality of life change over time and regular and tricuspid regurgitations
reassessment is recommended. Palliative scores provide an object- † Identification of indications for coronary angiography/revascu-
ive assessment of the patient’s symptoms and needs and may help larization in patients with HF and chronic stable CAD
establish the effectiveness of therapy. † Effects of novel LVADs as destination therapy and bridge to
Palliative outcome scores include the Palliative Care Outcome transplantation
Scale,657 Karnofsky Performance Status658 and Functional Assess- 5. Co-morbidities
ment of Chronic Illness Therapy – Palliative Care (FACIT-Pal).659
† A better understanding of pathophysiology and potential
treatments in specific HF populations, including the
† very elderly,
15. Gaps in evidence † young patients,
Clinicians responsible for managing patients with HF must frequently † eGFR ,30 mL/min,
make treatment decisions without adequate evidence or a consensus † diabetic patients,
of expert opinion. The following is a short list of selected, common † cardiotoxic chemotherapy-induced HF,
issues that deserve to be addressed in future clinical research. † muscular dystrophies,
† cachexia and depression.
1. Definition, diagnosis, epidemiology † Therapies for HF-related sleep-disordered breathing in HFrEF/
HFpEF/HFmrEF.
† For HFmrEF/HFpEF, research into the underlying characteris-
tics, pathophysiology and diagnosis (with new modalities) 6. Acute heart failure
† Updated epidemiology on HF incidence and prevalence includ-
ing patients from all continents † Prospective evaluation of the ‘time-to-treatment’ concept in AHF
† For imaging and biomarkers, studies on effects of specific im- † Evaluation of whether inadequate phenotyping is responsible
aging modalities and biomarkers to improve clinical outcome for the failure of treatments to improve outcome in AHF
(e.g. biomarker-guided therapies, detection of CAD/myocardial † Better definition and treatment of diuretic resistance
ischaemia, late-gadolinium enhancement CMR, echocardio- † Role of nitrates in the management of AHF
graphic strain measurements, stress echocardiography, etc.) † Treatments improving mortality and morbidity
† Increasing awareness of HF in the medical community, lay pub- † Strategies and therapies to prevent early rehospitalization after
lic and among policy makers. discharge for a hospital admission for AHF.

2. Strategies aimed at prevention and screening of HF 7. Other/remaining aspects

† Evaluate the comparative clinical effectiveness and cost- † Treatment algorithms for patients with HF excluded by pivotal
effectiveness of different strategies to screen for HF. clinical trials
† Palliative and end-of-life care management and assessment of
3. Pharmacological therapy
outcome
† Identification of non-responders to current guideline-advised † Optimal integration of multidisciplinary care, self-management
medical treatment of patients and their adherence.
2192 ESC Guidelines

16. To do and not to do messages from the Guidelines

Recommendations for cardiac imaging in patients with suspected or established heart failure Class a Level b
TTE is recommended for the assessment of myocardial structure and function in subjects with suspected HF in order to establish a
I C
diagnosis of either HFrEF, HFmrEF or HFpEF.
TTE is recommended for the assessment of LVEF in order to identify patients with HF who would be suitable for evidence-based
I C
pharmacological and device (ICD, CRT) treatment recommended for HFrEF.
Recommendations aiming to prevent or delay the development of overt heart failure or prevent death Class a Level b
before the onset of symptoms

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Treatment of hypertension is recommended to prevent or delay the onset of HF and prolong life. I A
ACE-I is recommended in patients with asymptomatic LV systolic dysfunction and a history of myocardial infarction in order to
I A
prevent or delay the onset of HF and prolong life.
Beta-blocker is recommended in patients with asymptomatic LV systolic dysfunction and a history of myocardial infarction, in order
I B
to prevent or delay the onset of HF and prolong life.
Pharmacological treatments indicated in patients with symptomatic heart failure with reduced ejection Class a Level b
fraction
An ACE-Ic is recommended, in addition to a beta-blocker, for symptomatic patients with HFrEF to reduce the risk of HF
I A
hospitalization and death.
A beta-blocker is recommended, in addition to an ACE-Ic, for patients with stable, symptomatic HFrEF to reduce the risk of HF
I A
hospitalization and death.
An MRA is recommended for patients with HFrEF, who remain symptomatic despite treatment with an ACE-I c and a beta-blocker, to
I A
reduce the risk of HF hospitalization and death.
Other pharmacological treatments recommended in selected patients with symptomatic heart failure with Class a Level b
reduced ejection fraction
Diuretics are recommended in order to improve symptoms and exercise capacity in patients with signs and/or symptoms of congestion. I B
Sacubitril/valsartan is recommended as a replacement for an ACE-I to further reduce the risk of HF hospitalization and death in
I B
ambulatory patients with HFrEF who remain symptomatic despite optimal treatment with an ACE-I, a beta-blocker and an MRA.
Treatments (or combinations of treatments) that may cause harm in patients with symptomatic (New York Class a Level b
Heart Association Class II–IV) heart failure with reduced ejection fraction
Diltiazem or verapamil are not recommended in patients with HFrEF, as they increase the risk of HF worsening and HF hospitalization. III C
The addition of an ARB (or a renin inhibitor) to the combination of an ACE-I and an MRA is not recommended in patients with HF,
III C
because of the increased risk of renal dysfunction and hyperkalaemia.
Class a Level b
Secondary prevention
An ICD is recommended to reduce the risk of sudden death and all-cause mortality in patients who have recovered from a ventricular I A
arrhythmia causing haemodynamic instability, and who are expected to survive for >1 year with good functional status.
Primary prevention
An ICD is recommended to reduce the risk of sudden death and all-cause mortality in patients with symptomatic HF (NYHA Class
II–III), and an LVEF ≤35% despite ≥3 months of OMT, provided they are expected to survive substantially longer than 1 year with good
functional status, and they have:
• IHD (unless they have had an MI in the prior 40 days) I A
• DCM I B
ICD implantation is not recommended within 40 days of an MI as implantation at this time does not improve prognosis. III A
a
Recommendations for cardiac resynchronization therapy implantation in patients with heart failure Class Level b

CRT is recommended for symptomatic patients with HF in sinus rhythm with a QRS duration ≥150 msec and LBBB QRS morphology and
I A
with LVEF ≤35% despite OMT in order to improve symptoms and reduce morbidity and mortality.
CRT is recommended for symptomatic patients with HF in sinus rhythm with a QRS duration of 130–149 msec and LBBB QRS
I B
morphology and with LVEF ≤35% despite OMT in order to improve symptoms and reduce morbidity and mortality.
CRT rather than RV pacing is recommended for patients with HFrEF regardless of NYHA Class who have an indication for ventricular
I A

CRT is contra-indicated in patients with a QRS duration <130 msec III A

continued
ESC Guidelines 2193

To do and not to do messages from the Guidelines (continued)

Not-recommended treatments of co-morbidities in patients with heart failure Class a Level b

Adaptive servo-ventilation is not recommended in patients with HFrEF and a predominant central sleep apnoea because of an
III B
increased all-cause and cardiovascular mortality.

Thiazolidinediones (glitazones) are not recommended in patients with HF, as they increase the risk of HF worsening and HF hospitalization. III A

NSAIDs or COX-2 inhibitors are not recommended in patients with HF, as they increase the risk of HF worsening and HF hospitalization. III B

Recommendations regarding diagnostic measurements in patients with suspected acute heart failure Class a Level b

Upon presentation a measurement of plasma natriuretic peptide level (BNP, NT-proBNP or MR-proANP) is recommended in all
I A

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patients with acute dyspnoea and suspected AHF to help in the differentiation of AHF from non-cardiac causes of acute dyspnoea.

Recommendations for the management of patients with acute heart failure – pharmacotherapy Class a Level b

I C
symptoms. It is recommended to regularly monitor symptoms, urine output, renal function and electrolytes during use of i.v. diuretics.
In patients with new-onset AHF or those with chronic, decompensated HF not receiving oral diuretics the initial recommended dose
should be 20–40 mg i.v. furosemide (or equivalent); for those on chronic diuretic therapy, initial i.v. dose should be at least equivalent to I B
oral dose.
It is recommended to give diuretics either as intermittent boluses or a continuous infusion, and the dose and duration should be
I B
adjusted according to the patients’ symptoms and clinical status.
Inotropic agents are not recommended unless the patient is symptomatically hypotensive or hypoperfused because of safety concern. III A
a
Recommendations regarding management of patients with cardiogenic shock Class Level b

In all patients with suspected cardiogenic shock, immediate ECG and echocardiography are recommended. I C
All patients with cardiogenic shock should be rapidly transferred to a tertiary care centre which has a 24/7 service of cardiac
I C
catheterization, and a dedicated ICU/CCU with availability of short-term mechanical circulatory support.

Recommendations regarding oral evidence-based disease-modifying therapies in patients with acute heart failure Class a Level b
In case of worsening of chronic HFrEF, every attempt should be made to continue evidence-based, disease-modifying therapies, in the
I C
absence of haemodynamic instability or contra-indications.

Recommendations for exercise, multidisciplinary management, and monitoring of patients with heart failure Class a Level b

It is recommended that regular aerobic exercise is encouraged in patients with HF to improve functional capacity and symptoms. I A
It is recommended that regular aerobic exercise is encouraged in stable patients with HFrEF to reduce the risk of HF hospitalization. I A
It is recommended that patients with HF are enrolled in a multidisciplinary care management programme to reduce the risk of HF
I A
hospitalization and mortality.

ACE-I ¼ angiotensin-converting enzyme inhibitor; AHF ¼ acute heart failure;; ARB ¼ angiotensin receptor blocker; AST ¼ aspartate aminotransferase; AV ¼ atrio-ventricular;
BNP ¼ B-type natriuretic peptide; CCU ¼ coronary care unit; COX-2 ¼ cyclooxygenase 2; CRT ¼ cardiac resynchronization therapy; CT ¼ computed tomography; DCM ¼
dilated cardiomyopathy; ECG ¼ electrocardiogram; HF ¼ heart failure; HFmrEF ¼ heart failure with mid-range ejection fraction; HFpEF ¼ heart failure with preserved ejection
fraction; HFrEF ¼ heart failure with reduced ejection fraction; ICD ¼ implantable cardioverter-defibrillator; ICU ¼ intensive care unit; i.v. ¼ intravenous; LBBB ¼ left bundle
branch block; LV ¼ left ventricular; LVEF ¼ left ventricular ejection fraction; MI ¼ myocardial infarction; MRA ¼ mineralocorticoid receptor antagonist; MR-proANP ¼ mid-
regional pro A-type natriuretic peptide; NSAIDs ¼ non-steroidal anti-inflammatory drugs; NT-proBNP ¼ N-terminal pro-B type natriuretic peptide; NYHA ¼ New York Heart
Association; OMT ¼ optimal medical therapy; QRS ¼ Q, R, and S waves (combination of three of the graphical deflections); RV ¼ right ventricular; TTE ¼ transthoracic
echocardiography.
a
Class of recommendation.
b
Level of evidence
c
Or ARB if ACEI is not tolerated/contra-indicated.

17. Web Addenda


All Web figures and Web tables are available in the Web addenda, available at European Heart Journal online and also via the ESC website.
2194 ESC Guidelines

18. Appendix Greece: Hellenic Cardiological Society, Christina Chrysohoou;


Hungary: Hungarian Society of Cardiology, Noémi Nyolczas; Ice-
ESC Committee for Practice Guidelines (CPG): Jose Luis Za- land: Icelandic Society of Cardiology, Gestur Thorgeirsson; Israel:
morano (Chairperson) (Spain), Victor Aboyans (France), Stephan Israel Heart Society, Jean Marc Weinstein; Italy: Italian Federation
Achenbach (Germany), Stefan Agewall (Norway), Lina Badimon of Cardiology, Andrea Di Lenarda; Kazakhstan: Association of
(Spain), Gonzalo Barón-Esquivias (Spain), Helmut Baumgartner Cardiologists of Kazakhstan, Nazipa Aidargaliyeva; Kosovo: Kosovo
(Germany), Jeroen J. Bax (The Netherlands), Héctor Bueno (Spain), Society of Cardiology, Gani Bajraktari; Kyrgyzstan: Kyrgyz Society
Scipione Carerj (Italy), Veronica Dean (France), Çetin Erol (Turkey), of Cardiology, Medet Beishenkulov; Latvia: Latvian Society of Car-
Donna Fitzsimons (UK), Oliver Gaemperli (Switzerland), Paulus diology, Ginta Kamzola; Lebanon: Lebanese Society of Cardiology,
Kirchhof (UK/Germany), Philippe Kolh (Belgium), Patrizio Lancellot- Tony Abdel-Massih; Lithuania: Lithuanian Society of Cardiology,
ti (Belgium), Gregory Y. H. Lip (UK), Petros Nihoyannopoulos (UK), Jelena Čelutkienė; Luxembourg: Luxembourg Society of Cardi-
Massimo F. Piepoli (Italy), Piotr Ponikowski (Poland), Marco Roffi

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ology, Stéphanie Noppe; Malta: Maltese Cardiac Society, Andrew
(Switzerland), Adam Torbicki (Poland), António Vaz Carneiro (Por- Cassar; Moldova: Moldavian Society of Cardiology, Eleonora Vata-
tugal), Stephan Windecker (Switzerland). man; Morocco: Moroccan Society of Cardiology, Saadia Abir-
ESC National Cardiac Societies actively involved in the re- Khalil; The Netherlands: Netherlands Society of Cardiology, Pet-
view process of the 2016 ESC Guidelines for the diagnosis and treat- ra van Pol; Norway: Norwegian Society of Cardiology, Rune Mo;
ment of acute and chronic heart failure Poland: Polish Cardiac Society, Ewa Straburzyńska-Migaj; Portu-
Armenia: Armenian Cardiologists Association, Hamayak gal: Portuguese Society of Cardiology, Cândida Fonseca; Romania:
S. Sisakian; Azerbaijan: Azerbaijan Society of Cardiology, Elnur Romanian Society of Cardiology, Ovidiu Chioncel; Russian Feder-
Isayev; Belarus: Belorussian Scientific Society of Cardiologists, Ale- ation: Russian Society of Cardiology, Evgeny Shlyakhto; San Mar-
na Kurlianskaya; Belgium: Belgian Society of Cardiology, Wilfried ino: San Marino Society of Cardiology, Marco Zavatta; Serbia:
Mullens; Bulgaria: Bulgarian Society of Cardiology, Mariya Tokma- Cardiology Society of Serbia, Petar Otasevic; Slovakia: Slovak So-
kova; Cyprus: Cyprus Society of Cardiology, Petros Agathangelou; ciety of Cardiology, Eva Goncalvesová; Slovenia: Slovenian Society
Czech Republic: Czech Society of Cardiology, Vojtech Melenovs- of Cardiology, Mitja Lainscak; Spain: Spanish Society of Cardiology,
ky; Denmark: Danish Society of Cardiology, Henrik Wiggers; Beatriz Dı́az Molina; Sweden: Swedish Society of Cardiology, Maria
Egypt: Egyptian Society of Cardiology, Mahmoud Hassanein; Es- Schaufelberger; Switzerland: Swiss Society of Cardiology, Thomas
tonia: Estonian Society of Cardiology, Tiina Uuetoa; Finland: Finn- Suter; Turkey: Turkish Society of Cardiology, Mehmet Birhan
ish Cardiac Society, Jyri Lommi; Former Yugoslav Republic of Yılmaz; Ukraine: Ukrainian Association of Cardiology, Leonid Vor-
Macedonia: Macedonian FYR Society of Cardiology, Elizabeta Srbi- onkov; United Kingdom: British Cardiovascular Society, Ceri
novska Kostovska; France: French Society of Cardiology, Yves Juil- Davies.
lière; Georgia: Georgian Society of Cardiology, Alexander
Aladashvili; Germany: German Cardiac Society, Andreas Luchner;

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Ghadanfar M, Bermann G, Noe A, Schweizer A, Maier T, Gheorghiade M. Inter- 7. McMurray JJ V, Adamopoulos S, Anker SD, Auricchio A, Böhm M, Dickstein K,
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congestive heart failure. Results of the Cooperative North Scandinavian Enalapril Deaton C, Fagard R, Funck-Brentano C, Hasdai D, Hoes A, Kirchhof P, Knuuti J,
Survival Study (CONSENSUS). N Engl J Med 1987;316:1429 –1435. Kolh P, McDonagh T, Moulin C, Reiner Z, Sechtem U, Sirnes PA, Tendera M,
3. McMurray JJJ V. Improving outcomes in heart failure: a personal perspective. Eur Torbicki A, Vahanian A, Windecker S, Bonet LA, Avraamides P, Ben Lamin HA,
Heart J 2015;36:3467 –3470. Brignole M, Coca A, Cowburn P, Dargie H, Elliott P, Flachskampf FA, Guida GF,
4. Wang TJ. Natural history of asymptomatic left ventricular systolic dysfunction in Hardman S, Iung B, Merkely B, Mueller C, Nanas JN, Nielsen OW, Orn S,
the community. Circulation 2003;108:977 –982. Parissis JT, Ponikowski P, Members AF, McMurray JJ V, Adamopoulos S,
5. The SOLVD Investigators. Effect of enalapril on mortality and the development of Anker SD, Auricchio A, Böhm M, Dickstein K, Falk V, Filippatos G, Fonseca C,
heart failure in asymptomatic patients with reduced left ventricular ejection frac- Gomez-Sanchez MA, Jaarsma T, Køber L, Lip GYH, Maggioni A Pietro,
tions. N Engl J Med 1992;327:685–691. Parkhomenko A, Pieske BM, Popescu BA, Rønnevik PK, Rutten FH, Schwitter J,
6. Butler J, Fonarow GC, Zile MR, Lam CS, Roessig L, Schelbert EB, Shah SJ, Seferovic P, Stepinska J, Trindade PT, Voors AA, Zannad F, Zeiher A, Guidelines
Ahmed A, Bonow RO, Cleland JGF, Cody RJ, Chioncel O, Collins SP, ESCC for P, Reviewers D. ESC Guidelines for the diagnosis and treatment of acute
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European Heart Journal (2018) 39, 213–254 ESC GUIDELINES
doi:10.1093/eurheartj/ehx419

2017 ESC focused update on dual antiplatelet


therapy in coronary artery disease developed
in collaboration with EACTS

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The Task Force for dual antiplatelet therapy in coronary artery
disease of the European Society of Cardiology (ESC) and of the
European Association for Cardio-Thoracic Surgery (EACTS)
Authors/Task Force Members: Marco Valgimigli* (Chairperson) (Switzerland),
Héctor Bueno (Spain), Robert A. Byrne (Germany), Jean-Philippe Collet (France),
Francesco Costa (Italy), Anders Jeppsson1 (Sweden), Peter Jüni (Canada),
Adnan Kastrati (Germany), Philippe Kolh (Belgium), Laura Mauri (USA),
Gilles Montalescot (France), Franz-Josef Neumann (Germany),
Mate Petricevic1 (Croatia), Marco Roffi (Switzerland), Philippe Gabriel Steg
(France), Stephan Windecker (Switzerland), and Jose Luis Zamorano (Spain)
Additional Contributor: Glenn N. Levine (USA)

Document Reviewers: Lina Badimon (CPG Review Coordinator) (Spain), Pascal Vranckx (CPG Review
Coordinator) (Belgium), Stefan Agewall (Norway), Felicita Andreotti (Italy), Elliott Antman (USA),
Emanuele Barbato (Italy), Jean-Pierre Bassand (France), Raffaele Bugiardini (Italy), Mustafa Cikirikcioglu1
(Switzerland), Thomas Cuisset (France), Michele De Bonis (Italy), Victora Delgado (The Netherlands),
Donna Fitzsimons (UK), Oliver Gaemperli (Switzerland), Nazzareno Galiè (Italy), Martine Gilard (France),

* Corresponding author: Marco Valgimigli, Cardiology, Inselspital, Freiburgstrasse 8, 3010 Bern, Switzerland. Tel: þ41 31 632 3077, Fax: þ41 10 7035258, E-mail: marco.valgimigli@insel.ch.
ESC Committee for Practice Guidelines (CPG) and National Cardiac Societies document reviewers: listed in the Appendix.
1
Representing the EACTS
ESC entities having participated in the development of this document:
Associations: Acute Cardiovascular Care Association (ACCA), European Association of Preventive Cardiology (EAPC), European Association of Percutaneous Cardiovascular
Interventions (EAPCI).
Working Groups: Cardiovascular Pharmacotherapy, Cardiovascular Surgery, Coronary Pathophysiology and Microcirculation, Peripheral Circulation, Pulmonary Circulation and
Right Ventricular Function, Thrombosis, Valvular Heart Disease.
The content of these European Society of Cardiology (ESC) Guidelines has been published for personal and educational use only. No commercial use is authorized. No part of the ESC
Guidelines may be translated or reproduced in any form without written permission from the ESC. Permission can be obtained upon submission of a written request to Oxford
University Press, the publisher of the European Heart Journal and the party authorized to handle such permissions on behalf of the ESC (journals.permissions@oxfordjournals.org).
Disclaimer. The ESC Guidelines represent the views of the ESC and were produced after careful consideration of the scientific and medical knowledge and the evidence available
at the time of their publication. The ESC is not responsible in the event of any contradiction, discrepancy and/or ambiguity between the ESC Guidelines and any other official recom-
mendations or guidelines issued by the relevant public health authorities, in particular in relation to good use of healthcare or therapeutic strategies. Health professionals are encour-
aged to take the ESC Guidelines fully into account when exercising their clinical judgment, as well as in the determination and the implementation of preventive, diagnostic or
therapeutic medical strategies; however, the ESC Guidelines do not override, in any way whatsoever, the individual responsibility of health professionals to make appropriate and
accurate decisions in consideration of each patient’s health condition and in consultation with that patient and, where appropriate and/or necessary, the patient’s caregiver. Nor do
the ESC Guidelines exempt health professionals from taking into full and careful consideration the relevant official updated recommendations or guidelines issued by the competent
public health authorities, in order to manage each patient’s case in light of the scientifically accepted data pursuant to their respective ethical and professional obligations. It is also the
health professional’s responsibility to verify the applicable rules and regulations relating to drugs and medical devices at the time of prescription.

The article has been co-published with permission in the European Heart Journal [DOI: 10.1093/eurheartj/ehx419] on behalf of the European Society of Cardiology and
European Journal of Cardio-Thoracic Surgery [DOI 10.1093/ejcts/ezx334] on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved in respect
of European Heart Journal, V C European Society of Cardiology 2017. The articles are identical except for minor stylistic and spelling differences in keeping with each journal’s

style. Either citation can be used when citing this article.


For permissions, please email journals.permissions@oup.com.
214 ESC Guidelines

Christian W. Hamm (Germany), Borja Ibanez (Spain), Bernard Iung (France), Stefan James (Sweden),
Juhani Knuuti (Finland), Ulf Landmesser (Germany), Christophe Leclercq (France), Maddalena Lettino
(Italy), Gregory Lip (UK), Massimo Francesco Piepoli (Italy), Luc Pierard (Belgium),
Markus Schwerzmann (Switzerland), Udo Sechtem (Germany), Iain A. Simpson (UK), Miguel Sousa Uva1
(Portugal), Eugenio Stabile (Italy), Robert F. Storey (UK), Michal Tendera (Poland), Frans Van de Werf
(Belgium), Freek Verheugt (The Netherlands), and Victor Aboyans (CPG Supervisor) (France)
The disclosure forms of all experts involved in the development of this focused update are available on
the ESC website http://www.escardio.org/guidelines.
The Addenda and Clinical Cases companion document of this focused update are available at: www.escardio.
org/Guidelines/Clinical-Practice-Guidelines/2017-focused-update-on-dual-antiplatelet-therapy-dapt

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Web addenda

Online publish-ahead-of-print 26 August 2017

...................................................................................................................................................................................................
Keywords Guidelines • Aspirin • Clopidogrel • Ticagrelor • Prasugrel • Dual antiplatelet therapy • Acute coronary
syndromes • Coronary artery bypass grafting • Coronary artery disease • Drug-eluting stents • Myocardial
infarction • Stent thrombosis • Bleeding • Percutaneous coronary intervention • Recommendation
• Revascularization • Risk stratification • Stents • Stable angina • Stable coronary artery disease • Oral
anticoagulant • Triple therapy • DAPT score • PRECISE-DAPT score • Non-cardiac surgery

..
Table of Contents .. 5. Dual antiplatelet therapy and cardiac surgery . . . . . . . . . . . . . . . . . . . . . .234
.. 5.1 Dual antiplatelet therapy in patients treated with coronary
..
Abbreviations and acronyms. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .215 .. artery bypass surgery for stable coronary artery disease . . . . . . . . . . .234
1. Preamble . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .216
.. 5.2 Dual antiplatelet therapy in patients treated with coronary
..
2. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .218 .. artery bypass surgery for acute coronary syndrome . . . . . . . . . . . . . . .234
2.1 Short- and long-term outcomes after percutaneous coronary
.. 5.3 Dual antiplatelet therapy for prevention of graft occlusion. . . . . .237
..
intervention . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .219 .. 5.4 Gaps in the evidence . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .237
2.2 Risk of stent thrombosis in relation to stent type. . . . . . . . . . . . . . .219
.. 6. Dual antiplatelet therapy for patients with medically managed
..
2.3 Short- and long-term outcomes after coronary artery bypass .. acute coronary syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .237
surgery. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .219
.. 7. Dual antiplatelet therapy for patients with indication for oral
..
2.4 Short- and long-term outcomes after medically managed acute .. anticoagulation. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .238
..
coronary syndrome. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .219 .. 7.1 Risk stratification and strategies to improve outcome after
3. Efficacy and safety of dual antiplatelet therapy and risk .. percutaneous coronary intervention. . . . . . . . . . . . . . . . . . . . . . . . . . . . . .238
..
stratification tools . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .219 .. 7.2 Duration of triple therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .239
3.1 Dual antiplatelet therapy for the prevention of stent .. 7.3 Cessation of all antiplatelet agents. . . . . . . . . . . . . . . . . . . . . . . . . . . . .242
..
thrombosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .219 .. 7.4 Type of anticoagulants. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .242
3.2 Dual antiplatelet therapy for the prevention of spontaneous .. 7.5 Type of stent. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .242
..
myocardial infarction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .219 .. 8. Elective non-cardiac surgery in patients on dual antiplatelet
3.3 Dual antiplatelet therapy and mortality rate. . . . . . . . . . . . . . . . . . . .219 .. therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .242
..
3.4 Safety of dual antiplatelet therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . .219 .. 9. Gender consideration and special populations. . . . . . . . . . . . . . . . . . . . .245
3.5 Risk stratification tools for ischaemia and bleeding risks . . . . . . . .219 .. 9.1 Gender specificities . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .245
..
3.6 Type of P2Y12 inhibitor and timing of initiation . . . . . . . . . . . . . . . . .221 .. 9.2 Diabetes mellitus. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .245
3.7 Measures to minimize bleeding while on dual .. 9.3 Lower-extremities artery disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . .245
..
antiplatelet therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .223 .. 9.4 Complex percutaneous coronary intervention . . . . . . . . . . . . . . . .248
3.8 Switching between oral P2Y12 inhibitors. . . . . . . . . . . . . . . . . . . . . . .225
.. 9.5 Dual antiplatelet therapy decision making in patients with
..
4. Dual antiplatelet therapy and percutaneous coronary .. stent thrombosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .248
intervention. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .226
.. 9.6 Patients who develop bleeding while on treatment. . . . . . . . . . . . .248
..
4.1 Dual antiplatelet therapy after percutaneous coronary .. 10. Key messages. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .249
intervention for stable coronary artery disease . . . . . . . . . . . . . . . . . . . .226
.. 11. Evidenced-based ‘to do and not to do’ messages . . . . . . . . . . . . . . . . .249
..
4.2 Dual antiplatelet therapy after percutaneous coronary .. 12. Web addenda and Clinical Cases companion document . . . . . . . . . .251
intervention for acute coronary syndrome . . . . . . . . . . . . . . . . . . . . . . . .231
.. 13. Appendix . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .251
..
4.3 Gaps in the evidence . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .233 .. 14. References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .252
ESC Guidelines 215

Abbreviations and acronyms ... CURE Clopidogrel in Unstable Angina to Prevent


.. Recurrent Events
ABC Age, Biomarkers (GDF-15, cTnT-hs, and
..
.. CYP Cytochrome P450
haemoglobin), and Clinical history .. DAPT Dual antiplatelet therapy
(previous bleeding)
..
.. DES Drug-eluting stent
ACCA Acute Cardiovascular Care Association .. EACTS European Association for Cardio-Thoracic
..
ACCOAST A Comparison of Prasugrel at the Time of .. Surgery
Percutaneous Coronary Intervention Or ..
.. EAPC European Association of Preventive
as Pretreatment At the Time of Diagnosis .. Cardiology
in Patients with Non-ST-Elevation ..
.. EAPCI European Association of Percutaneous
Myocardial Infarction .. Cardiovascular Interventions
ACS Acute coronary syndrome ..
.. ESC European Society of Cardiology

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ADP Adenosine 5’-diphosphate .. EXAMINATION Clinical Evaluation of the Xience-V stent
AF Atrial fibrillation ..
.. in Acute Myocardial INfArcTION
ANTARCTIC Platelet Function Monitoring to Adjust .. EXCELLENT Efficacy of Xience/Promus Versus Cypher
Antiplatelet Therapy in Elderly Patients ..
.. to Reduce Late Loss After Stenting
Stented for an Acute Coronary Syndrome .. FDA Food and Drug Administration
ARCTIC-Interruption Assessment by a Double Randomisation of a ..
.. GUSTO Global Use of Strategies to Open
Conventional Antiplatelet Strategy Versus a .. Occluded Coronary Arteries
Monitoring-Guided Strategy for Drug- ..
.. HAS-BLED Hypertension, Abnormal renal and liver
Eluting Stent Implantation and, of Treatment .. function, Stroke, Bleeding history or
Interruption Versus Continuation 1 Year
..
.. predisposition, Labile INR, Elderly
After Stenting-Interruption ... (> 65 years), Drugs and alcohol
ART Arterial Revascularisation Trial .. HR Hazard ratio
ASA Acetylsalicylic acid
..
.. I-LOVE-IT 2 Evaluate Safety and Effectiveness of the
ATACAS Aspirin and Tranexamic Acid for .. Tivoli DES and the Firebird DES for
Coronary Artery Surgery
..
.. Treatment of Coronary Revascularization
ATLANTIC Administration of Ticagrelor in the Cath .. INR International normalized ratio
..
Lab or in the Ambulance for New ST .. ISAR Intracoronary Stenting and
Elevation Myocardial Infarction to Open ..
.. Antithrombotic Regimen
the Coronary Artery .. ISAR-SAFE Intracoronary Stenting and
BARC Bleeding Academic Research Consortium ..
.. Antithrombotic Regimen: Safety and
b.i.d Bis in die (twice a day) .. Efficacy of 6 Months Dual Antiplatelet
BMS Bare-metal stent ..
.. Therapy After Drug-Eluting Stenting
CABG Coronary artery bypass graft surgery .. ISAR-TRIPLE Intracoronary Stenting and
CAD Coronary artery disease ..
.. Antithrombotic Regimen–Testing of a 6-
CHADS2 Cardiac failure, Hypertension, Age, .. Week Versus a 6-Month Clopidogrel
Diabetes, Stroke (Doubled) ..
.. Treatment Regimen in Patients With
CHA2DS2-VASc Cardiac failure, Hypertension, Age >_ 75 (2 .. Concomitant Aspirin and Oral
points), Diabetes, Stroke (2 points)–Vascular ..
.. Anticoagulant Therapy Following Drug-
disease, Age 65–74, Sex category .. Eluting Stenting
CHARISMA Clopidogrel for High Atherothrombotic ..
.. ITALIC Is There a Life for DES After
Risk and Ischemic Stabilization, .. Discontinuation of Clopidogrel
Management, and Avoidance
..
.. IVUS XPL Impact of Intravascular Ultrasound
CI Confidence interval .. Guidance on Outcomes of XIENCE
COGENT Clopidogrel and the Optimization of
..
.. PRIME Stents in Long Lesions
Gastrointestinal Events Trial .. LATE Late coronary Arterial Thrombotic Events
CORONARY CABG Off or On Pump Revascularization
..
.. LEAD Lower-extremities artery disease
Study .. LEADERS-FREE Prospective randomized comparison of
CPG Committee for Practice Guidelines
..
.. the BioFreedom biolimus A9 drug-coated
CrCl Creatinine clearance .. stent versus the gazelle bare-metal stent
..
CREDO Clopidogrel for the Reduction of Events .. in patients at high bleeding risk
During Observation ..
.. LVEF Left ventricular ejection fraction
CRUSADE Can Rapid risk stratification of Unstable .. MACCE Major adverse cardiac and
angina patients Suppress ADverse ..
.. cerebrovascular events
outcomes with Early implementation of .. MACE Major adverse cardiovascular events
the ACC/AHA Guidelines ..
216 ESC Guidelines

..
MATRIX Minimizing Adverse Haemorrhagic Events .. SECURITY Second Generation Drug-Eluting Stent
by TRansradial Access Site and Systemic .. Implantation Followed by Six- Versus
..
Implementation of angioX .. Twelve-Month Dual Antiplatelet Therapy
MI Myocardial infarction .. STEMI ST-segment elevation myocardial
..
NACE Net adverse clinical events .. infarction
NCDR National Cardiovascular Data Registry .. STREAM STrategic Reperfusion Early After
..
NNT Number needed to treat .. Myocardial Infarction
NOAC Non-vitamin K oral anticoagulant .. SYNTAX Synergy Between Percutaneous Coronary
..
NORSTENT NORwegian coronary STENT trial .. Intervention With Taxus and Cardiac
NSTE-ACS Non-ST elevation acute coronary syndrome .. Surgery
..
NSTEMI Non-ST-segment elevation myocardial .. TIA Transient ischaemic attack
infarction .. TIMI Thrombolysis In Myocardial Infarction

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..
OAC Oral anticoagulant .. TL-PAS Taxus Liberté Post Approval Study
o.d. Omni die (once a day)
.. TRA 2 P-TIMI 50 Thrombin Receptor Antagonist in
..
OPTIMIZE Optimized Duration of Clopidogrel .. Secondary Prevention of
Therapy Following Treatment With the
.. Atherothrombotic Ischemic Events
..
Zotarolimus-Eluting Stent in Real-World .. TRACER Thrombin Receptor Antagonist for
Clinical Practice
.. Clinical Event Reduction in Acute
..
OR Odds ratio .. Coronary Syndrome
PARIS Patterns of Nonadherence to Antiplatelet
.. TRILOGY ACS Targeted Platelet Inhibition to Clarify the
..
Regimens in Stented Patients .. Optimal Strategy to Medically Manage
..
PCI Percutaneous coronary intervention .. Acute Coronary Syndromes
PEGASUS-TIMI 54 Prevention of Cardiovascular Events in .. TRITON-TIMI 38 Trial to Assess Improvement in Therapeutic
..
Patients with Prior Heart Attack Using .. Outcomes by Optimizing Platelet Inhibition
Ticagrelor Compared to Placebo on a .. with Prasugrel–Thrombolysis in Myocardial
..
Background of Aspirin–Thrombolysis in .. Infarction
Myocardial Infarction 54 .. TROPICAL-ACS Testing Responsiveness to Platelet
..
PIONEER AF-PCI Rivaroxaban and a dose- adjusted oral .. Inhibition on Chronic Antiplatelet
vitamin K antagonist treatment strategy in .. Treatment For Acute Coronary
..
subjects with atrial fibrillation who .. Syndromes Trial
undergo percutaneous coronary .. VA Veterans’ Administration
..
intervention .. VKA Vitamin K antagonist
PLATO PLATelet inhibition and patient Outcomes .. WOEST What is the Optimal antiplatElet and
..
PPI Proton pump inhibitor .. anticoagulant therapy in patients with
PRECISE-DAPT PREdicting bleeding Complications In
.. OAC and coronary StenTing
..
patients undergoing Stent implantation .. ZES Zotarolimus-eluting stent
and subsEquent Dual Anti Platelet
.. ZEUS Zotarolimus-eluting Endeavor sprint stent
..
Therapy .. in Uncertain DES Candidates
PRODIGY PROlonging Dual antiplatelet treatment
.. 24/7 24 h a day, seven days a week
..
after Grading stent-induced intimal ..
hYperplasia study
..
..
.. 1. Preamble
PROTECT Patient-Related Outcomes With Endeavor
..
vs Cypher Stenting .. Guidelines and Focused Updates written under the auspices of the
q.d. Quaque die (one a day) .. European Society of Cardiology’s (ESC) Committee for Practice
..
RCT Randomized controlled trial .. Guidelines (CPG) summarize and evaluate available evidence with
REDUAL-PCI Evaluation of Dual Therapy With .. the aim of assisting health professionals in selecting the best manage-
..
Dabigatran vs. Triple Therapy With .. ment strategies for an individual patient with a given condition. The
Warfarin in Patients With AFib That .. CPG Guidelines’ and Focused Updates’ recommendations should
..
Undergo a PCI With Stenting .. facilitate decision making of health professionals in their daily practice.
RESET Real Safety and Efficacy of 3-Month Dual .. However, the final decisions concerning an individual patient must be
..
Antiplatelet Therapy Following Endeavor .. made by the responsible health professional(s) in consultation with
Zotarolimus-Eluting Stent Implantation .. the patient and caregiver as appropriate.
..
ROOBY Veterans Affairs Randomized On/Off .. A great number of guidelines and focused updates have been
Bypass trial .. issued in recent years by the ESC and by the European
..
RR Relative risk .. Association for Cardio-Thoracic Surgery (EACTS) as well as by
RRR Relative risk reduction .. other societies and organizations. Because of the impact on
ESC Guidelines 217

Table 1 Classes of recommendations

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clinical practice, quality criteria for the development of guidelines
Table 2 Levels of evidence
have been established in order to make all decisions transparent
to the user. The recommendations for formulating and issuing
ESC Guidelines can be found on the ESC website (http://www.
escardio.org/Guidelines-&-Education/Clinical-Practice-Guidelines/
Guidelines-development/Writing-ESC-Guidelines). ESC Guidelines
represent the official position of the ESC on a given topic and
are regularly updated.
Members of this Task Force were selected by the ESC and EACTS
to represent professionals involved with the medical care of patients
with this pathology. Selected experts in the field undertook a com-
prehensive review of the published evidence for management of a
given condition according to ESC Committee for Practice Guidelines
(CPG) policy and approved by the EACTS. A critical evaluation of
..
diagnostic and therapeutic procedures was performed, including .. experts, and in this case by EACTS-appointed experts. After appro-
assessment of the risk–benefit ratio. The level of evidence and the .. priate revisions the CPG documents are approved by all the experts
..
strength of the recommendation of particular management options .. involved in the Task Force. The finalized document is approved by
were weighed and graded according to predefined scales, as outlined .. the CPG for publication in the European Heart Journal and in the
..
in Tables 1 and 2. .. European Journal of Cardio-Thoracic Surgery. These CPG docu-
The experts of the writing and reviewing panels provided declara- .. ments were developed after careful consideration of the scientific
..
tion of interest forms for all relationships that might be perceived as .. and medical knowledge and the evidence available at the time of their
real or potential sources of conflicts of interest. These forms were
.. dating.
..
compiled into one file and can be found on the ESC website (http:// .. The task of developing this CPG Focused Update in collaboration
www.escardio.org/guidelines). Any changes in declarations of interest
.. with EACTS also includes the creation of educational tools and
..
that arise during the writing period were notified to the ESC and .. implementation programmes for the recommendations including
updated. The Task Force received its entire financial support from
.. condensed pocket guideline versions, summary slides, and an elec-
..
the ESC without any involvement from the healthcare industry. .. tronic version for digital applications (smartphones, etc.) as well as
The ESC CPG supervises and coordinates the preparation of new
.. other educational tools depending on the topic. These versions are
..
Guidelines and of its Focused Updates. The Committee is also .. abridged and thus, if needed, one should always refer to the full text
..
responsible for the endorsement process of these documents. These .. version, which is freely available via the ESC website and hosted on
CPG documents undergo extensive review by the CPG and external .. the EHJ website. The National Societies of the ESC are encouraged
218 ESC Guidelines

..
to endorse, translate and implement all ESC Guidelines. .. 2. Introduction
Implementation programmes are needed because it has been shown
..
..
that the outcome of disease may be favourably influenced by the .. The estimated number of patients requiring dual antiplatelet therapy
thorough application of clinical recommendations.
.. (DAPT), consisting of the combination of aspirin and an oral inhibitor
..
Surveys and registries are needed to verify that real-life daily prac- .. of the platelet P2Y12 receptor for adenosine 5’-diphosphate (ADP), is
.. considerable and has increased over time in Europe. Based on popu-
tice is in keeping with what is recommended in the guidelines, thus ..
completing the loop between clinical research, writing of guidelines .. lation estimates from 2015, in the region of 1 400 000 and 2 200 000
.. patients per year may have an indication for DAPT after coronary
and official focused updates, disseminating them and implementing ..
them into clinical practice. .. intervention or myocardial infarction (MI), respectively.1
.. This year, 2017, is the 21st anniversary of the publication of the
Health professionals are encouraged to take the ESC CPG ..
Guidelines and Focused Updates developed in collaboration with .. first randomized clinical trial to establish the superiority of DAPT
..
EACTS fully into account when exercising their clinical judgment, as .. over anticoagulant therapy among patients undergoing percutaneous

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well as in the determination and the implementation of preventive, .. coronary intervention (PCI) (Figure 1).2 Based on over 35 random-
..
diagnostic or therapeutic medical strategies. However, the CPG .. ized clinical trials, including more than 225 000 patients, DAPT is
documents do not override in any way whatsoever the individual .. among the most intensively investigated treatment options in the field
..
responsibility of health professionals to make appropriate and accu- .. of cardiovascular medicine. Along with progressive refinement of
rate decisions in consideration of each patient’s health condition and .. P2Y12 inhibition strategies—embracing firstly safer (from ticlopidine
..
in consultation with that patient or the patient’s caregiver where .. to clopidogrel) and then more potent and predictable (from clopi-
appropriate and/or necessary. It is also the health professional’s .. dogrel to ticagrelor or prasugrel) drugs—research has concomitantly
..
responsibility to verify the rules and regulations applicable to drugs .. focused on optimal treatment duration. The need to investigate lon-
and devices at the time of prescription.
.. ger DAPT regimens firstly arose from concerns over late and very

Figure 1 History of dual antiplatelet therapy (DAPT) in patients with coronary artery disease. The size of the circles denotes sample size. The col-
ours of perimeters identify the type of included patient populations within each study. The colours within each circle identify the antiplatelet agent(s)
investigated. Head-to-head studies comparing similar durations of two different antiplatelet strategies are shown with a vertical line, whereas those
investigating different treatment durations are shown with a horizontal line. Studies investigating different treatment strategies or regimens and not
treatment durations or type (e.g. pre-treatment in ACCOAST, tailored therapy in GRAVITAS, double dose of clopidogrel in CURRENT OASIS 7,
etc.) are represented with a single colour indicating the P2Y12 inhibitor, which was tested on top of aspirin.
pts = patients.
ESC Guidelines 219

..
late stent thrombosis occurring after first-generation drug-eluting .. Nonetheless, because continued antiplatelet therapy is also associ-
stent (DES) implantation.3 Yet, the advent of safer newer-generation .. ated with increased bleeding risk, it is necessary to weigh this risk
..
DESs and the results of the most recent randomized controlled trials .. against the potential benefit. Current evidence suggests that the risk
(RCTs) have established a major paradigm shift in the way DAPT .. of bleeding in patients on DAPT is proportionally related to its dura-
..
should be conceived and used in clinical practice. DAPT remains a .. tion both within and beyond 1 year of treatment duration. Since the
highly effective preventive treatment for stent thrombosis across the .. benefits of prolonged DAPT, especially for mortality endpoints,
..
board; however, the risks of late and (even more) very late stent .. appear highly dependent on prior cardiovascular history [such as
thrombosis have declined considerably since the advent of newer- .. prior acute coronary syndrome (ACS)/MI vs. stable CAD], and pre-
..
generation DESs. Hence, the risk of bleeding associated with DAPT .. diction models to estimate on-DAPT bleeding risk have been devel-
prolongation beyond 1 year does not seem to be justified by the small .. oped, an individualized approach based on ischaemic vs. bleeding risk
..
absolute benefit observed in terms of very late stent thrombosis pre- .. assessment is warranted.
vention. On the other hand, there is emerging evidence that DAPT ..
..

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reduces the long-term risk of non-stent-related MI as well as stroke. .. 3.1 Dual antiplatelet therapy for the
..
Hence, after 21 years of research, DAPT has moved from a local (i.e. .. prevention of stent thrombosis
stent-related) to a systemic treatment strategy (i.e. capable of pre- .. See Web Addenda.
venting thrombotic arterial vessel occlusion), conveying global
..
..
patient protection (Figure 1). .. 3.2 Dual antiplatelet therapy for the
There is, however, confusion in the community around the optimal
..
.. prevention of spontaneous myocardial
type and duration of DAPT in patients with established coronary ..
artery disease (CAD), undergoing coronary revascularization or
.. infarction
.. See Web Addenda.
not.4 This derives from apparently conflicting results arising from the ..
..
available studies and limited evidence on various patient subsets (e.g. ..
elderly patients, with comorbidities or at greater bleeding risk) in .. 3.3 Dual antiplatelet therapy and
.. mortality rate
whom the trade-off between the benefits and risks of DAPT may dif- ..
fer from those observed in more selected patient cohorts included in .. See Web Addenda.
..
trials. Therefore, the scope of this focused update is to address rec- ..
ommendations on DAPT in patients with CAD. .. 3.4 Safety of dual antiplatelet therapy
.. See Web Addenda.
..
2.1 Short- and long-term outcomes after ...
.. 3.5 Risk stratification tools for ischaemia
percutaneous coronary intervention ..
See Web Addenda. .. and bleeding risks
.. Given the trade-off between ischaemic vs. bleeding risks for any given
..
2.2 Risk of stent thrombosis in relation to ... DAPT duration, the use of scores might prove useful to tailor DAPT
.. duration in order to maximize ischaemic protection and minimize
stent type .. bleeding risks in the individual patient.6 Most of the frequently used
See Web Addenda. ..
.. risk scores for assessing ischaemic events7–9 and major bleeds10–12
.. were originally developed and validated for the prediction of events
2.3 Short- and long-term outcomes after .... occurring mainly during hospital stay or early on thereafter.13,14 As a
coronary artery bypass surgery .. result, the application of these risk scores to decide upon DAPT
..
See Web Addenda. .. duration remains problematic, as only limited data exist exploring
..
.. their value to guide DAPT duration.13 On the other hand, the use of
2.4 Short- and long-term outcomes after ... risk scores that were specifically designed to guide and inform deci-
medically managed acute coronary .. sion making on DAPT duration should be prioritized over other avail-
..
syndrome .. able risk scores (Table 3).
.. The DAPT score was developed from 11 648 patients enrolled in
See Web Addenda. ..
.. the DAPT trial and was initially validated in 8136 patients enrolled in
.. the Patient-Related Outcomes With Endeavor vs. Cypher Stenting
..
.. (PROTECT) trial.15 This prediction rule identified nine factors [age,
3. Efficacy and safety of dual .. congestive heart failure/low left ventricular ejection fraction (LVEF),
..
antiplatelet therapy and risk .. vein graft stenting, MI at presentation, prior MI or PCI, diabetes, stent
..
stratification tools .. diameter <3 mm, smoking, and paclitaxel-eluting stent] resulting in a
.. score ranging from -2 to þ 10. Within the DAPT trial, a high-risk
Current evidence suggests that DAPT mitigates the risk of stent ... score (i.e. a score >_2) selected patients who showed a reduction in
thrombosis across the whole spectrum, from acute to very late ... MI/stent thrombosis and cardiovascular or cerebrovascular events
events. However, treatment with DAPT beyond 1 year after MI, or ..
. risk [number needed to treat (NNT) for benefit for ischaemic event
after PCI, exerts the majority of its benefit by reducing the rate of ..
. reduction = 34] after a prolonged, 30-month DAPT, with only a
spontaneous MI, which is associated with mortality rates of 15%. 5 .. modest increase in bleeding risk (NNT for harm = 272). In turn, a
220 ESC Guidelines

Table 3 Risk scores validated for dual antiplatelet therapy duration decision-making

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CHF = congestive heart failure; CrCl = creatinine clearance; DAPT = dual antiplatelet therapy; Hb = haemoglobin; LVEF = left ventricular ejection fraction; MI = myocardial
infarction; PCI = percutaneous coronary intervention; PRECISE-DAPT = PREdicting bleeding Complications In patients undergoing Stent implantation and subsEquent Dual
Anti Platelet Therapy; WBC = white blood cell count.
a
For the PRECISE-DAPT score use the score nomogram: mark patient’s value for each of the five clinical variables of the score and draw a vertical line to the ‘Point’ axis to
determine the number of points obtained for each clinical variable. Then summate the points obtained for each clinical variable to the total score. A practical case example for
score calculation is provided in Web Figure 1 of the Web Addenda.
For the DAPT score summate positive points for each value and subtract values for age to the total score.

low-risk score (<2) selected patients recruited in the DAPT trial who
.. scores for DAPT type or duration guidance. A high ischaemic risk sta-
..
did not derive any reduction of ischaemic events from prolonging .. tus was observed in roughly 40% of high bleeding risk patients16 and
DAPT, with a significant increase in moderate/major bleeding (NNT
.. as many as 65.3% presented low ischaemic and bleeding risks.16
..
for harm = 64). As DAPT duration was not randomized in the .. Therefore, it remains unclear how DAPT duration should be guided
PROTECT trial, the value of the DAPT score in guiding the duration
.. by the simultaneous assessment of ischaemic and bleeding risk fea-
..
of therapy has so far only been shown for patients recruited to the .. tures according to PARIS.
DAPT trial. Additional validation of the DAPT score to guide DAPT
.. The PRECISE-DAPT (PREdicting bleeding Complications In
..
duration is needed, especially in the context of less well-selected .. patients undergoing Stent implantation and subsEquent Dual Anti
..
patients as compared to those recruited in the DAPT trial and under- .. Platelet Therapy) collaborative study included a total of 14 963
going treatment with new-generation DES only. .. patients with CAD who underwent elective, urgent, or emergent PCI
..
Two independent predictive scores for bleeding [age, body mass .. and generated a five-item (age, CrCl, haemoglobin, white blood cell
index, smoking, anaemia, creatinine clearance (CrCl), and triple ther- .. count, and prior spontaneous bleeding) prediction algorithm for out-
..
of-hospital bleeding in patients treated with DAPT.18
apy at discharge] and MI or stent thrombosis [diabetes mellitus, ACS,
...
smoking, CrCl, prior PCI, and prior coronary artery bypass graft sur- .. The predictive performance of this novel score was assessed in the
gery (CABG)] have also been developed from the Patterns of .. derivation cohort and validated in 8595 and 6172 patients treated with
..
Nonadherence to Antiplatelet Regimens in Stented Patients (PARIS) .. PCI from the PLATelet inhibition and patient Outcomes (PLATO) trial
registry.16 PARIS was a prospective, multicentre, observational study .. and the Bern PCI registry,19,20 respectively. The PRECISE-DAPT score
..
of patients undergoing PCI with stent implantation in the USA and .. showed improved integrated discrimination and reclassification per-
Europe, which was designed to examine the different modes of .. formance as compared to the PARIS bleeding score in both validation
..
DAPT cessation and to investigate the influence of these modes on .. cohorts.18 The usefulness of this score was also assessed within
subsequent clinical adverse events.17 This registry study included .. patients randomized to different DAPT durations (n = 10 081) to iden-
..
patients with an indication for oral anticoagulation. The value of the .. tify the effect on bleeding and ischaemia of a long (12–24 months) or
PARIS bleeding and/or ischaemic risk scores to tailor DAPT duration
.. short (3–6 months) treatment duration in relation to baseline bleeding
..
remains unclear, since therapy duration was not randomized in the .. risk. It was observed that among patients deemed at high bleeding risk
PARIS study and no study to date has applied the results of these
.. based on PRECISE-DAPT (PRECISE-DAPT score >_25), prolonged
ESC Guidelines 221

..
DAPT was associated with no ischaemic benefit but a remarkable .. to 7.1%; relative risk reduction (RRR) 23.9%, 95% CI 12.7–33.7; P <
bleeding burden leading to an NNT for harm of 38.18 On the other .. 0.001).23 There was no difference in the rates of either non-fatal
..
hand, longer treatment in patients without high bleeding risk .. stroke or cardiovascular death.
(PRECISE-DAPT score <25) was associated with no increase in bleed- .. Prasugrel was associated with a significant increase in the rate of
..
ing and a significant reduction in the composite ischaemic endpoint of .. non-CABG-related TIMI major bleeding (2.4% vs. 1.8%; HR 1.32, 95%
MI, definite stent thrombosis, stroke, and target vessel revasculariza- .. CI 1.03–1.68; P = 0.03). Life-threatening bleeding was significantly
..
tion, with an NNT for benefit of 65.18 Selecting a shorter than 12- .. increased under prasugrel compared with clopidogrel (1.4% vs. 0.9%;
month treatment duration in patients deemed at high bleeding risk .. HR 1.52, 95% CI 1.08–2.13; P = 0.01), as was fatal bleeding (0.4% vs.
..
upfront may therefore prevent their exposure to an excessive bleeding .. 0.1%, HR 4.19, 95% CI 1.58–11.11; P = 0.002). CABG-related bleed-
hazard. In turn, patients at non-high bleeding risk might receive a stand- .. ing was also higher in prasugrel-treated patients (13.4% vs. 3.2%; HR
..
ard (i.e. 12 months) or prolonged (i.e. >12 months) course of treat- .. 4.72, 95% CI 1.90–11.82; P < 0.001). There was evidence of net harm
ment if tolerated. .. with prasugrel in patients with a history of cerebrovascular events. In
..

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However, none of these risk prediction models have been pro- .. addition, there was no apparent net clinical benefit in patients
spectively tested in the setting of RCTs. Therefore, their value in .. >_75 years of age and in patients with low body weight (<60 kg).23
..
improving patient outcomes remains unclear. .. Prasugrel was not tested in medically managed ACS patients in the
.. setting of the TRITON-TIMI 38 study. In the Targeted Platelet
..
Use of risk scores as guidance for the duration of dual
.. Inhibition to Clarify the Optimal Strategy to Medically Manage Acute
.. Coronary Syndromes (TRILOGY ACS) study, which exclusively
antiplatelet therapy ..
.. included medically managed ACS patients, the primary endpoint of
.. death from cardiovascular causes, MI, or stroke among patients
Recommendations Classa Levelb ..
.. under the age of 75 years occurred in 13.9% of the prasugrel group
The use of risk scores designed to evaluate
..
.. and 16.0% of the clopidogrel group (HR 0.91, 95% CI 0.79–1.05; P =
the benefits and risks of different DAPT IIb A .. 0.21), at a median follow-up of 17 months.24 Similar results were
durationsc may be considered.15,18
..
.. observed in the overall population (i.e. also including elderly patients).
.. Hence, prasugrel is not indicated in medically managed ACS patients.
..
DAPT = dual antiplatelet therapy. .. The TRITON-TIMI 38 study mandated the use of prasugrel or clo-
a
Class of recommendation. .. pidogrel after coronary angiography if an indication to proceed to
b
Level of evidence. ..
c
The DAPT and PRECISE-DAPT scores are those currently fulfilling these .. PCI was established. Pre-treatment was allowed only in STEMI
requirements.
.. patients undergoing primary intervention (n = 2438).
..
.. For the comparison of prasugrel at the time of PCI, in the A
.. Comparison of Prasugrel at the Time of Percutaneous Coronary
..
.. Intervention Or as Pretreatment At the Time of Diagnosis in Patients
3.6 Type of P2Y12 inhibitor and timing of .. with Non-ST-Elevation Myocardial Infarction (ACCOAST), 4033
..
initiation .. patients with non-STEMI (NSTEMI) who were scheduled to undergo
Clopidogrel: Clopidogrel is associated with a better safety profile than
.. coronary angiography within 2–48 h after randomization were assigned
..
ticlopidine, mainly in terms of allergy, skin or gastrointestinal disor- .. to receive prasugrel (a 30 mg loading dose) before angiography (pre-
ders, and neutropenia, while it has a similar degree and consistency of
.. treatment group) or placebo (control group).25 When PCI was indi-
..
P2Y12 inhibition and bleeding risk.21,22 The wide variability in the .. cated, an additional 30 mg of prasugrel was given in the pre-treatment
pharmacodynamic response to ticlopidine and clopidogrel is linked
.. group at the time of PCI and 60 mg of prasugrel was given in the control
..
to several factors, including genotype polymorphisms.22 Clinical evi- .. group. The rate of the primary efficacy endpoint, a composite of death
.. from cardiovascular causes, MI, stroke, urgent revascularization, or gly-
dence with respect to the optimal duration of clopidogrel therapy ..
after PCI is discussed elsewhere (Chapter 4). .. coprotein IIb/IIIa inhibitor rescue therapy (glycoprotein IIb/IIIa bailout)
.. through day 7, did not differ significantly between the two groups (HR
Prasugrel: Prasugrel achieves a faster, greater, and more consistent ..
degree of P2Y12 inhibition as compared to clopidogrel. Prasugrel .. with pre-treatment 1.02, 95% CI 0.84–1.25; P = 0.81).25 The rate of the
..
requires two metabolic steps for formation of its active metabolite, .. key safety endpoint of all TIMI major bleeding episodes, whether related
which is chemically similar to the active metabolite of clopidogrel. .. to CABG or not, through day 7 was increased with pre-treatment (HR
..
The Trial to Assess Improvement in Therapeutic Outcomes by .. 1.90, 95% CI 1.19–3.02; P = 0.006). The rates of TIMI major bleeding
Optimizing Platelet Inhibition with Prasugrel–Thrombolysis in .. and life-threatening bleeding not related to CABG were increased by a
..
Myocardial Infarction (TRITON-TIMI 38) included P2Y12 inhibitor- .. factor of 3 and 6, respectively. Pre-treatment did not reduce the rate of
naı̈ve ACS patients in whom coronary anatomy was deemed suitable .. the primary outcome among patients undergoing PCI (69% of the
..
for PCI, or patients with ST-segment elevation myocardial infarction .. patients) but increased the rate of TIMI major bleeding at 7 days.25
(STEMI) referred for primary PCI.23 Duration of DAPT was up to .. Hence, prasugrel is not indicated in patients with ACS in whom cor-
..
15 months in both study arms. The composite primary endpoint (car- .. onary anatomy is not known and an indication for PCI is not clearly
diovascular death, non-fatal MI, or stroke) occurred in 9.3% of .. established, with the exception of STEMI patients scheduled to undergo
..
prasugrel-treated patients vs. 11.2% of clopidogrel-treated patients .. immediate coronary catheterization and PCI, if clinically indicated.
[hazard ratio (HR) 0.82, 95% confidence interval (CI) 0.73–0.93; P =
.. In the DAPT trial, 3461 patients (34.7% of the total trial population)
..
0.002], mostly driven by a significant risk reduction for MI [from 9.2% . who were treated with prasugrel within the first 12 months after
222 ESC Guidelines

..
intervention were randomly allocated to stop or continue the treat- .. There was no difference in the overall rates of fatal haemorrhage
ment for an additional 18 months.26 The type of P2Y12 inhibitor or stent .. between the groups (0.3% in both groups). The superiority of ticagre-
..
type were not randomized for. However, the largest cohort of prasu- .. lor over clopidogrel with respect to the primary study endpoint as
grel-treated patients (n = 2191) was provided by the TAXUS Liberté .. well as cardiovascular death or overall mortality was consistent across
..
Post Approval Study (TL-PAS), which was a prospective, multicentre, .. management strategies, i.e. patients undergoing PCI, those medically
open-label study developed to review the clinical performance of the .. managed, and patients who underwent CABG.20
..
Taxus Liberté paclitaxel-eluting stent in routine clinical practice in the .. No dedicated study exists assessing the value of early (i.e. before
USA.27 Enrolled TL-PAS patients received open-label prasugrel plus .. coronary angiography) vs. delayed (i.e. after coronary angiography)
..
aspirin for 12 months after stent placement; enrolment was not .. ticagrelor administration in patients with NSTE-ACS. The
restricted to patients presenting with ACS (i.e. those with an approved .. Administration of Ticagrelor in the Cath Lab or in the Ambulance for
..
indication for prasugrel). Rates of death and stroke were similar .. New ST Elevation Myocardial Infarction to Open the Coronary Artery
between groups, but MI was significantly reduced with prolonged prasu- .. (ATLANTIC) study involved 1862 patients with STEMI <6-h duration
..

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grel treatment (1.9% vs. 7.1%; HR 0.255; P < 0.001). The DAPT co- .. and compared pre-hospital (in the ambulance) vs. in-hospital (in the
primary endpoint, stent thrombosis, was also lower with longer therapy .. catheterization laboratory) treatment with ticagrelor.28 The co-
..
(0.2% vs. 2.9%; HR 0.063; P < 0.001). The safety endpoint of GUSTO .. primary endpoints were the proportion of patients who did not have
(Global Use of Strategies to Open Occluded Coronary Arteries) mod-
.. >_70% resolution of ST-segment elevation before PCI and the propor-
..
erate or severe bleeding was numerically increased in the patients con- .. tion of patients who did not have TIMI flow grade 3 in the infarct-
tinuing prasugrel to 30 months, although the difference was not
.. related artery at initial angiography. Secondary endpoints included the
..
statistically significant (2.4% vs. 1.7%; HR 1.438; P = 0.234).27 No sub- .. rates of major adverse cardiovascular events (MACE) and definite
group data have been provided among patients treated with prasugrel
.. stent thrombosis at 30 days. The median time difference between the
..
with respect to indication for PCI (i.e. ACS vs. stable CAD) or type of .. two treatment strategies was 31 min. The two co-primary endpoints
..
implanted stent (i.e. paclitaxel-eluting stent vs. other stent types). .. did not differ significantly between the pre-hospital and in-hospital
Ticagrelor: Ticagrelor belongs to a novel chemical class, cyclopentyl .. groups. The rates of definite stent thrombosis were lower in the pre-
..
triazolopyrimidine, and is a direct oral, reversibly binding P2Y12 inhibi- .. hospital group than in the in-hospital group (0% vs. 0.8%, P = 0.008 in
tor with a plasma half-life of 12 h. In the PLATO trial, ticagrelor .. the first 24 h; 0.2% vs. 1.2%, P = 0.02 at 30 days). Rates of major bleed-
..
proved to be superior to clopidogrel in ACS patients, who were .. ing events were low and virtually identical in the two groups, regardless
allowed to be pre-treated with clopidogrel at hospital admission, irre- .. of the bleeding definition used.28
..
spective of the final revascularization strategy (i.e. planned or not .. The value of ticagrelor beyond 12 months of therapy in patients
planned invasive management).20 Patients with either moderate- to .. with prior ACS has been investigated in the Prevention of
..
high-risk non-ST elevation ACS (NSTE-ACS) (planned for either .. Cardiovascular Events in Patients with Prior Heart Attack Using
conservative or invasive management) or STEMI planned for primary .. Ticagrelor Compared to Placebo on a Background of
..
PCI were randomized to either clopidogrel 75 mg daily, with a loading .. Aspirin–Thrombolysis in Myocardial Infarction (PEGASUS) trial,
dose of 300 mg, or ticagrelor 180 mg loading dose followed by 90 mg .. which is described in Chapter 4.29
..
twice daily.20 Patients undergoing PCI were allowed to receive an .. P2Y12 inhibitors in STEMI patients treated with lysis: Clopidogrel is the
additional blinded 300 mg loading dose of clopidogrel (total loading .. only P2Y12 inhibitor that has been properly investigated in patients
..
dose 600 mg) or its placebo, and were also recommended to receive .. with STEMI undergoing initial treatment with thrombolysis.31,32
an additional 90 mg of ticagrelor (or its placebo) if > 24 h after the ini-
.. Clopidogrel 300 mg loading dose has been investigated only in
..
tial loading dose. Treatment was continued for up to 12 months, with .. patients <_75 years of age.31 While not specifically investigating the
a minimum intended treatment duration of 6 months and a median
.. value of clopidogrel, in the STrategic Reperfusion Early After
..
duration of study drug exposure of 9 months.20 .. Myocardial Infarction (STREAM) study, patients aged 75 or more
In the overall cohort, the primary composite efficacy endpoint
.. received clopidogrel treatment without loading dose (i.e. initiated at
..
(death from vascular causes, MI, or stroke) was observed in 9.8% of .. 75 mg q.d.) in association with half dose of lytic therapy.30 Hence, the
the patients in the ticagrelor group and in 11.7% of the patients in the
.. administration of a clopidogrel loading dose in elderly patients
..
clopidogrel group (HR 0.84, 95% CI 0.77–0.92; P < 0.001).20 .. requires a patient-by-patient decision. While prasugrel33 or ticagre-
..
According to the pre-defined statistical analysis plan, death from vas- .. lor20 were allowed as per protocol in patients with prior treatment
cular causes was significantly reduced from 5.1% to 4.0% (HR 0.79, .. with lysis in P2Y12 inhibitor-naı̈ve patients or those with prior clopi-
..
95% CI 0.69–0.91; P = 0.001), and from MI from 6.9% to 5.8% (HR .. dogrel administration, respectively, there are insufficient safety data to
0.84, 95% CI 0.75–0.95; P = 0.005). There was no significant difference .. recommend their concomitant use during or soon after thrombolysis.
..
in the rates of stroke (1.3% vs. 1.5%; P = 0.22). The rate of definite .. Timing of initiation of P2Y12 inhibitor: The evidence (and lack thereof)
stent thrombosis was reduced from 1.9% to 1.3% (P < 0.01) and total .. on optimal timing for the initiation of P2Y12 inhibitors has been
..
mortality from 5.9% to 4.5% (P < 0.001). Overall, there was no signifi- .. extensively discussed in previous guidelines34 and reviewed else-
cant difference in PLATO-defined major bleeding rates between the .. where.35,36 A reasonable approach is to start treatment with a P2Y12
..
clopidogrel and ticagrelor groups (11.2% vs. 11.6%, respectively; P = .. inhibitor based on the timing with which the drug was investigated in
0.43). Major bleeding unrelated to CABG was increased from 3.8% in .. approval studies (i.e. start as soon as possible and deemed safe for
..
the clopidogrel group to 4.5% in the ticagrelor group (HR 1.19, 95% .. clopidogrel and ticagrelor or after the indication for PCI is established
CI 1.02–1.38; P = 0.03). Major bleeding related to CABG was similar .. based on coronary anatomy for prasugrel). The decision to withhold
..
with ticagrelor and clopidogrel (7.4% vs. 7.9%, respectively; P = 0.32). . early administration of P2Y12 inhibitors may also depend on planned
ESC Guidelines 223

use of cangrelor in the catheterization laboratory, which ensures ..


.. 3.7 Measures to minimize bleeding while
immediate inhibition of the target receptor in oral P2Y12 inhibitor- .. on dual antiplatelet therapy
naı̈ve patients. Timing of administration of P2Y12 inhibitors in patients ..
.. Bleeding events after successful PCI are independently associated
receiving cangrelor infusion at the time of PCI should be drug-spe- .. with increased mortality and morbidity and this association is likely
cific.37 While ticagrelor can be given any time before, during or at the ..
.. causal.41,42 Therefore, every effort should be made to minimize
end of cangrelor infusion, it is recommended that clopidogrel or pra- .. bleeding. Individualization of therapy is a key measure and includes
sugrel is given at the time of cangrelor infusion discontinuation (or
..
.. the identification of risk factors for bleeding, radial access site, dosing
within 30 minutes before the end of infusion in the case of prasugrel ..
administration).37 However, the comparative efficacy and safety of
.. of therapies, use of proton pump inhibitors (PPIs), and appropriate
.. selection of P2Y12 inhibitors.
routine early oral P2Y12 inhibitor administration vs. the use of cangre- ..
lor in the catheterization laboratory in patients with ACS undergoing
.. Vascular access site: The Minimizing Adverse Haemorrhagic Events
.. by Transradial Access Site and Systemic Implementation of angioX
invasive management deserves further investigation. If coronary anat- ..

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omy is known or the probability of PCI is high (such as for STEMI
.. (MATRIX) trial is the most contemporary and largest trial on access
.. site selection where 8404 ACS patients were randomly allocated to
patients), there is evidence and general consensus that early adminis- ..
.. radial or femoral access.43 The first co-primary outcome of 30-day
tration of oral P2Y12 inhibitors outweighs any potential risks. On the .. MACE—defined as death, MI, or stroke—occurred in 8.8% of patients
other hand, there are no convincing data that the benefits of early ..
.. with radial access and 10.3% of patients with femoral access [relative
administration of a P2Y12 inhibitor outweigh the possible risks in sta- .. risk (RR) 0.85, 95% CI 0.74–0.99; two-sided P = 0.031; formally non-
ble CAD patients undergoing diagnostic angiography. ..
. significant at the pre-specified a of 0.025]. The second co-primary

Recommendations on P2Y12 inhibitor selection and timing

Recommendations Classa Levelb

In patients with ACS, ticagrelor (180 mg loading dose, 90 mg twice daily) on top of aspirinc is recommended, regardless
of initial treatment strategy, including patients pre-treated with clopidogrel (which should be discontinued when ticagre- I B
lor is commenced) unless there are contraindications.20

In patients with ACS undergoing PCI, prasugrel (60 mg loading dose, 10 mg daily dose) on top of aspirin is recom-
mended for P2Y12 inhibitor-naı̈ve patients with NSTE-ACS or initially conservatively managed STEMI if indication for
I B
PCI is established, or in STEMI patients undergoing immediate coronary catheterizationc unless there is a high risk of
life-threatening bleeding or other contraindications.23

Pre-treatment with a P2Y12 inhibitor is generally recommended in patients in whom coronary anatomy is known and
I A
the decision to proceed to PCI is made as well as in patients with STEMI.20,23,38

In patients with NSTE-ACS undergoing invasive management, ticagrelor administration (180 mg loading dose, 90 mg
twice daily), or clopidogrel (600 mg loading dose, 75 mg daily dose) if ticagrelor is not an option, should be considered IIa C
as soon as the diagnosis is established.

In patients with stable CAD, pre-treatment with clopidogrel may be considered if the probability of PCI is high. IIb C

Clopidogrel (600 mg loading dose, 75 mg daily dose) on top of aspirin is recommended in stable CAD patients under-
going coronary stent implantation and in ACS patients who cannot receive ticagrelor or prasugrel, including those with I A
prior intracranial bleeding or indication for OAC.20,23,39,40

Clopidogrel (300 mg loading dose in patients aged <_75, 75 mg daily dose) is recommended on top of aspirin in STEMI
I A
patients receiving thrombolysis.31,32

Ticagrelor or prasugrel on top of aspirin may be considered instead of clopidogrel in stable CAD patients undergoing
PCI, taking into account the ischaemic (e.g. high SYNTAX score, prior stent thrombosis, location and number of IIb C
implanted stents) and bleeding (e.g. according to PRECISE-DAPT score) risks.

In NSTE-ACS patients in whom coronary anatomy is not known, it is not recommended to administer prasugrel.25 III B

ACS = acute coronary syndrome; CAD = coronary artery disease; DAPT = dual antiplatelet therapy; NSTE-ACS = non-ST-elevation acute coronary syndrome; OAC = oral
anticoagulant; PCI = percutaneous coronary intervention; PRECISE-DAPT = PREdicting bleeding Complications In patients undergoing Stent implantation and subsEquent Dual
Anti Platelet Therapy; STEMI = ST-elevation myocardial infarction; SYNTAX = Synergy Between Percutaneous Coronary Intervention With Taxus and Cardiac Surgery.
a
Class of recommendation.
b
Level of evidence.
c
Contraindications for ticagrelor: previous intracranial haemorrhage or ongoing bleeds. Contraindications for prasugrel: previous intracranial haemorrhage, previous ischaemic
stroke or transient ischaemic attack, or ongoing bleeds; prasugrel is not recommended for patients >_75 years of age or with a body weight <60 kg.
224 ESC Guidelines

..
outcome of 30-day net adverse clinical events (NACE) [MACE or .. variability in on-clopidogrel platelet reactivity can be explained by the
non-CABG BARC (Bleeding Academic Research Consortium) major .. differences in genotype.68,69
..
bleeding] was experienced in 9.8% and 11.7% of patients, respectively .. For these reasons, neither platelet function testing nor genetic testing
(RR 0.83, 95% CI 0.73–0.96; P = 0.009). Radial access was associated .. can be recommended for tailoring DAPT. It may be considered in spe-
..
with a lower risk of all-cause mortality (1.6% vs. 2.2%; RR 0.72, 95% CI .. cific situations (e.g. patients suffering from recurrent adverse events) if
0.53–0.99; P = 0.045). Major BARC 3 or 5 bleeding was significantly .. the results may change the treatment strategy. This is the case for
..
reduced in the radial group (1.6% vs. 2.3%; RR 0.67, 95% CI 0.49–0.92; .. patients undergoing CABG who are exposed to DAPT (see Chapter 5).
P = 0.013). Radial access was associated with significantly lower rates .. Proton pump inhibitors and DAPT: Gastrointestinal haemorrhage is
..
of surgical access site repair or transfusion of blood products. An .. the most common serious bleeding complication from the use of
updated meta-analysis including MATRIX found a significant reduction .. long-term antiplatelet therapy.70 RCTs have shown that PPIs reduce
..
in major bleeds; death, MI, or stroke; and in all-cause mortality associ- .. the rate of recurrent gastrointestinal bleeding in high-risk patients
ated with radial as compared to femoral access.44 .. receiving aspirin.71 Similar data exist regarding the use of famotidine,
..

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Aspirin dosing in patients treated with DAPT: Lower aspirin doses .. a histamine H2-receptor antagonist.72
(<_100 mg daily) have been consistently demonstrated to be associ- .. Clopidogrel requires metabolic transformation in the liver by CYP
..
ated with less major and total bleeding than higher doses, either .. isoenzymes (mainly CYP2C19) to elicit its antiplatelet effect. PPIs are
when used as monotherapy or when combined with the P2Y12 inhibi-
.. also metabolized by CYP enzymes, leading to a potential inhibition of
..
tor clopidogrel.45–52 This is because daily aspirin doses as low as .. CYP2C19 (mainly omeprazole and esomeprazole) translating into
30–50 mg are able to completely inactivate the platelet cyclooxyge-
.. reduced metabolic activation of clopidogrel when taken together.
..
nase-1 enzyme and inhibit thromboxane production.53,54 In addition, .. Pharmacodynamic studies demonstrated the reduction of
the efficacy of ticagrelor may be decreased in patients treated with
.. clopidogrel-induced antiplatelet effects when a PPI, mainly omepra-
..
higher aspirin doses (>_300 mg daily) vs. lower aspirin doses .. zole, was concomitantly administered.73–76 Based on drug–drug
..
(<_100 mg daily).55 Although the molecular mechanism behind this .. interaction studies, omeprazole and esomeprazole would appear to
finding is not entirely clear, it reinforces the use of low dose aspirin. .. have the highest propensity for clinically relevant interactions, lanso-
..
The optimal range of aspirin dose in patients treated with DAPT that .. prazole an intermediate probability, while pantoprazole and rabepra-
provides maximal protection from ischaemic events and minimizes .. zole have the lowest.77 However, importantly, no interaction
..
bleeding risk appears to be 75–100 mg. .. between concomitant use of PPIs and prasugrel or ticagrelor has
Platelet function testing, genetic testing, and switching of P2Y12 inhibitors: .. been observed.
..
High and low platelet reactivity on P2Y12 antagonist treatment pre- .. Only observational studies suggested an increased risk of cardio-
dicts ischaemic and bleeding risks, respectively.56 These data have led .. vascular ischaemic events when PPI therapy was administered con-
..
to the rationale for individualized antiplatelet therapy based on plate- .. comitantly with clopidogrel.78 Conversely, randomized trials and
let function monitoring to identify the patients out of the expected .. propensity score-matched studies did not support such
..
range of platelet inhibition.57 All randomized trials have failed to dem- .. concerns.76,79–81
onstrate any benefit of platelet function monitoring to adjust .. The Clopidogrel and the Optimization of Gastrointestinal Events
..
therapy.58–60 The low-risk level of the study populations, the exclu- .. Trial (COGENT) was a randomized, double-blind, double-dummy,
sive use of clopidogrel, and the P2Y12 reaction unit thresholds to .. placebo-controlled, phase III study of the efficacy and safety of a
..
define the optimal window of P2Y12 inhibition have been recognized .. fixed-dose combination of clopidogrel (75 mg) and omeprazole
as the main limitations of these trials.61–63
.. (20 mg), as compared with clopidogrel alone.79 Patients were eligible
..
The Platelet Function Monitoring to Adjust Antiplatelet Therapy in .. if they were 21 years of age or older and if the use of clopidogrel ther-
Elderly Patients Stented for an Acute Coronary Syndrome
.. apy with concomitant aspirin was anticipated for at least the next
..
(ANTARCTIC) trial has re-evaluated the concept of individualized .. 12 months, including patients presenting with an ACS or undergoing
antiplatelet therapy by selecting only ACS patients at high risk of both
.. placement of a coronary stent. Patients at high risk for gastrointestinal
..
ischaemic and bleeding events (based on age >_75 years) and more .. bleeding were excluded (i.e. those in whom the need for a PPI, an H2-
accurate thresholds in reflecting optimal P2Y12 inhibition.
.. receptor antagonist, sucralfate, or misoprostol was anticipated; with
..
Clopidogrel was replaced by prasugrel using the recommended daily .. pre-existing erosive oesophagitis or oesophageal or gastric variceal
..
dose of 5 mg for the elderly, with the possibility of adjustment up and .. disease or previous non-endoscopic gastric surgery; receipt of oral
down according to individual response. Platelet function monitoring .. anticoagulation therapy that could not be safely discontinued for the
..
performed 14 days after discharge and later if needed led to a change .. duration of the study; or recent fibrinolytic therapy). Therefore, fol-
of treatment in 45% of patients who were identified as being over- .. lowing previous evidence of benefit from a PPI or H2-receptor antag-
..
treated or undertreated by measurement of the P2Y12 inhibition .. onist in high-risk patients treated with aspirin monotherapy, the
level; however, this strategy did not improve ischaemic or safety out- .. COGENT study included patients at low risk of gastrointestinal
..
comes.64 The influence of genetic variants on the response to antipla- .. bleeding undergoing DAPT, under the rationale that the risk of gas-
telet agents, especially clopidogrel, has been well-established in .. trointestinal bleeding is higher in patients taking aspirin and clopidog-
..
patients with ACS and planned PCI.65 Rapidly-obtained genetic infor- .. rel as compared to aspirin alone. This study was prematurely
mation on the 2C19 genotype can help in reaching the optimal win- .. stopped with a total of 3761 patients instead of the planned 5000 due
..
dow of P2Y12 inhibition according to the cytochrome P450 (CYP) .. to financial reasons. The pre-specified primary gastrointestinal effi-
2C19 profile,66,67 but no randomized trial has ever demonstrated any .. cacy endpoint was the time from randomization to the first occur-
..
clinical benefit of such an approach. Moreover, only 6–12% of the . rence of a composite of upper gastrointestinal clinical events, which
ESC Guidelines 225

occurred in 1.1% of patients with omeprazole and 2.9% with placebo .. 3.8 Switching between oral P2Y
.. 12
at 180 days after randomization (HR 0.34, 95% CI 0.18–0.63; P < .. inhibitors
0.001).79 ..
.. Differences in the pharmacology of P2Y12 receptor inhibitors with
Furthermore, there was no significant increase in the risk of cardio- .. regard to their binding site, half-life, and speed of onset and offset of
vascular events with concomitant use of clopidogrel and omeprazole ..
.. action are important factors that might lead to drug interactions
(4.9%, 95% CI 3.4–6.4%, in the omeprazole group; and 5.7%, 95% CI .. when switching from one agent to another.
4.0–7.3%, in the placebo group; P = 0.98), a finding that was consistent ..
.. The transition from clopidogrel to ticagrelor is the only switch
even in high-risk subgroups and for individual endpoints. The rate of .. between P2Y inhibitors that has been investigated in a trial pow-
serious adverse events did not differ significantly between the two .. 12
.. ered for clinical endpoint, even if the study was not specifically
groups (10.1% with omeprazole and 9.4% with placebo, P = 0.48), nor ..
did the rate of overall adverse events (41.3 and 42.8%, respectively; P =
.. designed to assess the safety and efficacy of the transition from clo-
.. pidogrel to ticagrelor. In PLATO, nearly 50% of patients randomly
0.33). Diarrhoea was reported in 3.0% of patients receiving omepra- ..

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zole, as compared with 1.8% of those receiving placebo (P = 0.01).
.. allocated to receive ticagrelor had been pre-treated with clopidog-
.. rel, mostly given as a 300–600 mg loading dose.20 The efficacy and
There were no newly diagnosed cases of osteoporosis. One case of ..
peripheral neuropathy was reported in the placebo group.
.. safety of ticagrelor were not affected by previous clopidogrel expo-
.. sure.88 On the other hand, the TRITON-TIMI 38 trial mandated
No randomized data comparing use vs. non-use of PPI in patients ..
taking aspirin and prasugrel or ticagrelor exist. However, the risk of
. that previous exposure of patients to a P2Y12 receptor inhibitor
gastrointestinal bleeding is higher with DAPT in the form of prasu-
grel23 or ticagrelor82 as compared to clopidogrel. The short- and Switching between oral P2Y12 inhibitors
long-term safety profile of PPIs has been well-established.79 Impaired
magnesium absorption with PPIs has been reported only from studies Recommendations Classa Levelb
in which patients had received a PPI for at least 1 year.83
Magnesaemia monitoring is recommended at follow-up, especially In patients with ACS who were previously
for longer than 1 year of therapy. exposed to clopidogrel, switching from clopi-
Type, dose of P2Y12 inhibitor, and duration of treatment: The type and dogrel to ticagrelor is recommended early
dose of P2Y12 inhibitor are well-established according to the various set- after hospital admission at a loading dose of I B
tings of CAD. Previous intracranial haemorrhage or ongoing bleeds are 180 mg irrespective of timing and loading
common contraindications for prasugrel and ticagrelor, while prasugrel dosec of clopidogrel, unless contraindications
should be given with caution in patients >_75 years of age or with a body to ticagrelor exist.20
weight <60 kg. Patients with previous stroke or transient ischaemic
Additional switching between oral P2Y12
attack (TIA) may derive harm from prasugrel instead of clopidogrel.23
inhibitors may be considered in cases of
Prior stroke is a marker of frailty and of subsequent risk of haemorrhagic IIb C
side effects/drug intolerance according to
stroke, especially during the first year thereafter. Switching from prasu-
the proposed algorithms.
grel or ticagrelor to clopidogrel is a common practice, especially in cases
of minor bleeding or in patients with low platelet reactivity, a marker of
ACS = acute coronary syndrome.
major bleeding risk.56,84,85 There are no properly powered randomized a
Class of recommendation.
data on the long-term safety or efficacy of ‘switching’ patients treated b
Level of evidence.
c
for weeks or months with a P2Y12 inhibitor to a different P2Y12 inhibi- Contraindications for ticagrelor: previous intracranial haemorrhage or ongoing
bleeds.
tor. Therefore, this practice is generally discouraged.

Measures to minimize bleeding while on dual antiplatelet therapy

Recommendations Classa Levelb

Radial over femoral access is recommended for coronary angiography and PCI if performed by an expert radial operator.43,44 I A

In patients treated with DAPT, a daily aspirin dose of 75 - 100 mg is recommended.45–47,51,52 I A

A PPI in combination with DAPTc is recommended.70,79,80,86,87 I B

Routine platelet function testing to adjust antiplatelet therapy before or after elective stenting is not recommended.58–60 III A

DAPT = dual antiplatelet therapy; PCI = percutaneous coronary intervention; PPI proton pump inhibitor.
a
Class of recommendation.
b
Level of evidence.
c
While the evidence that a PPI does not increase the risk of cardiovascular events was generated with omeprazole, based on drug–drug interaction studies, omeprazole and
esomeprazole would appear to have the highest propensity for clinically relevant interactions, while pantoprazole and rabeprazole have the lowest.
226 ESC Guidelines

..
should be an exclusion criterion for study entry.23 While registry data .. Stenting (EXCELLENT) trial compared a 6-month DAPT [acetyl-
provide reassuring information with respect to the safety profile of .. salicylic acid (ASA) þ clopidogrel] duration with 1-year DAPT
..
switching from clopidogrel to prasugrel,89–91 no randomized data exist .. after DES.100 With 1443 patients randomized, the rates of target
in the setting of studies powered for clinical endpoint. Similarly, all .. vessel failure—defined as the composite of cardiac death, MI, or
..
other switching possibilities, including between prasugrel and tica- .. ischaemia-driven target vessel revascularization—at 12 months
grelor or from ticagrelor/prasugrel to clopidogrel, have not been .. were 4.8% in the 6-month DAPT group and 4.3% in the 12-month
..
investigated with outcome data.92–94 This practice is therefore dis- .. DAPT group (P = 0.001 for non-inferiority). There was a numeri-
couraged due to a lack of safety/efficacy data. As the need to switch .. cally lower risk of bleeding in the short DAPT arm (HR 0.50, 95%
..
between P2Y12 inhibitors may arise for clinical reasons (i.e. side .. CI 0.09–2.73). There was no signal of heterogeneity for the pri-
effects or drug intolerance), and registry data indicate that switch- .. mary study endpoint with respect to clinical presentation (i.e. sta-
..
ing is not infrequent in practice, switching algorithms based on .. ble CAD, n = 699 patients vs. ACS, n = 744 patients). The
pharmacodynamic studies are provided (Figure 2). .. PROlonging Dual antiplatelet treatment after Grading stent-
..

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.. induced intimal hYperplasia (PRODIGY) trial randomized 2013
.. patients101 to 6 or 24 months of DAPT (ASA þ clopidogrel) and
..
4. Dual antiplatelet therapy and ..
..
to one of four stent types (a four-by-two factorial design), includ-
.. ing BMS and three different DES types. The 2-year incidence of all-
percutaneous coronary .. cause death, MI, and stroke or cerebrovascular accident was
intervention .. 10.1% with 24-month DAPT compared with 10.0% with 6-month
..
.. DAPT (P = 0.91). There was a lower risk of major bleeding with
An overview of all studies investigating the benefits and risks .. shorter DAPT based on both the BARC (1.9% vs. 3.4%; HR 0.56,
of DAPT duration beyond 1 month, largely focusing on post-
..
.. 95% CI 0.32–0.98; P = 0.037) or the TIMI scale (0.6% vs. 1.6%; HR
PCI patients or those with prior ACS, is shown in Web addenda ..
Table S1 (A and B). An overview of recommendations endorsed
.. 0.38, 95% CI 0.15–0.97; P = 0.041). After censoring events that
.. occurred after 12 months, while keeping the original randomiza-
by these guidelines regarding DAPT duration after PCI, as well as ..
after CABG or in medically managed ACS patients, is provided in
.. tion design, the risk of TIMI major bleeding was 0.5% in the short-
.. term DAPT arm vs. 0.9% in the long-term DAPT arm (HR 0.56,
Figure 3. ..
.. 95% CI 0.19–1.66). In this trial, a total of 1465 (74.3%) patients
.. presented with ACS whereas 505 (25.7%) had stable CAD.99 No
4.1 Dual antiplatelet therapy after ..
.. heterogeneity was noted with respect to the primary efficacy end-
percutaneous coronary intervention for .. point. There was a borderline quantitative interaction between
..
stable coronary artery disease .. clinical presentations and bleeding outcomes (P values for interac-
DAPT is not indicated in purely medically managed patients (i.e. with- .. tion = 0.056 for BARC 2, 3, or 5; P = 0.091 for BARC 3 or 5), sug-
..
out prior PCI) with stable CAD and no history of prior MI. The .. gesting a higher hazard of bleeding in the 24-month DAPT arm
Clopidogrel for High Atherothrombotic Risk and Ischemic
.. when compared with the 6-month arm in the stable CAD patients,
..
Stabilization, Management, and Avoidance (CHARISMA) study .. which was not observed in the ACS patients.99 Analysis of
included patients with stable vascular disease or at risk of athero-
.. NACE—consisting of death, MI, cerebrovascular accident, or
..
thrombotic events, and showed that clopidogrel plus aspirin was not .. BARC 2, 3, or 5 bleeding—revealed significant harm from
significantly more effective than aspirin alone in reducing the rate of
.. extended DAPT in stable CAD patients (NACE in the 24-month
..
MI, stroke, or death from cardiovascular causes.95 .. vs. 6-month DAPT arm: 13.3% vs. 5.6%; HR 2.5, 95% CI 1.35–4.69,
After PCI with stent placement, DAPT is the standard of care. The
.. P = 0.004; NNT for harm = 13) and no benefit in the ACS popula-
..
Intracoronary Stenting and Antithrombotic Regimen (ISAR) trial2 and, .. tion (16.1% vs. 14.1%; HR 1.15, 95% CI 0.88–1.50; P = 0.29), with
..
subsequently, other studies96,97 established the 1-month course of .. positive quantitative interaction testing (P value for interaction =
DAPT after bare-metal stent (BMS). An arbitrary 12-month or more .. 0.024).99 Patients with high CRUSADE (Can Rapid risk stratifica-
.. tion of Unstable angina patients Suppress ADverse outcomes with
DAPT duration has been subsequently recommended based on expert ..
opinions after first generation DES, irrespective of clinical presentation. .. Early implementation of the ACC/AHA Guidelines) bleeding risk
..
No dedicated study exists focusing on stable CAD patients under- .. score treated with 24-month DAPT experienced a threefold
going PCI and being exposed to different DAPT durations. Hence, .. higher risk of major bleeding and a fivefold risk of red blood cell
..
recommendations regarding stable CAD patients undergoing PCI .. transfusion as compared with 6-month therapy, without clear evi-
derive from subgroup analyses from pertinent RCTs (Figure 4).98,99 .. dence of benefit.13
..
While no RCTs investigating the use of ticagrelor or prasugrel .. In 2014, three additional randomized studies were published
instead of clopidogrel in stable CAD patients undergoing PCI exist, this .. that compared 6 months of DAPT to 12 or 24 months of DAPT
..
treatment option may be considered in selected patients in whom the .. (ASA þ clopidogrel): Is There a Life for DES After
use of clopidogrel is unsatisfactory based on prior clinical outcomes or .. Discontinuation of Clopidogrel (ITALIC),102 Second Generation
..
potentially associated with higher risk of ischaemic events that bleeding .. Drug-Eluting Stent Implantation Followed by Six- Versus Twelve-
recurrences.
.. Month Dual Antiplatelet Therapy (SECURITY),103 and
..
Three- or 6- vs. at least 12-month DAPT duration: The Efficacy of .. Intracoronary Stenting and Antithrombotic Regimen: Safety and
Xience/Promus Versus Cypher to Reduce Late Loss After
.. Efficacy of 6 Months Dual Antiplatelet Therapy After Drug-Eluting
ESC Guidelines 227

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Ticagrelor MD (90 mg b.i.d.)
24h after last Prasugrel dose

Figure 2 Algorithm for switching between oral P2Y12 inhibitors in the acute and chronic setting. LD = loading dose; MD = maintenance dose.
Colour-coding refers to the ESC Classes of Recommendations (green = Class I; orange = Class IIb). The green arrow from clopidogrel to ticagrelor
highlights the only switching algorithm for which outcome data are available in patients with acute coronary syndrome. No outcome data (orange
arrows) are available for all other switching algorithms. Acute setting is considered as a switching occurring during hospitalization.

..
Stenting (ISAR-SAFE).104 ISAR-SAFE was the largest of these three .. patients with ACS.104 Consistent results were shown in the
studies, with 4005 randomized patients, and the only double-blind .. ITALIC and SECURITY trials. Two studies, Real Safety and Efficacy
..
investigation. It confirmed that a 12-month course of DAPT did .. of 3-Month Dual Antiplatelet Therapy Following Endeavor
not afford any benefit over a 6-month course with respect to .. Zotarolimus-Eluting Stent Implantation (RESET)105 and
..
ischaemic endpoints. Likewise, the net clinical benefit (composite .. Optimized Duration of Clopidogrel Therapy Following Treatment
of death, MI, stent thrombosis, stroke, and TIMI major bleeding) .. With the Zotarolimus-Eluting Stent in Real-World Clinical
..
was neutral. At subgroup analysis, there was no signal of heteroge- .. Practice (OPTIMIZE),106 investigated a 3-month duration of
neity with respect to the primary study endpoint among the 2394
.. DAPT (ASA þ clopidogrel). RESET randomized 2117 patients to
..
patients who presented with stable CAD as opposed to the 1601 . 3- or 12-month duration of DAPT and did not show significant
228

Figure 3 Algorithm for DAPT in patients with coronary artery disease. ACS = acute coronary syndrome, BMS = bare-metal stent; BRS = bioresorbable vascular scaffold; CABG = Coronary artery
bypass graft; DCB = drug-coated balloon; DES: drug-eluting stent; PCI = percutaneous coronary intervention; Stable CAD = stable coronary artery disease.
High bleeding risk is considered as an increased risk of spontaneous bleeding during DAPT (e.g. PRECISE-DAPT score >_25).
Colour-coding refers to the ESC Classes of Recommendations (green = Class I; yellow = Class IIa; orange = Class IIb).
Treatments presented within the same line are sorted in alphabetic order, no preferential recommendation unless clearly stated otherwise.
1
: After PCI with DCB 6 months. DAPT should be considered (Class IIa B).
2
: If patient presents with Stable CAD or, in case of ACS, is not eligible for a treatment with prasugrel or ticagrelor.
3
: If patient is not eligible for a treatment with prasugrel or ticagrelor.
4
: If patient is not eligible for a treatment with ticagrelor.
ESC Guidelines

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ESC Guidelines 229

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Figure 4 Algorithm for dual antiplatelet therapy (DAPT) in patients treated with percutaneous coronary intervention. ACS = acute coronary syn-
drome; BMS = bare-metal stent; BRS = bioresorbable vascular scaffold; CABG = coronary artery bypass graft surgery; DCB = drug-coated balloon;
DES: drug-eluting stent; PCI = percutaneous coronary intervention; Stable CAD = stable coronary artery disease.
High bleeding risk is considered as an increased risk of spontaneous bleeding during DAPT (e.g. PRECISE-DAPT score >_25).
Colour-coding refers to the ESC Classes of Recommendations (green = Class I; yellow = IIa; orange = Class IIb).
Treatments presented within the same line are sorted in alphabetic order, no preferential recommendation unless clearly stated
otherwise.
1
: After PCI with DCB 6 months. DAPT should be considered (Class IIa B).
2
: If patient presents with Stable CAD or, in case of ACS, is not eligible for a treatment with prasugrel or ticagrelor.
3
: If patient is not eligible for a treatment with prasugrel or ticagrelor.
4
: If patient is not eligible for a treatment with ticagrelor.
230 ESC Guidelines

..
harm with the shortened period (composite rates of any death, .. secondary prevention and reduction of stent thrombosis emerges.
MI, or stent thrombosis 0.8% vs. 1.3%; P = 0.48). Similar results .. However, this benefit is counterbalanced by an increased risk of
..
were achieved in OPTIMIZE with 3119 patients randomized. In .. bleeding and by a signal for increased mortality. Thus, systematic
this study, the 1-year incidence of MACE was 8.3% in the short- .. extension of DAPT beyond six months is not justified for all patients
..
term group and 7.4% in the long-term group (HR 1.12, 95% CI .. but should be based on the individual risk profile of the patient (see
0.87–1.45). Both studies mandated the use of the Endeavor .. section 3.5).
..
zotarolimus-eluting stent (ZES) in the 3-month DAPT arms, which .. Impact of type of DES on duration of DAPT: The benefit of
is no longer available on the market. It is not clear to what extent .. extended periods of DAPT varies with stent type. However, there
..
the results of RESET and OPTIMIZE are applicable to other types .. are differences between first- and newer-generation DES. In
of DES. .. PRODIGY, only patients with the paclitaxel-eluting stent benefit-
..
Palmerini et al performed a meta-analysis addressing the outcome .. ted from extended DAPT with a significant reduction of the risk of
of a <_6-month course of DAPT vs. a 1-year course after DES.107 The .. stent thrombosis.114 Likewise, in DAPT, the benefit of extended
..

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1-year course of therapy did not confer any advantage over the .. DAPT was largest with patients with a paclitaxel-eluting stent and
shorter course of DAPT with respect to survival, stent thrombosis, .. the smallest with an everolimus-eluting stent.110,115 There also was
..
or MI, but it increased the risk of major bleeding substantially. Similar .. a significant interaction between stent type and benefit of
results were obtained by other meta-analyses.108,109
.. extended DAPT with respect to MACCE.110 With an everolimus-
..
Twelve-month vs. >12-month DAPT duration: Following the pro- .. eluting stent, the 1-year NNT for prevention of stent thrombosis
posed landmark of 12 months as the standard DAPT duration
.. was 157, whereas the 1-year NNT for harm for moderate or
..
after DES, the DAPT trial investigated whether further extension .. severe bleeding was 56.115 In the meta-analysis by Giustino et al,109
of DAPT might be beneficial.110 The DAPT study enrolled patients
.. the reduction of stent thrombosis by extended DAPT was signifi-
..
who, at 12 months after placement of a DES, were still on DAPT .. cantly reduced with new-generation stents as compared with first-
..
and had not suffered an ischaemic or bleeding event. Patients .. generation DES, and statistical significance was lost within the
were randomly allocated to thienopyridine or placebo for another .. new-generation subset. No such interaction was found concerning
..
18 months. Aspirin was maintained throughout the study period. .. bleeding complications. Similar results were obtained in two other
Thirty-month DAPT as compared with 12-month DAPT .. meta-analyses (Sharma et al116 and Palmerini et al117).
..
reduced the rates of stent thrombosis (0.4% vs. 1.4%; P < 0.001) .. Bioresorbable stents and drug-coated balloons: No dedicated stud-
and of major adverse cardiac and cerebrovascular events .. ies examining the optimal duration of DAPT after implantation of a
..
(MACCE) (4.3% vs. 5.9%; P < 0.001). This included a substantial .. bioresorbable scaffold currently exist. In the largest randomized
reduction in the rate of MI (2.1% vs. 4.1%; P < 0.001); slightly .. clinical trial investigating the treatment of patients with a poly-lac-
..
more than half of this benefit could be attributed to the preven- .. tic acid-based bioresorbable scaffold, DAPT was recommended
tion of spontaneous MIs (see chapter 3.2). This ischaemic protec- .. for at least 12 months.118 However, meta-analysis has shown evi-
..
tion came at the cost of an increased risk of bleeding (GUSTO .. dence of an approximately twofold higher rate of stent thrombosis
moderate or severe bleeding 2.5% vs. 1.6%, P < 0.001) and an .. in comparison with conventional DES, especially in the first 30
..
increase in total mortality with borderline statistical significance .. days after implantation.119 This provides a rationale for considering
(see section 3.3). .. more potent P2Y12 inhibitors in these patients. In addition, some
..
Of 11 648 randomized patients within the DAPT trial (9961 .. concerns have been raised regarding late stent thrombosis beyond
treated with DES and 1687 with BMS), 30.7% presented with MI.98
.. 1 year after implantation120,121 and a longer duration of DAPT
..
The excess of mortality observed within the 30-month DAPT arm .. therapy may be advocated, at least in patients at low bleeding risk.
was entirely driven by fatalities, which occurred in patients without
.. No large-scale clinical trials are available concerning magnesium-
..
prior MI (2.1% for continued thienopyridine group vs. 1.5% for pla- .. based bioresorbable scaffolds.
cebo; HR 1.43, 95% CI 1.02–2.00; P = 0.04). Yet, the interaction
.. In patients treated with drug-coated balloons, dedicated clinical tri-
..
P value did not reach statistical significance (effect for MI vs. no MI .. als investigating the optimal duration of DAPT are lacking. In patients
interaction P = 0.13).99
.. treated for in-stent restenosis, the largest randomized trials investi-
..
Three independent meta-analyses, which included 5045 patients .. gating drug-coated balloon therapy have recommended a treatment
..
recruited within DES-Late coronary Arterial Thrombotic Events .. duration of between 3 - 12 months.122–124 In addition, some small
(LATE)111 and 1259 patients from the Assessment by a Double .. clinical trials, as well as larger registries, including patients with stable
..
Randomisation of a Conventional Antiplatelet Strategy Versus a .. CAD undergoing drug-coated balloon angioplasty have recom-
Monitoring-Guided Strategy for Drug-Eluting Stent Implantation and, .. mended DAPT duration of at least 1 month.125
..
of Treatment Interruption Versus Continuation 1 Year After .. Plain old balloon angioplasty: no data on DAPT or DAPT duration
Stenting-Interruption (ARCTIC-Interruption) trial,112 provided .. exist after plain old balloon angioplasty, which is currently
..
results consistent with a possible increase in mortality with pro- .. reserved for a small minority of patients in whom stent implanta-
longed DAPT as shown in the DAPT trial. A more recent meta- .. tion is not feasible (e.g. small calibre vessel or extreme vessel tor-
..
analysis of 11 RCTs that enrolled 33 051 patients who received pre- .. tuosity) or desirable (e.g. to avoid DAPT in patients referred to
dominantly newer-generation DES also provided weak evidence of .. CABG). The institution of DAPT and its duration, if implemented,
..
an increased mortality rate with prolonged DAPT.113 .. should depend on clinical profile (ischaemic vs. bleeding risks)
Thus, if DAPT is administered for a sufficient length of time after .. and/or the reasons (e.g. planned surgery) for avoiding stent
..
placement of DES for stable CAD, a substantial benefit in terms of . implantation.
ESC Guidelines 231

..
Dual antiplatelet therapy duration and related stent
.. previous guidelines (NSTE-ACS), and data supporting the superiority
.. of ticagrelor and prasugrel over clopidogrel in this setting are dis-
choices in patients with stable coronary artery disease ..
treated with percutaneous coronary intervention .. cussed in section 3.6.
.. Although both prasugrel and ticagrelor significantly increase the
..
Recommendations Classa Levelb
.. risk of TIMI major non-CABG related bleeds, the risk–benefit ratios
.. were favourable with NNT for benefit of 46 and 53, respectively, and
..
In patients with stable CAD treated with .. NNT for harm of 167 for both agents. These data established the 1-
coronary stent implantation, DAPT consist-
.. year course of DAPT, preferably with prasugrel or ticagrelor, for
..
ing of clopidogrel in addition to aspirin is I A .. patients undergoing PCI for ACS, unless there are contraindications
generally recommendedc for 6 months, irre-
.. (Figure 4).
..
spective of the stent type.100,101,104,126–130 .. Mounting evidence for secondary prevention by intensified antiplatelet
.. therapy: In patients presenting with ACS, the cardiovascular risk
..

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Irrespective of the intended DAPT duration,
I A .. remains substantially elevated beyond the first year, even if successful
DESc is the preferred treatment option.129–132 ..
.. revascularization has been achieved. In this setting, intensified antipla-
In patients with stable CAD considered at high .. telet therapy on top of aspirin has been shown to be an effective
..
bleeding risk (e.g. PRECISE-DAPT >_25), DAPT IIa B .. therapeutic strategy to prevent recurrent ischaemic events.
for 3 monthsd should be considered.105,106 ... However, the risk–benefit ratios seem less favourable than those
.. observed in studies assessing <_1-year DAPT duration. Relevant infor-
In patients with stable CAD treated with ..
.. mation has been provided by the prior MI patient subsets included in
drug-coated balloon, DAPT for 6 months IIa B .. the CHARISMA135 (n = 3846) and DAPT98 (n = 3576) trials, which
should be considered.122,124,133 ..
.. mainly compared clopidogrel with placebo on top of aspirin; by the
In patients with stable CAD treated with
.. subset of patients who underwent coronary angiography within the
..
bioresorbable vascular scaffolds, DAPT for IIa C .. TRILOGY136 trial, which compared prasugrel with clopidogrel; and
at least 12 months should be considered.
.. by the patients with prior MI within the Thrombin Receptor
..
.. Antagonist in Secondary Prevention of Atherothrombotic Ischemic
In patients with stable CAD who have toler- ..
.. Events (TRA 2 P-TIMI 50)137 (n = 17 779 ) trial, which compared
ated DAPT without a bleeding complication .. vorapaxar with placebo. Taken separately, these trial results are diffi-
and who are at low bleeding but high throm- ..
botic risk, continuation of DAPT with clopi-
IIb A .. cult to interpret because they are based on subgroup analyses.
.. Moreover, CHARISMA and TRILOGY had a neutral main outcome
dogrel for >6 months and <_30 months may ..
.. and the main results of TRA 2 P-TIMI 50 showed an unfavourable
be considered.26,107–109 ..
.. risk–benefit ratio. Therefore, a dedicated trial on prolonged DAPT
In patients with stable CAD in whom 3- .. for secondary prevention after ACS was needed. The PEGASUS trial
month DAPT poses safety concerns, DAPT IIb C .. filled this gap.29
..
for 1 monthe may be considered. .. DAPT with ticagrelor for secondary prevention after MI: PEGASUS
.. recruited 21 162 patients with spontaneous MI 1–3 years before
..
BMS = bare-metal stent; CAD = coronary artery disease; DAPT = dual antiplate- .. enrolment, who were at >_50 years old and had at least one additional
let therapy; DES = drug-eluting stent; MI = myocardial infarction; PRECISE-DAPT .. high-risk feature: age >_65 years, diabetes mellitus, a second spontane-
= PREdicting bleeding Complications In patients undergoing Stent implantation
..
.. ous MI, multivessel CAD, or chronic renal dysfunction.29 The patients
and subsEquent Dual Anti Platelet Therapy. .. were randomly assigned to ticagrelor 90 mg b.i.d., ticagrelor 60 mg
a
Class of recommendation. ..
b
Level of evidence. .. b.i.d., or placebo. All the patients received low-dose aspirin. Of the
c
These recommendations refer to stents that are supported by large-scale ..
randomized trials with clinical endpoint evaluation leading to unconditional CE .. patients included in PEGASUS, 53% were enrolled after a STEMI and
mark, as detailed in Byrne et al.134 .. 83% were previously treated by PCI. The primary efficacy endpoint
d
The evidence supporting this recommendation comes from two studies where
..
.. was the composite of cardiovascular death, MI, or stroke at 3 years
zotarolimus-eluting Endeavour sprint stent has been investigated in conjunction .. and was 7.85% in the 90 mg arm, 7.77% in the 60 mg arm, and 9.04%
with a 3-month DAPT regimen. ..
e
1-month DAPT following implantation of zotarolimus-eluting Endeavour sprint stent .. in the placebo arm (P = 0.008 and P = 0.004 for the higher and lower
or Biofreedom drug-coated stent reduced risks of re-intervention, myocardial infarc- .. doses, respectively, vs. placebo).29 There was a consistent reduction
tion and inconsistently of stent thrombosis compared to bare-metal stent under simi- ..
lar DAPT duration.129,130 It is unclear if this evidence applies to other contemporary .. in all components of the primary endpoint with ticagrelor vs. placebo,
DES.
.. which reached statistical significance for MI with both doses of tica-
..
.. grelor and for stroke with the lower dose. There was also a trend for
.. a reduction in cardiovascular mortality. Due to a non-significant yet
4.2 Dual antiplatelet therapy after ..
.. numerical increase in non-cardiovascular deaths in the two ticagrelor
percutaneous coronary intervention for .. arms, the outcome was neutral with respect to all-cause death. The
..
acute coronary syndrome .. primary safety endpoint of TIMI major bleeding was observed more
DAPT with novel P2Y12 inhibitors for 1 year after PCI for ACS: The evi-
.. frequently with ticagrelor (2.60% with 90 mg and 2.30% with 60 mg)
..
dence supporting the value of the combination of aspirin and clopi- .. than with placebo (1.06%) (P < 0.001 for each dose vs. placebo). The
dogrel in patients with ACS has been extensively reviewed in
.. NNT for benefit for the primary endpoint was 250 for the 90 mg
232 ESC Guidelines

dose and 238 for the 60 mg dose; the corresponding NNT for harm
.. duration of DAPT was similar among patients with or without MI.
..
was 244 and 322, respectively, with the two ticagrelor doses.29 .. The active comparator was prasugrel in one-third of the patients
With the 90 mg dose, the absolute benefit in terms of the primary
.. with MI and clopidogrel in two-thirds of the patients.
..
efficacy endpoint was in the same order as the absolute harm in .. In patients with MI, extended DAPT as compared with aspirin
..
terms of the primary safety endpoint, and with 60 mg the absolute .. alone reduced stent thrombosis significantly (0.5% vs. 1.9%; P <
benefit was only marginally larger than the absolute harm. However, .. 0.001). There also was a significant reduction of MACCE by extended
..
the relevance of the various endpoints to the patient’s overall well- .. DAPT (3.9% vs. 6.8%; P < 0.001). This included a major reduction in
being may differ and are, therefore, difficult to weigh against one .. the rate of recurrent MI (2.2% vs. 5.2%; P < 0.001). On the other side,
..
another. The impact of MI and bleeding on mortality was comparable .. GUSTO moderate or severe bleeding was significantly increased by
in previous studies.11,138 A post hoc analysis from the Thrombin .. extended DAPT (1.9% vs. 0.8%, P = 0.005). Contrary to the main
..
Receptor Antagonist for Clinical Event Reduction in Acute Coronary .. study, all-cause mortality was similar in the extended DAPT group as
Syndrome (TRACER) trial suggested that while bleeding according to .. compared with the placebo group (1.4% vs. 1.6%; P = 0.61), even if
..

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BARC 2 and 3a criteria was less prognostic for death than MI, the risk .. formal interaction testing was inconclusive.
of mortality was equivalent between BARC 3b bleeding and MI, and .. A meta-analysis on the effect of extended DAPT in patients
..
was higher following BARC 3c bleeding. Moreover, at variance with .. with previous MI comprising PEGASUS and MI subgroups of stud-
previous analyses, both MI and bleeding impacted mortality with simi- .. ies with thienopyridines—CHARISMA, PRODIGY, and DES-
..
lar time dependency.42 In view of these consistent findings through- .. LATE with clopidogrel as well as ARCTIC-Interruption and DAPT
out multiple independent studies, both the efficacy and the safety
.. with clopidogrel or prasugrel—has been recently published.141
..
endpoints deserve attention, as both most likely similarly impact .. Extended DAPT decreased the risk of MACCE compared with
mortality. With this background, the narrow risk–benefit ratio cau-
.. aspirin alone (6.4% vs. 7.5%; P = 0.001). There was a consistent sig-
..
tions against the universal long-term administration of ticagrelor for .. nificant reduction in each component of the primary endpoint (RR
secondary prevention after MI, and calls for individualized treatment
.. 0.85, 95% CI 0.74–0.98 for cardiovascular death; RR 0.70, 95% CI
..
decisions based on ischaemic and haemorrhagic risk. .. 0.55–0.88 for MI; RR 0.81, 95% CI 0.68–0.97 for stroke). This ben-
To this end, patients who continued their thienopyridine treat-
.. efit was achieved at the cost of a significantly increased risk of
..
ment without (a major) interruption (<_30 days) derived a larger .. major bleeding (1.85% vs. 1.09%; P = 0.004). Although the reduc-
..
benefit from extended ticagrelor intake than patients who inter- .. tion in cardiovascular mortality associated with prolonged DAPT
rupted their thienopyridine treatment for longer periods of .. was significant, the absolute risk reduction was small (0.3%). In
..
time.139 Depending on the actual discontinuation time frame of .. addition, there was no difference in all-cause mortality (4.0% in
previous thienopyridine therapy, the HRs (95% CI) of the primary .. the extended DAPT group and 4.2% in the aspirin alone group).
..
endpoint for ticagrelor (pooled doses) vs. placebo were 0.73 .. No significant difference between study heterogeneity was identi-
(0.61–0.87) for those who continued within 30 days, 0.86 .. fied across the appraised endpoints. This may suggest a consistent
..
(0.71–1.04) for those who interrupted for 30 days to 1 year, and .. class effect among the three P2Y12 inhibitors (clopidogrel, ticagre-
1.01 (0.80–1.27) for those who interrupted for more than 1 year .. lor, or prasugrel). However, caution should be used in interpreting
..
(P trend for interaction < 0.001).139 There was no significant inter- .. this finding, taking into account that the PEGASUS study alone
action of timing with the effect of ticagrelor on bleeding risk. These .. contributed >_60% to pooled endpoint estimates and that
..
findings suggest that patients who can continue their initial thieno- .. PEGASUS was the only trial included in its totality (and as such the
pyridine treatment are those deriving relatively greater benefit .. only properly powered study for post-MI patients), whereas post
..
from DAPT continuation with ticagrelor. Nevertheless, even in .. hoc subgroups of patients recruited in the other four investigations
this patient subset, the absolute increase in TIMI major bleeding .. were pooled. In addition, when the overall included populations
..
associated with extended ticagrelor was similar in magnitude as .. of the four available studies assessing DAPT for >1 year vs. 12-
compared to the absolute decrease in the composite ischaemic
.. month therapy are pooled, an extended treatment with ticagrelor,
..
endpoint (i.e. 1.9 percentage point difference for both the safety .. as compared to a similar strategy with thienopyridines, exerted a
and the efficacy endpoints).139
.. more favourable effect on all-cause mortality due to a trend
..
Patients with lower-extremities artery disease (LEAD), who are .. towards reduction of cardiovascular death and a null effect on
known to be at greater ischaemic risk, also derived heightened bene-
.. non-cardiovascular death.142 Finally, PEGASUS was the only trial
..
fit from extended ticagrelor.140 In these patients, the absolute .. that allowed patients who had stopped DAPT months or years
decreases in the primary efficacy endpoint achieved by ticagrelor vs.
.. before to randomly restart therapy; this likely resulted in relatively
..
placebo were 3.0% for the 90 mg dose and 5.2% for the 60 mg dose, .. lower efficacy endpoint estimates as compared to other studies
whereas the increases in TIMI major bleeding were only 0.22% and ... testing duration of thienopyridines where treatment was either
..
0.02%, respectively. In addition, ticagrelor was significantly associated .. permanently stopped or continued without treatment interrup-
with fewer events related to LEAD (i.e. acute limb ischaemia and .. tions in between. Therefore, it is reasonable to favour ticagrelor
..
peripheral revascularization procedures). .. 60 mg b.i.d. as the agent of choice for prolonging DAPT beyond
DAPT with thienopyridines (clopidogrel or prasugrel) for secondary pre- .. 12 months in stabilized post-MI patients at low bleeding risk, and
..
vention after MI: In the DAPT trial, 3567 patients had initially pre- .. to reserve the use of clopidogrel (or prasugrel, the least investi-
sented with MI.98 A non-prespecified analysis of these patients .. gated agent in this setting) as the alternative choice if ticagrelor
..
investigated whether the benefits and risks of extended vs. standard . therapy is not tolerated or feasible.
ESC Guidelines 233

Shortening of DAPT duration in patients at high bleeding risk: There is


.. associated with an estimated increase in the risk of MI or defi-
..
no dedicated RCT assessing the optimal DAPT duration in patients at .. nite/probable stent thrombosis from 1.7% to 2.4% compared
high bleeding risk. Moreover, many, if not all, available DAPT studies
.. with 1-year DAPT. Although this increase did not reach statisti-
..
formally excluded these patients from inclusion. The Zotarolimus- .. cal significance (HR 1.48, 95% CI 0.98–2.22; P = 0.059), it has
eluting Endeavor sprint stent in Uncertain DES Candidates (ZEUS)
.. to be kept in mind that the power of this analysis was limited
..
and the Prospective randomized comparison of the BioFreedom biol- .. since the number of patients with ACS included was roughly
imus A9 drug-coated stent versus the gazelle BMS in patients at high
.. only one-third or one-fourth of that in TRITON or PLATO,
..
bleeding risk (LEADERS-FREE) studies recruited a selected high .. which established the superiority of intensified antiplatelet ther-
..
bleeding risk population and randomized them to BMS or drug- apy over conventional 1-year DAPT with clopidogrel. Despite
...
coated stent under a protocol-mandated DAPT duration of .. this limitation, it is probably fair to conclude that the ischaemic
1 month.129,130 Both studies, as discussed in section 2.4, proved the .. risk of shortening DAPT to 6 months after PCI in ACS is low,
..
superiority of the investigated DES technologies as compared to BMS .. although not negligible. In this respect, it is also reassuring that

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despite a similarly short duration of DAPT. The trade-off between .. there was no signal with respect to cardiac or all-cause death
..
bleeding prevention and ischaemic protection of prolonging DAPT .. (HR 0.75, 95% CI 0.45–1.27 and HR 0.85, 95% CI 0.58–1.26,
beyond 1 month in this patient subset remains unclear. .. respectively). Only when DAPT duration was reduced to
..
As discussed in section 4.1, two studies compared 3- vs. 12-month .. 3 months did the risk of MI and definite/probable stent throm-
DAPT duration after DES. Patients were not selected based on high .. bosis increase substantially (HR 2.08, 95% CI 1.10–3.93).
..
bleeding risk criteria and both studies included only a minority of .. In summary, currently available evidence suggests considering
patients presenting with acute MI (14.3 and 5.4% in the RESET and .. discontinuation of P2Y12 inhibitor therapy after 6 months, when
..
OPTIMIZE trials, respectively).105,106 . the risk of bleeding is high.

Dual antiplatelet therapy duration in patients with acute coronary syndrome treated with percutaneous coronary
intervention

Recommendations Classa Levelb

In patients with ACS treated with coronary stent implantation, DAPT with a P2Y12 inhibitor on top of aspirin is rec-
ommended for 12 months unless there are contraindications such as excessive risk of bleeding (e.g. PRECISE-DAPT I A
>_25).20,23,40

In patients with ACS and stent implantation who are at high risk of bleeding (e.g. PRECISE-DAPT >_25), discontinua-
IIa B
tion of P2Y12 inhibitor therapy after 6 months should be considered.13,18,143

In patients with ACS treated with bioresorbable vascular scaffolds, DAPT for at least 12 months should be
IIa C
considered.

In patients with ACS who have tolerated DAPT without a bleeding complication, continuation of DAPT for longer
IIb A
than 12 months may be considered.26,139

In patients with MI and high ischaemic riskc who have tolerated DAPT without a bleeding complication, ticagrelor
IIb B
60 mg b.i.d. for longer than 12 months on top of aspirin may be preferred over clopidogrel or prasugrel.29,115,142

ACS = acute coronary syndrome; b.i.d. = bis in die; DAPT = dual antiplatelet therapy. MI = myocardial infarction; PRECISE-DAPT = PREdicting bleeding Complications In
patients undergoing Stent implantation and subsEquent Dual Anti Platelet Therapy.
a
Class of recommendation.
b
Level of evidence.
c
Defined as >_ 50 years of age, and one or more of the following additional high-risk features: age of 65 years or older, diabetes mellitus requiring medication, a second prior
spontaneous myocardial infarction, multivessel coronary artery disease, or chronic renal dysfunction, defined as an estimated creatinine clearance < 60 mL/min.
These recommendations refer to stents that are supported by large-scale randomized trials with clinical endpoint evaluation leading to unconditional CE mark, as detailed in
Byrne et al.134

After an ACS, high bleeding risk status poses even greater 4.3 Gaps in the evidence
challenges with respect to the choice of DAPT duration. The With a marginal overall benefit-to-risk ratio of extended DAPT beyond
risks of shortening DAPT below 1 year have been addressed by 1 year after DES placement, tools to identify ideal candidates for long-
an individual patient data meta-analysis.143 This meta-analysis term or even indefinite DAPT duration are critically needed. The DAPT
comprised six trials comparing three- or six-month DAPT with score15 as well as the subgroup analyses of PEGASUS139,140,144,145 are
12-month DAPT including 11 473 patients, 4758 of whom had important steps forward, but prospective validation in contemporary
ACS. In patients with ACS, shortening DAPT to <_ 6 months was cohorts of newer-generation DES patients is needed.
234 ESC Guidelines

The optimal level of platelet inhibition during the various stages of


CAD remains an open question. The risk of ischaemic complication is
highest immediately after PCI and then gradually declines. The same
is true for patients managed for ACS, although the risk remains ele-
vated above that of patients who never experienced an acute exacer-
bation for years. Thus, it is intuitive that during the chronic phase
after stabilization the level of platelet inhibition may be reduced as
compared with the acute phase. Until recently, there were only lim-
ited data addressing this issue from beyond the periprocedural phase
to 1 year. By now, two studies addressing such a step-down concept
have finished recruitment: Testing Responsiveness to Platelet
Inhibition on Chronic Antiplatelet Treatment For Acute Coronary

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Syndromes Trial (TROPICAL-ACS) (NCT01959451) with a step-
down from prasugrel to clopidogrel after the peri-interventional
phase in acute MI; and GLOBAL-LEADERS (NCT01813435)146 with
a step-down from DAPT to single antiplatelet therapy with ticagrelor
beyond the first month after PCI in an all-comers cohort with DES.
The risks and benefits of shortening DAPT to 3 months or even
shorter is another area with limited evidence. There are only two
randomized studies with a total of 5236 patients.105,106 Both studies
used the first-generation ZES that, due to its limited efficacy in sup-
pressing neointima formation, has been largely replaced by a newer
generation. Thus, in most cases with high bleeding risk, the decision
to shorten DAPT below 6 months needs to rely on circumstantial
evidence suggesting comparable safety of different stent types.
As outlined in section 4.1, there are no dedicated studies on the opti-
mal duration of DAPT after the application of drug-eluting balloons or
after implantation of a bioresorbable scaffold. It is also unclear whether,
early after placement of a bioresorbable stent, patients may benefit
from the more potent P2Y12 inhibition achieved by prasugrel or ticagre-
lor as compared with the current practice of clopidogrel administration.

5. Dual antiplatelet therapy and


cardiac surgery
5.1 Dual antiplatelet therapy in patients
treated with coronary artery bypass
surgery for stable coronary artery
disease
DAPT in ACS patients significantly reduces the risk of thrombotic com- Figure 5 Algorithm for dual antiplatelet therapy (DAPT) in
plications but increases the risk for both spontaneous and surgical patients with acute coronary syndrome undergoing coronary artery
bleeding complications.20,23,40 The bleeding risk as well as the ischaemic bypass grafting. High bleeding risk is considered as an increased risk of
benefit are further increased if ticagrelor or prasugrel are used instead spontaneous bleeding during DAPT (e.g. PRECISE-DAPT score >_25).
of clopidogrel.20,23 Unlike for ACS, there is currently no evidence of a Colour-coding refers to the ESC Classes of Recommendations
survival benefit or a reduction of thromboembolic complications with (green = Class I; yellow = IIa; orange = Class IIb). Treatments pre-
DAPT in patients with stable CAD undergoing CABG. However, there sented within the same line are sorted in alphabetic order, no prefer-
ential recommendation unless clearly stated otherwise.
is limited evidence suggesting that the use of DAPT in patients with sta-
1: if patient is not eligible for a treatment with prasugrel or
ble CAD mitigates the risk of vein (but not arterial) graft occlusions.
ticagrelor.

5.2 Dual antiplatelet therapy in patients


treated with coronary artery bypass
surgery for acute coronary syndrome .. However, there is limited evidence in patients undergoing CABG as no
..
Background: DAPT, as compared to aspirin monotherapy, has been pro- .. dedicated study exists. In the Clopidogrel in Unstable Angina to Prevent
ven to be beneficial in reducing ischaemic risk in ACS patients (Figure 5).
.. Recurrent Events (CURE) trial, the outcome in the CABG
ESC Guidelines 235

..
subpopulation was consistent with the overall results of the study.147 .. where a discontinuation period of 24 - 72 h was recommended. In a sin-
Further support has been presented in two meta-analyses.148,149 In the .. gle institution Dutch registry encompassing 705 consecutive patients
..
CABG substudies of the TRITON-TIMI 38 and the PLATO trials where, .. who underwent isolated on-pump CABG, ticagrelor discontinuation
respectively, prasugrel and ticagrelor were tested against clopidogrel in .. >72 h and clopidogrel discontinuation >120 h before surgery were not
..
combination with ASA, both newer P2Y12 inhibitors were more effec- .. associated with an increased risk of bleeding-related complications.153
tive than clopidogrel in preventing fatal outcomes, with a higher risk for .. Further evidence comes from a prospective, multicentre clinical
..
bleeding in the former but not the latter trial.150,151 .. trial performed at 15 European centres, where discontinuation of
Continuation of DAPT until CABG increases the risk of excessive .. ticagrelor >2 days before surgery was not associated with increased
..
perioperative bleeding, transfusions, and re-exploration for bleeding .. bleeding.160
as shown in RCTs,147,150,151 observational studies,152,153 and meta- .. It is unlikely that the optimal discontinuation period for any of
..
analyses.154,155 Therefore, it is recommended that the P2Y12 inhibitor .. the P2Y12 inhibitors will ever be tested in an RCT. As mentioned
be discontinued whenever possible before elective CABG.156,157 .. above, current guidelines recommend DAPT in all patients with
..

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Alternatively, elective operations may be postponed until the DAPT .. ACS, independent of revascularization strategy.34,161 This applies
treatment period is completed. In urgent cases, most often patients .. to patients undergoing CABG and other cardiac surgical proce-
..
with ACS, the risk of thrombotic episodes (stent thrombosis or MI) .. dures as well. Furthermore, the effect of DAPT or single antiplate-
while waiting for the effect of the P2Y12 inhibitor to cease must be
.. let therapy after CABG has been compared in two meta-analyses
..
weighed against the risk of perioperative bleeding complications. In .. based on RCTs148 or a combination of RCTs and observational
extreme high-risk patients, e.g. those with recent DES implantation,
.. studies.149 In the meta-analysis based on RCTs only (which
..
bridging therapy with cangrelor or a glycoprotein IIb/IIIa blocker may .. included 3717 ACS patients),148 there were no differences in all-
be considered.156,157
.. cause mortality in ASA þ clopidogrel vs. ASA only. Conversely,
..
P2Y12 inhibitors: The safe discontinuation interval varies between .. all-cause mortality was significantly lower in ASA þ ticagrelor and
..
the different P2Y12 inhibitors due to variations in platelet inhibitory .. ASA þ prasugrel vs. ASA þ clopidogrel RCTs (RR 0.49, 95 % CI
effect and pharmacodynamic and pharmacokinetic properties.158 For .. 0.33–0.71; P = 0.0002). There were no significant differences in
..
clopidogrel, it was shown in the CABG substudy of the CURE trial .. occurrence of MIs, strokes, composite outcomes, or major bleed-
that discontinuation >_5 days before CABG did not increase the risk .. ing (RR 1.31, 95 % CI 0.81–2.10, P = 0.27). The meta-analysis
..
of bleeding complications.147 For prasugrel, a longer time interval .. based on both RCTs and observational studies149 included only
(7 days) is recommended due to the longer offset time compared to .. DAPT patients treated with clopidogrel. In this analysis, in-
..
clopidogrel158 and the high incidence of CABG-related bleeding com- .. hospital or 30-day mortality was lower with ASA þ clopidogrel
plications reported in the CABG substudy of the TRITON-TIMI .. compared to ASA alone (RR 0.38, 95% CI 0.26–0.57; P < 0.001),
..
38 trial.151 In CABG patients treated pre-operatively with ticagrelor, .. while the risk of angina or perioperative MI was comparable (RR
5 days of discontinuation was initially recommended. This recom- .. 0.60, 95% CI 0.31–1.14; P = 0.12). Long-term mortality was not
..
mendation was based on pharmacokinetic studies and clinical data .. reported. Patients treated with ASA þ clopidogrel demonstrated a
from patients with stable CAD.159 However, recent data from large .. trend towards a higher incidence of major bleeding episodes as com-
..
observational studies in CABG patients challenge this recommenda- .. pared to patients treated with ASA alone (RR 1.17, 95% CI 1.00–1.37;
tion.152,153,160 In a Swedish nationwide study, CABG-related bleeding .. P = 0.05). In both meta-analyses, there was large heterogeneity
..
complications in patients treated with ticagrelor or clopidogrel were .. between the included studies regarding study drug (clopidogrel/prasu-
thoroughly investigated with respect to timing of P2Y12 inhibitor dis-
.. grel/ticagrelor), study design, patient inclusion (ACS vs. stable CAD,
..
continuation.152 When either drug was discontinued according to .. on-pump vs. off-pump surgery), study quality, and duration of follow-
the instructions for use (>120 h before surgery), there was no significant
.. up. The positive effect on survival appears to be more pronounced in
..
difference in the incidence of major bleeding complications between .. ACS patients and in patients treated with the second-generation P2Y12
ticagrelor- and clopidogrel-treated patients (9% vs. 12%; unadjusted OR
.. inhibitors ticagrelor and prasugrel. However, re-institution of DAPT
..
0.72, 95% CI 0.51–1.02; P = 0.065). Within the ticagrelor group, there .. after CABG may also slightly increase the risk of bleeding complica-
was no significant difference in major bleeding complications between
.. tions. Thus, it is recommended that DAPT is re-started as soon as it is
..
discontinuation 72–120 h or > 120 h before surgery (OR 0.93, 95% CI .. considered safe after CABG in ACS patients, with the exception of
..
0.53–1.64; P = 0.80), whereas discontinuation 0–72 h before surgery .. those on anticoagulation. There is currently no scientific support for
was associated with a significantly higher rate of major bleeding com- .. triple antithrombotic treatment after CABG. Resuming DAPT early
..
pared with both 72–120 h (OR 5.17, 95% CI 2.89–9.27; P < 0.0001) .. after CABG is most likely of special importance in patients with recent
and >120 h (OR 4.81, 95% CI 3.34–6.95; P < 0.0001). In contrast, .. stent implantation, although strong evidence is lacking. The optimal
..
clopidogrel-treated patients had a higher incidence of major bleeding .. timing of resuming DAPT remains unclear, but 24 - 96 h after the oper-
complications when discontinued 72–120 h compared with >120 h .. ation in patients without recent stent implantation appears reasonable.
..
before surgery (OR 1.71, 95% CI 1.04–2.79; P = 0.033). Likewise, in the .. One reason for not starting DAPT immediately after the operation is
clopidogrel group, discontinuation 0–72 h before surgery was associ- .. the considerable risk (30%) of atrial fibrillation (AF) during the first
..
ated with an increased incidence of major bleeding compared with .. post-operative days, which requires oral anticoagulation.162
72–120 h (OR 1.67, 95% CI 1.02–2.73; P = 0.042) and >120 h (OR .. Acetylsalicylic acid: A recent meta-analysis comparing pre-operative
..
2.85, 95% CI 1.98–4.10; P < 0.0001) (Web Figure 2, see Web .. ASA administration vs. no treatment or placebo in CABG patients
Addenda).152 Further support for using 3 days as the discontinuation .. included 13 trials with a total of 2399 patients.163 The meta-analysis
..
period in ticagrelor-treated patients comes from the PLATO trial, . showed that treatment with ASA reduced the risk of perioperative
236 ESC Guidelines

MI (OR 0.56, 95% CI 0.33–0.96) but not the mortality risk (OR 1.16,
.. Taken together, the evidence indicates that continuation of ASA
..
95% CI 0.42–3.22), while post-operative bleeding, red blood cell .. until cardiac surgery is associated with a moderately increased risk of
transfusions, and surgical re-explorations increased with ASA. The
.. bleeding complications and a significant reduction in the risk of perio-
..
authors pointed out that included studies had low methodological .. perative MI. If bleeding occurs during surgery, platelet transfusion has
quality. The recent Aspirin and Tranexamic Acid for Coronary
.. been shown to effectively counteract ASA effects.166–168 This finding
..
Artery Surgery (ATACAS) trial compared administration of ASA .. further supports the possibility of continuing ASA throughout the
..
(100 mg) on the day of surgery vs. placebo in CABG patients.164 The .. perisurgical period as ASA allows direct antiplatelet effect reversal if
study showed no significant effect of ASA treatment on perioperative .. clinically indicated. The increased risk of bleeding complications if
..
bleeding. On the other hand, ASA treatment did not reduce the inci- .. ASA and other antithrombotic drugs are not discontinued should be
dence of thrombotic events. It should be pointed out that the study .. weighed against the potentially increased risk of thrombotic compli-
..
did not directly compare discontinuation vs. no discontinuation, since .. cations during the pre-operative cessation period.
the included patients were only eligible for the trial if they were not .. Platelet function testing: Besides the variance in platelet inhibitory
..

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using ASA pre-operatively or had stopped ASA at least 4 days before .. effects between different P2Y12 inhibitors, there is also a large individ-
surgery. Thus, the ATACAS study does not directly apply to the .. ual variation in the magnitude and duration of the antiplatelet
..
ACS-CABG population and does not change current recommenda- .. effect.20,159,169–171 Because of the individual variation, the use of pla-
tions of maintaining ASA treatment during the perioperative period. .. telet function tests may aid the optimization of the timing of surgical
..
In a case-control study on 8641 CABG patients, those pre-treated .. procedures. However, platelet function tests could also be of value
with ASA were less likely to experience in-hospital mortality in uni- .. to establish the grade of platelet inhibition in patients in whom the
..
variate (OR 0.73, 95% CI 0.54–0.97) and multivariate (OR 0.55, 95% .. time since discontinuation is unclear, e.g. in unconscious or confused
CI 0.31–0.98) analysis relative to those not exposed to ASA.165 No
.. patients, and in patients with uncertain compliance to the treatment.
..
significant difference was seen in the amount of chest tube drainage, .. Treatment monitoring, using bedside tests, has been suggested as
transfusion of blood products, or need for re-exploration for bleed-
.. an option for guiding interruption of treatment, rather than the use
..
ing, between patients who were or were not exposed to ASA pre- .. of an arbitrary, specified period of time.156,157 Pre-operative ADP-
operatively.
.. dependent platelet aggregation capacity predicts CABG-related
.

Dual antiplatelet therapy in patients treated with cardiac surgery with stable or unstable coronary artery disease

Recommendations Classa Levelb

It is recommended that the heart team estimates the individual bleeding and ischaemic risks, and guides the timing of
I C
CABG as well as the antithrombotic management.

In patients on aspirin who need to undergo non-emergent cardiac surgery, it is recommended to continue aspirin at a low
I C
daily regimen throughout the perioperative period.

In patients treated with DAPT after coronary stent implantation who subsequently undergo cardiac surgery, it is recom-
mended to resume P2Y12 inhibitor therapy post-operatively as soon as is deemed safe so that DAPT continues until the I C
recommended duration of therapy is completed.

In patients with ACS (NSTE-ACS or STEMI) treated with DAPT, undergoing CABG, and not requiring long-term OAC ther-
apy, resumption of P2Y12 inhibitor therapy as soon as is deemed safe after surgery and continuation up to 12 months is I C
recommended.

In patients on P2Y12 inhibitors who need to undergo non-emergent cardiac surgery, postponing surgery for at least 3
days after discontinuation of ticagrelor, at least 5 days after clopidogrel, and at least 7 days after prasugrel should be IIa B
considered.152,153,160

In CABG patients with prior MI who are at high risk of severe bleeding (e.g. PRECISE-DAPT >_25), discontinuation of P2Y12
IIa C
inhibitor therapy after 6 months should be considered.

Platelet function testing may be considered to guide decisions on timing of cardiac surgery in patients who have recently
IIb B
received P2Y12 inhibitors.169,172–174

In patients perceived to be at high ischaemic risk with prior MI and CABG, who have tolerated DAPT without a bleed-
IIb C
ing complication, treatment with DAPT for longer than 12 and up to 36 months may be considered.

ACS = acute coronary syndrome; CABG = coronary artery bypass graft surgery; DAPT = dual antiplatelet therapy; MI = myocardial infarction; NSTE-ACS = non-ST-elevation
acute coronary syndrome; OAC = oral anticoagulant; PRECISE-DAPT = PREdicting bleeding Complications in patients undergoing Stent implantation and subsEquent Dual Anti
Platelet Therapy; STEMI = ST-elevation myocardial infarction.
a
Class of recommendation.
b
Level of evidence.
ESC Guidelines 237

..
bleeding complications in clopidogrel-172–174 and ticagrelor- .. clopidogrel,40,95 TRILOGY for prasugrel,24 and PLATO and
treated169 ACS patients, and a strategy based on pre-operative plate- .. PEGASUS for ticagrelor studies.20,29 There is no evidence in
..
let function testing, to determine the timing of CABG in clopidogrel- .. favour of prasugrel treatment in patients with ACS who are medi-
treated patients, led to a 50% shorter waiting time than that sug- .. cally managed, based on the negative results of the TRILOGY
..
gested by a simple discontinuation time-based strategy.175 It should .. study and the exclusion of this patient subset in the TRITON
be pointed out that the different platelet function tests and their .. study.23,24 The CURE study showed a consistent benefit in ACS
..
respective cut-off levels are not interchangeable.176 Taken together, .. patients undergoing an average mean of 9 months DAPT in the
these results suggest that platelet function testing in ACS patients
.. form of aspirin and clopidogrel as compared to 1-month therapy
..
referred for CABG is of potential value to guide the timing of surgery .. in NSTE-ACS patients, irrespective of the final management strat-
in patients treated with P2Y12 inhibitors. However, randomized stud-
.. egy, including or not including coronary revascularization.40 The
..
ies with clinically relevant endpoints are lacking. .. post-MI subset of patients in the CHARISMA trial derived signifi-
.. cant benefit with an NNT for benefit in the range of 100, which
..

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5.3 Dual antiplatelet therapy for .. came at the expense of higher major bleeding, with an NNT for
.. harm of 90.135 While the post-MI population represents only a
prevention of graft occlusion ..
Two meta-analyses have compared graft patency in patients treated
.. subset of those included in the CHARISMA study and the overall
..
with ASA alone or ASA þ clopidogrel after CABG.149,177 The studies .. results of the trial did not show benefit of DAPT as compared to
.. aspirin alone, it seems justifiable to give credit to this subanalysis
included in the meta-analyses comprised mainly patients with stable ..
CAD. In a meta-analysis by Deo et al,149 ASA þ clopidogrel was asso- .. based on the consistency of results within multiple recent studies;
.. these studies showed that the long-term administration of an
ciated with a significant reduction in saphenous vein graft occlusions ..
(RR 0.59, 95% CI 0.43–0.82; P = 0.02). In the meta-analysis by .. intensified antiplatelet regimen beyond 1 year of treatment
.. reduced long-term ischaemic recurrences, even if at the cost of
Nocerino et al,177 DAPT was consistently associated with a reduced ..
occlusion rate (RR 0.63, 95% CI 0.46–0.86). DAPT proved useful in .. higher bleeding.29,179
.. Patients medically managed in the PLATO trial derived consistent
preventing vein graft occlusion (RR 0.58, 95% CI 0.42–0.83), while no ..
clear effect was shown in arterial grafts (RR 0.85, 95% CI .. benefit from ticagrelor 90 mg b.i.d. as compared to clopidogrel.
.. Overall mortality was also reduced in patients treated with ticagrelor
0.39–1.85).177 Weak evidence indicates that DAPT may prevent graft ..
occlusion in patients undergoing off-pump CABG rather than on- .. 90 mg b.i.d.180
.. In the PEGASUS trial, 4271 patients had no prior coronary stent
pump CABG.178 Given the low risk of thrombotic events after ..
CABG in stable patients, there is insufficient evidence to generally .. implantation and they derived consistent benefits and risks from tica-
.. grelor vs. placebo on top of aspirin compared to patients with prior
recommend DAPT post-operatively to reduce vein graft occlusion in ..
this surgical patient subset. .. stenting.
.. Multiple sources have shown that medically managed ACS patients
..
5.4 Gaps in the evidence .. are less frequently treated with a DAPT regimen as compared to
.. patients who received PCI.181 Current evidence, especially for tica-
There are several gaps in the evidence that pertain to the use ..
.. grelor, does not support this practice and clinicians should refrain
of DAPT in cardiac surgery. Clear gaps in evidence related to DAPT .. from tailoring the implementation and/or duration of a DAPT regi-
in cardiac surgery patients include the question of whether DAPT ..
.. men depending on prior coronary stent implantation in the current
should be started after CABG in patients with stable CAD. Also, the .. era of newer-generation DES (Figure 6).
exact timing of post-operative DAPT restart remains unclear, and it ..
.. A special population that warrants specific consideration com-
remains uncertain for how long the post-operative DAPT should last. ..
Further gaps in the evidence relate to: the optimal time point for dis- .. prises patients with established NSTE-ACS in whom no lumen
.. obstruction at coronary angiography is detected. No dedicated
continuation of the different P2Y12 inhibitors; the optimal use of pla- ..
telet function testing in patients awaiting cardiac surgery; how to .. study exists assessing the benefits and risks of DAPT in this patient
.. subset. However, a high prevalence of ruptured plaques has been
manage perioperative bleeding complications in cardiac surgery ..
.. observed at intravascular imaging modalities in this population,182
patients caused by DAPT; and whether and how an incomplete .. suggesting that the benefits of DAPT in preventing recurrent MI
response or inadequate antiplatelet effect of aspirin after CABG ..
should be addressed.
.. should not be withheld from these patients if the risk of bleeding
.. does not outweigh the anticipated benefit.
..
.. The evidence in support of the DAPT treatment option in
.. patients with STEMI conservatively managed or with prior lysis is
6. Dual antiplatelet therapy for ..
.. limited to 1 month of treatment.31,32 Yet, in consideration of the
patients with medically managed .. fact that the majority of these patients would undergo invasive
..
acute coronary syndrome .. management afterwards, and evidence that DAPT may be benefi-
.. cial irrespective of whether revascularization takes place, it is rea-
..
The evidence for the use of DAPT in medically managed ACS .. sonable to prolong DAPT further in these patients depending on
patients comes from the CHARISMA and CURE for
.. the bleeding risk.
238 ESC Guidelines

Dual antiplatelet therapy duration in patients with acute coronary syndrome undergoing medical therapy
management.

Recommendations Classa Levelb

In patients with ACS who are managed with medical therapy alone and treated with DAPT, it is recommended to con-
I A
tinue P2Y12 inhibitor therapy (either ticagrelor or clopidogrel) for 12 months.20,40

Ticagrelor is recommended over clopidogrel, unless the bleeding risk outweighs the potential ischaemic benefit.20 I B

In patients with medically managed ACS who are at high risk of bleeding (e.g. PRECISE-DAPT >_25), DAPT for at least
IIa C
1 month should be considered.

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In patients with prior MI at high ischaemic riskc who are managed with medical therapy alone and have tolerated DAPT
without a bleeding complication, treatment with DAPT in the form of ticagrelor 60 mg b.i.d. on top of aspirin for longer IIb B
than 12 months and up to 36 months may be considered.139

In patients with prior MI not treated with coronary stent implantation, who have tolerated DAPT without a bleeding complica-
tion and who are not eligible for treatment with ticagrelor, continuation of clopidogrel on top of aspirin for longer than IIb C
12 months may be considered.

Prasugrel is not recommended in medically managed ACS patients.24 III B

ACS = acute coronary syndrome; b.i.d. = bis in die; CrCl = creatinine clearance; DAPT = dual antiplatelet therapy; MI = myocardial infarction; PRECISE-DAPT = PREdicting
bleeding Complications In patients undergoing Stent implantation and subsEquent Dual Anti Platelet Therapy.
a
Class of recommendation.
b
Level of evidence.
c
Defined as >_ 50 years of age, and one or more of the following additional high-risk features: age of 65 years or older, diabetes mellitus requiring medication, a second prior
spontaneous myocardial infarction, multivessel coronary artery disease, or chronic renal dysfunction, defined as an estimated creatinine clearance < 60 mL/min.

..
7. Dual antiplatelet therapy for .. scores also predict bleeding outcomes in AF,187 suggesting consider-
.. able overlap among risk factors associated with ischaemic and bleeding
patients with indication for oral ..
.. outcomes, multiple bleeding risk scores,188 including the HAS-BLED189
anticoagulation .. [Hypertension, Abnormal renal and liver function (1 point each),
..
.. Stroke, Bleeding history or predisposition, Labile INR, Elderly (>
7.1 Risk stratification and strategies to .. 65 years), Drugs and alcohol (1 point each)] score, have been shown
..
improve outcome after percutaneous .. to outperform CHADS2 [Cardiac failure, Hypertension, Age, Diabetes,
.. Stroke (Doubled)] or CHA2DS2-VASc in predicting bleeding risk.
coronary intervention ..
Approximately 6–8% of patients undergoing PCI have an indication for
.. Importantly, HAS-BLED draws attention to the reversible bleeding
..
long-term oral anticoagulants (OACs) due to various conditions such .. risk factors to be addressed by the responsible clinician during the fol-
as AF, mechanical heart valves, or venous thromboembolism.
.. low-up. Risk is not static and, particularly for bleeding, many risk factors
..
Compared with oral anticoagulation therapy alone, the addition of .. can be modified. Hence, a high risk of bleeding (e.g. HAS-BLED score
DAPT to OAC therapy results in at least a two- to threefold increase
.. >_3) is not a reason to withhold OAC; instead, such patients should be
..
in bleeding complications.183–186 Therefore, these patients should be .. ‘flagged-up’ for more careful review and follow-up.
.. More recently, the novel biomarker-based ABC [Age, Biomarkers
considered at high risk of bleeding, and the indication for OAC should ..
be reassessed and treatment continued only if a compelling indication .. (GDF-15, cTnT-hs, and haemoglobin), and Clinical history (previous
.. bleeding)]190 bleeding risk score has been generated and validated in
exists {e.g. paroxysmal, persistent, or permanent AF with a CHA2DS2- ..
VASc [Cardiac failure, Hypertension, Age >_75 (2 points), Diabetes, .. a broad AF population treated with both vitamin K antagonist (VKA)
.. and non-vitamin K oral anticoagulants (NOACs), and has shown
Stroke (2 points)–Vascular disease, Age 65–74, Sex category] score ..
>_1 in men, >_2 in women; mechanical heart valve; recent (i.e. 6 months) .. superior prediction capability as compared to HAS-BLED. However,
..
or a history of recurrent deep venous thrombosis or pulmonary .. similar to all other bleeding risk scores, none of these risk prediction
embolism}. Conversely, every effort should be undertaken to imple- .. models developed for OAC patients has been prospectively tested in
..
ment strategies to minimize PCI-related complications in these patients .. the setting of prospective RCTs. Therefore, their value in improving
(Table 4). In particular, the duration of triple therapy should be limited .. patient outcomes remains unclear.
..
or omitted after hospital discharge (i.e. confined to the periprocedural .. A comprehensive list of all risk factors that have been associated
phase with aspirin being stopped thereafter), taking into account the .. with greater bleeding risk has been previously published.162
..
ischaemic (e.g. complexity of treated CAD, amount of disease left .. In the absence of safety and efficacy data from RCTs [only 6% of
untreated, technical considerations regarding stent implantation techni-
.. patients were treated at baseline with ticagrelor or prasugrel in the
..
ques, and results) as well as the bleeding risks. While ischaemic risk . Rivaroxaban and a dose-adjusted oral VKA treatment strategy in
ESC Guidelines 239

Table 4 Strategies to avoid bleeding complications in


patients treated with oral anticoagulant

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ABC = Age, Biomarkers, Clinical history; CHA2DS2-VASc = Congestive heart
failure, Hypertension, Age >_75 years (doubled), Diabetes mellitus, prior Stroke
or transient ischaemic attack or thromboembolism (doubled), Vascular disease,
Age 65–74 years, Sex category; HAS-BLED = Hypertension, Abnormal renal/liver
function, Stroke, Bleeding history or predisposition, Labile INR, Elderly, Drugs/
alcohol concomitantly; NOAC = non-vitamin-K oral anticoagulant; INR = inter-
national normalized ratio; PCI = percutaneous coronary intervention; PPIs = pro-
ton pump inhibitors; VKA = vitamin K antagonist.
a
Apixaban 5 mg b.i.d or apixaban 2.5 mg b.i.d. if at least two of the following: age
>_80 years, body weight <_60 kg or serum creatinine level >_1.5 mg/dL (133 lmol/
L); dabigatran 110 mg b.i.d.; edoxaban 60 mg q.d. or edoxaban 30 mg q.d. if any of
the following: creatinine clearance (CrCl) of 30–50 mL/min, body weight <_60 kg,
concomitant use of verapamil or quinidine or dronedarone; rivaroxaban 20 mg
q.d. or rivaroxaban 15 mg q.d. if CrCl 30–49 mL/min.

..
.. lowest effective tested dose for stroke prevention should be applied
.. and criteria for drug accumulation for each approved NOAC should
..
.. be carefully assessed. Lower NOAC regimens as compared to those
.. tested in approval studies are expected to decrease bleeding risk, but
..
.. the trade-off between bleeding and ischaemic (i.e. stroke prevention)
.. outcomes remains largely undefined. The PIONEER AF-PCI study191
..
.. (described in detail below) tested two lower rivaroxaban doses
Figure 6 Algorithm for dual antiplatelet therapy (DAPT) in .. (15 mg o.d. and 2.5 mg b.i.d.) as compared to the approved drug regi-
patients with acute coronary syndrome undergoing medical manage- ..
.. men in AF patients (20 mg q.d.). The Evaluation of Dual Therapy With
ment. High bleeding risk is considered as an increased risk of sponta- .. Dabigatran vs. Triple Therapy With Warfarin in Patients With AF
neous bleeding during DAPT (e.g. PRECISE-DAPT score >_25). ..
Colour-coding refers to the ESC Classes of Recommendations
.. That Undergo a PCI With Stenting (REDUAL-PCI; NCT02164864)
.. will compare two dabigatran doses (150 mg b.i.d. and 110 mg b.i.d.) vs.
(green = Class I; yellow = IIa; orange = Class IIb). Treatments pre- ..
sented within the same line are sorted in alphabetic order, no prefer- .. VKA and will provide additional insights with respect to the balance
.. between efficacy and safety for each one. Whether there are differ-
ential recommendation unless clearly stated otherwise. ..
1: if patient is not eligible for a treatment with ticagrelor .. ences according to the type of OAC (NOACs vs. VKA) or stent plat-
..
.. form as well the duration of triple therapy is further discussed. These
.. considerations do not pertain to medically managed patients or to
subjects with atrial fibrillation who undergo percutaneous coronary ..
.. patients eligible for CABG surgery in whom DAPT should be avoided
intervention (PIONEER AF-PCI) study191] and worrisome bleeding .. on top of OAC.
signals in registries, the use of prasugrel or ticagrelor as part of triple ..
..
therapy should be avoided.192 Gastric protection with a PPI is recom- ..
mended. The dose intensity of OAC should be carefully monitored .. 7.2 Duration of triple therapy
..
with a target international normalized ratio (INR) in the lower part of .. Cessation of aspirin after PCI while maintaining clopidogrel has been
the recommended target range; in patients treated with NOACs, the .. evaluated in the What is the Optimal antiplatElet and anticoagulant
240 ESC Guidelines

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Figure 7 Algorithm for dual antiplatelet therapy (DAPT) in patients with an indication for oral anticoagulation undergoing percutaneous coronary
intervention (PCI). Colour-coding refers to the number of concomitant antithrombotic medication(s). Triple therapy denotes treatment with DAPT
plus oral anticoagulant (OAC). Dual therapy denotes treatment with a single antiplatelet agent (aspirin or clopidogrel) plus OAC.
ABC = age, biomarkers, clinical history; ACS = acute coronary syndrome; mo. = month(s); PCI = percutaneous coronary intervention.
1: Periprocedural administration of aspirin and clopidogrel during PCI is recommended irrespective of the treatment strategy.
2: High ischaemic risk is considered as an acute clinical presentation or anatomical/procedural features which might increase the risk for
myocardial infarction.
3: Bleeding risk can be estimated by HAS-BLED or ABC score.

therapy in patients with OAC and coronary StenTing (WOEST) trial, .. More recently, the PIONEER AF-PCI study randomized 2124
which randomized 573 patients (of whom 69% of patients had AF) to
... patients with non-valvular AF who had undergone PCI with stenting
..
dual therapy with OAC and clopidogrel (75 mg/day) or to triple ther- .. to receive, in a 1:1:1 ratio: low-dose rivaroxaban (15 mg o.d.) plus a
apy with OAC, clopidogrel, and aspirin 80 mg/day.193 Treatment was
.. P2Y12 inhibitor (and no ASA) for 12 months; very-low-dose rivaroxa-
..
continued for 1 month after BMS placement and for 1 year after DES .. ban (2.5 mg b.i.d.) plus DAPT for 1, 6, or 12 months; or standard ther-
placement (65% of patients). PCI was performed on VKA therapy in
.. apy with a dose-adjusted VKA plus DAPT for 1, 6, or 12 months.191
..
half of the patients. The primary endpoint of any TIMI bleeds assessed .. The primary safety endpoint, consisting of TIMI clinically significant
at 1-year follow-up was significantly reduced in the dual-therapy arm
.. bleeding, was lower in the two groups receiving rivaroxaban than in
..
(19.5% vs. 44.9%; HR 0.36, 95% CI 0.26–0.50; P < 0.001), while no sig- .. the group receiving standard therapy [16.8% in patients treated with
..
nificant difference in major bleeding was observed. The rates of MI, .. rivaroxaban 15 mg, 18% in patients treated with rivaroxaban 2.5 mg,
stroke, target vessel revascularization, or stent thrombosis did not .. and 26.7% in patients treated with triple therapy (HR 0.59, 95% CI
..
differ significantly, but all-cause mortality was lower in the dual- .. 0.47–0.76; P < 0.001, and HR 0.63, 95% CI 0.50–0.80; P < 0.001,
therapy group (2.5% vs. 6.4%; P = 0.027) at 1 year. .. respectively)]. It is worth mentioning that as many as 49% of patients
ESC Guidelines 241

in both DAPT groups continued triple therapy for 12 months and no


Dual antiplatelet therapy duration in patients with indi-
difference in major bleeding or transfusion was observed across the
cation for oral anticoagulation
groups. Moreover, an INR range of 2–3 was recommended, instead
of 2–2.5, which may have inflated bleeding risk in the control group.
Recommendations Classa Levelb
The rates of all-cause death, death from cardiovascular causes, MI, or
stroke were similar in the three groups.194 However, this study, simi- It is recommended to administer periproce-
lar to WOEST, was largely underpowered for the assessment of durally aspirin and clopidogrel in patients I C
meaningful differences in the incidence of relevant ischaemic events undergoing coronary stent implantation.
such as stent thrombosis or stroke rates. Therefore, uncertainty
remains regarding the comparative performance of three tested In patients treated with coronary stent implan-
antithrombotic regimens in patients at high stroke and/or stent tation, triple therapy with aspirin, clopidogrel,
IIa B
thrombosis risk. Procedural characteristics of coronary intervention and OAC should be considered for 1 month,

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have not been reported so far and patients with prior stroke were irrespective of the type of stent used.195
excluded from participation. As a result, the balance of ischaemic and Triple therapy with aspirin, clopidogrel, and
bleeding risks of relatively short (i.e. 6 months or less) triple therapy OAC for longer than 1 month and up to
duration (possibly with NOAC instead of VKA) as compared to dou- 6 months should be considered in patients
ble therapy consisting of clopidogrel and OAC remains unknown and IIa B
with high ischaemic risk due to ACS or
requires a patient-by-patient decision. other anatomical/procedural characteristics
Dual therapy with clopidogrel and OAC after PCI remains an that outweigh the bleeding risk.195
appealing alternative to triple therapy given that patients exposed to
OAC are at high bleeding risk, but more data, especially on efficacy Dual therapy with clopidogrel 75 mg/day
and particularly in patients at high risk for stroke and/or recurrent and OAC should be considered as an alter-
ACS, are needed. Cessation of clopidogrel while maintaining aspirin native to 1-month triple antithrombotic IIa A
has also been tested in the Triple Therapy in Patients on Oral therapy in patients in whom the bleeding
Anticoagulation After Drug Eluting Stent Implantation (ISAR-TRIPLE) risk outweighs the ischaemic risk.191,193
trial, where 614 patients (one-third with ACS) undergoing stenting Discontinuation of antiplatelet treatment in
and requiring OAC were randomly assigned to receive either 6- patients treated with OAC should be con- IIa B
week or 6-month clopidogrel therapy in addition to aspirin and sidered at 12 months.198
VKA.195 The primary endpoint of death, MI, stent thrombosis, ischae-
mic stroke, or TIMI major bleeding at 9 months did not differ In patients with an indication for VKA in combi-
between the 6-week and 6-month triple therapy (9.8% vs. 8.8%; HR nation with aspirin and/or clopidogrel, the dose
1.14, 95% CI 0.68–1.91; P = 0.63); the same was true for the com- intensity of VKA should be carefully regulated
IIa B
bined incidence of death, MI, stent thrombosis, and ischaemic stroke with a target INR in the lower part of the rec-
(4.0% vs. 4.3%; HR 0.93, 95% CI 0.43–2.05; P = 0.87). Furthermore, ommended target range and a time in the ther-
no difference in TIMI major bleeding (5.3% vs. 4.0%; HR 1.35, 95% CI apeutic range >65–70%.193,195
0.64–2.84; P = 0.44) was observed.
When a NOAC is used in combination with
In all three studies, roughly one-third of patients presented with ACS.
aspirin and/or clopidogrel, the lowest approved
There was no interaction between the duration of triple therapy and clini- IIa C
dose effective for stroke prevention tested in
cal presentation (ACS vs. no ACS), which may reflect a real lack of c
AF trials should be considered.
increased coronary ischaemic risk in these patients or a lack of power to
detect clinically meaningful differences in coronary ischaemic outcomes if When rivaroxaban is used in combination with
these patients undergo shorter duration of DAPT regimen (i.e. 1 month195 aspirin and/or clopidogrel, rivaroxaban 15 mg q.d. IIb B
or immediate discontinuation of aspirin after PCI191,193). The rate of bleed- may be used instead of rivaroxaban 20 mg q.d.191
ing events peaked within the first 30 days of initiation of triple therapy
The use of ticagrelor or prasugrel is not rec-
and was twice as high when compared with the rate of acute coronary
ommended as part of triple antithrombotic III C
events including recurrent MI and stent thrombosis. These observa-
therapy with aspirin and OAC.
tions are consistent with the nationwide Danish registry of AF all-
comers with MI, where the 90-day bleeding risk was increased on triple
ACS = acute coronary syndrome; AF = atrial fibrillation; b.i.d. = bis in die; CrCl = creati-
therapy compared with OAC plus a single antiplatelet agent (HR 1.47, nine clearance; INR = international normalized ratio; NOAC = non-vitamin K oral anti-
95% CI 1.04–2.08), with a consistent trend at 360 days (HR 1.36, 95% coagulant; OAC = oral anticoagulant; q.d. = quaque die; VKA = vitamin K antagonist.
a
CI 0.95–1.95), without differences in ischaemic events (HR 1.15, 95% Class of recommendation.
b
Level of evidence.
CI 0.95–1.40).196 The same registry suggests that warfarin plus clopi- c
Apixaban 5 mg b.i.d or apixaban 2.5 mg b.i.d. if at least two of the following: age
dogrel resulted in a non-significant reduction in major bleeds (HR 0.78, >_80 years, body weight <_60 kg or serum creatinine level >_1.5 mg/dL (133 lmol/
95% CI 0.55–1.12) compared with triple therapy, with a non-significant L); dabigatran 110 mg b.i.d.; edoxaban 60 mg q.d. or edoxaban 30 mg q.d. if any of
the following: CrCl of 30–50 mL/min, body weight <_60 kg, concomitant use of
reduction in MI or coronary death (HR 0.69, 95% CI 0.55–1.12).197 For verapamil, quinidine, or dronedarone; rivaroxaban 20 mg q.d. or rivaroxaban
these reasons, duration of triple therapy should be minimized depend- 15 mg q.d. if CrCl 30–49 mL/min.
ing on bleeding and ischaemic risks (Figure 7; Tables 5 and 6).
242 ESC Guidelines

..
Table 5 High-risk features of stent-driven recurrent
.. underpowered for ischaemic endpoints. Therefore, no conclusion can
.. be made on the advantages and limitations of each OAC as compared
ischaemic events ..
.. to others. However, there was an excess of stroke events in the 2.5 mg
.. b.i.d. rivaroxaban arm in combination with 6-month DAPT as compared
..
.. to VKA and 6-month DAPT (6 vs. 0 events; P = 0.02).
.. In the four phase III NOAC AF trials, no interactions were demon-
..
.. strated between treatment effect and outcome according to prior
.. coronary status (ACS vs. no ACS), and it is likely that the benefit of
..
.. NOAC over VKA is preserved in CAD patients with AF.199–202 At
.. least, this was the case among patients exposed to antiplatelet ther-
..
.. apy. There is no strong evidence for choosing one NOAC over
.. another. Dabigatran is the only NOAC that has been tested in a
..

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.. phase III trial at reduced daily regimen (i.e. 110 mg b.i.d.) and for which
.. non-inferiority vs. warfarin was shown.199 Although lower doses of
..
.. other NOACs (i.e. apixaban 2.5 mg b.i.d. or edoxaban 30 mg o.d.)
.. might be considered to reduce bleeding risk, these dosages have
..
.. been evaluated only in a subset of patients in the phase III trials based
.. on prespecified dosing algorithms. Their benefit in stroke prevention
..
Table 6 Unfavourable patient profile for a combina-
.. in patients with a normal renal function is uncertain. Three ongoing
.. large-scale outcome studies are evaluating combinations of NOACs
tion of oral anticoagulant and antiplatelet therapy ..
.. or VKAs with antiplatelet therapy in AF patients undergoing stent-
..
.. PCI (NCT02164864, NCT02415400, and NCT02866175). Various
.. dose regimens of NOAC, different types of P2Y12 inhibitors, and dif-
..
.. ferent exposure times are being evaluated.
..
..
.. 7.5 Type of stent
..
.. The choice of newer-generation DES vs. BMS in patients requiring
.. long-term anticoagulation is no longer controversial. First, data from
..
.. the DAPT trial indicate a similar impact of prolonged DAPT adminis-
.. tration irrespective of stent type (BMS vs. DES),128 and the risk of
..
.. adverse events among patients with DAPT cessation and patients
.. undergoing non-cardiac surgery indicate no differences between
..
.. BMS and DES.17,129,203 Second, two randomized trials have demon-
.. strated the superiority of newer-generation DES over BMS in high
..
.. bleeding risk patients who cannot tolerate long-term exposure to
.. DAPT,130,204 such as those needing chronic OAC (section 2.2).
7.3 Cessation of all antiplatelet agents ..
.. Altogether, both trials suggest that second-generation DES should
Data on the timing of cessation of any antiplatelet agents in stented .. be the default choice in patients with high bleeding risk.
..
patients requiring chronic OAC are scarce. In stabilized event-free ..
patients, discontinuation of any antiplatelet agent at 1 year after stent- ..
..
ing is encouraged in this patient population based on studies demon- .. 8. Elective non-cardiac surgery in
strating that OACs alone are superior to aspirin post-ACS, and OAC ..
.. patients on dual antiplatelet
þ aspirin may not be more protective but associated with excess ..
bleeding.198 Dual therapy with OAC and one antiplatelet agent ..
.. therapy
(aspirin or clopidogrel) may be considered beyond 1 year in patients ..
at very high risk of coronary events as defined in Table 534 and in .. It is estimated that 5–25% of patients with coronary stents may
..
patients with mechanical prosthesis and atherosclerotic disease. .. require non-cardiac surgery within 5 years after stent implantation.205
.. Management of patients on DAPT who are referred for surgical pro-
..
.. cedures involves consideration of: (1) the risk of stent thrombosis
7.4 Type of anticoagulants .. (particularly if DAPT needs to be interrupted); (2) the consequences
..
PIONEER AF-PCI is the only randomized study comparing VKAs and .. of delaying the surgical procedure; and (3) the increased intra- and
NOACs in patients with AF undergoing PCI for ACS or for stable CAD .. periprocedural bleeding risk and possible consequences of such
..
(i.e. patients who have an indication to receive DAPT).191 However, in .. bleeding if DAPT is continued.206–208 Given the complexity of these
this study, two non-approved rivaroxaban regimens for AF patients .. considerations, a multidisciplinary approach—involving interven-
..
were tested and a low (i.e. 15 mg q.d.) or very low (i.e. 2.5 mg b.i.d.) rivar- .. tional cardiologists, cardiologists, anaesthetists, haematologists, and
oxaban dose in combination with a single P2Y12 inhibitor or DAPT was
.. surgeons—is required to determine the patient’s risk for bleeding
..
compared to VKA plus DAPT, respectively. The study was . and thrombosis and to choose the best management strategy.
ESC Guidelines 243

..
Surgical interventions can be divided into low-risk, intermediate-risk, .. group, these findings are potentially influenced by the type and
and high-risk groups, with estimated 30-day cardiac event rates .. urgency of the surgical procedures. To overcome this limitation, two
..
for cardiac death or MI of < 1%, 1–5%, and >_5%, respectively.205,209 .. large matched cohorts of patients undergoing surgery were recently
A practical classification of the bleeding risk associated with each type .. reported. Using Danish population-based registries and individual-
..
of non-cardiac surgery has been recently proposed by the Stent .. based record linkage of Danish registries, 4303 DES-PCI-treated
After Surgery group.210 .. patients who underwent a surgical procedure within 12 months were
..
In surgical procedures with low bleeding risk, every effort should be .. identified and were compared with a control group of patients with-
taken not to discontinue DAPT perioperatively. In surgical procedures .. out established stable CAD undergoing similar surgical procedures (n
..
with moderate bleeding risk, patients should be maintained on aspirin .. = 20 232).226 This evaluation of the comparative risk associated with
while P2Y12 inhibitor therapy should be discontinued whenever possi- .. surgery in DES-PCI-treated patients vs. patients without known sta-
..
ble. More challenging decision making is to be faced among patients on .. ble CAD revealed an increased overall risk for MI and cardiac death
DAPT who undergo high bleeding risk non-cardiac surgeries, including .. in the patients with previous DES-PCI, owing to higher MI rates but
..

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vascular reconstructions, complex visceral procedures, neurosurgery, .. similar mortality risk.226 However, this difference was highly time-
and transbronchial operations.211–213 In these cases, particular atten- .. dependent and limited to the first month after DES-PCI.226 These
..
tion should be paid to timely discontinuation of P2Y12 inhibitor therapy .. data suggest that surgery, if possible, should be delayed for at least
to minimize the off-therapy period before surgical intervention.
.. 1 month after DES-PCI. Data for patients with coronary stents
..
Discontinuation before non-cardiac surgery: To reduce the risk of .. implanted in a Veterans’ Administration (VA) hospital from 2000 to
bleeding and transfusion, it is recommended to postpone elective
.. 2010 were also recently matched with VA Surgical Quality
..
non-cardiac surgery until completion of the full course of DAPT. In .. Improvement Program data to identify non-cardiac surgery within
most clinical situations, aspirin provides benefit that outweighs the
.. 24 months of stent placement.227 Each patient with a stent(s) was
..
bleeding risk and should be continued.214,215 Possible exceptions to .. matched with two surgical patients without stents on surgical charac-
..
this recommendation include intracranial procedures, transurethral .. teristics and cardiac risk factors. The two groups had similar risk of
prostatectomy, intraocular procedures, and operations with .. adverse cardiac events during 2 years of follow-up. However, patients
..
extremely high bleeding risk.157 .. with stents had a higher risk of adverse cardiac events within the
A higher risk of ischaemic events in the case of non-cardiac surgery .. 30-day post-operative period.227 The incremental risk did not vary by
..
has been reported after first-generation DES203 and a higher risk for .. stent type.227 In both studies, roughly 50% of patients underwent
MACE has also been shown during the first weeks after non-cardiac .. stenting because of ACS and no incremental risk was observed in this
..
surgery in patients with implanted stents.203,216,217 Furthermore, sur- .. higher risk population as compared to stable CAD patients.
gery per se, irrespective of the timing of DAPT discontinuation, is .. Therefore, a minimum of 1 month of DAPT should be considered,
..
associated with pro-inflammatory and pro-thrombotic effects, .. independently of the type of implanted stent (i.e. BMS or newer-gen-
thereby increasing the risk of coronary thrombosis at the level of the .. eration DES), in cases when surgery cannot be delayed for a longer
..
stented vascular segment as well as throughout the coronary vascula- .. period; however, such surgical procedures should be performed in
ture.218,219 Therefore, in patients undergoing non-cardiac surgery .. hospitals where catheterization laboratories are available 24/7, so as
..
after recent ACS or stent implantation, the benefits of early surgery .. to treat patients immediately in case of perioperative thrombotic
for a specific pathology (e.g. malignant tumours or vascular aneurysm .. events (Figure 8). In patients at high ischaemic risk due to ACS pre-
..
repair) should be balanced against the risk of cardiovascular events .. sentation or complex coronary revascularization procedure, delaying
and the strategy should be discussed by a multidisciplinary team.
.. surgery up to 6 months after index ACS or PCI may be reasonable as
..
Prior recommendations with regard to duration of DAPT220,221 .. an additional safeguard to minimize the risk of perisurgical MI, and
and the timing of non-cardiac surgery207,222 in patients treated with
.. based on unmatched retrospective registry data if the risks of further
..
DES were based on observations of those treated with first- .. delaying surgery are acceptable.
generation DES. Compared with first-generation DES, currently used
.. In patients needing surgery within a few days, it was previously rec-
..
newer-generation DES are associated with a lower risk of stent .. ommended to withhold clopidogrel and ticagrelor for 5 days and pra-
thrombosis and appear to require a shorter minimum duration of
.. sugrel for 7 days prior to surgery unless there is a high risk of
..
DAPT.100,103,104,223–225 Furthermore, in the PARIS registry, interrup- .. thrombosis.228 However, emerging evidence, which is extensively
..
tion of DAPT grounded on physician judgment in patients undergoing .. discussed in Chapter 5, challenges such a long discontinuation period
surgery at any time point after PCI was not associated with an .. for ticagrelor before a safe surgical procedure can be undertaken
..
increased risk of MACE.17 .. (Figure 9).152,153
In the absence of a surgical control group, it remains challenging to .. Although these data refer to patients undergoing cardiac surgery,
..
identify a clear time frame after ACS or coronary stenting where .. it is rational to extend these findings to the non-cardiac surgery popu-
there is no additional risk or the risk is acceptably low for patients to .. lation, given the same offset kinetics and principally lower risk of
..
undergo surgery. Therefore, almost all registries have attempted to .. bleeding in non-cardiac surgeries relative to cardiac surgery proce-
identify such landmarks by looking at the time course of the surgical .. dures (Figure 9). In cases where the consequences of even minor
..
ischaemic risk over time in order to identify when it levels off and .. bleeding would be unacceptable (e.g. spinal surgery or other neuro-
remains stable thereafter following an ACS or stent implantation pro- .. surgical procedures) or the bleeding risk largely outweighs the ischae-
..
cedure.17 By doing so, many registries have reported that surgery- .. mic risk (e.g. a medium- to high-risk surgical bleeding procedure is
associated risk in DES-PCI-treated patients reaches a stable level .. undertaken 6 months or more after single stent implantation for sta-
..
after 3–6 months.17,214,215 However, without a surgical control . ble CAD indication), P2Y12 inhibitors may be discontinued for a
244 ESC Guidelines

.. as possible (within 48 h), given the substantial thrombotic hazard


..
.. associated with lack of platelet inhibition early after surgery in
..
.. patients with recent stent implantation and/or an ACS episode
.. (Figure 9).232,233
..
.. The time for restarting P2Y12 inhibitors after surgery should ulti-
.. mately be determined via a multidisciplinary discussion before sur-
..
.. gery and traced in the patient file.

Dual antiplatelet therapy in patients undergoing elec-


tive non-cardiac surgery

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Recommendations Classa Levelb

It is recommended to continue aspirin peri-


operatively if the bleeding risk allows, and to
resume the recommended I B
antiplatelet therapy as soon as possible
post-operatively.232–236

After coronary stent implantation, elective


surgery requiring discontinuation of the
P2Y12 inhibitor should be considered after
IIa B
1 month, irrespective of the stent type, if
aspirin can be maintained throughout the
perioperative period.227

Discontinuation of P2Y12 inhibitors should


be considered at least 3 days before surgery
for ticagrelor, at least 5 days for IIa B
clopidogrel, and at least 7 days for
prasugrel.152,153,160

Figure 8 Timing for elective non-cardiac surgery in patients A multidisciplinary expert team should be
treated with dual antiplatelet therapy (DAPT) after percutaneous considered for pre-operative evaluation of
IIa C
coronary intervention (PCI). Colour-coding refers to the ESC patients with an indication for DAPT before
Classes of Recommendations (green = Class I; yellow = IIa; orange elective surgery.
= Class IIb).
ACS = acute coronary syndromes. In patients with recent MI or other high
1
Availability of H24 cath-lab service in place is suggested in ischaemic risk featuresc requiring DAPT,
IIb C
case of major surgery within 6 months after PCI. elective surgery may be postponed for up
2
High ischaemic risk features are presented in Table 5. to 6 months.17,214,215,234

If both oral antiplatelet agents have to be


discontinued perioperatively, a bridging
longer duration of time to ensure no residual platelet inhibition at the
strategy with intravenous antiplatelet agents
time of planned surgery. For patients with a very high risk of stent IIb C
may be considered, especially if surgery has
thrombosis, bridging therapy with intravenous, reversible glycopro-
to be performed within 1 month after stent
tein inhibitors, such as eptifibatide or tirofiban,229 may be considered.
implantation.229,237–239
Cangrelor, a reversible intravenous P2Y12 inhibitor, has been shown
to provide effective platelet inhibition230 and is an appealing alterna- It is not recommended to discontinue
tive to glycoprotein IIb/IIIa inhibitors,231 given the well-known role of DAPT within the first month of treatment
III B
P2Y12 inhibition in preventing stent thrombosis and the quicker offset in patients undergoing elective non-cardiac
of action as compared to tirofiban or eptifibatide. Concomitant surgery.203
parenteral anticoagulation therapy in conjunction with cangrelor or
reversible glycoprotein inhibitors is not recommended to minimize DAPT = dual antiplatelet therapy; MI = myocardial infarction.
a
bleeding risk while awaiting surgical procedures. Class of recommendation.
b
Level of evidence.
Restart after surgery: If P2Y12 inhibitor therapy has been stopped c
High ischaemic risk features are provided in Table 5.
before a surgical procedure, therapy should be restarted as soon
ESC Guidelines 245

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Figure 9 Minimal discontinuation and re-implementation time frames of dual antiplatelet therapy (DAPT) for patients undergoing elective surgery
OAC = oral anticoagulant.

..
9. Gender consideration and .. presence of diabetes should affect decision making with respect to
.. the choice of P2Y12 inhibitors.
special populations ..
.. As it related to DAPT duration, the DAPT study found a slightly
.. lower relative risk reduction for MI endpoint in patients with diabetes
9.1 Gender specificities ..
.. as compared to those without diabetes (Pint = 0.02).242 However,
There is no convincing evidence for a gender-related difference in the .. there was no signal for heterogeneity with respect to the concomitant
efficacy and safety of currently available DAPT type or duration across ..
.. presence of diabetes mellitus across all other ischaemic or safety end-
studies. No single trial or pooled analysis of investigations assessing a .. points. Finally, no difference with respect to the presence or absence
shorter than 1 year vs. at least 1 year DAPT duration has shown heter- ..
.. of diabetes was observed for the primary efficacy endpoint in the
ogeneous findings across genders.26,112,240,241 In the DAPT trial, there .. PEGASUS study (P = 0.99).145 Altogether, current evidence suggests
was a borderline quantitative interaction suggesting a lower relative .. int
.. that diabetes mellitus should not be the only appraised patient-specific
treatment benefit for stent thrombosis reduction with prolonged .. feature when deciding upon the type or duration of DAPT.
DAPT in female as compared to male patients (Pint =0.04).26 ..
..
However, no such signal was apparent for MACCE (Pint = 0.46) or ..
bleeding (Pint = 0.40) endpoints. Within the PEGASUS trial, there was ..
.. 9.3 Lower-extremities artery disease
no signal suggesting heterogeneity across the primary study endpoint .. Patients with LEAD are at heightened risk of ischaemic complications
with respect to gender (Pint = 0.84).29 On the other hand, there was a ..
.. and mortality. The combination of symptomatic LEAD and CAD is
positive quantitative interaction (Pint = 0.03) suggesting that female .. associated with further heightened ischaemic risk beyond that associ-
patients may derive a relatively greater treatment benefit with respect
..
.. ated with symptomatic disease in either vascular bed alone.243 In 3096
to stroke prevention from prolonged treatment with aspirin and tica- ..
grelor as compared to aspirin alone. However, no such signal was evi-
.. patients with LEAD included in the CHARISMA trial, DAPT was asso-
.. ciated with a lower rate of MI and hospitalization for ischaemic events
dent for cardiovascular death, MI, or safety endpoints. ..
.. but not the overall composite primary endpoint. There was no differ-
.. ence between the groups in moderate, severe, or fatal bleeding, but
..
9.2 Diabetes mellitus .. there was an increase in minor bleeding in the DAPT group.244 The
Patients with diabetes mellitus presenting with both stable and unsta- .. PEGASUS investigators recently examined a subgroup of 1143 patients
..
ble CAD carry a worse prognosis in terms of short- and long-term .. with LEAD and found that patients with prior MI with LEAD had a 60%
risks of fatal and non-fatal ischaemic events, with enhanced platelet .. increased risk of MACE relative to patients without LEAD, even after
..
hyperactivity playing a putative causal role. In the CURE trial, patients .. adjusting for differences in baseline characteristics.140 This increased
with diabetes derived a similar treatment benefit from the addition of .. ischaemic risk translated into a robust absolute risk reduction of 5.2%
..
clopidogrel on top of aspirin as compared to patients without.40 No .. at 3 years with ticagrelor 60 mg b.i.d. compared with placebo. In the set-
signal for greater treatment benefit was apparent in TRITON-TIMI .. ting of this robust ischaemic risk reduction, there were significant
..
38 in patients with diabetes as compared to those without with .. reductions in cardiovascular and all-cause mortality. Treatment with
respect to the study primary endpoint, and a consistent lack of heter-
.. ticagrelor vs. placebo reduced the risk of adverse limb events in addi-
..
ogeneity signal with respect to diabetes mellitus was observed in the .. tion to the benefits observed for MACE and mortality. Reductions in
PLATO trial.20,23 Hence, there is no convincing evidence that the
.. acute limb ischaemia have also been shown with other antiplatelet
246 ESC Guidelines

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Figure 10 Practical recommendations for the management of bleeding in patients treated with dual antiplatelet therapy with or without concomi-
tant oral anticoagulation. Practical recommendations for the management of bleeding in patients treated with dual antiplatelet therapy with or with-
out concomitant oral anticoagulation. Blue boxes refer to management of antiplatelet therapy. Dark-red boxes refer to the management of oral
anticoagulation. Light-green boxes refer to general recommendation for patients’ safety.
ACS = acute coronary syndrome; CHA2DS2-VASc= cardiac failure, hypertension, age >_75 (2 points), diabetes, stroke (2 points)–vascu-
lar disease, age 65–74, sex category; DAPT = dual antiplatelet therapy; GI = gastrointestinal; HB = haemoglobin; INR = international
normalized ratio; i.v. = intravenous; OAC = oral anticoagulant; NOAC = non-vitamin-K antagonist; PPI = proton pump inhibitor; RBC
= red blood cell; SAPT = single antiplatelet therapy.
ESC Guidelines 247

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Figure 10 Continued

agents, such as vorapaxar, demonstrating that this morbidity is modifi- .. Prolonged vs. short DAPT conveyed a lower risk of the primary effi-
..
able with potent and prolonged antithrombotic strategies.245 In the all- .. cacy endpoint in LEAD patients (16.1% vs. 27.3%; HR 0.54, 95% CI
comer PRODIGY trial, 246 (12.5%) patients were included with symp-
.. 0.31–0.95; P = 0.03) but not in patients without LEAD (9.3% vs. 7.4%;
..
tomatic LEAD. LEAD status was associated with a higher risk of death .. HR 1.28, 95% CI 0.92–1.77; P = 0.14), with positive interaction (P =
and ischaemic events (HR 2.80, 95% CI 2.05–3.83; P < 0.001).246
.. 0.01). The risk of definite or probable stent thrombosis as well as
248 ESC Guidelines

overall mortality was significantly lower in LEAD patients treated with .. cannot be regarded as an effective treatment option. Considering the
..
prolonged DAPT as compared with those receiving short DAPT. .. long-term risk of recurrence after first stent thrombosis, it may be rea-
.. sonable to make every effort to maintain DAPT for a very long-term
..
9.4 Complex percutaneous coronary .. period in this highly selected high-risk patient population, if tolerated.
..
intervention ..
..
While high PCI complexity intuitively represents a driver for favouring .. 9.6 Patients who develop bleeding while
a prolonged over a shortened DAPT duration, the evidence regarding ..
.. on treatment
optimal DAPT duration based on complexity of intervention is limited. .. Patients who develop bleeding complications while on DAPT repre-
In a patient-level meta-analysis from six RCTs investigating DAPT ..
.. sent a challenging patient population for whom no guidance from
durations after coronary stenting, including 9577 patients, complex .. RCTs is available.
PCI was defined as the composite of at least three stents implanted, at ..
.. The decision to withhold or continue DAPT in this setting largely

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least three lesions treated, bifurcation with two stents implanted, total .. depends on ischaemic (e.g. indication for DAPT and time from last
stent length >60 mm, and chronic total occlusion as target lesion.247
..
.. stent insertion, if any, to bleeding) vs. recurrent/prolonged bleeding
Patients who underwent complex PCI had a two-fold increase of .. risks. A practical flow chart in order to manage this challenging popu-
MACE (5.0% vs. 2.5%; P = 0.001). Long- and short-DAPT were
..
.. lation is provided in Figure 10 and additional information on practical
defined as a DAPT duration >_12 months and <_6 months, respectively. .. management can be found elsewhere.249 As bleeding is an independ-
Compared with short-DAPT, long-DAPT was associated with a signif-
..
.. ent predictor of recurrent bleeding,250 type, dose, and duration of
icant reduction in MACE in the complex PCI group (4.0% vs. 6.0%; .. DAPT should be reassessed in this setting.
adjusted HR 0.56, 95% CI 0.35–0.89) vs. the non-complex PCI group
(2.5% vs. 2.6%; adjusted HR 1.01, 95% CI 0.75–1.35; Pint = 0.01). The
Gender considerations and special populations
magnitude of the reduction in MACE with long-DAPT increased pro-
gressively as the degree of procedural complexity was greater. Long-
DAPT was overall associated with increased risk of major bleeding, Recommendations Classa Levelb
which was uniform in magnitude between groups (Pint = 0.15). Similar type and duration of DAPT are rec-
ommended in male and female I A
9.5 Dual antiplatelet therapy decision patients.26,240
making in patients with stent thrombosis It is recommended to reassess the type,
Patients presenting with stent thrombosis represent a challenging dose, and duration of DAPT in patients with
patient population in whom no randomized clinical evidence is available I C
actionable bleeding complications while on
to guide decision making. Observational studies have shown that the treatment.
risk of stent thrombosis recurrence after the first episode of stent
thrombosis is worrisome. Armstrong et al reported on a combined ret- Similar type and duration of DAPT should
rospective and prospective observational California registry of angio- be considered in patients with and without IIa B
graphic definite stent thrombosis at five academic hospitals from 2005 diabetes mellitus.145,242
to 2013.248 The entry criterion was the occurrence of a definite stent
Prolonged (i.e. >12 monthsc) DAPT dura-
thrombosis, which was observed in 221 patients overall out of an
tion should be considered in patients with
unknown number of patients at risk. With the important caveat of not
prior stent thrombosis, especially in the
knowing for each stent type the exact timing of the first stent thrombo- IIa C
absence of correctable causes (e.g. lack of
sis event after the index procedure, 104 (47%) patients had received a
adherence or correctable mechanical stent-
first generation DES, 51 (23%) a BMS, and 19 (9%) a second generation
related issues).
DES. After a median follow-up of 3.3 years, 29 patients developed defi-
nite or probable recurrent stent thrombosis, while 19 presented angio- Prolonged (i.e. >12 months) DAPT duration
graphic definite recurrent stent thrombosis. The cumulative hazard of may be considered in CAD patients with IIb B
definite or probable recurrent stent thrombosis was 16% at 1 year and LEAD.140,246
24% at 5 years. The cumulative hazard of angiographic definite recurrent
Prolonged (i.e. >6 months) DAPT durationd
stent thrombosis was 11% at 1 year and 20% at 5 years. Taken together,
may be considered in patients who under- IIb B
these findings confirm the high risk of stent thrombosis recurrence after
went complex PCI.247
the first stent thrombosis. An additional piece of information, which is
conveyed by this important analysis, is that the risk of recurrence is high-
CAD = coronary artery disease; DAPT = dual antiplatelet therapy; LEAD =
est in the first few months after the first event and that it does not abate lower-extremities artery disease; PCI = percutaneous coronary intervention.
entirely over time. Both prasugrel and ticagrelor have been shown to a
Class of recommendation.
b
be associated with a significant reduction of definite and definite or Level of evidence.
c
Possibly for as long as can be tolerated.
probable stent thrombosis as compared to clopidogrel.20,23 Moreover, d
Complex PCI defined as the composite of at least three stents implanted, at
both studies indicated that the number of recurrent events is also signifi- least three lesions treated, bifurcation with two stents implanted, total stent
cantly decreased by treatment with ticagrelor or prasugrel as compared length >60 mm, and chronic total occlusion as target lesion.
to clopidogrel. Hence, the use of clopidogrel after stent thrombosis
ESC Guidelines 249

..
10. Key messages .. therapy may be considered in ACS patients who have tolerated
.. DAPT without a bleeding complication.
(1) Benefits and risks of DAPT: DAPT reduces the risk of stent throm- .. (9) Patients with indication for oral anticoagulation: Compared with
..
bosis across the entire spectrum of events, from acute to very late .. OAC therapy alone, the addition of DAPT to OAC therapy results
occurrences. However, treatment with DAPT beyond 1 year after .. in at least a two- to three-fold increase in bleeding complications.
..
MI, or after PCI, exerts the majority of its benefit by reducing the .. Therefore, these patients should be considered at high risk of
rate of spontaneous MI. The risk of bleeding in patients on DAPT is
.. bleeding and the indication for OAC should be reassessed and
..
proportionally related to its duration both within and beyond .. treatment continued only if a compelling indication exists.
1 year of treatment duration. Since the benefits of prolonged
.. The duration of triple therapy should be limited up to a maximum
..
DAPT, especially for mortality endpoints, appear highly dependent .. of 6 months or omitted after hospital discharge, taking into account
on prior cardiovascular history (such as prior ACS/MI vs. stable
..
.. the ischaemic (e.g. complexity of treated CAD, amount of disease
CAD), and prediction models to estimate on-DAPT bleeding risk .. left untreated, technical considerations regarding stent implantation
..

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have been developed, an individualized approach based on ischae- .. techniques, and results) as well as the bleeding risk. The use of tica-
mic vs. bleeding risk assessment is warranted. .. grelor or prasugrel in this setting is not recommended.
..
(2) Bleeding mitigation strategy: Every effort should be pursued to mit- .. (10) Patients undergoing elective non-cardiac surgery after coronary stent
igate the risk of bleeding complications while the patient is on .. implantation: A multidisciplinary expert team should be considered
..
DAPT, including access site selection, modulation of modifiable .. for pre-operative evaluation of patients with an indication for DAPT
risk factors for bleeding, low dose aspirin, low dose of P2Y12 .. before elective surgery. Scheduled surgery requiring discontinuation
..
inhibitor as appropriate, and routine use of PPI. .. of the P2Y12 inhibitor should be considered after at least 1 month,
(3) P2Y12 inhibitor selection: Clopidogrel is considered the default .. irrespective of the stent type, if aspirin can be maintained throughout
..
P2Y12 inhibitor in patients with stable CAD treated with PCI, .. the perioperative period. If both oral antiplatelet agents have to be
those with indication to concomitant oral anticoagulation, as well .. discontinued perioperatively, a bridging strategy with cangrelor, tirofi-
..
as in ACS patients in whom ticagrelor or prasugrel are contraindi- .. ban, or eptifibatide may be considered, especially if surgery has to be
cated. Ticagrelor or prasugrel is recommended in ACS patients .. performed within 1 month after stent implantation.
..
unless drug-specific contraindications exist. .. (11) Gender consideration and special populations: Similar type and dura-
(4) Timing of P2Y12 inhibitor initiation: The timing of initiation of a .. tion of DAPT are recommended in male and female patients, as well
..
P2Y12 inhibitor is both drug- (i.e. ticagrelor or clopidogrel vs. pra- .. as in patients with and without diabetes mellitus. Patients with prior
sugrel) and disease-specific (i.e. SCAD vs. ACS and type thereof).
.. stent thrombosis, especially in the absence of correctable causes,
..
(5) Stable CAD patients treated with PCI: Irrespective of the type of met- .. should receive prolonged DAPT. A prolonged DAPT regimen may
allic stent implanted, the duration of DAPT is 1–6 month(s) depending
.. also be considered in patients with LEAD or who have undergone
..
on the bleeding risk. For patients in whom the ischaemic risk prevails .. complex PCI. It is recommended to reassess the type, dose, and dura-
over the risk of bleeding, a longer DAPT duration may be considered. ... tion of DAPT in patients with actionable bleeding complications while
(6) Metallic stent type and DAPT duration: The need for a short
..
.. on treatment. In patients with active bleeding while on DAPT, the
DAPT regimen should no longer justify the use of BMS instead of .. decision to stop both antiplatelet agents, especially if shortly after PCI,
newer-generation DES. DAPT duration in each individual patient
..
.. should be taken only if the bleeding is life-threatening and the source
should be guided by an individualized approach based on ischaemic .. has not been or cannot be treated. In such a rare case scenario, the
..
vs. bleeding risk assessment and not by the stent type. .. patient should be transferred to a primary PCI facility centre.
(7) Stable CAD patients treated with CABG: There is insufficient data ..
..
to recommend DAPT in this patient population. ..
(8) ACS patients: Irrespective of the final revascularization strategy ..
.. 11. Evidenced-based ‘to do and
(e.g. medical therapy, PCI, or CABG), the default DAPT duration ..
in these patients is 12 months. Six-month therapy duration should .. not to do’ messages
..
be considered in high bleeding risk patients, whereas >12-month ..
.

Recommendations that are class I or III with a level of evidence A or B

Recommendations on P2Y12 inhibitor selection and timing Classa Levelb

In patients with ACS, ticagrelor (180 mg loading dose, 90 mg b.i.d.) on top of aspirin is recommended, regardless of initial
treatment strategy, including patients pre-treated with clopidogrel (which should be discontinued when ticagrelor is com- I B
c
menced) unless there are contraindications.

In patients with ACS undergoing PCI, prasugrel (60 mg loading dose, 10 mg o.d.) on top of aspirin is recommended for P2Y12 inhibi-
tor-naı̈ve patients with NSTE-ACS or initially conservatively managed STEMI if indication for PCI is established, or in STEMI patients I B
undergoing immediate coronary catheterization unless there is a high risk of life-threatening bleeding or other contraindications.c
Continued
250 ESC Guidelines

Pre-treatment with a P2Y12 inhibitor is generally recommended in patients in whom coronary anatomy is known and the
I A
decision to proceed to PCI is made, as well as in patients with STEMI.

Clopidogrel (600 mg loading dose, 75 mg o.d.) on top of aspirin is recommended in stable CAD patients undergoing
coronary stent implantation and in ACS patients who cannot receive ticagrelor or prasugrel, including those with prior I A
intracranial bleeding or indication for OAC.

Clopidogrel (300 mg loading dose in patients aged <_75, 75 mg o.d.) is recommended on top of aspirin in STEMI patients
I A
receiving thrombolysis.

In NSTE-ACS patients in whom coronary anatomy is not known, it is not recommended to administer prasugrel. III B

Measures to minimize bleeding while on dual antiplatelet therapy

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Radial over femoral access is recommended for coronary angiography and PCI if performed by an expert radial operator. I A

In patients treated with DAPT, a daily aspirin dose of 75 - 100 mg is recommended. I A

A PPI in combination with DAPT is recommended.d I B

Routine platelet function testing to adjust antiplatelet therapy before or after elective stenting is not recommended. III A

Switching between oral P2Y12 inhibitors

In patients with ACS who were previously exposed to clopidogrel, switching from clopidogrel to ticagrelor is
recommended early after hospital admission at a loading dose of 180 mg irrespective of timing and loading dose of I B
clopidogrel, unless contraindications to ticagrelor exist.c

Dual antiplatelet therapy duration in patients with acute coronary syndrome treated with percutaneous coronary intervention

In patients with ACS treated with coronary stent implantation, DAPT with a P2Y12 inhibitor on top of aspirin is
recommended for 12 months unless there are contraindications such as excessive risk of bleeding (e.g. I A
PRECISE-DAPT >_25).

Dual antiplatelet therapy duration in patients with acute coronary syndrome undergoing medical therapy management

In patients with ACS who are managed with medical therapy alone and treated with DAPT, it is recommended to continue
I A
P2Y12 inhibitor therapy (either ticagrelor or clopidogrel) for 12 months.

Ticagrelor is recommended over clopidogrel, unless the bleeding risk outweighs the potential ischaemic benefit. I B

Prasugrel is not recommended in medically managed ACS patients. III B

Dual antiplatelet therapy in patients undergoing elective cardiac and non-cardiac surgery

It is recommended to continue aspirin perioperatively if the bleeding risk allows, and to resume the recommended
I B
antiplatelet therapy as soon as possible post-operatively.

It is not recommended to discontinue DAPT within the first month of treatment in patients undergoing elective non-cardiac
III B
surgery.

Gender considerations

Similar type and duration of DAPT are recommended in male and female patients. I A

ACS = acute coronary syndrome; CAD = coronary artery disease; DAPT = dual antiplatelet therapy; NSTE-ACS = non-ST elevation acute coronary syndrome; OAC = oral
anticoagulant; PCI = percutaneous coronary intervention; PPI = proton pump inhibitor; PRECISE-DAPT = PREdicting bleeding Complications In patients undergoing Stent
implantation and subsEquent Dual Anti Platelet Therapy; STEMI = ST-elevation myocardial infarction; TIA = transient ischaemic attack.
a
Class of recommendation.
b
Level of evidence.
c
Contraindications for ticagrelor: previous intracranial haemorrhage or ongoing bleeds. Contraindications for prasugrel: previous intracranial haemorrhage, previous ischaemic
stroke or TIA, or ongoing bleeds; prasugrel is not recommended for patients >_75 years of age or with a body weight <60 kg.
d
While the evidence that a PPI does not increase the risk of cardiovascular events was generated with omeprazole, based on drug–drug interaction studies, omeprazole and
esomeprazole would appear to have the highest propensity for clinically relevant interactions, while pantoprazole and rabeprazole have the lowest.
ESC Guidelines 251

What is new in the 2017 ESC focussed update on DAPT?

Change in recommendaons New recommendaons 2017


B e for e 2017
New/revised concepts

Pretreatment with P2Y12 inhibitors The occurrence of aconable bleeding while Metallic stent and DAPT duraon
when PCI is planned on DAPT should prompt reconsideraon of
type and duraon of DAPT regimen.
Switch between P2Y12 inhibitors
Liberal use of PPI to migate GI bleeding
risk The decision for DAPT duraon should be Risk scores to guide DAPT duraon
dynamic and reassessed during the course −PRECISE DAPT score
Elecve surgery requiring disconnuaon of the inially selected DAPT regimen.
−DAPT score
of the P2Y12 inhibitor aer 1 month

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Disconnuaon of P2Y12 inhibitor therapy Specific profiling
Ticagrelor interrupon of 3 days prior aer 6 months when stenng ACS paents
with PRECISE-DAPT ≥ 25
−Definion of complex PCI
elecve surgery
−Unfavourable profile for OAC and APT
−Gender consideraons and
Dual therapy as an alternave to triple 6-month DAPT regimen In paents with
therapy when bleeding risk outweighs the SCAD treated with drug-coated balloon special populaons
ischaemic risk
Early administraon of cagrelor/ clopidogrel
DAPT duraon without stenng
in NSTE-ACS with invasive approach −Medical management
Disconnuaon of anplatelet treatment
in paents treated with OAC should be −CABG or cardiac surgery
considered at 12 months. Ticagrelor 60 mg b.i.d preferred over other
oral P2Y12 inhibitors for DAPT connuaon Ancoagulaon and DAPT
Roune platelet funcon tesng to adjust >12 months in post-MI −Acute and chronic seng
therapy −Dosing regimen
I IIA IIB III

ACS ¼ acute coronary syndrome; APT ¼ anti-platelet therapy; CABG ¼ coronary artery bypass graft; DAPT ¼ dual antipla-
telet therapy; MI ¼ myocardial infarction; NSTE¼ Non-st-segment elevation; OAC ¼ oral anti-coagulant;PCI ¼ percuatenous
coronary intervention; PRECISE-DAPT ¼ PREdicting bleeding Complications In patients undergoing Stent implantation and
subsEquent Dual Anti Platelet Therapy; Stable CAD ¼ stable coronary artery disease.

..
12. Web addenda and Clinical ..
..
antiplatelet therapy in coronary artery disease in collabora-
tion with EACTS:
Cases companion document ..
.. Austria: Austrian Society of Cardiology, Franz Xaver Roithinger;
.. Azerbaijan: Azerbaijan Society of Cardiology, Farid Aliyev;
All Web figures, Web tables, and the Clinical Cases companion docu- ..
ment are available at the European Heart Journal online and also via .. Belarus: Belorussian Scientific Society of Cardiologists, Valeriy
.. Stelmashok; Belgium: Belgian Society of Cardiology, Walter
the ESC Web site at: www.escardio.org/guidelines ..
.. Desmet; Bulgaria: Bulgarian Society of Cardiology, Arman
.. Postadzhiyan; Cyprus: Cyprus Society of Cardiology, Georgios P.
..
13. Appendix .. Georghiou; Czech Republic: Czech Society of Cardiology, Zuzana
.. Motovska; Denmark: Danish Society of Cardiology, Erik Lerkevang
..
ESC Committee for Practice Guidelines (CPG): Stephan .. Grove; Estonia: Estonian Society of Cardiology, Toomas Marandi;
.. Finland: Finnish Cardiac Society, Tuomas Kiviniemi; The Former
Windecker (Chairperson) (Switzerland), Victor Aboyans (France), ..
Stefan Agewall (Norway), Emanuele Barbato (Italy), Héctor Bueno .. Yugoslav Republic of Macedonia: Macedonian Society of
.. Cardiology, Sasko Kedev; France: French Society of Cardiology,
(Spain), Antonio Coca (Spain), Jean-Philippe Collet (France), Ioan ..
Mircea Coman (Romania), Veronica Dean (France), Victoria Delgado .. Martine Gilard; Germany: German Cardiac Society, Steffen
..
(The Netherlands), Donna Fitzsimons (UK), Oliver Gaemperli .. Massberg; Greece: Hellenic Society of Cardiology, Dimitrios
(Switzerland), Gerhard Hindricks (Germany), Bernard Iung (France), .. Alexopoulos; Hungary: Hungarian Society of Cardiology, Robert
..
Peter Jüni (Canada), Hugo A. Katus (Germany), Juhani Knuuti .. Gabor Kiss; Iceland: Icelandic Society of Cardiology, Ingibjorg Jona
(Finland), Patrizio Lancellotti (Belgium), Christophe Leclercq .. Gudmundsdottir; Ireland: Irish Cardiac Society, Eugène P.
..
(France), Theresa McDonagh (UK), Massimo Francesco Piepoli .. McFadden; Israel: Israel Heart Society, Eli Lev; Italy: Italian
(Italy), Piotr Ponikowski (Poland), Dimitrios J. Richter (Greece), .. Federation of Cardiology, Leonardo De Luca; Kazakhstan:
..
Marco Roffi (Switzerland), Evgeny Shlyakhto (Russia), Iain A. Simpson .. Association of Cardiologists of Kazakhstan, Akhmetzhan Sugraliyev;
(UK), and Jose Luis Zamorano (Spain)
.. Kosovo: Kosovo Society of Cardiology, Edmond Haliti;
..
ESC National Cardiac Societies actively involved in the .. Kyrgyzstan: Kyrgyz Society of Cardiology, Erkin Mirrakhimov,
review process of the 2017 ESC focused update on dual
.. Latvia: Latvian Society of Cardiology, Gustavs Latkovskis;
ESC/EAS GUIDELINES
European Heart Journal (2019) 00, 178
doi:10.1093/eurheartj/ehz455

2019 ESC/EAS Guidelines for the management

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of dyslipidaemias: lipid modification to reduce
cardiovascular risk
The Task Force for the management of dyslipidaemias of the
European Society of Cardiology (ESC) and European
Atherosclerosis Society (EAS)

Authors/Task Force Members: François Mach* (Chairperson) (Switzerland),


Colin Baigent* (Chairperson) (United Kingdom), Alberico L. Catapano1*
(Chairperson) (Italy), Konstantinos C. Koskinas (Switzerland), Manuela Casula1
(Italy), Lina Badimon (Spain), M. John Chapman1 (France), Guy G. De Backer
(Belgium), Victoria Delgado (Netherlands), Brian A. Ference (United Kingdom),
Ian M. Graham (Ireland), Alison Halliday (United Kingdom), Ulf Landmesser
(Germany), Borislava Mihaylova (United Kingdom), Terje R. Pedersen (Norway),
Gabriele Riccardi1 (Italy), Dimitrios J. Richter (Greece), Marc S. Sabatine (United
States of America), Marja-Riitta Taskinen1 (Finland), Lale Tokgozoglu1 (Turkey),
Olov Wiklund1 (Sweden)

The three chairpersons contributed equally to the document.


*Corresponding authors: François Mach, Cardiology Department, Geneva University Hospital, 4 Gabrielle-Perret-Gentil, 1211 Geneva, Switzerland. Tel: þ41 223 727 192,
Fax: þ41 223 727 229, Email: francois.mach@hcuge.ch. Colin Baigent, Nuffield Department of Population Health, University of Oxford, Richard Doll Building, Roosevelt Drive,
Oxford OX3 7LF, United Kingdom. Tel: þ44 1865 743 741, Fax: þ44 1865 743 985, Email: colin.baigent@ndph.ox.ac.uk. Alberico L. Catapano, Department of Pharmacological
and Biomolecular Sciences, University of Milan, Via Balzaretti, 9, 20133 Milan, and Multimedica IRCCS, Milan, Italy. Tel: þ39 02 5031 8401, Fax: þ39 02 5031 8386,
Email: alberico.catapano@unimi.it.
ESC Committee for Practice Guidelines (CPG), National Cardiac Societies document reviewers and Author/Task Force Member affiliations: listed in the Appendix.
1
Representing the EAS.
ESC entities having participated in the development of this document:
Associations: Acute Cardiovascular Care Association (ACCA), Association of Cardiovascular Nursing & Allied Professions (ACNAP), European Association of Cardiovascular
Imaging (EACVI), European Association of Preventive Cardiology (EAPC), European Association of Percutaneous Cardiovascular Interventions (EAPCI).
Councils: Council for Cardiology Practice, Council on Hypertension, Council on Stroke.
Working Groups: Aorta and Peripheral Vascular Diseases, Atherosclerosis and Vascular Biology, Cardiovascular Pharmacotherapy, e-Cardiology, Thrombosis.
The content of these European Society of Cardiology (ESC) Guidelines has been published for personal and educational use only. No commercial use is authorized. No part of
the ESC Guidelines may be translated or reproduced in any form without written permission from the ESC. Permission can be obtained upon submission of a written request to
Oxford University Press, the publisher of the European Heart Journal and the party authorized to handle such permissions on behalf of the ESC (journals.permissions@oxfordjour-
nals.org).
Disclaimer. The ESC/EAS Guidelines represent the views of the ESC and EAS, and were produced after careful consideration of the scientific and medical knowledge, and the
evidence available at the time of their publication. The ESC and EAS is not responsible in the event of any contradiction, discrepancy, and/or ambiguity between the ESC/EAS
Guidelines and any other official recommendations or guidelines issued by the relevant public health authorities, in particular in relation to good use of healthcare or therapeutic
strategies. Health professionals are encouraged to take the ESC/EAS Guidelines fully into account when exercising their clinical judgment, as well as in the determination and the
implementation of preventive, diagnostic, or therapeutic medical strategies; however, the ESC/EAS Guidelines do not override, in any way whatsoever, the individual responsibil-
ity of health professionals to make appropriate and accurate decisions in consideration of each patient’s health condition and in consultation with that patient and, where appro-
priate and/or necessary, the patient’s caregiver. Nor do the ESC/EAS Guidelines exempt health professionals from taking into full and careful consideration the relevant official
updated recommendations or guidelines issued by the competent public health authorities, in order to manage each patient’s case in light of the scientifically accepted data pur-
suant to their respective ethical and professional obligations. It is also the health professional’s responsibility to verify the applicable rules and regulations relating to drugs and
medical devices at the time of prescription.
C The European Society of Cardiology and the European Atherosclerosis Association 2019. All rights reserved.
V
For permissions please email: journals.permissions@oup.com.
2 ESC/EAS Guidelines

Document Reviewers: Christian Mueller (ESC Review Coordinator) (Switzerland), Heinz Drexel
(EAS Review Coordinator) (Austria), Victor Aboyans (France), Alberto Corsini1 (Italy), Wolfram Doehner
(Germany), Michel Farnier (France), Bruna Gigante (Sweden), Meral Kayikcioglu1 (Turkey),
Goran Krstacic (Croatia), Ekaterini Lambrinou (Cyprus), Basil S. Lewis (Israel), Josep Masip (Spain),
Philippe Moulin1 (France), Steffen Petersen (United Kingdom), Anna Sonia Petronio (Italy),
Massimo Francesco Piepoli (Italy), Xavier Pinto  1 (Spain), Lorenz Ra
€ ber (Switzerland), Kausik K. Ray1
1

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(United Kingdom), Zeljko Reiner (Croatia), Walter F. Riesen (Switzerland), Marco Roffi (Switzerland),
Jean-Paul Schmid (Switzerland), Evgeny Shlyakhto (Russian Federation), Iain A. Simpson (United
Kingdom), Erik Stroes1 (Netherlands), Isabella Sudano (Switzerland), Alexandros D. Tselepis1 (Greece),
Margus Viigimaa1 (Estonia), Cecile Vindis (France), Alexander Vonbank (Austria), Michal Vrablik1 (Czech
Republic), Mislav Vrsalovic (Croatia), José Luis Zamorano Gomez (Spain), Jean-Philippe Collet (ESC CPG
Supervisor) (France)
The disclosure forms of all experts involved in the development of these Guidelines are available on the
ESC website www.escardio.org/guidelines

For the Supplementary Data which include background information and detailed discussion of the data
that have provided the basis for the Guidelines see https://academic.oup.com/eurheartj/article-lookup/doi/
10.1093/eurheartj/ehz455#supplementary-data

...................................................................................................................................................................................................
Keywords Guidelines • dyslipidaemias • cholesterol • triglycerides • low-density lipoproteins • high-density lipopro-
teins • apolipoprotein B • lipoprotein(a) • lipoprotein remnants • total cardiovascular risk • treatment
(lifestyle) • treatment (drugs) • treatment (adherence) • very low-density lipoproteins • familial
hypercholesterolaemia

..
Table of contents .. 5.3.4 Lipoprotein(a) and risk of atherosclerosis . . . . . . . . . . . . . . . . 19
.. 5.4 Laboratory measurement of lipids and lipoproteins . . . . . . . . . . . 19
Abbreviations and acronyms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4
.. 5.4.1 Lipoprotein measurement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19
..
1 Preamble . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6 .. 5.4.2 Lipid measurements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20
2 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8
.. 5.4.3 Fasting or non-fasting? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20
..
2.1 What is new in the 2019 Guidelines? . . . . . . . . . . . . . . . . . . . . . . . . . . 8 .. 5.5 Recommendations for measuring lipids and lipoproteins to
3 What is cardiovascular disease prevention? . . . . . . . . . . . . . . . . . . . . . . . . 8
.. estimate risk of atherosclerotic cardiovascular disease . . . . . . . . . . . . 20
..
3.1 Definition and rationale . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8 .. 6 Treatment targets and goals . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21
..
3.2 Development of the Joint Task Force Guidelines for the .. 7 Lifestyle modifications to improve the plasma lipid profile . . . . . . . . . . 22
management of dyslipidaemias . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8 .. 7.1 Influence of lifestyle on total cholesterol and low-density
..
4 Total cardiovascular risk . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8 .. lipoprotein cholesterol levels . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24
4.1 Total cardiovascular risk estimation . . . . . . . . . . . . . . . . . . . . . . . . . . . 8 .. 7.2 Influence of lifestyle on triglyceride levels . . . . . . . . . . . . . . . . . . . . . 24
..
4.1.1 Rationale for assessing total cardiovascular disease risk . . . . 11 .. 7.3 Influence of lifestyle on high-density lipoprotein cholesterol
4.1.2 How to use the risk estimation charts . . . . . . . . . . . . . . . . . . . . 14 .. levels . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25
..
4.2 Risk levels . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15 .. 7.4 Lifestyle recommendations to improve the plasma lipid
4.2.1 Role of non-invasive cardiovascular imaging .. profile . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25
..
techniques in the assessment of total cardiovascular .. 7.4.1 Body weight and physical activity . . . . . . . . . . . . . . . . . . . . . . . . . 25
disease risk . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16 .. 7.4.2 Dietary fat . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25
..
4.2.2 Risk-based intervention strategies . . . . . . . . . . . . . . . . . . . . . . . . 17 .. 7.4.3 Dietary carbohydrate and fibre . . . . . . . . . . . . . . . . . . . . . . . . . . 26
5 Lipids and lipoproteins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17 .. 7.4.4 Alcohol . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26
..
5.1 Biological role of lipids and lipoproteins . . . . . . . . . . . . . . . . . . . . . . . 17 .. 7.4.5 Smoking . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26
5.2 Role of lipids and lipoproteins in the pathophysiology of .. 7.5 Dietary supplements and functional foods for the
..
atherosclerosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17 .. treatment of dyslipidaemias . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26
5.3 Evidence for the causal effects of lipids and lipoproteins on
.. 7.5.1 Phytosterols . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26
..
the risk of atherosclerotic cardiovascular disease . . . . . . . . . . . . . . . . . 18 .. 7.5.2 Monacolin and red yeast rice . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26
5.3.1 Low-density lipoprotein cholesterol and risk of
.. 7.5.3 Dietary fibre . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27
..
atherosclerosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18 .. 7.5.4 Soy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27
5.3.2 Triglyceride-rich lipoproteins and risk of atherosclerosis . . 18
.. 7.5.5 Policosanol and berberine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27
..
5.3.3 High-density lipoprotein cholesterol and risk of .. 7.5.6 n-3 unsaturated fatty acids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27
atherosclerosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19
.
ESC/EAS Guidelines 3

8 Drugs for treatment of dyslipidaemias . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27


.. 8.12 Strategies to control plasma cholesterol . . . . . . . . . . . . . . . . . . . . . 35
..
8.1 Statins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27 .. 8.13 Strategies to control plasma triglycerides . . . . . . . . . . . . . . . . . . . . 35
..
8.1.1 Mechanism of action . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27 .. 9 Management of dyslipidaemias in different clinical settings . . . . . . . . . 38
8.1.2 Effects on lipids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27 .. 9.1 Familial dyslipidaemias . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 38
..
8.1.2.1 Low-density lipoprotein cholesterol . . . . . . . . . . . . . . . . . . . . . . 27 .. 9.1.1 Familial combined hyperlipidaemia . . . . . . . . . . . . . . . . . . . . . . . 38
8.1.2.2 Triglycerides . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27 .. 9.1.2 Familial hypercholesterolaemia . . . . . . . . . . . . . . . . . . . . . . . . . . 38
..
8.1.2.3 High-density lipoprotein cholesterol . . . . . . . . . . . . . . . . . . . . . 27 .. 9.1.2.1 Heterozygous familial hypercholesterolaemia . . . . . . . . . . . . 38

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8.1.2.4 Lipoprotein(a) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27 .. 9.1.2.2 Homozygous familial hypercholesterolaemia . . . . . . . . . . . . 41
..
8.1.3 Other effects of statins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 28 .. 9.1.2.3 Familial hypercholesterolaemia in children . . . . . . . . . . . . . . . 41
8.1.3.1 Effect on cardiovascular morbidity and mortality . . . . . . . . . . 28 .. 9.1.3 Familial dysbetalipoproteinaemia . . . . . . . . . . . . . . . . . . . . . . . . . 41
..
8.1.4 Adverse effects and interactions of statins . . . . . . . . . . . . . . . . 28 .. 9.1.4 Genetic causes of hypertriglyceridaemia . . . . . . . . . . . . . . . . . . 41
8.1.4.1 Adverse effects on muscle . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 28 .. 9.1.4.1 Action to prevent acute pancreatitis in severe
..
8.1.4.2 Adverse effects on the liver . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29 .. hypertriglyceridaemia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 41
8.1.4.3 Increased risk of new-onset diabetes mellitus . . . . . . . . . . . . . 29 .. 9.1.5 Other genetic disorders of lipoprotein metabolism . . . . . . . 42
..
8.1.4.4 Increased risk of haemorrhagic stroke . . . . . . . . . . . . . . . . . . . 29 .. 9.2 Women . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 42
8.1.4.5 Adverse effects on kidney function . . . . . . . . . . . . . . . . . . . . . . 29
.. 9.2.1 Effects of statins in primary and secondary prevention . . . . . 42
..
8.1.4.6 Interactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29 .. 9.2.2 Non-statin lipid-lowering drugs . . . . . . . . . . . . . . . . . . . . . . . . . . 42
8.2 Cholesterol absorption inhibitors . . . . . . . . . . . . . . . . . . . . . . . . . . . . 30
.. 9.2.3 Hormone therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 42
..
8.2.1 Mechanism of action . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 30 .. 9.3 Older people . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 42
8.2.2 Effects on lipids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 30
.. 9.3.1 Effects of statins in primary and secondary prevention . . . . . 43
..
8.2.3 Effect on cardiovascular morbidity and mortality . . . . . . . . . . 30 .. 9.3.2 Adverse effects, interactions, and adherence . . . . . . . . . . . . . . 43
8.2.4 Adverse effects and interactions . . . . . . . . . . . . . . . . . . . . . . . . . 30
.. 9.4 Diabetes and metabolic syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . 43
..
8.3 Bile acid sequestrants . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 30 .. 9.4.1 Specific features of dyslipidaemia in insulin resistance
..
8.3.1 Mechanism of action . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 30 .. and type 2 diabetes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 43
8.3.2 Effects on lipids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 30 .. 9.4.2 Evidence for lipid-lowering therapy . . . . . . . . . . . . . . . . . . . . . . 44
..
8.3.3 Effect on cardiovascular morbidity and mortality . . . . . . . . . . 30 .. 9.4.2.1 Low-density lipoprotein cholesterol . . . . . . . . . . . . . . . . . . . . . . 44
8.3.4 Adverse effects and interactions . . . . . . . . . . . . . . . . . . . . . . . . . 31 .. 9.4.2.1 Triglycerides and high-density lipoprotein cholesterol . . . . . . 44
..
8.4 Proprotein convertase subtilisin/kexin type 9 inhibitors . . . . . . . . 31 .. 9.4.3 Type 1 diabetes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 45
8.4.1 Mechanism of action . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 31 .. 9.4.4 Management of dyslipidaemia for pregnant women
..
8.4.2 Effects on lipids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 31 .. with diabetes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 45
8.4.2.1 Low-density lipoprotein cholesterol . . . . . . . . . . . . . . . . . . . . . . 31 .. 9.5 Patients with acute coronary syndromes and patients
..
8.4.2.2 Triglycerides and high-density lipoprotein cholesterol . . . . . . 31 .. undergoing percutaneous coronary intervention . . . . . . . . . . . . . . . . . 46
8.4.2.3 Lipoprotein(a) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 31 .. 9.5.1 Lipid-lowering therapy in patients with acute
..
8.4.3 Effect on cardiovascular morbidity and mortality . . . . . . . . . . 31 .. coronary syndromes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 46
8.4.4 Adverse effects and interactions . . . . . . . . . . . . . . . . . . . . . . . . . 32 .. 9.5.1.1 Statins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 46
..
8.5 Lomitapide . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 32 .. 9.5.1.2 Ezetimibe . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 46
8.6 Mipomersen . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 32 .. 9.5.1.3 Proprotein convertase subtilisin/kexin type 9 inhibitors . . . . . 46
..
8.7 Fibrates . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 32 .. 9.5.1.4 n-3 polyunsaturated fatty acids . . . . . . . . . . . . . . . . . . . . . . . . . 47
8.7.1 Mechanism of action . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 32
.. 9.5.1.5 Cholesteryl ester transfer protein inhibitors . . . . . . . . . . . . . . . 47
..
8.7.2 Effects on lipids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 32 .. 9.5.2 Lipid-lowering therapy in patients undergoing
8.7.3 Effect on cardiovascular morbidity and mortality . . . . . . . . . . 33
.. percutaneous coronary intervention . . . . . . . . . . . . . . . . . . . . . . . . . . 47
..
8.7.4 Adverse effects and interactions . . . . . . . . . . . . . . . . . . . . . . . . . 33 .. 9.6 Stroke . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 48
8.8 n-3 fatty acids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33
.. 9.7 Heart failure and valvular diseases . . . . . . . . . . . . . . . . . . . . . . . . . . . . 48
..
8.8.1 Mechanism of action . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33 .. 9.7.1 Prevention of incident heart failure in coronary artery
8.8.2 Effects on lipids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33
.. disease patients . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 48
..
8.8.3 Effect on cardiovascular morbidity and mortality . . . . . . . . . . 33 .. 9.7.2 Chronic heart failure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 48
..
8.8.4 Safety and interactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 34 .. 9.7.3 Valvular heart diseases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 48
8.9 Nicotinic acid . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 34 .. 9.8 Chronic kidney disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 49
..
8.10 Cholesteryl ester transfer protein inhibitors . . . . . . . . . . . . . . . . . 34 .. 9.8.1 Lipoprotein profile in chronic kidney disease . . . . . . . . . . . . . . 49
8.11 Future perspectives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 34 .. 9.8.2 Evidence for risk reduction through statin-based
..
8.11.1 New approaches to reduce low-density lipoprotein .. therapy in patients with chronic kidney disease . . . . . . . . . . . . . . . . . 49
cholesterol . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 34 .. 9.8.3 Safety of lipid management in patients with chronic
..
8.11.2 New approaches to reduce triglyceride-rich .. kidney disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 49
lipoproteins and their remnants . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 34 .. 9.9 Transplantation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 50
..
8.11.3 New approaches to increase high-density lipoprotein .. 9.10 Peripheral arterial disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 50
cholesterol . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 35 .. 9.10.1 Lower extremity arterial disease . . . . . . . . . . . . . . . . . . . . . . . . 50
..
8.11.4 New approaches to reduce lipoprotein(a) levels . . . . . . . . . 35 . 9.10.2 Carotid artery disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 51
4 ESC/EAS Guidelines

..
9.10.3 Retinal vascular disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 51 ..
..
List of tables
9.10.4 Secondary prevention in patients with
.. Table 1 Classes of recommendations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7
abdominal aortic aneurysm . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 51 .. Table 2 Levels of evidence . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7
9.10.5 Renovascular atherosclerosis . . . . . . . . . . . . . . . . . . . . . . . . . . . 51 ..
.. Table 3 New recommendations, and new and revised concepts . . . . . . 9
9.11 Other special populations at risk of atherosclerotic .. Table 4 Cardiovascular risk categories . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15
cardiovascular disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 51 ..
.. Table 5 Intervention strategies as a function of total cardiovascular
10 Inflammation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 51 ..

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.. risk and untreated low-density lipoprotein cholesterol levels . . . . . . . . 16
11 Monitoring of lipids and enzymes in patients on lipid-lowering
.. Table 6 Physical and chemical characteristics of human plasma
therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 52 .. lipoproteins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18
12 Cost-effectiveness of cardiovascular disease prevention by ..
.. Table 7 Treatment targets and goals for cardiovascular disease
lipid modification . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 52 ..
13 Strategies to encourage adoption of healthy lifestyle .. prevention . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23
.. Table 8 Impact of specific lifestyle changes on lipid levels . . . . . . . . . . . . 24
changes and adherence to lipid-modifying therapies . . . . . . . . . . . . . . . . . 56 ..
14 Key messages . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 56 .. Table 9 Food choices to lower low-density lipoprotein
.. cholesterol and improve the overall lipoprotein profile . . . . . . . . . . . . . . 25
15 Gaps in evidence . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 57 ..
16 Evidence-based ‘to do’ and ‘not to do’ messages from the
.. Table 10 Drugs potentially interacting with statins metabolized by
.. cytochrome P450 3A4 leading to increased risk of myopathy and
Guidelines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 58 ..
17 Supplementary data . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 60
.. rhabdomyolysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29
.. Table 11 Genetic disorders of lipoprotein metabolism . . . . . . . . . . . . . . 39
18 Appendix . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 60 ..
19 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 61
.. Table 12 Dutch Lipid Clinic Network diagnostic criteria for familial
.. hypercholesterolaemia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 39
..
.. Table 13 Summary of recommendations for monitoring lipids
.. and enzymes in patients, before and on lipid-lowering therapy . . . . . . . 53
..
Tables of Recommendations ..
..
..
Recommendations for cardiovascular imaging for risk
.. List of figures
assessment of atherosclerotic cardiovascular disease . . . . . . . . . . . . . . . . 17 ..
Recommendations for cardiovascular disease risk estimation . . . . . . . . 17 .. Figure 1 Systematic Coronary Risk Estimation chart for European
.. populations at high cardiovascular disease risk . . . . . . . . . . . . . . . . . . . . . . 12
Recommendations for lipid analyses for cardiovascular disease ..
risk estimation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21 .. Figure 2 Systematic Coronary Risk Estimation chart for European
.. populations at low cardiovascular disease risk . . . . . . . . . . . . . . . . . . . . . . . 13
Recommendations for treatment goals for low-density ..
lipoprotein cholesterol . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22 .. Figure 3 Expected clinical benefit of low-density lipoprotein
.. cholesterol-lowering therapies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 36
Recommendations for pharmacological low-density lipoprotein ..
cholesterol lowering . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 35
.. Figure 4 Treatment goals and algorithm for low-density lipoprotein
.. cholesterol-lowering according to cardiovascular disease risk . . . . . . . . 37
Recommendations for drug treatment of patients with ..
hypertriglyceridaemia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 38
.. Figure 5 Health impact pyramid . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 54
.. Figure 6 Absolute reductions in major vascular events with statin
Recommendations for the detection and treatment of patients ..
with heterozygous familial hypercholesterolaemia . . . . . . . . . . . . . . . . . . 40
.. therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 55
..
Recommendations for the treatment of dyslipidaemias in ..
older people (aged >65 years) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 43
..
.. List of boxes
Recommendations for the treatment of dyslipidaemias in ..
.. Box 1 How to use the risk estimation charts . . . . . . . . . . . . . . . . . . . . . . . . 14
diabetes mellitus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 45 ..
Recommendations for lipid-lowering therapy in very- .. Box 2 Risk estimation charts for different countries . . . . . . . . . . . . . . . . . 14
.. Box 3 Qualifiers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14
high-risk patients with acute coronary syndromes . . . . . . . . . . . . . . . . . . . 47 ..
Recommendations for lipid-lowering therapy in very-high-risk .. Box 4 Factors modifying Systematic Coronary Risk Estimation risks . . 14
.. Box 5 Risk estimation: key messages . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15
patients undergoing percutaneous coronary intervention . . . . . . . . . . . 47 ..
Recommendations for lipid-lowering therapy for prevention .. Box 6 Management of dyslipidaemia in women . . . . . . . . . . . . . . . . . . . . . . 42
.. Box 7 Summary of dyslipidaemia in metabolic syndrome and
of atherosclerotic cardiovascular disease events in patients ..
with prior ischaemic stroke . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 48 .. type 2 diabetes mellitus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 44
.. Box 8 Key messages . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 55
Recommendations for the treatment of dyslipidaemias in ..
chronic heart failure or valvular heart diseases . . . . . . . . . . . . . . . . . . . . . . 49 .. Box 9 Gaps in the evidence . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 55
..
Recommendations for lipid management in patients with .. Box 10 Methods for enhancing adherence to lifestyle changes . . . . . . . 56
moderate to severe (Kidney Disease Outcomes Quality ..
..
Initiative stages 35) chronic kidney disease . . . . . . . . . . . . . . . . . . . . . . . . 49 ..
Recommendations for low-density lipoprotein lowering in
.. Abbreviations and acronyms
.. ABI Anklebrachial index
solid organ transplant patients . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 50 ..
Recommendations for lipid-lowering drugs in patients with
.. ACCELERATE Assessment of Clinical Effects of Cholesteryl
..
peripheral arterial disease (including carotid artery disease) . . . . . . . . . . 51 . Ester Transfer Protein Inhibition with
ESC/EAS Guidelines 5

Evacetrapib in Patients at a High-Risk for ... eGFR Estimated glomerular filtration rate
Vascular Outcomes
.. EMA European Medicines Agency
..
ACCORD Action to Control Cardiovascular Risk in Diabetes .. EPA Eicosapentaenoic acid
ACS Acute coronary syndrome
.. ESC European Society of Cardiology
..
ALT Alanine aminotransferase .. EVOLVE EpanoVa fOr Lowering Very high
ANGPTL3 Angiopoietin-like protein 3
.. triglyceridEs
..
Apo Apolipoprotein .. EVOPACS EVOlocumab for early reduction of LDL-

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..
ART Antiretroviral treatment .. cholesterol levels in patients with Acute
ASCEND A Study of Cardiovascular Events iN Diabetes .. Coronary Syndromes
..
ASCOT-LLA Anglo-Scandinavian Cardiac Outcomes Trial  .. FCH Familial combined hyperlipidaemia
Lipid-Lowering Arm .. FCS Familial chylomicronaemia syndrome
..
ASCVD Atherosclerotic cardiovascular disease .. FDA US Food and Drug Administration
ASSIGN CV risk estimation model from the Scottish .. FH Familial hypercholesterolaemia
..
Intercollegiate Guidelines Network .. FIELD Fenofibrate Intervention and Event Lowering
AURORA A study to evaluate the Use of Rosuvastatin in .. in Diabetes
..
subjects On Regular haemodialysis: an .. FOCUS Fixed-Dose Combination Drug for Secondary
Assessment of survival and cardiovascular events .. Cardiovascular Prevention
..
b.i.d. Twice a day (bis in die) .. FOURIER Further Cardiovascular Outcomes Research
BIOSTAT-CHF BIOlogy Study to TAilored Treatment in .. with PCSK9 Inhibition in Subjects with
..
Chronic Heart Failure .. Elevated Risk
BIP Bezafibrate Infarction Prevention .. GFR Glomerular filtration rate
..
BMI Body mass index .. GI Gastrointestinal
BP Blood pressure ... GISSI Gruppo Italiano per lo Studio della
CABG Coronary artery bypass graft surgery
.. Sopravvivenza nell’Infarto Miocardico
..
CAC Coronary artery calcium .. HbA1c Glycated haemoglobin
CAD Coronary artery disease
.. HeFH Heterozygous familial hypercholesterolaemia
..
CANTOS Canakinumab Antiinflammatory Thrombosis .. HDL High-density lipoprotein
Outcome Study
.. HDL-C High-density lipoprotein cholesterol
..
CETP Cholesteryl ester transfer protein .. HF Heart failure
..
CHD Coronary heart disease .. HHS Helsinki Heart Study
CI Confidence interval .. HIV Human immunodeficiency virus
..
CIID Chronic immune-mediated inflammatory diseases .. HMG-CoA Hydroxymethylglutaryl-coenzyme A
CIRT Cardiovascular Inflammation Reduction Trial .. HoFH Homozygous familial hypercholesterolaemia
..
CK Creatine kinase .. HPS2-THRIVE Heart Protection Study 2-Treatment of HDL
CKD Chronic kidney disease .. to Reduce the Incidence of Vascular Events
..
COM-B Capability, Opportunity and Motivation .. HR Hazard ratio
CORONA Controlled Rosuvastatin Multinational Trial in .. HTG Hypertriglyceridaemia
..
Heart Failure .. IDEAL Incremental Decrease In End-points Through
CPG Committee for Practice Guidelines .. Aggressive Lipid-lowering
..
CT Computed tomography .. IDL Intermediate-density lipoproteins
CTT Cholesterol Treatment Trialists .. IL Interleukin
..
CV Cardiovascular .. ILLUMINATE Investigation of Lipid Level Management to
CVD Cardiovascular disease .. Understand its Impact in Atherosclerotic
..
CYP Cytochrome P450 .. Events
4D Die Deutsche Diabetes Dialyse Studie
.. IMPROVE-IT Improved Reduction of Outcomes: Vytorin
..
dal-OUTCOMES Effects of Dalcetrapib in Patients with a Recent .. Efficacy International Trial
Acute Coronary Syndrome
.. IPD Individual participant data
..
DASH Dietary Approaches to Stop Hypertension .. JUPITER Justification for the Use of Statins in
DGAT-2 Diacylglycerol acyltransferase-2
.. Prevention: an Intervention Trial Evaluating
..
DHA Docosahexaenoic acid .. Rosuvastatin
DM Diabetes mellitus
.. KDIGO Kidney Disease: Improving Global Outcomes
..
EAPC European Association of Preventive Cardiology .. LCAT Lecithin cholesterol acyltransferase
..
EAS European Atherosclerosis Society .. LDL Low-density lipoprotein
EBBINGHAUS Evaluating PCSK9 Binding Antibody Influence .. LDL-C Low-density lipoprotein cholesterol
..
on Cognitive Health in High Cardiovascular .. LDLR Low-density lipoprotein receptor
Risk Subjects .. LEAD Lower extremity arterial disease
..
6 ESC/EAS Guidelines

LEADER Lower Extremity Arterial Disease Event Reduction


.. TC Total cholesterol
..
LPL Lipoprotein lipase .. T1DM Type 1 diabetes mellitus
Lp(a) Lipoprotein(a) ... T2DM Type 2 diabetes mellitus
mAb Monoclonal antibody
.. TGs Triglycerides
..
MACE Major adverse cardiovascular events .. TIA Transient ischaemic attack
MESA Multi-Ethnic Study of Atherosclerosis
.. TIMI Thrombolysis In Myocardial Infarction
..
MetS Metabolic syndrome .. TNF Tumour necrosis factor

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MI Myocardial infarction
.. TNT Treating to New Targets
..
mRNA Messenger RNA .. TRL Triglyceride-rich lipoprotein
..
MTP Microsomal triglyceride transfer protein .. ULN Upper limit of normal
NAFLD Non-alcoholic fatty liver disease .. VA-HIT Veterans Affairs High Density Lipoprotein
..
NNT Number needed to treat .. Intervention Trial
NPC1L1 Niemann-Pick C1-like protein 1 .. VITAL VITamin D and OmegA-3 Trial
..
NSTE-ACS Non-ST elevation acute coronary syndrome .. VLDL Very low-density lipoprotein
o.d. Once a day (omni die) .. WHO World Health Organization
..
ODYSSEY Evaluation of Cardiovascular Outcomes After .. WOSCOPS West of Scotland Coronary Prevention Study
Outcomes an Acute Coronary Syndrome During ..
..
Treatment With Alirocumab ..
PAD Peripheral arterial disease ..
.. 1 Preamble
PCI Percutaneous coronary intervention ..
PCSK9 Proprotein convertase subtilisin/kexin type 9 .. Guidelines summarize and evaluate available evidence with the aim of
.. assisting health professionals in proposing the best management
PPAR-a Peroxisome proliferator-activated receptor-a ..
PREDIMED Prevencion con Dieta Mediterranea .. strategies for an individual patient with a given condition. Guidelines
.. and their recommendations should facilitate decision making of
PROCAM Prospective Cardiovascular Munster Study ..
PROMINENT Pemafibrate to Reduce Cardiovascular
.. health professionals in their daily practice. However, the final deci-
.. sions concerning an individual patient must be made by the responsi-
OutcoMes by Reducing Triglycerides IN ..
PatiENts With DiabeTes
.. ble health professional(s) in consultation with the patient and
.. caregiver as appropriate.
PUFA Polyunsaturated fatty acid ..
PURE Prospective Urban Rural Epidemiology
.. A great number of guidelines have been issued in recent years by
.. the European Society of Cardiology (ESC) and its partners such as
RA Rheumatoid arthritis ..
RCT Randomized controlled trial
.. European Atherosclerosis Society (EAS), as well as by other societies
.. and organisations. Because of their impact on clinical practice, quality
REDUCE-IT Reduction of Cardiovascular Events with EPA- ..
.. criteria for the development of guidelines have been established in
Intervention Trial .. order to make all decisions transparent to the user. The recommen-
REVEAL Randomized EValuation of the Effects of ..
.. dations for formulating and issuing ESC Guidelines can be found on
Anacetrapib Through Lipid modification .. the ESC website (http://www.escardio.org/Guidelines-&-Education/
RR Relative risk ..
.. Clinical-Practice-Guidelines/Guidelines-development/Writing-ESC-
RYR Red yeast rice .. Guidelines). The ESC Guidelines represent the official position of the
SAMS Statin-associated muscle symptoms ..
.. ESC on a given topic and are regularly updated.
SBP Systolic blood pressure ..
.. The ESC carries out a number of registries which are essential to
SCORE Systematic Coronary Risk Estimation .. assess diagnostic/therapeutic processes, use of resources and adher-
SEAS Simvastatin and Ezetimibe in Aortic Stenosis ..
SECURE-PCI Statins Evaluation in Coronary Procedures and .. ence to Guidelines. These registries aim at providing a better under-
.. standing of medical practice in Europe and around the world, based
Revascularization ..
SFA Saturated fatty acid .. on data collected during routine clinical practice.
.. The guidelines are developed together with derivative educational
SHARP Study of Heart and Renal Protection ..
siRNA Small interfering RNA
.. material addressing the cultural and professional needs for cardiolo-
.. gists and allied professionals. Collecting high-quality observational
SMI Severe mental illness ..
SPARCL Stroke Prevention by Aggressive Reduction in
.. data, at appropriate time interval following the release of ESC
.. Guidelines, will help evaluate the level of implementation of the
Cholesterol Levels ..
STAREE STAtin Therapy for Reducing Events in the
.. Guidelines, checking in priority the key end points defined with the
.. ESC Guidelines and Education Committees and Task Force members
Elderly ..
STEMI ST-elevation myocardial infarction
.. in charge.
.. The Members of this Task Force were selected by the ESC and
STRENGTH Outcomes Study to Assess STatin Residual ..
.. EAS, including representation from relevant ESC sub-specialty
Risk Reduction with EpaNova in HiGh CV Risk ..
.. groups, in order to represent professionals involved with the medical
PatienTs with Hypertriglyceridemia
. care of patients with this pathology. Selected experts in the field from
ESC/EAS Guidelines 7

..
both societies undertook a comprehensive review of the published .. The ESC CPG supervises and coordinates the preparation of new
evidence for management of a given condition according to ESC .. Guidelines. The Committee is also responsible for the endorsement
..
Committee for Practice Guidelines (CPG) policy. A critical evaluation .. process of these Guidelines. The ESC Guidelines undergo extensive
of diagnostic and therapeutic procedures was performed, including .. review by the CPG and external experts. After appropriate revisions
..
assessment of the riskbenefit ratio. The level of evidence and the .. the Guidelines are approved by all the experts involved in the Task
strength of the recommendation of particular management options
.. Force. The finalized document is approved by the CPG and EAS for
..
were weighed and graded according to predefined ESC scales, as out- .. publication in the European Heart Journal and Atherosclerosis

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lined in the tables below.
.. Journal. The Guidelines were developed after careful consideration
..
The experts of the writing and reviewing panels provided declara- .. of the scientific and medical knowledge and the evidence available at
tion of interest forms for all relationships that might be perceived as
.. the time of their dating.
..
real or potential sources of conflicts of interest. These forms were .. The task of developing ESC/EAS Guidelines also includes the crea-
compiled into one file and can be found on the ESC website (http://
.. tion of educational tools and implementation programmes for the
..
www.escardio.org/guidelines). Any changes in declarations of interest .. recommendations including condensed pocket guideline versions,
..
that arise during the writing period were notified to the ESC and EAS .. summary slides, booklets with essential messages, summary cards for
Chairpersons and updated. The Task Force received its entire finan- .. non-specialists and an electronic version for digital applications
..
cial support from the ESC and EAS without any involvement from .. (smartphones, etc.). These versions are abridged and thus, for more
the healthcare industry. .. detailed information, the user should always access the full text

Table 1 Classes of recommendations

Wording to use
Classes of recommendations

Class I Evidence and/or general agreement Is recommended or is indicated


that a given treatment or procedure is

Class II

Class IIa Weight of evidence/opinion is in Should be considered

Class IIb May be considered


established by evidence/opinion.

Class III Evidence or general agreement that the Is not recommended ©ESC 2019
given treatment or procedure is not
useful/effective, and in some cases
may be harmful.

Table 2 Levels of evidence

Level of Data derived from multiple randomized clinical trials


evidence A or meta-analyses.

Level of Data derived from a single randomized clinical trial


evidence B or large non-randomized studies.
©ESC 2019

Level of Consensus of opinion of the experts and/or small studies,


evidence C retrospective studies, registries.
8 ESC/EAS Guidelines

..
version of the Guidelines, which is freely available via the ESC and .. 2.1 What is new in the 2019 Guidelines?
EAS websites and hosted on their journals’ websites (EHJ and .. New recommendations, and new and revised concepts, are pre-
..
Atherosclerosis Journal). The National Cardiac Societies of the ESC .. sented in Table 3.
are encouraged to endorse, translate and implement all ESC ..
..
Guidelines. Implementation programmes are needed because it has ..
..
been shown that the outcome of disease may be favourably influ-
.. 3 What is cardiovascular disease
enced by the thorough application of clinical recommendations. ..

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Health professionals are encouraged to take the ESC/EAS .. prevention?
..
Guidelines fully into account when exercising their clinical judgment, ..
as well as in the determination and the implementation of preventive, .. 3.1 Definition and rationale
.. Cardiovascular disease (CVD), of which ASCVD is the major compo-
diagnostic or therapeutic medical strategies. However, the ESC/EAS ..
Guidelines do not override in any way whatsoever the individual .. nent, is responsible for >4 million deaths in Europe each year. It kills
.. more women (2.2 million) than men (1.8 million), although CV deaths
responsibility of health professionals to make appropriate and accu- ..
rate decisions in consideration of each patient’s health condition and .. before the age of 65 years are more common in men (490 000 vs.
.. 193 000).3 Prevention is defined as a co-ordinated set of actions,
in consultation with that patient or the patient’s caregiver where ..
appropriate and/or necessary. It is also the health professional’s
.. either at the population or individual level, aimed at eliminating or min-
.. imizing the impact of CV diseases and their related disabilities. More
responsibility to verify the rules and regulations applicable in each ..
country to drugs and devices at the time of prescription.
.. patients are surviving their first CVD event and are at high-risk of
.. recurrences. In addition, the prevalence of some risk factors, notably
..
.. diabetes (DM) and obesity, is increasing. The importance of ASCVD
.. prevention remains undisputed and should be delivered at the general
..
2 Introduction .. population level by promoting healthy lifestyle behaviour,4 and at the
.. individual level by tackling unhealthy lifestyles and by reducing
The previous ESC/EAS lipid Guidelines were published in August ..
.. increased levels of causal CV risk factors, such as LDL cholesterol or
2016.1 The emergence of a substantial body of evidence over the last ..
few years has required new, up-to-date Guidelines. .. blood pressure (BP) levels.
..
New evidence has confirmed that the key initiating event in athe- ..
rogenesis is the retention of low-density lipoprotein (LDL) choles- .. 3.2 Development of the Joint Task Force
.. Guidelines for the management of
terol (LDL-C) and other cholesterol-rich apolipoprotein (Apo) B- ..
containing lipoproteins within the arterial wall.2 Several recent .. dyslipidaemias
..
placebo-controlled clinical studies have shown that the addition of .. The present Guidelines represent an evidence-based consensus of
either ezetimibe or anti-proprotein convertase subtilisin/kexin type 9 .. the European Task Force, including the ESC and the EAS.
..
(PCSK9) monoclonal antibodies (mAbs) to statin therapy provides a .. By appraising the current evidence and identifying remaining
further reduction in atherosclerotic cardiovascular disease (ASCVD)
.. knowledge gaps in the management of dyslipidaemias, the Task Force
..
risk, which is directly and positively correlated with the incrementally .. has formulated recommendations to guide action in clinical practice
achieved absolute LDL-C reduction. Furthermore, these clinical trials
.. to prevent ASCVD by modifying plasma lipid levels.
..
have clearly indicated that the lower the achieved LDL-C values, the .. This document has been developed for healthcare professionals to
lower the risk of future cardiovascular (CV) events, with no lower
.. facilitate informed communication with individuals about their CV
..
limit for LDL-C values, or ‘J’-curve effect. In addition, studies of the .. risk and the benefits of adopting and sustaining a healthy lifestyle, and
clinical safety of these very low achieved LDL-C values have proved
..
.. of early modification of their lipid-related CV risk. In addition, the
reassuring, albeit monitoring for longer periods is required. For rais- .. Guidelines provide tools for healthcare professionals to promote up-
..
ing high-density lipoprotein (HDL) cholesterol (HDL-C), recent stud- .. to-date intervention strategies, integrate these strategies into national
ies have indicated that the currently available therapies do not reduce .. or regional prevention frameworks, and to translate them into locally
..
the risk of ASCVD. Finally, human Mendelian randomization studies .. delivered healthcare services, in line with the recommendations of
have demonstrated the critical role of LDL-C, and other cholesterol- .. the World Health Organization (WHO) Global Status Report on
..
rich ApoB-containing lipoproteins, in atherosclerotic plaque forma- .. Noncommunicable Diseases 2014.5
tion and related subsequent CV events. Thus, there is no longer an .. A lifetime approach to CV risk should be considered.1 This implies
..
‘LDL-C hypothesis’, but established facts that increased LDL-C values .. that—apart from improving lifestyle habits and reducing risk factor
are causally related to ASCVD, and that lowering LDL particles and .. levels in patients with established ASCVD, and in those at increased
..
other ApoB-containing lipoproteins as much as possible reduces CV .. risk of developing ASCVD—people of all ages should be encouraged
events. .. to adopt or sustain a healthy lifestyle.
..
In order to be aligned with these new findings, the ESC/EAS Task ..
Force members who have written these Guidelines have proposed ..
..
new LDL-C goals, as well as a revised CV risk stratification, which are ..
..
4 Total cardiovascular risk
especially relevant to high- and very-high-risk patients. ..
These novel ESC/EAS Guidelines on lipids provide important new .. 4.1 Total cardiovascular risk estimation
advice on patient management, which should enable more clinicians
.. CV risk in the context of these Guidelines means the likelihood of a
..
to efficiently and safely reduce CV risk through lipid modification. . person developing an atherosclerotic CV event over a defined period
ESC/EAS Guidelines 9

Table 3 New recommendations, and new and revised concepts

New recommendations
Cardiovascular imaging for assessment of ASCVD risk
Assessment of arterial (carotid and/or femoral) plaque burden on arterial ultrasonography should be considered as a risk modifier in individuals
at low or moderate risk.

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Cardiovascular imaging for assessment of ASCVD risk
CAC score assessment with CT may be considered as a risk modifier in the CV risk assessment of asymptomatic individuals at low or moderate risk.
Lipid analyses for CVD risk estimation
Lp(a) measurement should be considered at least once in each adult person’s lifetime to identify those with very high inherited Lp(a) levels >180 mg/dL
(>430 nmol/L) who may have a lifetime risk of ASCVD equivalent to the risk associated with heterozygous familial hypercholesterolaemia.
Drug treatments of patients with hypertriglyceridaemia
In high-risk (or above) patients with TG between 1.5 and 5.6 mmol/L (135 - 499 mg/dL) despite statin treatment, n-3 PUFAs
(icosapent ethyl 2  2g/day) should be considered in combination with statins.
Treatment of patients with heterozygous FH
In primary prevention, for individuals with FH at very-high risk, an LDL-C reduction of >_50% from baseline and an LDL-C goal of <1.4 mmol/L
(<55 mg/dL) should be considered.
Treatment of dyslipidaemias in older people
Treatment with statins is recommended for primary prevention, according to the level of risk, in older people aged <_75.
Treatment of dyslipidaemias in older people
Initiation of statin treatment for primary prevention in older people aged >75 may be considered, if at high risk or above.
Treatment of dyslipidaemias in DM
In patients with T2DM at very-high risk, an LDL-C reduction of >_50% from baseline and an LDL-C goal of <1.4 mmol/L (<55mg/dL) is recommended.
In patients with T2DM at high risk, an LDL-C reduction of >_50% from baseline and an LDL-C goal of <1.8 mmol/L (<70 mg/dL) is recommended.
Statins are recommended in patients with T1DM who are at high or very-high risk.
Treatment of dyslipidaemias in DM
Intensification of statin therapy should be considered before the introduction of combination therapy.
If the goal is not reached, statin combination with ezetimibe should be considered.
Treatment of dyslipidaemias in DM
Statin therapy is not recommended in pre-menopausal patients with DM who are considering pregnancy or not using adequate contraception.
Lipid-lowering therapy in patients with ACS
For patients who present with an ACS, and whose LDL-C levels are not at goal despite already taking a maximally tolerated statin dose and
ezetimibe, adding a PCSK9 inhibitor early after the event (if possible, during hospitalization for the ACS event) should be considered.
Changes in recommendations
Upgrades
2016 2019
Lipid analyses for CVD risk estimation Lipid analyses for CVD risk estimation
ApoB should be considered as an alternative risk marker whenever available, ApoB analysis is recommended for risk assessment, particularly in
especially in individuals with high TG. people with high TG, DM, obesity or metabolic syndrome, or very low
LDL-C. It can be used as an alternative to LDL-C, if available, as the
primary measurement for screening, diagnosis, and management,
and may be preferred over non-HDL-C in people with high TG, DM,
obesity, or very low LDL-C.
Pharmacological LDL-C lowering Pharmacological LDL-C lowering
If the LDL goal is not reached, statin combination with a cholesterol If the goals are not achieved with the maximum tolerated dose of statin,
absorption inhibitor should be considered. combination with ezetimibe is recommended.
Pharmacological LDL-C lowering Pharmacological LDL-C lowering
In patients at very-high risk, with persistent high LDL-C despite treatment For secondary prevention, patients at very-high risk not achieving their
with maximal tolerated statin dose, in combination with ezetimibe or in goal on a maximum tolerated dose of statin and ezetimibe, a combination
patients with statin intolerance, a PCSK9 inhibitor may be considered. with a PCSK9 inhibitor is recommended.
For very-high-risk FH patients (that is, with ASCVD or with another
major risk factor) who do not achieve their goals on a maximum
tolerated dose of statin and ezetimibe, a combination with a PCSK9
inhibitor is recommended.
Continued
10 ESC/EAS Guidelines

Drug treatments of hypertriglyceridaemia Drug treatments of hypertriglyceridaemia


Statin treatment may be considered as the first drug of choice for Statin treatment is recommended as the first drug of choice for reducing
reducing CVD risk in high-risk individuals with hypertriglyceridaemia. CVD risk in high-risk individuals with hypertriglyceridaemia
[TG >2.3 mmol/L (200 mg/dL)].
Treatment of patients with heterozygous FH Treatment of patients with heterozygous FH
Treatment should be considered to aim at reaching an LDL-C <2.6 mmol/L For FH patients with ASCVD who are at very-high risk, treatment to

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(<100 mg/dL) or in the presence of CVD <1.8 mmol/L (<70 mg/dL). achieve at least a 50% reduction from baseline and an LDL-C
If targets cannot be reached, maximal reduction of LDL-C should be <1.4 mmol/L (<55 mg/dL) is recommended. If goals cannot be achieved,
considered using appropriate drug combinations. a drug combination is recommended.
Treatment of patients with heterozygous FH Treatment of patients with heterozygous FH
Treatment with a PCSK9 antibody should be considered in FH patients with Treatment with a PCSK9 inhibitor is recommended in very-high-risk
CVD or with other factors putting them at very-high risk for CHD, FH patients if the treatment goal is not achieved on maximal tolerated
such as other CV risk factors, family history, high Lp(a), or statin intolerance. statin plus ezetimibe.
Treatment of dyslipidaemias in older adults Treatment of dyslipidaemias in older people
Since older people often have comorbidities and have It is recommended that the statin is started at a low dose if there is
altered pharmacokinetics, lipid-lowering medication should be started significant renal impairment and/or the potential for drug interactions,
at a lower dose and then titrated with caution to achieve target lipid and then titrated upwards to achieve LDL-C treatment goals.
levels that are the same as in younger people.
Lipid-lowering therapy in patients with ACS Lipid-lowering therapy in patients with ACS
If the LDL-C target is not reached with the highest tolerated statin dose If the LDL-C goal is not achieved after 4 - 6 weeks despite maximal
and/or ezetimibe, PCSK9 inhibitors may be considered on top of tolerated statin therapy and ezetimibe, addition of a PCSK9 inhibitor
lipid-lowering therapy; or alone or in combination with ezetimibe in is recommended.
statin-intolerant patients or in whom a statin is contraindicated.
Recommendation grading
Class I Class IIa Class IIb Class III
New sections
• A new section is focused on the utility of non-invasive CV imaging for classification of total CVD risk, with implications for recommended
lipid-modifying therapies.
• More data are provided on the biology and physiology of lipids and lipoproteins, and on their roles in pathophysiology. Emerging evidence from observa-
tional studies, RCTs, and genetic (Mendelian randomization) studies unequivocally showing a causal effect of LDL-C in the development of ASCVD is dis-
cussed, and newer evidence regarding the effects of TGs and HDL on ASCVD risk is presented.
• New sections describe novel lipid-modifying medications as well as emerging approaches for lowering LDL-C, TGs, and Lp(a).
• A new section discusses the inflammation-related risk in very high-risk patients and the potential role of inflammation as a therapeutic target to lower ASCVD risk.
• New/revised concepts
More intensive reduction of LDL-C across CV risk categories
• For secondary prevention in very-high-risk patients, an LDL-C reduction of >_50% from baseline and an LDL-C goal of <1.4 mmol/L (<55 mg/dL) are recommended.
 For patients with ASCVD who experience a second vascular event within 2 years (not necessarily of the same type as the first event) while taking maximally toler-
ated statin therapy, an LDL-C goal of <1.0 mmol/L (<40 mg/dL) may be considered.
• In primary prevention, for individuals at very-high risk but without FH, an LDL-C reduction of >_50% from baseline and an LDL-C goal of <1.4 mmol/L
(<55 mg/dL) are recommended. For individuals at very-high risk (that is, with another risk factor but without ASCVD), in primary prevention the same
goals for LDL-C lowering should be considered.
• For patients at high risk, an LDL-C reduction of >_50% from baseline and an LDL-C goal of <1.8 mmol/L (<70 mg/dL) are recommended.
• For individuals at moderate risk, an LDL-C goal of <2.6 mmol/L (<100 mg/dL) should be considered.
• For individuals at low risk, an LDL-C goal of <3.0 mmol/L (<116 mg/dL) may be considered.
The rationale for the revised, lower LDL-C goals across CV risk categories is discussed, based on a critical synthesis of available evidence
from lipid-modifying interventions resulting in reductions in CV risk.
Pharmacological LDL-C-lowering strategies
The section on pharmacological strategies to lower LDL-C emphasizes the concept that the absolute LDL-C reduction (determined by pre-treatment LDL-
C levels and the LDL-lowering efficacy of the medications) dictates the relative risk reduction, which in turn—depending on the baseline CV risk—defines
the associated absolute CV risk reduction in individual patients.
Risk classification in patients with FH
Patients with FH and ASCVD, or another major risk factor, are classified as very-high-risk, and those without known ASCVD and without other risk factors
as high-risk. Recommended treatment goals are defined accordingly.
Adverse effects of statins
The distinction between formal statin myopathy vs. so-called statin-associated muscle symptoms is emphasized, and the discordance in reported frequency
of symptoms in RCTs vs. observational studies are critically discussed on the basis of new relevant evidence.
Continued
ESC/EAS Guidelines 11

PCSK9 inhibitors
New outcome study data of PCSK9 inhibitors are presented, and updated recommendations for their clinical use are provided.
Cost-effectiveness
The issue of cost-effectiveness of lipid-modifying interventions is updated in view of changes in the availability of generic products for statins and ezetimibe,
and of PCSK9 inhibitors.
ACS = acute coronary syndrome; ApoB = apolipoprotein B; ASCVD = atherosclerotic cardiovascular disease; CAC = coronary artery calcium; CHD = coronary heart disease;

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CT = computed tomography; CV = cardiovascular; CVD = cardiovascular disease; DM = diabetes mellitus; FH = familial hypercholesterolaemia; HDL = high-density lipopro-
tein; LDL-C = low-density lipoproteins cholesterol; Lp(a) = lipoprotein(a); PCSK9 = proprotein convertase subtilisin/kexin type 9; PUFAs = polyunsaturated fatty acids; RCTs
= randomized controlled trials; T1DM = type 1 diabetes mellitus; T2DM = type 2 diabetes mellitus; TGs = triglycerides.

of time. Total CVD risk expresses the combined effect of a number .. diagnostic tests, and methods of ascertainment, all of which can vary,
..
of risk factors on this risk estimate. In these Guidelines, we address .. resulting in very variable multipliers to convert fatal to total events. In
the lipid-related contribution to total CV risk and how to manage it
.. addition, total event charts, in contrast to those based on mortality,
..
at the clinical level. .. are more difficult to recalibrate to suit different populations. That said,
.. work is in progress to produce regional total event charts.
..
4.1.1 Rationale for assessing total cardiovascular disease .. The SCORE data indicate that the total CVD event risk is about
.. three times higher than the risk of fatal CVD for men, so a SCORE
risk ..
All current guidelines on the prevention of ASCVD in clinical practice .. risk of 5% translates into a CVD risk of 15% of total (fatal þ non-
..
recommend the assessment of total CVD risk. Prevention of ASCVD .. fatal) CVD endpoints; the multiplier is higher in women and lower in
in a given person should relate to his or her total CV risk: the higher .. older people.
..
the risk, the more intense the action should be. .. Clinicians often ask for thresholds to trigger certain interventions.
Many risk assessment systems are available and have been compre- ... This is problematic since risk is a continuum and there is no threshold
hensively reviewed (Supplementary Table 1 in the Supplementary .. at which, for example, a drug is automatically indicated. This is true
..
Data). Most guidelines use one of these risk assessment systems.68 .. for all continuous risk factors such as plasma cholesterol or systolic
Ideally, risk charts should be based on country-specific cohort data. .. BP (SBP). Therefore, the goals that are proposed in this document
..
These are not available for most countries. The SCORE (Systematic .. reflect this concept.
Coronary Risk Estimation) system can be recalibrated for use in dif- .. A particular problem relates to young people with high levels of risk
..
ferent populations by adjusting for secular changes in CVD mortality .. factors; a low absolute risk may conceal a very high relative risk requir-
and risk factor prevalence. Calibrated country-specific versions are .. ing at least intensive lifestyle advice. To motivate young people (i.e.
..
available for many European countries and can be found at http:// .. aged <40 years) not to delay changing their unhealthy lifestyle, an esti-
www.heartscore.org. These are now being updated to provide recali- .. mate of their relative risk—illustrating that lifestyle changes can reduce
..
brated, contemporaneous country-specific charts for all European .. relative risk substantially—may be helpful (Supplementary Figure 1).
countries. Other risk estimation systems—using both fatal and non-
.. Another approach to this problem is to use CV risk age. The risk
..
fatal events—can also be recalibrated, but the process is easier and .. age of a person with several CV risk factors is the age of a person
scientifically more robust for mortality than for total events. The
.. with the same level of risk but with ideal levels of risk factors. Thus, a
..
European Guidelines on CVD prevention in clinical practice (both .. high-risk 40-year-old would have a risk age >_65 years. Risk age can be
the 20129 and 201610 versions) recommend the use of the SCORE
.. estimated visually by looking at the SCORE chart (as illustrated in
..
system because it is based on large, representative European cohort .. Supplementary Figure 2). In this chart, the risk age of a person with risk
data sets and because it is relatively straightforward to recalibrate for
.. factors is defined as the age at which a person with ideal risk factor
..
individual countries. .. levels would reach the same risk level. Ideal risk factors are non-
.. smoking, total cholesterol (TC) <_4 mmol/L (<_155 mg/dL), and SBP
Persons with documented ASCVD, type 1 or type 2 DM (T1DM ..
and T2DM, respectively), very high levels of individual risk factors, or .. <_120 mmHg. Risk age is also automatically calculated as part of the
..
chronic kidney disease (CKD) are generally at very-high or high total .. latest revision of HeartScore (http://www.HeartScore.org).
CV risk. No risk estimation models are needed for such persons; .. Risk age has been shown to be independent of the CV endpoint
..
they all need active management of all risk factors. For other, appa- .. used,6,8 can be used in any population regardless of baseline risk or
rently healthy people, the use of a risk estimation system such as .. secular changes in mortality, and therefore avoids the need for
..
SCORE, which estimates the 10 year cumulative risk of a first fatal .. recalibration.
atherosclerotic event, is recommended to estimate total CV risk, .. Lifetime risk is another approach to illustrate the impact of risk fac-
..
since many people have several risk factors that, in combination, may .. tors that may be useful in younger people.12 The greater the burden
result in high levels of total CV risk. .. of risk factors, the higher the lifetime risk. This approach produces
..
Risk estimates have been produced as charts for high- and low-risk .. higher risk figures for younger people because of their longer expo-
regions in Europe (Figures 1 and 2).11 All International Classification of .. sure times. Therefore, it is more useful as a way of illustrating risk
..
Diseases codes that are related to deaths from vascular origin caused .. than as a guide to treatment, because therapeutic trials have been
by atherosclerosis are included. The reasons for retaining a system
.. based on a fixed follow-up period and not on lifetime risk.
..
that estimates fatal as opposed to total fatal þ non-fatal events are .. Another problem relates to older people. In some age categories,
that non-fatal events are dependent on definition, developments in
.. the majority of people, especially males, will have estimated 10 year
12 ESC/EAS Guidelines

SCORE Cardiovascular Risk Chart


10-year risk of fatal CVD
High-risk regions of Europe

WOMEN MEN

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Non-smoker Smoker Age Non-smoker Smoker
180 12 13 14 15 17 19 20 21 24 26 30 33 33 36 40 45
160 10 11 12 13 14 15 16 18 20 22 25 28 27 31 34 39
140
70
8 9 10 10 12 13 14 15 16 18 21 24 23 26 29 33
120 7 7 8 9 10 10 11 12 13 15 17 20 19 22 25 28

180 7 8 8 9 11 12 13 15 15 17 20 23 23 26 30 34
160 5 6 6 7 9 9 10 11 12 14 16 18 18 21 24 27
140
65
4 4 5 5 7 7 8 9 9 11 12 14 14 16 19 22
120 3 3 4 4 5 5 6 7 7 8 10 11 11 13 15 17
Systolic blood pressure (mmHg)

180 4 4 5 5 7 8 9 10 10 11 13 15 16 19 22 25
160 3 3 3 4 5 6 6 7 7 8 10 11 12 14 16 19
60
140 2 2 2 3 4 4 4 5 5 6 7 8 9 10 12 14
120 1 1 2 2 3 3 3 3 4 4 5 6 6 7 9 10

180 2 2 3 3 5 5 6 7 6 7 9 10 11 13 16 18
160 1 2 2 2 3 3 4 4 4 5 6 7 8 9 11 13
55
140 1 1 1 1 2 2 2 3 3 3 4 5 5 6 7 9
120 1 1 1 1 1 1 2 2 2 2 3 3 4 4 5 6

180 1 1 2 2 3 3 4 4 4 5 6 7 8 9 11 13
160 1 1 1 1 2 2 2 3 2 3 3 4 5 6 7 9
50
140 0 0 1 1 1 1 1 2 2 2 2 3 3 4 5 6
120 0 0 0 0 1 1 1 1 1 1 1 2 2 2 3 4

180 0 0 1 1 1 1 2 2 2 2 2 3 4 4 5 7
160 0 0 0 0 1 1 1 1 1 1 1 2 2 2 3 4
140
40
0 0 0 0 0 0 0 1 0 1 1 1 1 1 2 2
120 0 0 0 0 0 0 0 0 0 0 0 1 1 1 1 1
4 5 6 7 4 5 6 7 4 5 6 7 4 5 6 7

©ESC 2019
Total cholesterol (mmol/L)

<3% 3–4% 5–9% ≥10%

Figure 1 Systematic Coronary Risk Estimation chart for European populations at high cardiovascular disease risk. The 10-year risk of fatal cardiovascular
disease in populations at high cardiovascular disease risk based on the following risk factors: age, gender, smoking, systolic blood pressure, and total choles-
terol. To convert the risk of fatal cardiovascular disease to risk of total (fatal þ non-fatal) cardiovascular disease, multiply by 3 in men and by 4 in women,
and slightly less in older people. Note: the Systematic Coronary Risk Estimation chart is for use in people without overt cardiovascular disease, diabetes
(type 1 and 2), chronic kidney disease, familial hypercholesterolaemia, or very high levels of individual risk factors because such people are already at high-
risk and need intensive risk factor management. Cholesterol: 1 mmol/L = 38.67 mg/dL. The SCORE risk charts presented above differ slightly from those in
the 2016 European Society of Cardiology/European Atherosclerosis Society Guidelines for the management of dyslipidaemias and the 2016 European
Guidelines on cardiovascular disease prevention in clinical practice, in that: (i) age has been extended from age 65 to 70; (ii) the interaction between age
and each of the other risk factors has been incorporated, thus reducing the overestimation of risk in older persons in the original Systematic Coronary
Risk Estimation charts; and (iii) the cholesterol band of 8 mmol/L has been removed, since such persons will qualify for further evaluation in any event.
SCORE = Systematic Coronary Risk Estimation.
ESC/EAS Guidelines 13

SCORE Cardiovascular Risk Chart


10-year risk of fatal CVD
Low-risk regions of Europe

WOMEN MEN

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Non-smoker Smoker Age Non-smoker Smoker
180 7 8 8 9 11 11 12 13 12 14 15 17 18 20 22 24
160 6 6 7 7 9 9 10 11 10 11 13 14 15 16 18 20
140
70
5 5 6 6 7 8 8 9 8 9 10 12 12 13 15 17
120 4 4 5 5 6 6 7 7 7 8 9 10 10 11 12 14

180 4 4 5 5 7 7 8 9 8 9 10 12 12 14 16 18
160 3 3 4 4 5 6 6 7 6 7 8 9 9 11 12 14
140
65
2 3 3 3 4 4 5 5 5 5 6 7 7 8 9 11
120 2 2 2 2 3 3 3 4 3 4 5 5 5 6 7 8
Systolic blood pressure (mmHg)

180 2 3 3 3 4 5 5 6 5 6 7 8 8 10 11 13
160 2 2 2 2 3 3 4 4 4 4 5 5 6 7 8 9
60
140 1 1 1 2 2 2 3 3 3 3 3 4 4 5 6 7
120 1 1 1 1 2 2 2 2 2 2 2 3 3 4 4 5

180 1 1 2 2 3 3 3 4 3 4 4 5 6 7 8 9
160 1 1 1 1 2 2 2 3 2 2 3 3 4 4 5 6
55
140 1 1 1 1 1 1 1 2 1 2 2 2 3 3 3 4
120 0 0 0 1 1 1 1 1 1 1 1 2 2 2 2 3

180 1 1 1 1 2 2 2 3 2 2 3 3 4 5 5 6
160 0 0 1 1 1 1 1 2 1 1 2 2 2 3 3 4
50
140 0 0 0 0 1 1 1 1 1 1 1 1 1 2 2 3
120 0 0 0 0 0 0 0 1 0 1 1 1 1 1 1 2

180 0 0 0 0 1 1 1 1 1 1 1 1 2 2 3 3
160 0 0 0 0 0 0 0 1 0 0 1 1 1 1 1 2
140
40
0 0 0 0 0 0 0 0 0 0 0 0 1 1 1 1
120 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 1
4 5 6 7 4 5 6 7 4 5 6 7 4 5 6 7

©ESC 2019
Total cholesterol (mmol/L)

<3% 3–4% 5–9% ≥10%

Figure 2 Systematic Coronary Risk Estimation chart for European populations at low cardiovascular disease risk. The 10-year risk of fatal cardiovascular
disease in populations at low cardiovascular disease risk based on the following risk factors: age, gender, smoking, systolic blood pressure, and total choles-
terol. To convert the risk of fatal cardiovascular disease to risk of total (fatal þ non-fatal) cardiovascular disease, multiply by 3 in men and by 4 in women,
and slightly less in older people. Note: the Systematic Coronary Risk Estimation chart is for use in people without overt cardiovascular disease, diabetes
(type 1 and 2), chronic kidney disease, familial hypercholesterolaemia, or very high levels of individual risk factors because such people are already at high-
risk and need intensive risk factor management. Cholesterol: 1 mmol/L=38.67 mg/dL. The SCORE risk charts presented above differ slightly from those in
the 2016 European Society of Cardiology/European Atherosclerosis Society Guidelines for the management of dyslipidaemias and the 2016 European
Guidelines on cardiovascular disease prevention in clinical practice, in that: (i) age has been extended from age 65 to 70; (ii) the interaction between age
and each of the other risk factors has been incorporated, thus reducing the overestimation of risk in older persons in the original Systematic Coronary
Risk Estimation charts; and (iii) the cholesterol band of 8 mmol/L has been removed since such persons will qualify for further evaluation in any event.
SCORE = Systematic Coronary Risk Estimation.
14 ESC/EAS Guidelines

cumulative CV death risks exceeding the 510% level, based on age


Box 2 Risk estimation charts for different countries
only, even when other CV risk factor levels are relatively low.
Therefore, before initiating treatment in the elderly, clinicians should The low-risk charts should be considered for use in Austria, Belgium,
evaluate patients carefully. The relative strengths of risk factors vary Cyprus, Denmark, Finland, France, Germany, Greece, Iceland, Ireland,
with age and SCORE overestimates risk in older people (that is, those Israel, Italy, Luxembourg, Netherlands, Norway, Malta, Portugal, Slovenia,
aged >65 years).11 These Guidelines include illustrative charts for Spain, Sweden, Switzerland, and the UK.
older people (see Figures 1 and 2). While older people benefit from The high-risk charts should be considered for use in Albania, Algeria,

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smoking cessation, and control of hypertension and hyperlipidaemia Armenia, Bosnia and Herzegovina, Croatia, Czech Republic, Estonia,
(see section 9.3), clinical judgement is required to avoid side effects Hungary, Latvia, Lebanon, Libya, Lithuania, Montenegro, Morocco,
from overmedication. Poland, Romania, Serbia, Slovakia, Tunisia, and Turkey.
The additional impact of HDL-C on risk estimation is illustrated in Some countries have a cardiovascular disease mortality rate >350/100
Supplementary Figures 3 and 4; HDL-C can be used to increase the 000, and the high-risk chart may underestimate risk. These are
accuracy of the risk evaluation. In these charts, HDL-C is used cate- Azerbaijan, Belarus, Bulgaria, Egypt, Georgia, Kazakhstan, Kyrgyzstan,
gorically. The electronic version of SCORE, HeartScore (http://www. North Macedonia, Republic of Moldova, Russian Federation, Syria,
heartscore.org/en_GB/), has been modified to take HDL-C into con- Tajikistan, Turkmenistan, Ukraine, and Uzbekistan.
sideration as a continuous variable. Clinicians should be aware that at
See http://apps.who.int/gho/data/node.home.
extremely high values [above 2.3 mmol/L (90 mg/dL)] of HDL-C
there appears to be an increased risk of ASCVD, so at such levels
HDL-C cannot be used as a risk predictor.
Box 3 Qualifiers
4.1.2 How to use the risk estimation charts
The charts can assist in risk assessment and management, but must be
Use of the low- or the high-risk SCORE charts will depend on the
interpreted in light of the clinician’s knowledge and experience, and of
CVD mortality experience in each country. While any cut-off point is
the patient’s pre-test likelihood of CVD.
arbitrary and open to debate, in these Guidelines, the cut-off point
Risk will be overestimated in countries with decreasing CVD mortality,
for calling a country ‘low CVD risk’ is based on WHO data derived
and underestimated in countries in which mortality is increasing. This is
from the Global Burden of Disease Study.
dealt with by recalibration (http://www.heartscore.org/en_GB/).
Countries are categorized as low-risk if their age-adjusted 2016
CVD mortality rate was <150/100 000 (for men and women Risk estimates are lower in women than in men. However, risk is only
together) (http://www.who.int/healthinfo/global_burden_disease/esti deferred in women; the risk of a 60-year-old woman is similar to that of a
mates/en/). Countries with a CVD mortality rate of >_150/100 000 or 50-year-old man. Ultimately, more women die from CVD than men.
more are considered to be at high-risk. Relative risks may be unexpectedly high in young persons, even if abso-
Boxes 1 to 5 summarize the main points regarding the risk estima- lute risk levels are low. The relative risk chart (Supplementary Figure 1)
tion charts and their use. and the estimated risk age (Supplementary Figure 2) may be helpful in
identifying and counselling such persons.
Box 1 How to use the risk estimation charts CVD = cardiovascular disease.

To estimate a person’s 10-year risk of CVD death, find the table for his/
her gender, smoking status, and age. Within the table, find the cell nearest
to the person’s BP and TC. Risk estimates will need to be adjusted
Box 4 Factors modifying Systematic Coronary Risk
Estimation risks
upwards as the person approaches the next age category.
Risk is initially assessed on the level of TC and systolic BP before treat- Social deprivation: the origin of many of the causes of CVD.
ment, if known. The longer the treatment and the more effective it is, the Obesity and central obesity as measured by the body mass index and
greater the reduction in risk, but in general it will not be more than about waist circumference, respectively.
one-third of the baseline risk. For example, for a person on antihyperten- Physical inactivity.
sive drug treatment in whom the pre-treatment BP is not known, if the Psychosocial stress including vital exhaustion.
total CV SCORE risk is 6%, then the pre-treatment total CV risk may Family history of premature CVD (men: <55 years and women: <60
have been 9%. years).
Low-risk persons should be offered advice to maintain their low-risk sta- Chronic immune-mediated inflammatory disorder.
tus. While no threshold is universally applicable, the intensity of advice
Major psychiatric disorders.
should increase with increasing risk.
Treatment for human immunodeficiency virus infection.
The charts may be used to give some indication of the effects of reducing
Atrial fibrillation.
risk factors, given that there is apparently a time lag before the risk
Left ventricular hypertrophy.
reduces. In general, people who stop smoking halve their cumulative risk
over a relatively short period of time. Chronic kidney disease.
Obstructive sleep apnoea syndrome.
BP = blood pressure; CV = cardiovascular; CVD = cardiovascular disease;
SCORE = Systematic Coronary Risk Estimation; TC = total cholesterol. Non-alcoholic fatty liver disease.
CVD = cardiovascular disease.
ESC/EAS Guidelines 15

Social deprivation and psychosocial stress set the scene for


.. Low-risk people should be given advice to help them maintain this
..
increased risk.13 For those at moderate risk, other factors—including .. status. Thus, the intensity of preventive actions should be tailored to
metabolic factors such as increased ApoB, lipoprotein(a) [Lp(a)], tri-
.. the patient’s total CV risk. The strongest driver of total CV risk is age,
..
glycerides (TGs), or C-reactive protein; the presence of albuminuria; .. which can be considered as ‘exposure time’ to risk factors.
the presence of atherosclerotic plaque in the carotid or femoral
.. For these reasons, the Task Force suggests the following catego-
..
arteries; or the coronary artery calcium (CAC) score—may improve .. ries of risk and LDL-C goals, based on the best available evidence and
risk classification. Many other biomarkers are also associated with
.. in an ideal setting with unlimited resources. These categories repre-
..

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increased CVD risk, although few of these have been shown to be .. sent a counsel of perfection, but these ideals are for guidance only
..
associated with appreciable reclassification. Total CV risk will also be and practical decision-making must be based on what is appropriate
...
higher than indicated in the SCORE charts in asymptomatic persons .. to the local situation.
with abnormal markers of subclinical atherosclerotic vascular dam- .. With these considerations, we propose the levels of total CV risk
..
age. Reclassification is of value in people identified as being at moder- .. presented in Table 4.
ate CV risk by using markers such as CAC score >100 Agatston .
units, anklebrachial index (ABI) <0.9 or >1.40, carotidfemoral Table 4 Cardiovascular risk categories
pulse wave velocity >10 m/s, or the presence of plaques at carotid or
Very-high- People with any of the following:
femoral ultrasonography. In studies comparing these markers, CAC
risk Documented ASCVD, either clinical or unequivocal
had the best reclassification ability.1416
on imaging. Documented ASCVD includes previous
Some factors such as a high HDL-C up to 2.3 mmol/L (90mg/dL)17
ACS (MI or unstable angina), stable angina, coronary
or a family history of longevity can also be associated with lower risk.
revascularization (PCI, CABG, and other arterial
revascularization procedures), stroke and TIA, and
peripheral arterial disease. Unequivocally docu-
Box 5 Risk estimation: key messages mented ASCVD on imaging includes those findings
In apparently healthy persons, CVD risk is most frequently the result of that are known to be predictive of clinical events,
multiple, interacting risk factors. This is the basis for total CV risk estima- such as significant plaque on coronary angiography
tion and management. or CT scan (multivessel coronary disease with two
Risk factor screening including the lipid profile should be considered in men major epicardial arteries having >50% stenosis), or
>40 years old, and in women >50 years of age or post-menopausal. on carotid ultrasound.
DM with target organ damage,a or at least three major
A risk estimation system such as SCORE can assist in making logical man-
risk factors, or early onset of T1DM of long duration
agement decisions, and may help to avoid both under- and
(>20 years).
overtreatment.
Severe CKD (eGFR <30 mL/min/1.73 m2).
Certain individuals declare themselves to be at high or very high CVD risk
A calculated SCORE >_10% for 10-year risk of fatal
without needing risk scoring, and all risk factors require immediate attention.
CVD.
This is true for patients with documented CVD, older individuals with long-
FH with ASCVD or with another major risk factor.
standing DM, familial hypercholesterolaemia, chronic kidney disease, carotid
High-risk People with:
or femoral plaques, coronary artery calcium score >100, or extreme Lp(a)
Markedly elevated single risk factors, in particular TC
elevation.
>8 mmol/L (>310 mg/dL), LDL-C >4.9 mmol/L
All risk estimation systems are relatively crude and require attention to
(>190 mg/dL), or BP >_180/110 mmHg.
qualifying statements.
Patients with FH without other major risk factors.
Additional factors affecting risk can be accommodated in electronic risk
Patients with DM without target organ damage,a with DM
estimation systems such as HeartScore (www.heartscore.org).
duration >_10 years or another additional risk factor.
The total risk approach allows flexibility; if optimal control cannot be
Moderate CKD (eGFR 3059 mL/min/1.73 m2).
achieved with one risk factor, trying harder with the other factors can still
A calculated SCORE >_5% and <10% for 10-year risk
reduce risk.
of fatal CVD.
CV = cardiovascular; CVD = cardiovascular disease; DM = diabetes mellitus;
Moderate-risk Young patients (T1DM <35 years; T2DM <50 years)
SCORE = Systematic Coronary Risk Estimation.
with DM duration <10 years, without other risk fac-
tors. Calculated SCORE >_1 % and <5% for 10-year
4.2 Risk levels risk of fatal CVD.

A total CV risk estimate is part of a continuum. The cut-off points Low-risk Calculated SCORE <1% for 10-year risk of fatal CVD.
that are used to define high-risk are, in part, both arbitrary and based ASCVD = atherosclerotic cardiovascular disease; ACS = acute coronary syn-
drome; BP = blood pressure; CABG = coronary artery bypass graft surgery;
on the risk levels at which benefit is evident in clinical trials. In clinical CKD = chronic kidney disease; CT = computed tomography; CVD = cardiovas-
practice, consideration should be given to practical issues in relation cular disease; DM = diabetes mellitus; eGFR = estimated glomerular filtration
to the local healthcare systems. Not only should those at high risk be rate; FH = familial hypercholesterolaemia; LDL-C = low-density lipoprotein cho-
lesterol; MI = myocardial infarction; PCI = percutaneous coronary intervention;
identified and managed, but those at moderate risk should also SCORE = Systematic Coronary Risk Estimation; T1DM = type 1 DM; T2DM =
receive professional advice regarding lifestyle changes; in some cases, type 2 DM; TC = total cholesterol; TIA = transient ischaemic attack.
a
drug therapy will be needed to reduce atherosclerotic risk. Target organ damage is defined as microalbuminuria, retinopathy, or neuropathy.
16 ESC/EAS Guidelines

4.2.1 Role of non-invasive cardiovascular imaging techni-


.. reclassification.19 Assessment of carotid or femoral plaque burden
..
ques in the assessment of total cardiovascular disease risk .. with ultrasound has also been demonstrated to be predictive of CV
.. events, comparable to CAC,2023 while the measurement of the car-
Non-invasive imaging techniques can detect the presence, estimate ..
the extent, and evaluate the clinical consequences of atherosclerotic .. otid intimamedia thickness is inferior to CAC score and carotid pla-
..
vascular damage. Detection of coronary artery calcification with non- .. que detection.16,24,25
contrast computed tomography (CT) gives a good estimate of the .. In asymptomatic patients at low or moderate risk who would be
..
atherosclerotic burden and is strongly associated with CV events.18 .. eligible for statin therapy (see Table 5), assessment of ASCVD with

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A recent meta-analysis from the US Preventive Services Task Force .. imaging may have an impact on medical treatment, both from the
..
summarized the available evidence on the value of non-traditional .. physician’s and the patient’s points of view. Data from the Multi-
risk factors for risk prediction, and found that, although there are no .. Ethnic Study of Atherosclerosis (MESA) showed that 4157% of
..
randomized trials showing that the use of CAC reduces health out- .. individuals who would be eligible for statin therapy had a CAC score
comes, nevertheless it improves both discrimination and .. of zero and the rate of atherosclerotic CVD events in the 10 year
.

Table 5 Intervention strategies as a function of total cardiovascular risk and untreated low-density lipoprotein choles-
terol levels
Total CV risk Untreated LDL-C levels
(SCORE) %
........................................................................................................................................................................
<1.4 mmol/L 1.4 to <1.8 1.8 to <2.6 2.6 to <3.0 3.0 to <4.9 4.9 mmol/L
(55 mg/dL) mmol/L (55 mmol/L (70 mmol/L (100 mmol/L (116 to (190 mg/dL)
to <70 mg/dL) to <100 mg/dL) to <116 mg/dL) <190 mg/dL)
Primary <1, low-risk Lifestyle Lifestyle advice Lifestyle advice Lifestyle advice Lifestyle inter- Lifestyle inter-
prevention advice vention, con- vention and
sider adding concomitant
drug if drug
uncontrolled intervention
Classa/Levelb I/C I/C I/C I/C IIa/A IIa/A
1 to <5, or Lifestyle Lifestyle advice Lifestyle advice Lifestyle inter- Lifestyle inter- Lifestyle inter-
moderate risk advice vention, con- vention, con- vention and
(see Table 4) sider adding sider adding concomitant
drug if drug if drug
uncontrolled uncontrolled intervention
Classa/Levelb I/C I/C IIa/A IIa/A IIa/A IIa/A
5 to <10, or Lifestyle Lifestyle advice Lifestyle inter- Lifestyle inter- Lifestyle inter- Lifestyle inter-
high-risk advice vention, con- vention and con- vention and vention and
(see Table 4) sider adding comitant drug concomitant concomitant
drug if intervention drug drug
uncontrolled intervention intervention
Classa/Levelb IIa/A IIa/A IIa/A I/A I/A I/A
10, or at Lifestyle Lifestyle inter- Lifestyle inter- Lifestyle inter- Lifestyle inter- Lifestyle inter-
very-high advice vention, con- vention and vention and con- vention and vention and
risk due sider adding concomitant comitant drug concomitant concomitant
to a risk condi- drug if drug intervention drug drug
tion uncontrolled intervention intervention intervention
(see Table 4)
Classa/Levelb IIa/B IIa/A I/A I/A I/A I/A
Secondary Very-high-risk Lifestyle inter- Lifestyle inter- Lifestyle inter- Lifestyle inter- Lifestyle inter- Lifestyle inter-
prevention vention, con- vention and vention and vention and con- vention and vention and
sider adding concomitant concomitant comitant drug concomitant concomitant
drug if drug drug intervention drug drug
uncontrolled intervention intervention intervention intervention
Classa/Levelb IIa/A I/A I/A I/A I/A I/A
CV = cardiovascular; LDL-C = low-density lipoprotein cholesterol; SCORE = Systematic Coronary Risk Estimation.
a
Class of recommendation.
b
Level of evidence.
ESC/EAS Guidelines 17

follow-up period was low (1.54.9%).26 In contrast, the rates of .. reduction is proportional to the absolute reduction in LDL-C and the
..
ASCVD and coronary heart disease (CHD) events in individuals with .. absolute reduction in LDL-C resulting from a particular drug regimen
a CAC score >100 Agatston were 18.9 and 12.7 per 1000 person-
.. depends only on baseline LDL-C, at any given level of baseline risk the
..
years, respectively.18 Compared with a strategy of treating all .. higher the initial LDL-C level the greater the absolute reduction in
patients, the use of CAC score to guide long-term statin therapy has
.. risk. Advice on individual drug treatments is given in section 8.
been shown to be cost-effective.27 Note that CAC score is often
very low in patients younger than 45 years of age with severe familial Recommendations for cardiovascular disease risk

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hypercholesterolaemia (FH), including homozygous FH (HoFH), and estimation
has low specificity in this population.
Assessment of coronary luminal stenosis >50% and plaque com- Recommendations Classa Levelb
position with coronary CT angiography also provides incremental Total risk estimation using a risk estimation
prognostic value over traditional risk stratification models.28 As a system such as SCORE is recommended for
result, in asymptomatic individuals with moderate risk, the presence asymptomatic adults >40 years of age without
I C
of a CAC score >100 Agatston, and carotid or femoral plaque bur- evidence of CVD, DM, CKD, familial hyper-
den on ultrasonography, may reclassify them to a higher risk cate- cholesterolaemia, or LDL-C >4.9 mmol/L
gory. Therefore, the use of methods to detect these markers should (>190 mg/dL).
be of interest in that group (see Recommendations for cardiovascular It is recommended that high- and very-high-
imaging for risk assessment of atherosclerotic cardiovascular disease risk individuals are identified on the basis of
below).1416 Overall, CAC score assessment with CT may be con- documented CVD, DM, moderate-to-severe
sidered in individuals at low or moderate risk in whom the respective renal disease, very high levels of individual risk
LDL-C goal is not achieved with lifestyle intervention alone, and phar- I C
factors, FH, or a high SCORE risk. It is recom-
macological therapy is an option (see Table 5). The use of imaging mended that such patients are considered as a
techniques to determine the presence and extent of atherosclerotic priority for advice and management of all risk
vascular damage in low-risk individuals not being considered for statin factors.
therapy is not justified due to low prognostic yield, and the associated
Risk scores developed for the general popula-
costs and radiation hazards when measuring CAC score, particularly III C
tion are not recommended for CV risk assess-
among low-risk women.29 Of note, CAC score is increased following
ment in patients with DM or FH.
statin treatment; therefore, the CAC scores of statin-treated patients
should be interpreted with caution. CKD = chronic kidney disease; CV= cardiovascular; CVD = cardiovascular dis-
ease; DM = diabetes mellitus; FH = familial hypercholesterolaemia; LDL-C = low-
density lipoprotein cholesterol; SCORE = Systematic Coronary Risk Estimation.
a
Class of recommendation.
b
Level of evidence.
Recommendations for cardiovascular imaging for risk
assessment of atherosclerotic cardiovascular disease

Recommendations Classa Levelb


5 Lipids and lipoproteins
Arterial (carotid and/or femoral) plaque bur-
den on arterial ultrasonography should be 5.1 Biological role of lipids and
IIa B
considered as a risk modifier in individuals at lipoproteins
low or moderate risk.29,30 Lipoproteins in plasma transport lipids to tissues for energy utiliza-
CAC score assessment with CT may be con- tion, lipid deposition, steroid hormone production, and bile acid for-
sidered as a risk modifier in the CV risk assess- mation. Lipoproteins consist of esterified and unesterified
IIb B
ment of asymptomatic individuals at low or cholesterol, TGs, and phospholipids and protein components named
moderate risk.1416,24,26 apolipoproteins that act as structural components, ligands for cellular
receptor binding, and enzyme activators or inhibitors.
CAC = coronary artery calcium; CT = computed tomography; CV =
cardiovascular. There are six major lipoproteins in blood: chylomicrons, very low-
a
Class of recommendation. density lipoprotein (VLDL), intermediate-density lipoprotein (IDL),
b
Level of evidence.
LDL; Lp(a), and HDL (Table 6 and Supplementary Figure 5).

4.2.2 Risk-based intervention strategies


Table 5 presents suggested intervention strategies as a function of total 5.2 Role of lipids and lipoproteins in the
CV risk and LDL-C level. This graded approach is based on evidence pathophysiology of atherosclerosis
from multiple meta-analyses and individual randomized controlled tri- All ApoB-containing lipoproteins <70 nm in diameter, including
als (RCTs), which show a consistent and graded reduction in ASCVD smaller TG-rich lipoproteins and their remnant particles, can cross
risk in response to reductions in TC and LDL-C levels (see the endothelial barrier, especially in the presence of endothelial dys-
Recommendations for cardiovascular disease risk estimation below).3141 function, where they can become trapped after interaction with
These data are consistent in showing that, since the relative risk extracellular structures such as proteoglycans.42 ApoB-containing
18 ESC/EAS Guidelines

Table 6 Physical and chemical characteristics of human plasma lipoproteins


Density Diameter TGs (%) Cholesteryl PLs (%) Cholesterol (%) Apolipoproteins
(g/mL) (nm) esters (%)
......................................................
Major Others
Chylomicrons <0.95 80100 9095 24 26 1 ApoB-48 ApoA-I, A-II, A-IV, A-V
VLDL 0.951.006 3080 5065 814 1216 47 ApoB-100 ApoA-I, C-II, C-III, E, A-V
IDL 1.0061.019 2530 2540 2035 1624 711 ApoB-100 ApoC-II, C-III, E

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LDL 1.0191.063 2025 46 3435 2226 615 ApoB-100
HDL 1.0631.210 813 7 1020 55 5 ApoA-I ApoA-II, C-III, E, M
Lp(a) 1.0061.125 2530 48 3546 1724 69 Apo(a) ApoB-100
Apo = apolipoprotein; HDL = high-density lipoprotein; IDL = intermediate-density lipoprotein; LDL = low-density lipoprotein; Lp(a) = lipoprotein(a); PLs = phospholipids; TGs
= triglycerides; VLDL = very low-density lipoprotein.

..
lipoproteins retained in the arterial wall provoke a complex process .. between the absolute changes in plasma LDL-C and the risk of
that leads to lipid deposition and the initiation of an atheroma.43 .. ASCVD.34,4550 The remarkable consistency among these studies, in
..
Continued exposure to ApoB-containing lipoproteins leads to .. addition to biological and experimental evidence, provides compel-
additional particles being retained over time in the artery wall, and to .. ling evidence that LDL-C is causally associated with the risk of
..
the growth and progression of atherosclerotic plaques. On average, .. ASCVD, and that lowering LDL-C reduces the risk of ASCVD pro-
people with higher concentrations of plasma ApoB-containing lipo- .. portionally to the absolute achieved reduction in LDL-C.2,51
..
proteins will retain more particles and accumulate lipids faster, result- .. Furthermore, Mendelian randomization studies have demon-
ing in more rapid growth and the progression of atherosclerotic .. strated that long-term exposure to lower LDL-C levels is associated
..
plaques. .. with a much lower risk of CV events as compared with shorter-term
Because atherosclerotic plaques grow over time as additional .. exposure to lower LDL-C (as achieved, for example, in randomized
..
ApoB-containing lipoprotein particles are retained, the size of the .. trials).48,52 These data provide strong support for the concept that
total atherosclerotic plaque burden is likely to be determined by
.. LDL particles have both a causal and cumulative effect on the risk of
..
both the concentration of circulating LDL-C and other ApoB-con- .. ASCVD. Therefore, the effect of LDL-C on the risk of ASCVD
taining lipoproteins, and by the total duration of exposure to these
.. appears to be determined by both the absolute magnitude and the
..
lipoproteins. Therefore, a person’s total atherosclerotic plaque bur- .. total duration of exposure to LDL-C.2
den is likely to be proportional to the cumulative exposure to these
.. The clinical benefit of lowering LDL-C is determined by the reduc-
..
lipoproteins.44 .. tion in circulating LDL particles as estimated by ApoB, which is usually
Eventually, the increase of the atherosclerotic plaque burden along
.. mirrored by a reduction of cholesterol carried by those particles.2,53
..
with changes in the composition of the plaque reaches a critical point .. Therefore, the clinical benefit of therapies that lower LDL-C by
..
at which disruption of a plaque can result, with the formation of an .. reducing LDL particle mass will be proportional to the absolute
overlying thrombus that acutely obstructs blood flow resulting in .. reduction in LDL-C, because—on average—the reduction in LDL-C
..
unstable angina, myocardial infarction (MI), or death. Therefore, the .. and LDL particles will be concordant.34,50,54,55 In contrast, the clinical
risk of experiencing an acute ASCVD event rises rapidly as more .. benefit of therapies that lower LDL-C by a mechanism that may dra-
..
ApoB-containing lipoproteins become retained and the atherosclerotic .. matically modify their composition may not be proportional to the
plaque burden increases. This provides the rationale for encouraging a .. observed absolute reduction in LDL-C, but instead would be
..
healthy lifestyle to maintain low levels of ApoB-containing lipoproteins .. expected to be proportional to the absolute change in LDL particle
throughout life to slow the progression of atherosclerosis; it also .. concentration as measured by a reduction in ApoB.2,53
..
explains the motivation to recommend treatment to lower LDL-C and ..
other ApoB-containing lipoproteins, for both the primary prevention ..
.. 5.3.2 Triglyceride-rich lipoproteins and risk of
of ASCVD and the secondary prevention of recurrent CV events.44 ..
.. atherosclerosis
.. TG-rich VLDL particles and their remnants carry most of the circulat-
5.3 Evidence for the causal effects of ..
.. ing TGs. Therefore, the plasma TG concentration reflects the con-
lipids and lipoproteins on the risk of .. centration of circulating ApoB-containing TG-rich lipoproteins.
..
atherosclerotic cardiovascular disease .. Elevated plasma TG levels are associated with an increasing risk of
5.3.1 Low-density lipoprotein cholesterol and risk of .. ASCVD, but this association becomes null after adjusting for non-
..
atherosclerosis .. HDL-C, an estimate of the total concentration of all ApoB-containing
Plasma LDL-C is a measure of the cholesterol mass carried by LDL .. lipoproteins.45 Similarly, lowering TG with fibrates reduces the risk of
..
particles, by far the most numerous of the ApoB-containing lipopro- .. CV events by the same amount as LDL-C-lowering therapies when
teins, and is an estimate of the concentration of circulating LDL.
.. measured per unit change of non-HDL-C,50 suggesting that the effect
..
Numerous epidemiological studies, Mendelian randomization studies, .. of plasma TGs on ASCVD is mediated by changes in the concentra-
and RCTs have consistently demonstrated a log-linear relationship
.. tion of TG-rich lipoproteins as estimated by non-HDL-C.
ESC/EAS Guidelines 19

..
Mendelian randomization studies also suggest that the association .. plasminogen, and it has pro-inflammatory effects most likely related
between plasma TGs and the risk of CHD may be causal; however, .. to the oxidized phospholipid load carried by Lp(a).71
..
this evidence must be interpreted with caution because nearly all var- .. Higher plasma Lp(a) concentrations are associated with an
iants associated with TGs are also associated with HDL-C, LDL-C, or .. increased risk of ASCVD, but it appears to be a much weaker risk fac-
..
Lp(a).5659 A recent Mendelian randomization study demonstrated .. tor for most people than LDL-C.72,73 In contrast, Mendelian random-
that TG-lowering lipoprotein lipase (LPL) variants and LDL-C-lower- .. ization studies have consistently demonstrated that lifelong exposure
..
ing LDL receptor variants had the same effect on the risk of ASCVD .. to higher Lp(a) levels is strongly and causally associated with an

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per unit change of ApoB, suggesting that all ApoB-containing lipopro- .. increased risk of ASCVD.74,75 While randomized trials evaluating
..
teins have the same effect on the risk of CHD.53 Together, these .. therapies that lower Lp(a) by 2030% (including niacin and CETP
studies strongly suggest that the causal effect of TG-rich lipoproteins .. inhibitors) have not provided evidence that lowering Lp(a) reduces
..
and their remnants on the risk of ASCVD is determined by the circu- .. the risk of ASCVD beyond that which would be expected from the
lating concentration of ApoB-containing particles, rather than by the .. observed reduction in ApoB-containing lipoproteins, recent data
..
TG content itself. .. with PCSK9 inhibitors have suggested a possible role for Lp(a) lower-
.. ing in reducing CV risk.76
..
.. This conflicting evidence appears to have been reconciled by a
5.3.3 High-density lipoprotein cholesterol and risk of .. recent Mendelian randomization study that showed that the
atherosclerosis ..
.. causal effect of Lp(a) on the risk of ASCVD is proportional to the
The inverse association between plasma HDL-C and the risk of .. absolute change in plasma Lp(a) levels. Importantly, this study also
ASCVD is among the most consistent and reproducible associa- ..
.. suggested that people with extremely high Lp(a) levels >180 mg/
tions in observational epidemiology.45,60 In contrast, Mendelian .. dL (>430 nmol/L) may have an increased lifetime risk of ASCVD
randomization studies do not provide compelling evidence that ..
.. similar to that of people with heterozygous FH (HeFH). Because
HDL-C is causally associated with the risk of ASCVD.49,61,62 ..
However, this evidence must be interpreted with caution because .. about 90% of a person’s Lp(a) level is inherited, extremely ele-
.. vated Lp(a) may represent a new inherited lipid disorder that is
most genetic variants associated with HDL-C are also associated ..
with directionally opposite changes in TGs, LDL-C, or both, thus
.. associated with extremely high lifetime risk of ASCVD and is two-
.. fold more prevalent than HeFH.77 However, this study77 and
making estimates of the effect of HDL-C on the risk of ASCVD ..
very difficult using the Mendelian randomization study design.
.. another based on the Heart Protection Study 2-Treatment of
.. HDL to Reduce the Incidence of Vascular Events (HPS2-THRIVE)
Furthermore, there is no evidence from randomized trials that ..
therapeutically increasing plasma HDL-C reduces the risk of CV
.. trial78 have shown that large absolute changes in Lp(a) may be
.. needed to produce a clinically meaningful reduction in the risk of
events.6367 In the Effects of Dalcetrapib in Patients with a Recent ..
Acute Coronary Syndrome (dal-OUTCOMES) trial, treatment
.. ASCVD events.
..
with the cholesteryl ester transfer protein (CETP) inhibitor dalce- ..
.. 5.4 Laboratory measurement of lipids
trapib increased HDL-C without any effect on LDL-C or ApoB, ..
but did not reduce the risk of major CV events.65 Similarly, in the .. and lipoproteins
..
Assessment of Clinical Effects of Cholesteryl Ester Transfer .. Measurement of lipids and lipoproteins is used to estimate the risk of
Protein Inhibition with Evacetrapib in Patients at a High-Risk for .. ASCVD and guide therapeutic decision-making. Quantification of
..
Vascular Outcomes (ACCELERATE) and Randomized Evaluation .. plasma lipids can be performed on whole plasma and quantification
of the Effects of Anacetrapib Through Lipid Modification .. of lipoproteins can be achieved by measuring their protein compo-
..
(REVEAL) trials, treatment with CETP inhibitors more than .. nent. Operationally, lipoproteins are classified based on their
doubled HDL-C levels, but did not appear to reduce the risk of .. hydrated density (see Table 6).
..
ASCVD events beyond that expected from the modest reductions ..
in ApoB levels.2,63,64 Furthermore, several randomized trials have ..
.. 5.4.1 Lipoprotein measurement
shown that directly infused HDL mimetics increase plasma HDL- ..
C concentrations, but do not reduce the progression of athero- .. Given the central causal role of ApoB-containing lipoproteins in the
.. initiation and progression of atherosclerosis, direct measurement of
sclerosis as measured by intravascular ultrasound.68,69 ..
Therefore, there is currently no randomized trial or genetic evi-
.. the circulating concentration of atherogenic ApoB-containing lipo-
.. proteins to both estimate risk and guide treatment decisions would
dence to suggest that raising plasma HDL-C is likely to reduce the ..
risk of ASCVD events. Whether therapies that alter the function of
.. be ideal. Because all ApoB-containing lipoproteins—including VLDL,
.. TG-rich remnant particles, and LDL—contain a single ApoB mole-
HDL particles will reduce the risk of ASCVD is unknown. ..
.. cule, quantitation of ApoB directly estimates the number of athero-
.. genic particles in plasma.
..
5.3.4 Lipoprotein(a) and risk of atherosclerosis .. Standardized, automated, accurate, and inexpensive methods to
Lp(a) is an LDL particle with an Apo(a) moiety covalently bound to .. measure ApoB are available. Fasting is not required because even in
..
its ApoB component.70 It is <70 nm in diameter and can freely flux .. the post-prandial state, ApoB48-containing chylomicrons typically
across the endothelial barrier, where it can become—similarly to .. represent <1% of the total concentration of circulating ApoB-con-
..
LDL—retained within the arterial wall and thus may increase the risk .. taining lipoproteins. Furthermore, the analytical performances of
of ASCVD. Pro-atherogenic effects of Lp(a) have also been attrib-
.. ApoB measurement methods are superior to the measurement or
..
uted to pro-coagulant effects as Lp(a) has a similar structure to . calculation of LDL-C and non-HDL-C.79
20 ESC/EAS Guidelines

..
5.4.2 Lipid measurements .. needed to establish a reliable and reproducible method for the quan-
In clinical practice, the concentration of plasma lipoproteins is not .. tification of Lp(a) mass or particle number.92
..
usually measured directly but is instead estimated by measuring their ..
cholesterol content. TC in humans is distributed primarily among ..
.. 5.4.3 Fasting or non-fasting?
three major lipoprotein classes: VLDL, LDL, and HDL. Smaller .. Traditionally, blood sampling for lipid analyses has been recom-
amounts of cholesterol are also contained in two minor lipoprotein
..
.. mended in the fasting state. Recent systematic studies comparing fast-
classes: IDL and Lp(a). A standard serum lipid profile measures the .. ing and non-fasting samples have suggested that the difference is

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..
concentration of TC and HDL-C, as well as TG. With these values, .. small for most lipid parameters.85,94100 Non-fasting sampling
the LDL-C concentration can be estimated. .. has been used in large population-based studies.100 In most studies,
Plasma LDL-C can be measured directly using enzymatic techni-
..
.. non-fasting samples display a higher TG level of 0.3 mmol/L (27 mg/
ques or preparative ultracentrifugation, but in clinical medicine it is .. dL).100,101 On average, and for most individuals, this increment will be
most often calculated using the Friedewald formula:
..
.. of no clinical significance. Indeed, a number of guidelines recommend
.. non-fasting sampling.100,102,103
LDL-C ¼ TC  HDL-C  (TG/2.2) in mmol/L ..
.. For general risk screening, non-fasting samples seem to have at
or .. least the same prognostic value as fasting samples.104 The practical
LDL-C ¼ TC  HDL-C  (TG/5) in mg/dL ... advantages of non-fasting samples, including better patient acceptabil-
..
Although convenient, the Friedewald calculated value of LDL-C
.. ity, outweigh the potential imprecision in some patients, although the
.. determination of some key analytes, such as fasting glucose, may be
has several well-established limitations: (i) methodological errors ..
.. compromised. Furthermore, even if non-fasting sampling can be used
may accumulate since the formula necessitates three separate analy- .. in most cases, in patients with metabolic syndrome (MetS), DM, or
ses of TC, TGs, and HDL-C; and (ii) a constant cholesterol/TG ratio ..
.. hypertriglyceridaemia (HTG), calculated LDL-C should be inter-
in VLDL is assumed. With high TG values (>4.5 mmol/L or >400 mg/ .. preted with caution.
dL) the formula cannot be used. This should especially be considered ..
..
in non-fasting samples. ..
To overcome the problems associated with calculated LDL-C, .. 5.5 Recommendations for measuring
.. lipids and lipoproteins to estimate risk of
direct enzymatic methods for the measurement of LDL-C have ..
been developed. These methods are commercially available as .. atherosclerotic cardiovascular disease
..
ready to use tools for automatic analysis. The definition of LDL-C .. Measurement of plasma TC is needed to calculate risk using SCORE,
by the Friedewald equation and by direct measurement is the .. while the inclusion of plasma HDL-C level can improve risk estima-
..
same: non-HDL-C  VLDL-C, representing the sum of the choles- .. tion using the online SCORE calculator. Therefore, both TC and
terol carried by the biochemically defined LDL, IDL, and Lp(a) .. HDL-C should be measured to estimate a person’s risk of ASCVD
..
subfractions. .. using SCORE, or one of the other risk calculators (almost all of which
For the general population, calculated LDL-C and direct LDL-C .. also include measurements of TC and HDL-C).
..
show very strong correlations.8083 However, calculated LDL-C has .. Plasma LDL-C should be measured to estimate the risk of ASCVD
been found to underestimate LDL-C at concentrations of TG >_2
.. that can be modified with LDL-C-lowering therapies, and to identify
..
mmol/L (177 mg/dL).81,82 Equally, at very low levels of LDL-C, calcu- .. whether markedly elevated LDL-C levels are present that may sug-
lated LDL-C may be misleading, especially in the presence of high
.. gest a lifetime high-risk of ASCVD due to lifelong cumulative expo-
..
TG.81,8486 To avoid some of the problems with the Friedewald for- .. sure to high levels of atherogenic lipoproteins, such as in FH. Plasma
mula, a number of modifications for the calculation of LDL-C have
.. LDL-C can be either calculated or measured directly.
..
been suggested, but it remains to be proved whether these modifica- .. Plasma TG should be assessed to identify people who may have a
tions are superior to Friedewald’s formula for the estimation of CV
..
.. greater modifiable risk of ASCVD than is reflected by LDL-C, due to
risk.81,8587 It is important to note that direct LDL-C measurements .. the presence of an increased concentration of atherogenic ApoB-
..
also have limitations, including systematic bias and inaccuracy in .. containing TG-rich lipoproteins and their remnants, and to identify
patients with dyslipidaemia, especially for high TG levels.8890 .. people in whom calculated and directly measured LDL-C may under-
..
As an alternative calculated LDL-C, non-HDL-C can be calculated .. estimate the risk of ASCVD by underestimating either the concentra-
as TC  HDL-C and is a measure of the TC carried by all atherogenic .. tion of circulating LDL particles or the cholesterol content carried by
..
ApoB-containing lipoproteins, including TG-rich particles in VLDL .. those particles, such as those with very low levels of LDL. This may
and their remnants.100 .. be especially relevant in patients with DM or MetS.
..
Several methods for the determination of Lp(a) are available. The .. In general, LDL-C, non-HDL-C, and ApoB concentrations are very
complex molecular structure of Lp(a) and the variation in size of .. highly correlated. As a result, under most circumstances, they pro-
..
Apo(a) has been a challenge in the development of analytical meth- .. vide very similar information about ASCVD risk.45,105108 However,
ods for Lp(a). Available methods are, to a varying degree, influenced .. under certain circumstances—including among people with elevated
..
by the Apo(a) isoform.91 Furthermore, the concentration of Lp(a) is .. TG levels, DM, obesity, or very low achieved LDL-C levels—the cal-
reported as either a molar concentration (nmol/L) or as a mass (mg/ .. culated or directly measured LDL-C level may underestimate both
..
dL) by the various assays, and conversion between molar and mass .. the total concentration of cholesterol carried by LDL and, more
concentrations has been found to be both size- and concentration- .. importantly, underestimate the total concentration of ApoB-contain-
..
dependent.9193 Therefore, standardization between assays is . ing lipoproteins, thus underestimating the risk of ASCVD. In around
ESC/EAS Guidelines 21

..
20% of patients there may be discordance between measured LDL-C ..
..
6 Treatment targets and goals
and ApoB levels.85,109
..
Considering the potential inaccuracy of LDL-C in dyslipidaemia, .. In previous EAS/ESC Guidelines for the management of dyslipidae-
among patients with DM or high TG levels, and in patients with very .. mias1,113 and other major guidelines on the treatment of blood cho-
..
low LDL-C levels, measurement of both ApoB and non-HDL-C is .. lesterol to reduce atherosclerotic CV risk in adults,40,114 the
recommended as part of routine lipid analysis for risk evaluation in .. importance of LDL-C lowering to prevent ASCVD is strongly
..
patients with elevated plasma TGs. Because ApoB provides an accu- .. emphasized. The European Task Force felt that limiting the current

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rate estimate of the total concentration of atherogenic particles .. knowledge on CV prevention only to results from RCTs reduces the
..
under all circumstances, it is the preferred measurement to further .. exploitation of the potential that is available for the prevention of
refine the estimate of ASCVD risk that is modifiable by lipid-lowering
.. ASCVD. It is the concordance of the conclusions from many different
..
therapy. .. approaches (from basic science, clinical observations, genetics, epi-
Lp(a) has a similar structure to plasminogen and binds to the plas-
.. demiology, RCTs, etc.) that contributes to the understanding of the
..
minogen receptor, leading to increased thrombosis (pro-thrombotic .. causes of ASCVD and to the potential of prevention. The Task Force
factor). Measurement of Lp(a) should be considered at least once in
.. is aware of the limitations of some of the sources of evidence and
..
each person’s lifetime, if available, to identify people who have inher- .. accepts that RCTs have not examined different LDL-C goals system-
ited an extremely elevated level of Lp(a) >_180 mg/dL (>_430 nmol/L)
.. atically, but felt that it was appropriate to look at the totality of the
..
and therefore have a very high lifetime risk of ASCVD that is approxi- .. evidence. Particular consideration was given to results from meta-
.. analyses confirming the dose-dependent reduction in ASCVD with
mately equivalent to the risk associated with HeFH. In addition, this
... LDL-C-lowering agents; the greater the absolute LDL-C reduction,
strategy can identify people with less-extreme Lp(a) elevations who ..
may be at a higher risk of ASCVD, which is not reflected by the .. the greater the CV risk reduction.35,36,50,115 The benefits related to
.. LDL-C reduction are not specific for statin therapy.33 No level of
SCORE system, or by other lipid or lipoprotein measurements. ..
Measurement of Lp(a) has been shown to provide clinically significant .. LDL-C below which benefit ceases or harm occurs has been defined.
.. There is considerable individual variability in the LDL-C response
improved risk reclassification under certain conditions, and therefore ..
should be considered in patients who have an estimated 10-year risk .. to dietary and drug treatments,31 which is traditionally taken to sup-
..
of ASCVD that is close to the threshold between high and moderate .. port a tailored approach to management. Total CV risk reduction
risk.110112 .. should be individualized, and this can be more specific if goals are
..
Recommendations for measuring lipids and lipoproteins to esti- .. defined. The use of goals can also aid patientdoctor communica-
mate the risk of ASCVD are summarized below. .. tion. It is judged that a goal approach may facilitate adherence to

Recommendations for lipid analyses for cardiovascular disease risk estimation

Recommendations Classa Levelb

TC is to be used for the estimation of total CV risk by means of the SCORE system. I C
HDL-C analysis is recommended to further refine risk estimation using the online SCORE system. I C
LDL-C analysis is recommended as the primary lipid analysis method for screening, diagnosis, and management. I C
TG analysis is recommended as part of the routine lipid analysis process. I C
Non-HDL-C evaluation is recommended for risk assessment, particularly in people with high TG levels, DM, obesity, or
I C
very low LDL-C levels.
ApoB analysis is recommended for risk assessment, particularly in people with high TG levels, DM, obesity, metabolic syn-
drome, or very low LDL-C levels. It can be used as an alternative to LDL-C, if available, as the primary measurement for
I C
screening, diagnosis, and management, and may be preferred over non-HDL-C in people with high TG levels, DM, obesity,
or very low LDL-C levels.
Lp(a) measurement should be considered at least once in each adult person’s lifetime to identify those with very high
inherited Lp(a) levels >180 mg/dL (>430 nmol/L) who may have a lifetime risk of ASCVD equivalent to the risk associated IIa C
with heterozygous familial hypercholesterolaemia.
Lp(a) should be considered in selected patients with a family history of premature CVD, and for reclassification in people
IIa C
who are borderline between moderate and high-risk.

Apo = apolipoprotein; ASCVD = atherosclerotic cardiovascular disease; CV = cardiovascular; CVD = cardiovascular disease; DM = diabetes mellitus; HDL-C = high-density lip-
oprotein cholesterol; LDL-C = low-density lipoprotein cholesterol; Lp(a) = lipoprotein(a); SCORE = Systematic Coronary Risk Estimation; TC = total cholesterol; TG =
triglyceride.
22 ESC/EAS Guidelines

treatment, although this consensus opinion has not been fully tested.
.. Secondary goals have also been defined by inference for non-
..
For all these reasons, the European Task Force retains a goal .. HDL-C and for ApoB; they receive a moderate grading, as they have
approach to lipid management and treatment goals are tailored to ... not been extensively studied in RCTs. The specific goal for non-
..
the total CV risk level. There is also evidence suggesting that lowering .. HDL-C should be 0.8 mmol/L (30 mg/dL) higher than the corre-
of LDL-C beyond the goals that were set in the previous EAS/ESC .. sponding LDL-C goal; the adjustment of lipid-lowering therapy in
..
Guidelines is associated with fewer ASCVD events.34,116,117 .. accordance with these secondary goals may be considered in patients
Therefore, it seems appropriate to reduce LDL-C to as low a level as .. at very high CV risk after achievement of an LDL-C goal, although the
..

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possible, at least in patients at very high CV risk, and for this reason a .. clinical advantages of this approach with respect to outcomes remain
minimum 50% reduction is suggested for LDL reduction, together .. to be addressed. When secondary targets are used the recommenda-
..
with reaching the tailored goal. .. tions are: (i) non-HDL-C <2.2 mmol/L (<85 mg/dL), <2.6 mmol/L
The lipid goals are part of a comprehensive CV risk reduction .. (<100 mg/dL), and <3.4 mmol/L (<130 mg/dL) in people at very high,
..
strategy and are summarized in Table 7. The rationales for the non- .. high, and moderate CV risk, respectively;121123 and (ii) ApoB <65
lipid targets are given in the 2016 ESC Joint Prevention Guidelines.10 .. mg/dL, <80 mg/dL, and <100 mg/dL in very-high, high, and moderate
..
The targeted approach to lipid management is primarily aimed at .. total CV risk, respectively.121,123,124
reducing atherosclerotic risk by substantially lowering LDL-C to lev- .. To date, no specific goals for HDL-C or TG levels have been
..
els that have been achieved in recent large-scale trials of PCSK-9 .. determined in clinical trials, although increases in HDL-C predict
inhibitors. Therefore, for patients at very high CV risk, whether in
.. atherosclerosis regression, and low HDL-C is associated with excess
..
secondary prevention or (rarely) in primary prevention, LDL-C .. events and mortality in coronary artery disease (CAD) patients, even
reduction of >_50% from baseline and an LDL-C goal of <1.4 mmol/L
.. at low LDL levels. Clinicians should use clinical judgment when con-
..
(<55 mg/dL) are recommended. For patients with ASCVD who .. sidering further treatment intensification in patients at high or very
experience a second vascular event within 2 years (not necessarily of
.. high total CV risk.
..
the same type as the first event) while taking maximally tolerated ..
statin-based therapy, an LDL-C goal <1.0 mmol/L (<40 mg/dL) may
..
..
be considered.119,120 For people at high CV risk, an LDL-C reduction ..
.. 7 Lifestyle modifications to
of >_50% from baseline and an LDL-C goal <1.8 mmol/L (<70 mg/dL) ..
are recommended. In patients at moderate CV risk, an LDL-C goal .. improve the plasma lipid profile
..
<2.6 mmol/L (<100 mg/dL) should be considered, while for low-risk .. The pivotal role of nutrition in the prevention of ASCVD has been
individuals a goal of <3.0 mmol/L (<116 mg/dL) may be considered ..
.. extensively reviewed.125129 Dietary factors influence the develop-
(see Recommendations for treatment goals for low-density lipoprotein cho- .. ment of CVD either directly or through their action on traditional
lesterol below and Supplementary Table 2). ..
. risk factors, such as plasma lipids, BP, or glucose levels.

Recommendations for treatment goals for low-density lipoprotein cholesterol

Recommendations Classa Levelb

In secondary prevention for patients at very-high risk,c an LDL-C reduction of >_50% from baselined and an LDL-C goal of
I A
<1.4 mmol/L (<55 mg/dL) are recommended.3335,119,120
In primary prevention for individuals at very-high risk but without FH,c an LDL-C reduction of >_50% from baselined and
I C
an LDL-C goal of <1.4 mmol/L (<55 mg/dL) are recommended.3436
In primary prevention for individuals with FH at very-high risk, an LDL-C reduction of >_50% from baseline and an LDL-C
IIa C
goal of <1.4 mmol/L (<55 mg/dL) should be considered.
For patients with ASCVD who experience a second vascular event within 2 years (not necessarily of the same type as the
first event) while taking maximally tolerated statin-based therapy, an LDL-C goal of <1.0 mmol/L (<40 mg/dL) may be IIb B
considered.119,120
In patients at high risk,c an LDL-C reduction of >_50% from baselined and an LDL-C goal of <1.8 mmol/L (<70 mg/dL) are
I A
recommended.34,35
In individuals at moderate risk,c an LDL-C goal of <2.6 mmol/L (<100 mg/dL) should be considered.34 IIa A
c 36
In individuals at low risk, an LDL-C goal <3.0 mmol/L (<116 mg/dL) may be considered. IIb A

ASCVD = atherosclerotic cardiovascular disease; FH = familial hypercholesterolaemia; LDL-C = low-density lipoprotein cholesterol.
a
Class of recommendation.
b
Level of evidence.
c
For definitions see Table 4.
d
The term ‘baseline’ refers to the LDL-C level in a person not taking any LDL-C-lowering medication. In people who are taking LDL-C-lowering medication(s), the projected
baseline (untreated) LDL-C levels should be estimated, based on the average LDL-C-lowering efficacy of the given medication or combination of medications.
ESC/EAS Guidelines 23

Table 7 Treatment targets and goals for cardiovascular disease prevention

Smoking No exposure to tobacco in any form.


Diet Healthy diet low in saturated fat with a focus on wholegrain products, vegetables, fruit, and fish.
Physical activity 3.57 h moderately vigorous physical activity per week or 3060 min most days.
Body weight BMI 2025 kg/m2, and waist circumference <94 cm (men) and <80 cm (women).
Blood pressure <140/90 mmHg.a

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LDL-C Very-high risk in primary or secondary prevention:
A therapeutic regimen that achieves >_50% LDL-C reduction from baselineb and an LDL-C goal of <1.4 mmol/L (<55 mg/dL).
No current statin use: this is likely to require high-intensity LDL-lowering therapy.
Current LDL-lowering treatment: an increased treatment intensity is required.
High risk: A therapeutic regimen that achieves >_50% LDL-C reduction from baselineb and an LDL-C goal of <1.8 mmol/L
(<70 mg/dL).
Moderate risk:
A goal of <2.6 mmol/L (<100 mg/dL).
Low risk:
A goal of <3.0 mmol/L (<116 mg/dL).
Non-HDL-C Non-HDL-C secondary goals are <2.2, 2.6, and 3.4 mmol/L (<85, 100, and 130 mg/dL) for very-high-, high-, and moderate-risk
people, respectively.
ApoB ApoB secondary goals are <65, 80, and 100 mg/dL for very-high-, high-, and moderate-risk people, respectively.
Triglycerides No goal, but <1.7 mmol/L (<150 mg/dL) indicates lower risk and higher levels indicate a need to look for other risk factors.
Diabetes HbA1c: <7% (<53 mmol/mol).
Apo = apolipoprotein; BMI = body mass index; HbA1c = glycated haemoglobin; HDL-C = high-density lipoprotein cholesterol; LDL-C = low-density lipoprotein cholesterol.
a
Lower treatment targets are recommended for most treated hypertensive patients, provided that the treatment is well tolerated.118
b
The term ‘baseline’ refers to the LDL-C level in a person not taking any lipid-lowering medication, or to the extrapolated baseline value for those who are on current
treatment.

Convincing evidence of the causal association between diet and


.. meats, foods higher in refined carbohydrates, and salt, is associ-
..
ASCVD risk is, nevertheless, available indirectly from randomized .. ated with a lower incidence of CV events.131 Moreover, it indi-
..
‘metabolic ward’ studies showing that high saturated fat intake causes .. cates that the replacement of animal fats, including dairy fat, with
increased LDL-C concentrations, and from cohort studies, genetic .. vegetable sources of fats and polyunsaturated fatty acids (PUFAs)
..
epidemiological studies, and randomized trials showing that higher .. may decrease the risk of CVD.132
LDL-C levels cause ASCVD. .. Dietary patterns that have been more extensively evaluated are
..
The lack of concordance between studies is due both to methodo- .. the Dietary Approaches to Stop Hypertension (DASH) diet—partic-
logical problems (particularly inadequate sample sizes or short study .. ularly in relation to BP control—and the Mediterranean diet; both
..
durations) and the difficulties of evaluating the impact of a single diet- .. have proved to be effective in reducing CV risk factors and, possibly,
ary factor independently of any other changes in the diet.130 In fact, as .. to contribute to ASCVD prevention.133 The most relevant difference
..
foods are mixtures of different nutrients and other components, it is .. between the Mediterranean and the DASH diet is the emphasis of
not appropriate to attribute the health effects of a food to only one .. the former on extra-virgin olive oil. The Mediterranean diet is associ-
..
of its components. Moreover, if energy intake must be kept constant, .. ated with a reduced incidence of CV and other non-communicable
eating less of one macronutrient implies necessarily eating more of .. diseases in epidemiological studies,134,135 and has been proved in
..
others. The quality of the replacement (for instance, unsaturated fat .. RCTs to be effective in reducing CV events in primary and secondary
vs. highly refined grains) can influence the effect observed, significantly ... prevention.136 In particular, the Prevenci on con Dieta Mediterranea
modifying the impact on health of the nutrient replaced. These limita-
.. (PREDIMED) trial indicated that participants allocated to a
..
tions suggest caution in interpreting the results of RCTs or even .. Mediterranean-type diet, supplemented with extra-virgin olive oil or
meta-analyses of RCTs in relation to the effect of a single dietary
.. nuts, had a significantly lower (around 30%) incidence of major CV
..
change on ASCVD.130 .. events compared with those who were on a low-fat diet.137
To overcome, at least in part, these problems, in recent years
.. In summary, despite the results of PREDIMED and a few other
..
nutrition research has focused on the relationship between .. intervention studies with ASCVD endpoints that support a healthy
ASCVD on the one hand, and foods and dietary patterns—rather
.. lifestyle for ASCVD prevention, RCTs cannot represent the sole
..
than single nutrients—on the other. Consistent evidence from .. grounds on which dietary recommendations should rely. They also
..
epidemiological studies indicates that higher consumption of fruit, .. need to be based on the combination of large observational cohort
non-starchy vegetables, nuts, legumes, fish, vegetable oils, yoghurt, .. studies and relatively short-term randomized trials having intermedi-
..
and wholegrains, along with a lower intake of red and processed .. ate risk factors (such as blood lipids) as outcomes.
24 ESC/EAS Guidelines

Table 8 Impact of specific lifestyle changes on lipid levels


Magnitude of the effect Level Reference
Lifestyle interventions to reduce TC and LDL-C levels
129,138
Avoid dietary trans fats þþ A
129,139
Reduce dietary saturated fats þþ A
140,141
Increase dietary fibre þþ A

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142,143
Use functional foods enriched with phytosterols þþ A
144146
Use red yeast rice nutraceuticals þþ A
147,148
Reduce excessive body weight þþ A
149,150
Reduce dietary cholesterol þ B
151
Increase habitual physical activity þ B
Lifestyle interventions to reduce TG-rich lipoprotein levels
147,148
Reduce excessive body weight þ A
152,153
Reduce alcohol intake þþþ A
151,154
Increase habitual physical activity þþ A
147,155
Reduce total amount of dietary carbohydrates þþ A
156,157
Use supplements of n-3 polyunsaturated fats þþ A
158,159
Reduce intake of mono- and disaccharides þþ B
129,137
Replace saturated fats with mono- or polyunsaturated fats þ B
Lifestyle interventions to increase HDL-C levels
129,160
Avoid dietary trans fats þþ A
151,161
Increase habitual physical activity þþþ A
147,148
Reduce excessive body weight þþ A
147,162
Reduce dietary carbohydrates and replace them with unsaturated fats þþ A
153
Modest consumption in those who take alcohol may be continued þþ B
163
Quit smoking þ B
The magnitude of the effect (þþþ = >10%, þþ = 510%, þ = <5%) and the level of evidence refer to the impact of each dietary modification on plasma levels of a specific lip-
oprotein class.
HDL-C = high-density lipoprotein cholesterol; LDL-C = low-density lipoprotein cholesterol; TC = total cholesterol; TG = triglyceride.

Table 8 summarizes the currently available evidence on the influen- .. ranges from 0.26.5% of the total energy intake in different popula-
..
ces of lifestyle changes and functional foods on lipoproteins, indicat- .. tions.165 Unsaturated fat-rich oils from safflower, sunflower,
ing the magnitudes of the effects and the levels of evidence in relation
.. rapeseed, flaxseed, corn, olives, or soybean were shown to reduce
..
to the impacts on the specific lipoprotein class; for the reasons out- .. LDL-C levels (-0.42 to -0.20 mmol/L) when used in substitution of
lined above, the levels of evidence are not based on RCTs with
.. SFA-rich foods like butter or lard.166 The effects of carbohydrate
..
ASCVD endpoints. Moreover, within the Guidelines on the manage- .. consumption on LDL-C are described in section 7.4.3.
ment of dyslipidaemias, information on the potential to improve
.. Body weight reduction also influences TC and LDL-C levels, but
..
plasma lipoprotein profiles by dietary means is clinically relevant, .. the magnitude of the effect is small: in obese people, a decrease in
..
even in the absence of a clear demonstration of CV benefits. .. LDL-C concentration of 0.2 mmol/L (8 mg/dL) is observed for every
.. 10 kg of weight loss.147,167 The reduction of LDL-C levels induced by
..
7.1 Influence of lifestyle on total .. regular physical exercise is even smaller.151,168 The benefits of weight
cholesterol and low-density lipoprotein ... reduction and physical exercise on the CV risk profile likely impact
.. on other risk factors, especially hypertension and diabetes.
cholesterol levels ..
.. Table 9 summarizes the possible choices of foods to lower TC and
Saturated fatty acids (SFAs) are the dietary factor with the greatest .. LDL-C levels. Given the cultural diversity of the European popula-
impact on LDL-C levels (0.020.04 mmol/L or 0.81.6 mg/dL of ..
.. tions, they should be translated into practical behaviours, considering
LDL-C increase for every additional 1% energy coming from satu- .. local habits and socio-economic factors.
rated fat).164 Quantitatively, dietary trans fatty acids have a similar ele- ..
..
vating effect on LDL-C to that of SFAs; however, while SFAs increase ..
HDL-C levels, trans fats decrease them.137 Trans unsaturated fatty .. 7.2 Influence of lifestyle on triglyceride
..
acids can be found in limited amounts (usually <5% of total fat) in .. levels
dairy products and in meats from ruminants. ‘Partially hydrogenated
.. Weight reduction improves insulin sensitivity and decreases TG lev-
..
fatty acids’ of industrial origin represent the major source of trans .. els. Regular physical exercise reduces plasma TG levels over and
fatty acids in the diet; the average consumption of trans fatty acids
.. above the effect of weight reduction.151,168,169 Alcohol intake has a
ESC/EAS Guidelines 25

Table 9 Food choices to lower low-density lipoprotein cholesterol and improve the overall lipoprotein profile
To be preferred To be used in moderation To be chosen occasionally in
limited amounts
Cereals Wholegrains Refined bread, rice, and pasta, bis- Pastries, muffins, pies, croissants
cuits, corn flakes
Vegetables Raw and cooked vegetables Potatoes Vegetables prepared in butter or

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cream
Legumes Lentils, beans, fava beans, peas,
chickpeas, soybean
Fruit Fresh or frozen fruit Dried fruit, jelly, jam, canned fruit,
sorbets, ice lollies/popsicles, fruit
juice
Sweets and sweeteners Non-caloric sweeteners Sucrose, honey, chocolate, sweets/ Cakes, ice creams, fructose, soft
candies drinks
Meat and fish Lean and oily fish, poultry without Lean cuts of beef, lamb, pork, and Sausages, salami, bacon, spare ribs,
skin veal, seafood, shellfish hot dogs, organ meats
Dairy food and eggs Skimmed milk and yoghurt Low-fat milk, low-fat cheese and Regular cheese, cream, whole milk
other milk products, eggs and yoghurt
Cooking fat and dressings Vinegar, mustard, fat-free dressings Olive oil, non-tropical vegetable Trans fats and hard margarines
oils, soft margarines, salad dressing, (better to avoid them), palm and
mayonnaise, ketchup coconut oils, butter, lard, bacon fat
Nuts/seeds All, unsalted (except coconut) Coconut
Cooking procedures Grilling, boiling, steaming Stir-frying, roasting Frying

..
major impact on TG levels, particularly in individuals with HTG.153,170 .. particularly to people at increased CV risk, may also be able to mod-
The detrimental effects of a high-carbohydrate diet on TGs occur .. ify plasma TG and HDL-C levels (Table 9). This section focuses on
..
mainly when refined carbohydrate-rich foods are consumed, while .. dietary and other lifestyle factors that may be implemented to
they are much less prominent if the diet is based largely on fibre-rich, .. improve the overall lipoprotein profile.
..
low-glycaemic index foods. This applies particularly to people with ..
DM or MetS.171,172 ..
.. 7.4.1 Body weight and physical activity
Habitual consumption of significant amounts (>10% energy) of .. Since overweight, obesity, and—in particular—abdominal adiposity
dietary fructose contributes to TG elevation, particularly in people ..
.. often contribute to dyslipidaemia, caloric intake should be reduced
with HTG or abdominal obesity. These effects are dose-dependent; .. and energy expenditure increased in those with excessive weight
with a habitual fructose consumption between 1520% of total ..
.. and/or abdominal adiposity.
energy intake, plasma TG increases by as much as 3040%. Sucrose, .. In the case of excess weight, body weight reduction, even if modest
a disaccharide containing glucose and fructose, represents an impor-
..
.. (510% of basal body weight), improves lipid abnormalities and
tant source of fructose in the diet.159,173,174 .. favourably affects the other CV risk factors often present in dyslipidae-
..
.. mic individuals.148 While the beneficial effects of weight reduction on
7.3 Influence of lifestyle on high-density .. metabolic and surrogate markers have been demonstrated, the bene-
..
lipoprotein cholesterol levels .. fits of weight loss on mortality and CV outcome are less clear.175
Weight reduction increases HDL-C levels; a 0.01 mmol/L (0.4 mg/ .. Weight reduction can be achieved by decreasing the consumption
..
dL) increase is observed for every kilogram decrease in body weight .. of energy-dense foods, inducing a caloric deficit of 300500 kcal/day.
when weight reduction has stabilized. Aerobic physical activity, such
.. The intervention should combine diet and exercise; this approach
..
as 2530 km of brisk walking per week (or any equivalent activity), .. also leads to the greatest improvement in physical performance and
may increase HDL-C levels by 0.080.15 mmol/L (3.16 mg/dL).169
.. quality of life, and mitigates reductions in muscle and bone mass, par-
..
Smoking cessation may also contribute to HDL-C elevation, provided .. ticularly in older people.176 It is always appropriate to advise people
that weight gain is prevented.163
.. with dyslipidaemia to engage in regular physical exercise of moderate
..
.. intensity for >_30 min/day, even if they are not overweight.168
7.4 Lifestyle recommendations to ..
..
improve the plasma lipid profile .. 7.4.2 Dietary fat
..
LDL-C lowering represents the primary target for reducing CV risk .. Avoiding any consumption of trans fat is a key measure of the dietary
and therefore deserves special emphasis in the evaluation of lifestyle
.. prevention of CVD. The trans fatty acids produced in the partial hydro-
..
measures. The diet recommended to the general population, and . genation of vegetable oils account for 80% of total intake. Thanks to
26 ESC/EAS Guidelines

..
efforts made in different parts of the world, the intake of trans fatty .. 7.4.5 Smoking
acids has decreased substantially over the past 1015 years. .. Smoking cessation has clear benefits regarding overall CV risk, and
..
As for saturated fat, its consumption should be <10% of the total .. specifically on HDL-C levels.163
caloric intake and should be further reduced (<7% of energy) in the ..
..
presence of hypercholesterolaemia. For most individuals, a wide .. 7.5 Dietary supplements and functional
range of total fat intakes is acceptable, and will depend upon individ- ..
.. foods for the treatment of dyslipidaemias
ual preferences and characteristics. However, fat intakes >3540% .. Nutritional evaluation of functional foods includes not only the

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of calories are generally associated with increased intakes of both ..
.. search for clinical evidence of beneficial effects relevant to improved
saturated fat and calories. Conversely, low intakes of fats and oils .. health or the reduction of disease risk, but also the demonstration of
increase the risk of inadequate intakes of vitamin E and of essential ..
.. good tolerability. Overall, the available evidence on functional foods
fatty acids, and may contribute to a reduction of HDL-C.164 .. so far identified in this field is incomplete; the major gap is an absence
Fat intake should predominantly come from sources of monounsa- ..
.. of diet-based intervention trials of enough duration to be relevant for
turated fatty acids, including both n-6 and n-3 PUFAs. Not enough .. the natural history of dyslipidaemia and CVD.
data are available to make a recommendation regarding the optimal ..
..
n-3:n-6 fatty acid ratio.177,178 The cholesterol intake in the diet should ..
be reduced (<300 mg/day), particularly in people with high plasma
.. 7.5.1 Phytosterols
.. The principal phytosterols are sitosterol, campesterol, and stigmas-
cholesterol levels. ..
.. terol; they occur naturally in vegetable oils and in smaller amounts in
..
.. vegetables, fresh fruits, nuts, grains, and legumes. The dietary intake
7.4.3 Dietary carbohydrate and fibre .. of plant sterols ranges between an average of 250 mg/day in
Dietary carbohydrate has a ‘neutral’ effect on LDL-C, although exces- ..
.. Northern Europe to 500 mg/day in Mediterranean countries.
sive consumption is represented by untoward effects on plasma TGs .. Phytosterols compete with cholesterol for intestinal absorption,
and HDL-C levels.164 Dietary fibre (particularly of the soluble ..
.. thereby modulating TC levels.
type)—which is present in legumes, fruits, vegetables, and wholegrain .. Daily consumption of 2 g of phytosterols can effectively lower TC
cereals (e.g. oats and barley)—has a hypocholesterolaemic effect and
..
.. and LDL-C levels by 710% in humans (with a certain degree of het-
represents a good dietary substitute for saturated fat to maximize .. erogeneity among individuals), while it has little or no effect on HDL-
the effects of the diet on LDL-C levels, and to minimize the untoward
..
.. C and TG levels.143 However, to date no studies have been per-
effects of a high-carbohydrate diet on other lipoproteins.140,179 .. formed on the subsequent effect on CVD. Based on LDL-C lowering
Carbohydrate intake should range between 4555% of total
..
.. and the absence of adverse signals, functional foods with plant ster-
energy intake, since both higher and lower percentages of carbohy- .. ols/stanols (>_2 g/day with the main meal) may be considered: (i) in
drate diets are associated with increased mortality.180,181 A fat-
..
.. individuals with high cholesterol levels at intermediate or low global
modified diet that provides 2540 g per day of total dietary fibre, .. CV risk who do not qualify for pharmacotherapy; (ii) as an adjunct to
..
including >_713 g of soluble fibre, is well tolerated, effective, and .. pharmacological therapy in high- and very-high-risk patients who fail
recommended for plasma lipid control; conversely, there is no justifi- .. to achieve LDL-C goals on statins or could not be treated with sta-
..
cation for the recommendation of very low-carbohydrate diets.182 .. tins; and (iii) in adults and children (aged >6 years) with FH, in line
Intake of added sugar should not exceed 10% of total energy (in .. with current guidance.142
..
addition to the amount present in natural foods such as fruits and dairy ..
products); more restrictive advice concerning sugars may be useful for ..
.. 7.5.2 Monacolin and red yeast rice
those needing to lose weight or with high plasma TG values, MetS, or .. Red yeast rice (RYR) is a source of fermented pigment that has been
DM. Soft drinks should be used with moderation by the general popu- ..
.. used in China as a food colorant and flavour enhancer for centuries.
lation, and should be drastically limited in those individuals with ele- ..
vated TG values or visceral adiposity.158,159,174 The Prospective Urban .. Hypocholesterolaemic effects of RYR are related to a statin-like
.. mechanism—inhibition of hydroxymethylglutaryl-coenzyme A
Rural Epidemiology (PURE) study was a large, epidemiological cohort ..
study of 135 335 individuals enrolled in 18 countries with food fre- .. (HMG-CoA) reductase—of monacolins, which represent the bioac-
.. tive ingredient. Different commercial preparations of RYR have dif-
quency questionnaires recorded. Total fat and types of fat were not ..
associated with CVD, MI, or CVD mortality, whereas saturated fat had
.. ferent concentrations of monacolins, and lower TC and LDL-C levels
.. to variable extents, but the consumer is not able to make that distinc-
an inverse association with stroke.181 However, a meta-analysis of epi- ..
demiological studies including the PURE study showed a U-shaped
.. tion.144,185 Moreover, the long-term safety of the regular consump-
.. tion of these products has not been fully documented and safety
relationship between carbohydrate intake and mortality: diets associ- ..
ated with the highest mortality rate had carbohydrate intakes >70%
.. issues due to the possible presence of contaminants in some prepara-
.. tions have been raised. Side effects like those observed with statins
and <40% of energy, with minimal risk observed when carbohydrate ..
intake was between 4555% of total energy intake.180
.. have also been reported.
.. In the only available RCT in patients with ASCVD, a partially puri-
..
.. fied extract of RYR reduced recurrent events by 45%.146 A clinically
7.4.4 Alcohol .. relevant hypocholesterolaemic effect (up to a 20% reduction) has
..
Moderate alcohol consumption [<_10 g/day (1 unit) for men and .. been observed with RYR preparations providing an o.d. [once daily
women] is acceptable for those who drink alcoholic beverages, if TG
.. (omni die)] dose of 2.510 mg monacolin K.145 Nutraceuticals con-
..
levels are not elevated.183,184 . taining purified RYR may be considered in people with elevated
ESC/EAS Guidelines 27

..
plasma cholesterol concentrations who do not qualify for treatment .. 8 Drugs for treatment of
with statins in view of their global CV risk. However, there is a clear ..
.. dyslipidaemias
need for better regulation of RYR supplements. Information regard- ..
ing the precise composition of these products, the quantities of their ..
.. 8.1 Statins
components, and their purity should be implemented.185 .. 8.1.1 Mechanism of action
..
.. Statins reduce the synthesis of cholesterol in the liver by competi-
..

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7.5.3 Dietary fibre .. tively inhibiting the enzyme HMG-CoA reductase, the rate-limiting
Available evidence consistently demonstrates a TC- and LDL-C- .. step in cholesterol biosynthesis. The reduction in intracellular choles-
lowering effect of b-glucan, a viscous fibre from oat and barley. Foods
..
.. terol promotes increased LDL receptor (LDLR) expression at the
enriched with these fibres or supplements are well tolerated, effec- .. surface of the hepatocytes, which in turn results in increased uptake
..
tive, and recommended for LDL-C lowering.186 However, the dosage .. of LDL from the blood, and decreased plasma concentrations of
needed to achieve a clinically relevant reduction in levels of LDL-C of .. LDL- and other ApoB-containing lipoproteins, including TG-rich
..
35% varies from 310 g per day according to the specific type of .. particles.
fibre.187 ..
..
.. 8.1.2 Effects on lipids
..
7.5.4 Soy .. 8.1.2.1 Low-density lipoprotein cholesterol. The degree of LDL-C reduc-
The cholesterol-lowering effect of soy is generally attributed to its
..
.. tion is dose-dependent and varies between the different statins. A high-
isoflavone and phytoestrogen content, which decreases progressively .. intensity regimen is defined as the dose of a statin that, on average,
..
with the increasing degree of soybean processing. Soy protein has .. reduces LDL-C by >_50%; moderate-intensity therapy is defined as the
also been indicated as being able to induce a modest LDL-C-lowering .. dose expected to reduce LDL-C by 3050%. Notably, there is consid-
..
effect when replacing animal protein foods. However, this was not .. erable interindividual variation in LDL-C reduction with the same dose
confirmed when changes in other dietary components were taken .. of drug.31 Poor responses to statin treatment in clinical studies are to
..
into account.187,188 .. some extent caused by poor compliance, but may also be explained by
.. genetic backgrounds.195,196 Interindividual variations in statin responses
..
7.5.5 Policosanol and berberine
.. warrant monitoring of responses on initiation of therapy.
.. Among patients who cannot tolerate the recommended intensity
Policosanol is a natural mixture of long-chain aliphatic alcohols ..
extracted primarily from sugarcane wax.189 Studies show that polico-
.. of a statin because of adverse effects or those who do not reach their
.. goal, the addition of a non-statin lipid-modifying agent to a maximally
sanol from sugarcane, rice or wheat germ has no significant effect on ..
.. tolerated statin is recommended.197,198
LDL-C, HDL-C, TG, ApoB, Lp(a), homocysteine, high-sensitivity C- ..
reactive protein, fibrinogen, or blood coagulation factor levels.190 ..
.. 8.1.2.2 Triglycerides. Statins usually reduce TG levels by 1020% from
As for berberine, a recent meta-analysis evaluated its effects .. baseline values.199 More potent statins (atorvastatin, rosuvastatin,
on plasma lipids in humans.191 The comparative evaluation of berber- ..
.. and pitavastatin) demonstrate robust lowering of TG levels, espe-
ine and lifestyle intervention or placebo indicated that in the berber- .. cially at high doses and in patients with elevated TGs (HTG), in
ine group, LDL-C and plasma TG levels were more effectively ..
.. whom the absolute risk, and therefore the absolute risk reduction,
reduced than in the control group. However, due to the lack of .. is larger.
high-quality randomized clinical trials, the efficacy of berberine for ..
.. The mechanism of the TG-lowering effect has not been fully eluci-
treating dyslipidaemia needs to be further validated. Moreover, the .. dated, but it seems to be partly independent of the LDLR pathway. It
bioavailability of the different berberine preparations is a matter of ..
.. may involve the upregulation of VLDL uptake by hepatocytes, as well
debate.187 ..
.. as a reduction of the production rate of VLDLs; these effects seem to
.. be dependent on pre-treatment VLDL concentrations.200
..
7.5.6 n-3 unsaturated fatty acids ..
Observational evidence indicates that consumption of fish (at least .. 8.1.2.3 High-density lipoprotein cholesterol. In a meta-analysis,201 eleva-
..
twice a week) and vegetable foods rich in n-3 fatty acids (a-linoleic .. tions in HDL-C levels varied with dose among the respective statins;
acid is present in walnuts, some vegetables, and some seed oils) is .. such elevations ranged from 110%. However, given the marked
..
associated with lower risk of CV death and stroke, but has no major .. statin-mediated decrement in atherogenic ApoB-containing lipopro-
effects on plasma lipoprotein metabolism.178,192 Pharmacological .. teins, the extent to which the very modest effect on HDL-C levels
..
doses of long-chain n-3 fatty acids (23 g/day) reduce TG levels by .. might contribute to the overall observed reductions in CV risk con-
about 30% and also reduce the post-prandial lipaemic response, but a .. sistently observed in statin intervention trials cannot reliably be
..
higher dosage may increase LDL-C levels. a-Linolenic acid is less .. disentangled.
effective at altering TG levels.156,193 Recently, a significantly lower ..
..
risk of ischaemic events, including CV death, was observed in patients .. 8.1.2.4 Lipoprotein(a). Statins only marginally affect Lp(a) plasma levels.
with elevated TG levels despite the use of statins treated with 2 g of .. Previous studies have reported either no effect on or an increase of
..
icosapent ethyl b.i.d. [twice a day].194 .. Lp(a) levels after statin treatment.202,203 The mechanisms by which
Other features of a healthy diet contributing to CVD prevention
.. statins raise oxidized phospholipids on Lp(a) require further
..
are presented in the Supplementary Data. . investigation.
28 ESC/EAS Guidelines

8.1.3 Other effects of statins


.. These are general criteria for the choice of drug. Factors such as
..
Although reduction of LDL-C levels is the major effect of statins, a .. the clinical condition of the patient, concomitant medications, drug
number of other, potentially important effects have been suggested
.. tolerability, local treatment tradition, and drug cost will play major
..
(pleiotropic effects of statins).204,205 Among such effects that are .. roles in determining the final choice of drug and dose.
potentially relevant for the prevention of CVD are the anti-
.. Furthermore, the effects of statins on a number of other clinical
..
inflammatory and antioxidant effects of statin treatment. These .. conditions have been evaluated. For cancer, a meta-analysis of IPD
effects have been shown in vitro and in experimental systems, but
.. from randomized trials has shown that statins do not have any signifi-
..

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their clinical relevance remains unproven.18,206 .. cant effect on cancer, at least over a period of 5 years.223 Other
.. conditions, such as dementia,224 hepatic steatosis,225 venous throm-
..
8.1.3.1 Effect on cardiovascular morbidity and mortality. A large number .. boembolism,226 atrial fibrillation,227,228 and polycystic ovary syn-
of meta-analyses have been performed to analyse the effects of ... drome229 have also been studied, and no effect of statins on these
..
statins in populations and in subgroups.3436,38,51,207214 In the .. conditions has been reliably demonstrated.
Cholesterol Treatment Trialists (CTT) meta-analysis of individual .. The suggested effect on Alzheimer’s disease was recently reviewed
..
participant data (IPD) from >170 000 participants in 26 RCTs of a .. in a Cochrane analysis reporting no conclusive effect from statins.230
statin vs. control or a more vs. less intensive statin regimen,34 for .. Furthermore, neurocognitive functions were extensively investigated
..
each 1 mmol/L reduction in LDL-C, statin/more statin reduced .. in the Evaluating PCSK9 Binding Antibody Influence on Cognitive
major vascular events (MI, CAD death, or any stroke or coronary .. Health in High Cardiovascular Risk Subjects (EBBINGHAUS)
..
revascularization) by 22%, major coronary events by 23%, CAD .. study231 and no excess risk was observed among patients on a statin
death by 20%, total stroke by 17%, and total mortality by 10% over .. regimen randomized to a PCSK9 mAb.
..
5 years. The proportional effects (per mmol/L reduction in LDL-C) ..
on major vascular events were similar in all subgroups examined, so ..
..
the absolute risk reduction was proportional to the absolute base- .. 8.1.4 Adverse effects and interactions of statins
line risk. The relative benefits were half as large in the first year as
.. Statins differ in their absorption, bioavailability, plasma protein
..
compared with subsequent years. There was no increased risk for .. binding, excretion, and lipophilicity. Evening administration is usu-
any non-CV cause of death, including cancer, in those allocated sta-
.. ally recommended. Lovastatin and simvastatin are prodrugs,
..
tins. The absolute benefit from statin treatment was lower in people .. whereas the other available statins are administered in their active
in primary prevention, who are typically at lower risk.36,38,214,215 In
.. form. Their bioavailability is relatively low, owing to a first-pass
..
the CTT meta-analysis of treatment in people with a low-risk of vas- .. effect in the liver, and many statins undergo significant hepatic
cular disease,36 the relative risk reduction of major vascular events
.. metabolism via cytochrome P450 (CYP) isoenzymes, except pra-
..
per mmol/L reduction in LDL-C was at least as large in low-risk indi- .. vastatin, rosuvastatin, and pitavastatin. These enzymes are
.. expressed mainly in the liver and gut wall. Although statins are
viduals (i.e. in primary prevention). In those without a history of vas- ..
cular disease, statin therapy reduced the risk of all-cause mortality by .. generally very well tolerated, they do have some specific adverse
.. effects on muscle, glucose haemostasis, and haemorrhagic stroke.
9% per mmol/L reduction in LDL cholesterol. Similar results were ..
reported in a Cochrane review in 2013.213 The West of Scotland .. However, there is also widespread misinformation about poten-
.. tial adverse effects, as reviewed recently.232,233
Coronary Prevention Study (WOSCOPS) data were recently reana- ..
lysed, and demonstrated that even people without DM and a 10 year ..
.. 8.1.4.1 Adverse effects on muscle. Myopathy is the most clinically rele-
predicted ASCVD risk of <7.5% benefit from statin treatment. There ..
was also a legacy effect with a mortality benefit of 18% in all-cause .. vant adverse effect of statins. Among the risk factors for myopathy, it
..
death over 20 years.216 Statins are effective for the prevention of .. is particularly important that interaction with concomitant drug ther-
ASCVD in the elderly, including those aged >75 years.217 Statins are .. apy is considered (see below). Rhabdomyolysis is the most severe
..
not effective in a few specific groups, notably those with heart failure .. form of statin-induced muscle damage, characterized by severe mus-
(HF) or patients receiving haemodialysis.214,218222 .. cular pain, muscle necrosis, and myoglobinuria potentially leading to
..
Current available evidence from meta-analyses suggests that the .. renal failure and death. In rhabdomyolysis, creatine kinase (CK) levels
clinical benefit of statin treatment is largely a class effect, driven by .. are elevated by >_10 times, and often >_40 times, the upper limit of
..
the absolute LDL-C reduction; therefore, the type of statin used .. normal (ULN).234 The frequency of rhabdomyolysis has been esti-
should reflect the treatment goals for a given patient. .. mated to represent 13 cases/100 000 patient-years.235 Patients tak-
..
The following scheme may be proposed. .. ing statin therapy frequently report muscle symptoms [so-called
.. ‘statin-associated muscle symptoms’ (SAMS)], and in non-
• Evaluate the total CV risk of the individual. ..
.. randomized, observational studies, statins are associated with muscu-
• Determine the treatment goals (depending on current risk). .. lar pain and tenderness (myalgia) without CK elevation or major
• Involve the patient in decisions on CV risk management. ..
.. functional loss, with the reported frequency of SAMS in such studies
• Choose a statin regimen and, where necessary, additional treat- ..
ments (e.g. ezetimibe or PCSK9 inhibitors) that can meet the .. varying between 1015% among statin-treated individuals.236238
treatment goals (per cent and absolute value). .. However, in part because individuals in observational studies are not
.. blind to the treatment they are receiving, such studies are unreliable
• Response to statin treatment is variable, therefore uptitration of ..
the statin dose may be required before additional LDL-lowering .. when used to assess the adverse effects of statins.233 In contrast, in
treatments are started.
.. blinded randomized trials of statins vs. placebo there is no, or only a
ESC/EAS Guidelines 29

slightly, increased frequency of muscle symptoms in statin- .. have yielded conflicting findings and there is a need for further explo-
..
allocated groups.239,240 The Anglo-Scandinavian Cardiac .. ration of the risk of haemorrhagic stroke in particular types of
Outcomes Trial  Lipid-Lowering Arm (ASCOT-LLA) study .. patients. Note, however, that the overall benefit on other stroke sub-
..
addressed this issue by comparing the incidence of four different .. types greatly outweighs this small (and uncertain) hazard.34,36
adverse events, including muscle-related symptoms, during both
..
..
the blinded, placebo-controlled trial and its open-label extension .. 8.1.4.5 Adverse effects on kidney function. There is no clear evidence
study.238 They concluded that a nocebo effect (i.e. one caused by
.. that statins have a clinically significant beneficial or adverse effect on
..

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negative expectations) may partly explain the higher frequency of .. renal function.253 An increased frequency of proteinuria has been
SAMS in observational studies compared with in trials. Suggested
.. reported for all statins, but has been analysed in more detail for rosu-
..
practical management of muscular symptoms is shown in .. vastatin. With a dose of 80 mg, a frequency of 12% was reported.
Supplementary Figure 6.198,234,241 Several studies have shown a
.. With the approved doses of <40 mg, the frequency is much lower
..
considerable LDL-C-lowering effect of alternative dosing, such as .. and in line with the frequency for other statins. The proteinuria
..
every other day or twice a week, with atorvastatin or rosuvasta- .. induced by statins is of tubular origin, usually transitory, and is
tin.242 Although no clinical endpoint trials are available, this strat- .. believed to be due to reduced tubular reabsorption and not to glo-
..
egy should be considered in high-risk patients in whom statin .. merular dysfunction.254,255 In clinical trials, the frequency of proteinu-
treatment with daily doses is not possible. .. ria is generally low and, in most cases, is not higher than for
..
.. placebo.256
8.1.4.2 Adverse effects on the liver. The activity of alanine aminotrans- ..
..
ferase (ALT) in plasma is commonly used to assess hepatocellular .. 8.1.4.6 Interactions. A number of important drug interactions with sta-
damage. Mild elevation of ALT occurs in 0.52.0% of patients on sta- .. tins have been described that may increase the risk of adverse effects.
..
tin treatment, more commonly with potent statins or high doses. .. Inhibitors and inducers of enzymatic pathways involved in statin
The common definition of clinically relevant ALT elevation has been .. metabolism are summarized in Table 10. All currently available sta-
..
an increase of three times the ULN on two consecutive occasions. .. tins—except pravastatin, rosuvastatin, and pitavastatin—undergo
Mild elevation of ALT has not been shown to be associated with true .. major hepatic metabolism via the CYPs. These isoenzymes are mainly
..
hepatotoxicity or changes in liver function. Progression to liver failure .. expressed in the liver and intestine. Pravastatin does not undergo
is exceedingly rare, therefore routine monitoring of ALT during statin
.. metabolism through the CYP system, but is metabolized by sulfation
..
treatment is no longer recommended.243 Patients with mild ALT ele- .. and conjugation. CYP3A4 isoenzymes are the most abundant, but
vation due to steatosis have been studied during statin treatment and
.. other isoenzymes such as CYP2C8, CYP2C9, CYP2C19, and
..
there is no indication that statins cause any worsening of liver .. CYP2D6 are frequently involved in the metabolism of statins. Thus,
disease.244246
.. other pharmacological substrates of these CYPs may interfere with
..
.. statin metabolism. Conversely, statin therapy may interfere with the
8.1.4.3 Increased risk of new-onset diabetes mellitus. Patients on statin
.. catabolism of other drugs that are metabolized by the same enzy-
..
treatment have been shown to exhibit an increased risk of dysglycae- .. matic system.
..
mia and development of type 2 diabetes mellitus (T2DM). Several stud- Combination of statins with gemfibrozil enhances the risk of myo-
...
ies have shown that this is a consistent, dose-related effect.232 A minor, .. pathy, and its association with statins must be avoided. There is no or
not clinically relevant elevation of glycated haemoglobin (HbA1c) has .. very little increased risk for myopathy when combining statins with
..
also been observed. The number needed to cause one case of diabetes . other fibrates, such as fenofibrate, bezafibrate, or ciprofibrate.259,260
has been estimated as 255 over 4 years of statin treatment.247
However, the risk is higher with the more potent statins at high Table 10 Drugs potentially interacting with statins
doses,248 and is also higher in the elderly, and in the presence of other metabolized by cytochrome P450 3A4 leading to
risk factors for diabetes such as overweight or insulin resistance.249 increased risk of myopathy and rhabdomyolysis
Overall, the absolute reduction in the risk of CVD in high-risk patients Anti-infective Calcium Other
clearly outweighs the possible adverse effects of a small increase in the agents antagonists
incidence of diabetes.233 This effect is probably related to the mecha- Itraconazole Verapamil Ciclosporin
nism of action of statins, as Mendelian randomization studies have con- Ketoconazole Diltiazem Danazol
firmed the increased risk of DM in individuals with HMG-CoA Posaconazole Amlodipine Amiodarone
reductase polymorphisms that reduce cholesterol synthesis.250
Erythromycin Ranolazine
Clarithromycin Grapefruit juice
8.1.4.4 Increased risk of haemorrhagic stroke. In observational studies,
Telithromycin Nefazodone
TC is negatively associated with haemorrhagic stroke, and in the
CTT meta-analysis, there was a 21% [95% confidence interval (CI) HIV protease inhibitors Gemfibrozil
541%; P=0.01] relative increase per mmol/L lower LDL choles- Adapted from Egan and Colman,257 and Wiklund et al.258
HIV = human immunodeficiency virus.
terol in haemorrhagic stroke.34,251,252 However, other meta-analyses
30 ESC/EAS Guidelines

..
8.2 Cholesterol absorption inhibitors .. although significant and in line with the CTT expectations.268
8.2.1 Mechanism of action
.. Therefore, the study supports the proposition that LDL-C lowering
..
Ezetimibe inhibits intestinal uptake of dietary and biliary cholesterol .. by means other than statins is beneficial and safe. The beneficial effect
.. of ezetimibe is also supported by genetic studies of mutations in
at the level of the brush border of the intestine [by interacting with ..
the Niemann-Pick C1-like protein 1 (NPC1L1)] without affecting the .. NPC1L1; naturally occurring mutations that inactivate the protein
.. were found to be associated with reduced plasma LDL-C and
absorption of fat-soluble nutrients. By inhibiting cholesterol absorp- ..
tion, ezetimibe reduces the amount of cholesterol delivered to the .. reduced risk for CAD.55,269,270

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.. Taken together with other studies,271 IMPROVE-IT supports the
liver. In response to reduced cholesterol delivery, the liver reacts by ..
upregulating LDLR expression, which in turn leads to increased clear- .. proposal that ezetimibe should be used as second-line therapy in
.. association with statins when the therapeutic goal is not achieved at
ance of LDL from the blood. ..
.. the maximal tolerated statin dose, or in cases where a statin cannot
.. be prescribed.272,273
8.2.2 Effects on lipids ..
..
In clinical studies, ezetimibe in monotherapy at 10 mg/day reduces ..
LDL-C in hypercholesterolaemic patients by 1522% with relatively
.. 8.2.4 Adverse effects and interactions
..
high interindividual variation.261 A meta-analysis of RCTs that .. Ezetimibe is rapidly absorbed and extensively metabolized to phar-
included over 2700 people showed an 18.5% reduction in LDL-C as
.. macologically active ezetimibe glucuronide. The recommended dose
..
compared with placebo.262 In addition, there was a significant 3% .. of ezetimibe of 10 mg/day can be administered in the morning or eve-
increase in HDL-C, a significant 8% reduction in TGs, and a 13%
.. ning irrespective of food intake. There are no clinically significant
..
reduction in TC with ezetimibe as compared with placebo. .. effects of age, sex, or race on ezetimibe pharmacokinetics, and no
Ezetimibe added to ongoing statin therapy reduces LDL-C levels
.. dosage adjustment is necessary in patients with mild hepatic impair-
..
by an additional 2127% compared with placebo in patients with .. ment or mild-to-severe renal insufficiency. Life-threatening liver fail-
.. ure with ezetimibe as monotherapy or in combination with statins is
hypercholesterolaemia with or without established CHD. In statin- ..
naı̈ve patients, ezetimibe and statin combination therapy has resulted .. extremely rare. The addition of ezetimibe to statin therapy does not
.. appear to increase the incidence of elevated CK levels beyond what
in around a 15% greater reduction in LDL-C when compared with ..
the same statins and doses in monotherapy. In other studies, this .. is noted with statin treatment alone.261
..
combination has also significantly improved reductions in LDL-C lev- ..
els when compared with doubling of the statin dose (1320%), and ..
.. 8.3 Bile acid sequestrants
after switching from statin monotherapy to ezetimibe and statin com- .. 8.3.1 Mechanism of action
bination therapy (1115%).263 ..
.. Bile acids are synthesized in the liver from cholesterol and are
Co-administration of ezetimibe and bile acid sequestrants (colese- .. released into the intestinal lumen, but most of the bile acid is
velam, colestipol, or cholestyramine) has been reported to result in ..
.. returned to the liver from the terminal ileum via active absorption.
an additional reduction of LDL-C levels by 1020% when compared .. The two older bile acid sequestrants, cholestyramine and colestipol,
with the stable bile acid sequestrant regimen alone.264 Co- ..
.. are both bile acid-binding exchange resins. The synthetic drug colese-
administration of ezetimibe with PCSK9 inhibitors also results in an .. velam is also available in some countries. As bile acid sequestrants are
additional effect.265 ..
.. not systemically absorbed or altered by digestive enzymes, the bene-
.. ficial clinical effects are indirect. By binding the bile acids, the drugs
..
8.2.3 Effect on cardiovascular morbidity and mortality .. prevent the reabsorption of both the drug and cholesterol into the
The efficacy of ezetimibe in association with simvastatin has been
.. blood, and thereby remove a large portion of the bile acids from the
..
addressed in people with aortic stenosis in the Simvastatin and .. enterohepatic circulation. The liver, depleted of bile, synthesizes
.. more from hepatic cholesterol, therefore increasing the hepatic
Ezetimibe in Aortic Stenosis (SEAS) trial,266 and in patients with CKD ..
in the Study of Heart and Renal Protection (SHARP) trial.222 In both .. demand for cholesterol and increasing LDLR expression, which
.. results in a decrease of circulating LDL.
the SEAS and SHARP trials, a reduction in CV events was demon- ..
strated in the simvastatinezetimibe arm vs. placebo.266,267 ..
..
In the Improved Reduction of Outcomes: Vytorin Efficacy .. 8.3.2 Effects on lipids
International Trial (IMPROVE-IT), ezetimibe was added to simvasta- ..
.. At the top daily dose of 24 g of cholestyramine, 20 g of colestipol, or
tin (40 mg) in patients after acute coronary syndrome (ACS).33 A .. 4.5 g of colesevelam, a reduction in LDL-C of 1825% has been
total of 18 144 patients were randomized to statin or statin plus eze- ..
.. observed. No major effect on HDL-C has been reported, while TGs
timibe, and 5314 patients over 7 years experienced a CV event; 170 .. may increase in some predisposed patients.274 Colesevelam can also
fewer events (32.7 vs. 34.7%) were recorded in the group taking sim- ..
.. reduce glucose levels in hyperglycaemic patients.275
vastatin plus ezetimibe (P=0.016). The average LDL-C during the ..
study was 1.8 mmol/L (70 mg/dL) in the simvastatin group and 1.4 ..
..
mmol/L (55 mg/dL) in patients taking ezetimibe plus simvastatin. Also, .. 8.3.3 Effect on cardiovascular morbidity and mortality
ischaemic stroke was reduced by 21% in this trial (P=0.008). There .. In clinical trials, bile acid sequestrants have contributed greatly to the
..
was no evidence of harm caused by ezetimibe or the further LDL-C .. demonstration of the efficacy of LDL-C lowering in reducing CV
reduction. In this group of patients already treated with statins to
.. events in hypercholesterolaemic people, with a benefit proportional
..
reach goals, the absolute CV benefit from added ezetimibe was small, . to the degree of LDL-C lowering. Of note, these studies were
ESC/EAS Guidelines 31

..
performed before many of the modern treatment options were .. majority of patients, including those with HeFH and, albeit to a lower
available.276278 .. level, those with HoFH with residual LDLR expression. Receptor-
..
.. deficient HoFH responds poorly to the therapy.285
..
8.3.4 Adverse effects and interactions ..
Gastrointestinal (GI) adverse effects (most commonly flatulence, .. 8.4.2.2 Triglycerides and high-density lipoprotein cholesterol. These
.
constipation, dyspepsia, and nausea) are often present with these .. highly efficacious LDL-lowering agents also lower TG levels, and
.
drugs, even at low doses, which limits their practical use. These .. increase those of HDL-C and ApoA-I as a function of the dosing regi-

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.
adverse effects can be attenuated by beginning treatment at low .. men. In phase II trials, evolocumab lowered TG levels by 26%, and
.
doses and ingesting ample fluid with the drug. The dose should be ... raised HDL-C and ApoA-I by 9 and 4%, respectively; similar findings
increased gradually. Reduced absorption of fat-soluble vitamins has ... have been reported for alirocumab.286,287 However, the TG effect
been reported. Furthermore, these drugs may increase circulating ... must be confirmed in populations with higher starting plasma TG
TG levels in certain patients. .. levels.
.
Bile acid sequestrants have major drug interactions with several ...
commonly prescribed drugs, and must therefore be administered ...
8.4.2.3 Lipoprotein(a). In contrast to statins, inhibiting PCSK9 with
either 4 h before or 1 h after other drugs. Colesevelam is better tol- ..
. mAbs also reduces Lp(a) plasma levels. Pooled results of phase II
erated and has fewer interactions with other drugs, and can be taken ..
. trials have shown that treatment leads to an Lp(a) reduction of
279 .. about 3040%.288,289 While recent investigations have attempted
together with statins and several other drugs. ..
.. to unravel the mechanism, it remains unclear. However, it appears
. to be distinct from that of statins, which also enhance LDLR func-
8.4 Proprotein convertase subtilisin/kexin ... tion but do not lower circulating Lp(a) levels in humans. The rela-
type 9 inhibitors ..
.. tive contribution of this effect to the reduction of risk remains to be
8.4.1 Mechanism of action .. addressed in appropriately designed studies.
.
Recently, a new class of drugs, PCSK9 inhibitors, has become avail- ..
.
able that targets a protein (PCSK9) involved in the control of the ..
.
LDLR.280 Elevated concentration or function of this protein in ..
. 8.4.3 Effect on cardiovascular morbidity and mortality
plasma reduces LDLR expression by promoting, upon binding, ... Early preliminary data from phase III trials suggests a reduction of CV
LDLR lysosomal catabolism and a subsequent increase in plasma ... events in line with the LDL-C reduction achieved.286,290,291
LDL concentrations, while lower concentration or function of ... Recently, two major studies were completed: the Further
PCSK9 is related to lower plasma LDL-C levels.281 Therapeutic ... Cardiovascular Outcomes Research with PCSK9 Inhibition in
strategies have been developed mainly using mAbs; the mecha- ... Subjects with Elevated Risk (FOURIER) and the Evaluation of
nism of action relates to the reduction of the plasma level of ... Cardiovascular Outcomes After an Acute Coronary Syndrome
PCSK9, which in turn is not available to bind the LDLR. Since this ... During Treatment With Alirocumab (ODYSSEY Outcomes) tri-
interaction triggers the intracellular degradation of the LDLR, ..
.
. als.119,120 The designs of the trials were similar with regard to the set-
lower levels of circulating PCSK9 will result in increased expres- .. tings of secondary prevention and background therapy; however, the
sion of LDLRs at the cell surface and therefore in a reduction of ..
.
. populations enrolled had either stable CHD, peripheral arterial dis-
circulating LDL-C levels. Currently, the only approved PCSK9 ..
281
ease (PAD), or stroke; or a recent (median 2.6 months) ACS, respec-
inhibitors are two fully human mAbs, alirocumab and evolocumab. ..
.
. tively. The relative benefit ranged from 1520% reductions in the
Statin treatment increases circulating PCSK9 serum levels, and .. 282
risk of the primary endpoints. Both studies had relatively short
thus the best effect of these mAbs has been demonstrated in com- ..
.
.. follow-up periods and the evidence from statin trials indicates that
bination with statins. .. the clinical benefits of LDL-lowering may only emerge after about 1
..
.. year,51 so these trials may have underestimated the potential impact
8.4.2 Effects on lipids .. of longer-term treatment.120,290
.
8.4.2.1 Low-density lipoprotein cholesterol. In clinical trials, alirocumab .. In the FOURIER trial,119 27 564 patients with atherosclerotic
.
and evolocumab—either alone or in combination with statins, and/or .. CVD, and LDL-C levels of 1.8 mmol/L (70 mg/dL) or higher who
.
other lipid-lowering therapies—have been shown to significantly .. were receiving statin therapy, were randomly assigned to receive
.
reduce LDL-C levels on average by 60%, depending on dose. The effi- .. evolocumab or placebo. Allocation to evolocumab reduced median
.
cacy appears to be largely independent of any background therapy. In .. LDL-C from 2.38 mmol/L (92 mg/dL) at baseline to a mean of 0.78
.
combination with high-intensity or maximally tolerated statins, aliro- .. mmol/L (30 mg/dL) at 48 weeks. After a median follow-up of 2.2
.
cumab and evolocumab reduced LDL-C by 4673% more than pla- ... years, evolocumab treatment significantly reduced the risk of the pri-
cebo, and by 30% more than ezetimibe. Among patients in whom ... mary endpoint (composite of CV death, MI, stroke, hospitalization
statins cannot be prescribed, PCSK9 inhibition reduced LDL-C when ... for unstable angina, or coronary revascularization) by 15% [hazard
administered in combination with ezetimibe.283 Both alirocumab and ... ratio (HR) 0.85, 95% CI 0.790.92]. An analysis of the time to benefit
evolocumab have also been shown to effectively lower LDL-C levels ... also showed that there was a lower benefit in the first year than in
in patients who are at high CV risk, including those with DM.284 .. subsequent years, consistent with the effects of statins observed
..
Given the mechanism of action, these drugs are effective at reduc- .. within the CTT meta-analysis.268 In the FOURIER trial, allocation to
ing LDL-C in all patients capable of expressing LDLR in the liver. ..
. evolocumab did not reduce the risk of CV mortality (HR 1.05, 95%
Therefore, this pharmacological approach is effective in the vast .
. CI 0.881.25) or all-cause mortality.
32 ESC/EAS Guidelines

..
The ODYSSEY Outcomes trial randomized 18 924 patients after .. Lomitapide is an MTP inhibitor designed for o.d. oral treatment of
hospitalization for acute MI or unstable angina, treated with statins, .. HoFH. In an open-label, single-arm titration study evaluating lomita-
..
and with LDL-C >_1.8 mmol/L (>_70 mg/dL), non-HDL cholesterol .. pide as adjunct therapy to statins, with or without apheresis and a
>_2.6 mmol/L (>_100 mg/dL), or ApoB >_80 mg/dL, to receive injec- .. low-fat diet,301 LDL-C was reduced by 50% from baseline at 26
..
tions of alirocumab or matching placebo. Allocation to alirocumab .. weeks and by 44% at 56 weeks. Lomitapide was also shown to
reduced the mean baseline LDL-C from 2.38 mmol/L (92 mg/dL) to .. decrease the frequency of apheresis in HoFH patients. It should be
..
1.24 mmol/L (48 mg/dL) at 12 months. There was a 15% relative .. noted that the drug’s effect on CV outcomes has not yet been

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reduction in the primary outcome (composite of CHD death, non- .. determined.
..
fatal MI, ischaemic stroke, or unstable angina requiring hospitaliza- .. As a consequence of its mechanism of action, lomitapide has been
tion) (HR 0.85, 95% CI 0.780.93) after a median follow-up of 2.8 .. shown to be associated with increased aminotransferase levels, which
..
years.120 Although there was a significant reduction in all-cause mor- .. most likely reflects the increased fat in the liver, as well as poor GI
tality in the ODYSSEY trial, this was an exploratory outcome and .. tolerability.301,302 The GI side effects were the most frequent reasons
..
was not supported by a significant effect on CV death. .. preventing a further increase in the dose of lomitapide in clinical tri-
.. als.301 However, it has been noted that the frequency and intensity of
..
.. GI side effects generally decrease with time. Therefore, prescription
8.4.4 Adverse effects and interactions .. of lomitapide requires careful patient education and liver function
Anti-PCSK9 mAbs are injected subcutaneously, every other week or ..
.. monitoring during therapy.
once a month, at different doses depending on the agent used. The ..
potential for interaction with orally absorbed drugs is absent, as they ..
.. 8.6 Mipomersen
will not interfere with pharmacokinetics or pharmacodynamics. ..
Among the most frequently reported side effects are itching at the .. Mipomersen is an antisense oligonucleotide able to bind the messen-
.. ger RNA (mRNA) of ApoB-100, which triggers the selective degrada-
site of injection and flu-like symptoms.292 In some studies, an increase ..
of patient-reported neurocognitive effects has been described.293
.. tion of mRNA molecules. After subcutaneous injection, the
..
However, the EBBINGHAUS trial,231 which was specifically designed .. oligonucleotide is preferentially transported to the liver, where it
to detect neurocognitive function changes, was reassuring, as were
.. binds to a specific mRNA preventing the translation of ApoB protein
..
the safety reports in both the FOURIER and ODYSSEY trials. .. and, consequently, reducing the production of atherogenic lipids and
Mendelian randomization studies have also suggested that PCSK9
.. lipoproteins, including LDL and Lp(a).303 An adjunct to lipid-lowering
..
inhibition may increase the risk of DM with an LDL-C-related effect, .. medications and diet, mipomersen is indicated to reduce LDL-C in
as apparently occurs for statins.294 To date, no signal has emerged
.. patients with HoFH. Mipomersen is currently approved by the US
..
from RCTs.295297 Although large long-term trials of PCSK9 inhibi- .. Food and Drug Administration (FDA), but not by the European
.. Medicines Agency (EMA).
tors are needed to rule out these and other potential side effects of ..
inhibition of PCSK9,298 7 year data from the IMPROVE-IT study have .. Reactions at the injection site are the most common adverse
.. effects observed in patients treated with mipomersen.304 However,
shown that prolonged low LDL-C concentrations are not associated ..
with any clear adverse effects.299 .. the main concerns regarding mipomersen’s safety are related to liver
.. toxicity. Mipomersen may lead to the development of steatosis.
A potential problem of long-term antibody treatment is the occur- ..
rence of autoantibodies. Evolocumab and alirocumab are fully human .. Treated patients have shown a higher increase of liver fat from base-
.. line compared with patients randomized to placebo.303 The efficacy
antibodies and, therefore, theoretically less likely to induce autoanti- ..
bodies. To date, only very few cases of antidrug antibodies have been .. and safety of long-term mipomersen treatment are currently under
.. evaluation in patients with severe HeFH, and in statin-‘intolerant’
reported, and no reduction of LDL-C lowering has been observed, ..
but long-term use needs to be monitored. Indeed, the development .. patients.
..
programme for a third PCSK9 inhibitor, bococizumab, a humanized ..
antibody, was discontinued because of an increase of neutralizing .. 8.7 Fibrates
..
antibodies, which resulted in the attenuation of the LDL-C-lowering .. 8.7.1 Mechanism of action
effect over time, as well as a higher rate of injection site reactions.300
.. Fibrates are agonists of peroxisome proliferator-activated receptor-
..
However, although PCSK9 inhibitors are very effective drugs that can .. a (PPAR-a), acting via transcription factors regulating, among other
reduce LDL-C and CV events on top of statin and/or ezetimibe treat-
..
.. things, various steps in lipid and lipoprotein metabolism. As a conse-
ment, considering the costs of the treatments and the limited data on .. quence, fibrates have good efficacy in lowering fasting TG levels, as
long-term safety, these drugs are likely to be considered cost-
..
.. well as post-prandial TGs and TG-rich lipoprotein (TRL) remnant
effective only in those patients at very high-risk of ASCVD, and their .. particles.
use may not be possible in some countries with limited healthcare
..
..
resources. ..
.. 8.7.2 Effects on lipids
.. Clinical impacts on lipid profiles vary among members of the fibrate
..
8.5 Lomitapide .. class, but are estimated to reach a 50% reduction of the TG level, a
The microsomal TG transfer protein (MTP) transfers TGs and phos- .. <_20% reduction of the LDL-C level (but a paradoxical small LDL-C
..
pholipids from the endoplasmic reticulum to ApoB, as a necessary .. increase may be observed with high TG levels), and an increase of
step in the formation of VLDL. MTP inhibition thus prevents the for-
.. the HDL-C level of <_20%. The magnitude of effect is highly depend-
..
mation of VLDL in the liver and of chylomicrons in the intestine. . ent on the baseline lipid levels.305 Both the HDL-raising and
ESC/EAS Guidelines 33

..
TG-lowering effects of fibrates have been reported to be markedly .. As a class, fibrates have been reported to raise both serum creati-
less (5 and 20%, respectively) in long-term intervention trials in .. nine and homocysteine levels in both short- and long-term studies.
..
people with T2DM but without elevated levels of TGs.306,307 .. The increase of serum creatinine by fibrate therapy seems to be fully
.. reversible when the drug is stopped. Data from meta-analyses sug-
..
.. gest that a reduction of calculated glomerular filtration rate (GFR)
8.7.3 Effect on cardiovascular morbidity and mortality .. does not reflect any adverse effects on kidney function.315 Fibrates
..
The clinical effects of fibrates have been primarily illustrated by six .. are associated with a slightly increased risk of pancreatitis.321 The

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RCTs: the Helsinki Heart Study (HHS), Veterans Affairs High Density .. increase in homocysteine levels caused by fibrates has been consid-
..
Lipoprotein Intervention Trial (VA-HIT), Bezafibrate Infarction .. ered to be relatively neutral with respect to CVD risk. However, a
Prevention (BIP), Lower Extremity Arterial Disease Event Reduction .. fibrate-induced increase in homocysteine may blunt elevation of both
..
(LEADER), Fenofibrate Intervention and Event Lowering in Diabetes .. HDL-C and ApoA1 levels, and this effect may contribute to the
(FIELD), and Action to Control Cardiovascular Risk in Diabetes .. smaller than estimated benefits of fenofibrate in CV outcome
..
(ACCORD) trials; in the latter trial, fenofibrate was added to statin .. parameters.322
therapy.306311 In CV outcome trials of fibrates, the risk reduction
..
..
appeared to be proportional to the degree of non-HDL-C .. 8.8 n-3 fatty acids
lowering.50
..
.. 8.8.1 Mechanism of action
Although the HHS reported a significant reduction in CVD out- .. The n-3 (or omega-3) fatty acids [eicosapentaenoic acid (EPA) and
comes with gemfibrozil, neither the FIELD nor the ACCORD studies
..
.. docosahexaenoic acid (DHA)] can be used at pharmacological doses
involving fenofibrate showed a reduction in total CVD outcomes. .. to lower TGs. n-3 fatty acids (24 g/day) affect serum lipids and lipo-
..
The LEADER trial included male participants with lower-extremity .. proteins, in particular VLDL concentrations. The underlying mecha-
arterial disease and failed to show that bezafibrate could lead to a .. nism is poorly understood, although it may be related, at least in part,
..
clinically important reduction in CVD combined endpoints. .. to their ability to interact with PPARs and to decreased secretion of
Decreases in the rates of non-fatal MI were reported, although often .. ApoB.
..
as a result of post hoc analyses. The effect was most evident in people ..
with elevated TG/low HDL-C levels. However, the data on other ..
.. 8.8.2 Effects on lipids
outcome parameters have remained equivocal. Only one study, ..
ACCORD, has analysed the effect of a fibrate as an add-on treatment .. n-3 fatty acids reduce TGs, but their effects on other lipoproteins are
.. trivial. More detailed data on clinical outcomes are needed to justify
to a statin. No overall benefit was reported in two recent meta-analy- ..
ses.312,313 Results from other meta-analyses suggest reduced major .. wide use of prescription n-3 fatty acids.323 The recommended doses
.. of total EPA and DHA to lower TGs have varied between 24 g/day.
CVD events in patients with high TGs and low HDL-C in fibrate- ..
treated patients, but no decrease in CVD or total mortality.314316 .. Three recent studies in people with high TGs using EPA reported a
.. significant reduction in serum TG levels of up to 45% in a dose-
Thus, the overall efficacy of fibrates on CVD outcomes is much less ..
robust than that of statins. Recently, a new selective PPAR-a modula- .. dependent manner.324326 The efficacy of omega-3 fatty acids in low-
.. ering serum TGs has also been reported in meta-analyses.157
tor (pemafibrate) has been reported to have marked efficacy in ..
reducing TRLs.317 The study, Pemafibrate to Reduce Cardiovascular
.. Recently, the EpanoVa fOr Lowering Very high triglyceridEs II
.. (EVOLVE II) trial confirmed the efficacy of omega-3 fatty acids in low-
OutcoMes by Reducing Triglycerides IN PatiENts With DiabeTes ..
(PROMINENT), is an ongoing CVD outcome trial designed to evalu-
.. ering serum TGs.327
..
ate the efficacy of pemafibrate in some 10 000 high-risk diabetic ..
patients with high TG and low HDL-C levels.318 Overall, the potential
.. 8.8.3 Effect on cardiovascular morbidity and mortality
..
CV benefits of fibrates require further confirmation. .. A Cochrane meta-analysis, including 112 059 people from 79 trials,
..
.. reported no overall effect of omega-3 PUFAs on total mortality (rela-
.. tive risk 0.98, 95% CI 0.901.03) or CV events (relative risk 0.99,
..
8.7.4 Adverse effects and interactions .. 95% Cl 0.941.04), with only a suggestion that omega-3 fatty acids
Fibrates are generally well tolerated with mild adverse effects, GI dis- .. reduced CHD events (relative risk 0.93, 95% Cl 0.880.97).328
..
turbances being reported in <5% of patients, and skin rashes in .. Recently, the A Study of Cardiovascular Events iN Diabetes
2%.319 In general, myopathy, liver enzyme elevations, and cholelithia- .. (ASCEND) trial,329 which randomly assigned 15 480 patients with
..
sis represent the most well-known adverse effects associated with .. DM but without atherosclerotic CV disease to n-3 fatty acids or pla-
fibrate therapy.319 The risk of myopathy has been reported to be 5.5- .. cebo, showed no significant difference in the risk of serious vascular
..
fold greater with fibrate monotherapy (mainly with gemfibrozil) com- .. events after a mean follow-up of 7.4 years (relative risk 1.00, 95% Cl
pared with a statin, and it varies with different fibrates and statins .. 0.911.09).
..
used in combination. This is explained by the pharmacological inter- .. The data remain inconclusive and the clinical efficacy of omega-3
actions between the metabolism of different fibrates and pathways of .. fatty acids appears to be related to non-lipid effects.330,331 Moreover,
..
glucuronidation of statins. Gemfibrozil inhibits the metabolism of sta- .. studies with omega-3 fatty acids have suffered from the dose used
tins via the glucuronidation pathway, which leads to marked increases .. (1 g/day), which does not affect plasma lipids to a large extent, as the
..
in plasma concentrations of statins.320 As fenofibrate does not share .. dose required to decrease plasma TGs is >2 g/day. The Reduction of
the same pharmacokinetic pathways as gemfibrozil, the risk of myo-
.. Cardiovascular Events with EPA-Intervention Trial (REDUCE-IT)195
..
pathy is much less with this combination therapy.319 . aimed to evaluate the potential benefits of omega-3 oil (EPA) on
34 ESC/EAS Guidelines

..
ASCVD outcomes in people with elevated serum TGs; the trial .. which raises HDL-C levels by 130% and lowers LDL-C by 37%, was
enrolled 8000 patients on statin therapy, with LDL-C levels .. studied in the ACCELERATE trial,63 which was terminated due to
..
between 1.02.6 mmol/L (41100 mg/dL) and various CV risk fac- .. futility. Recently, anacetrapib, which raises HDL-C and ApoA-I levels
tors, including persistent elevated TGs between 1.75.6 mmol/L .. (by 104 and 36%, respectively), and lowers LDL-C and ApoB (by 17
..
(150499 mg/dL), and either established ASCVD or DM, and at least .. and 18%, respectively), was studied in the REVEAL trial. Anacetrapib
one other CV risk factor. Use of high doses (2 g b.i.d.) of EPA as com- .. reduced major coronary events by 9% over a median of 4.1 years.64
..
pared with placebo (mineral oil) resulted in a 25% relative risk .. The magnitude of the relative risk reduction appeared to be consis-

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reduction (P < 0.001) in major adverse CV events (MACE). Another .. tent with the magnitude of LDL-C- or non-HDL-C-level lowering.337
..
randomized placebo-controlled trial, Outcomes Study to Assess .. This drug has not been submitted for regulatory approval.
STatin Residual Risk Reduction with EpaNova in HiGh CV Risk ..
..
PatienTs with Hypertriglyceridemia (STRENGTH),332 which aims to .. 8.11 Future perspectives
determine whether reduction of TRLs and remnants in statin-treated ..
.. 8.11.1 New approaches to reduce low-density lipoprotein
patients will provide additional ASCVD risk reduction, is ongoing. ..
The VITamin D and OmegA-3 TriaL (VITAL), which reported .. cholesterol
.. An alternative approach targeting PCSK9 consists of RNA interfer-
recently, was a 22 factorial design study in which healthy partici- ..
pants were randomized in a 1:1 fashion to either vitamin D3 (at a
.. ence. In a phase I and a phase II trial, the small interfering RNA
.. (siRNA) molecule inclisiran—which inhibits the synthesis of
dose of 2000 IU per day) vs. matching placebo, and n-3 fatty acids (1 ..
g per day as a fish-oil capsule containing 840 mg of n-3 fatty acids,
.. PCSK9—reduced LDL-C by up to 50% and the reduction was dose-
.. dependent. Reductions in PCSK9 and LDL-C levels were maintained
including 460 mg of EPA and 380 mg of DHA) vs. matching placebo. ..
It showed that supplementation with either n-3 fatty acids at a dose
.. for <_6 months.338,339 No specific serious adverse events were
.. observed. HPS4/TIMI65/ORION4, with a planned mean duration of
of 1 g/day, or vitamin D3 at a dose of 2000 IU/day, was not effective ..
.. 5 years, is currently comparing inclisiran vs. placebo among 15 000
for primary prevention of CV or cancer events among healthy .. patients with a prior MI or stroke.
middle-aged men and women over 5 years of follow-up.333 ..
.. Bempedoic acid is a novel, first-in-class, oral small molecule that
.. inhibits cholesterol synthesis by inhibiting the action of ATP citrate
..
8.8.4 Safety and interactions .. lyase, a cytosolic enzyme upstream of 3-hydroxy-3-methylglutaryl-
The administration of n-3 fatty acids appears to be safe and devoid of .. coenzyme A reductase.340 So far, it has been tested in diabetic patients,
..
clinically significant interactions. The most common side effect is GI .. and patients with or without statin ‘intolerance’. In monotherapy, bem-
disturbance. The antithrombotic effects may increase the propensity .. pedoic acid reduces LDL-C levels by 30% and by about 50% in com-
..
for bleeding, especially when given in addition to aspirin/clopidogrel. .. bination with ezetimibe. Bempedoic acid is currently being tested in
Recently, data from one study have associated a risk of prostate can- .. phase III trials and some trials have been completed.341,342
..
cer with high dietary intake of n-3 PUFAs.334 ..
..
.. 8.11.2 New approaches to reduce triglyceride-rich lipo-
8.9 Nicotinic acid ..
.. proteins and their remnants
Nicotinic acid has key action sites in both the liver and adipose tissue. .. As genetic studies indicate that angiopoietin-like protein 3
In the liver, nicotinic acid inhibits diacylglycerol acyltransferase-2 ..
.. (ANGPTL3) deficiency protects against atherosclerotic disease and
resulting in decreased secretion of VLDL particles, which is also .. that this relationship is causal,343 an ANGPTL3 antibody (evinacu-
reflected in reductions of plasma levels of both IDL and LDL par- ..
.. mab) is being developed. Evinacumab has been shown to decrease
ticles.335 Nicotinic acid primarily raises HDL-C and ApoA1 by stimu- .. TGs, LDL-C, and Lp(a) levels in HoFH patients.344 Another approach
lating ApoA1 production in the liver.335 Two large randomized trials ..
.. that is currently being investigated is the inhibition of ANGPTL3 pro-
with nicotinic acid—one with extended-release niacin66 and one with ..
niacin plus laropiprant67—have shown no beneficial effect and an
.. duction by antisense oligonucleotides.345 IONIS-ANGPTL3-LRx, an
.. antisense oligonucleotide targeting ANGPTL3, another critical pro-
increased frequency of serious adverse effects. No medication con- ..
taining nicotinic acid is currently approved in Europe.
.. tein in the clearance of TRLs, reduces plasma TGs by about 85%.
.. Thus, the future may yield tools to improve TRL clearance that will
..
.. be reflected in the atherogenic load of the remnant particles.
8.10 Cholesteryl ester transfer protein .. The rapid development of gene-silencing technology has allowed
..
inhibitors .. proteins (ApoC-III) that are critical in the regulation of TRL clearance
To date, the pharmacological approach that has led to the greatest .. processes to be targeted. A second-generation antisense oligonu-
..
elevations in HDL-C levels has been direct inhibition of CETP by .. cleotide targeting ApoC-III mRNA has been developed.346 Two
small-molecule inhibitors, which may induce an increase in HDL-C by .. phase III trials have evaluated the safety and efficacy of volanesorsen
..
>_100% on a dose-dependent basis. Torcetrapib was studied in the .. in patients with elevated TG levels.347,348 Volanesorsen reduced
Investigation of Lipid Level Management to Understand its Impact in .. plasma TGs by 70% and ApoC-III by 8090%.349 The EMA recently
..
Atherosclerotic Events (ILLUMINATE) trial, which was stopped early .. issued a marketing authorization for Waylivra (volanesorsen) as an
due to increased mortality.336 Dalcetrapib raises HDL-C levels by .. adjunct to diet in adult patients with genetically confirmed familial
..
3040% with no appreciable effect on LDL-C, offering specific insight .. chylomicronaemia syndrome (FCS) who are at high-risk for pancrea-
into pure HDL-C raising. However, dalcetrapib failed to show any
.. titis, in whom response to diet and TG-lowering therapy has been
..
benefit in ACS patients in the dal-OUTCOMES trial. Evacetrapib, . inadequate.
ESC/EAS Guidelines 35

8.11.3 New approaches to increase high-density lipopro-


.. Although LDL-C goals are attained with monotherapy in many
..
tein cholesterol .. patients, a significant proportion of patients at high-risk or with very
Although genetic studies suggest that low HDL-C levels are not a
.. high LDL-C levels need additional treatment. In this case, combina-
..
cause of ASCVD, casting doubt on the possibilities of future treat- .. tion therapy is reasonable. In patients at very-high risk and with per-
ment options to raising HDL-C levels with attenuation of CVD,
.. sistent high-risk despite being treated with a maximally tolerated
..
major developments in the search for efficacious agents to raise .. statin, combination with ezetimibe is recommended and, if still not at
.. goal, the addition of a PCSK9 inhibitor is recommended (see Figure 4
HDL-C and ApoA1 levels with concomitant benefits on atheroscle- ..

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rosis and CV events are on the horizon. On the one hand, interest is .. and Recommendations for pharmacological low-density lipoprotein choles-
..
focused on ApoA1 mimetic peptides and recombinant forms of HDL .. terol lowering). Of note, addition of a PCSK9 inhibitor directly to a sta-
possessing potential for in vivo HDL particle remodelling and .. tin is also feasible120,290 (Figure 4).
..
enhanced cardioprotective activity.350 On the other, agents that .. As shown in Figure 3, the expected clinical benefit of treatment to
enhance catabolism of TG-rich lipoproteins, such as the antisense oli- .. lower the LDL-C level of any person can be estimated; it depends on
..
gonucleotide to ApoC-III, and which lead to a concomitant reduction .. the intensity of therapy, the baseline LDL-C level, and the baseline
in TGs (70%) and a marked elevation in HDL-C (40%) in hyper- .. estimated risk of ASCVD. This simple algorithm can be used to help
..
triglyceridemia, are under development.351 Importantly, however, we .. clinicians select the appropriate therapy and quantify the expected
currently lack understanding of the relationship between the modal- .. benefits of LDL-C-lowering therapy to help inform discussions with
..
ity of raising HDL/ApoA-I levels and a possible antiatherogenic func- .. patients. For ease of reference, Supplementary Table 3 provides a
tion of HDL particles. .. summary of the absolute LDL-C reductions that can be achieved
..
.. with various therapeutic approaches at particular baseline levels of
8.11.4 New approaches to reduce lipoprotein(a) levels
.. LDL-C.
..
Another approach under study is the selective decrease of Lp(a) con- ..
..
centrations. RNA-based therapies are now being evaluated in clinical .. 8.13 Strategies to control plasma
settings. Results from studies of an antisense oligonucleotide in ..
.. triglycerides
patients with normal Lp(a) values as well as in patients with elevated .. Although CVD risk is increased when fasting TGs are >1.7 mmol/L
Lp(a) concentrations have shown a reduction of >90%.352 These ..
.. (>150 mg/dL),56 the use of drugs to lower TG levels may only be
approaches are currently being evaluated in phase IIIII studies and .. considered in high-risk patients when TGs are >2.3 mmol/L (>200
an outcome trial is planned to study whether Lp(a) reduction trans- ..
.. mg/dL) and TGs cannot be lowered by lifestyle measures. The avail-
lates into risk reduction. .. able pharmacological interventions include statins, fibrates, PCSK9
..
.. inhibitors, and n-3 PUFAs. A meta-analysis of 10 trials included peo-
8.12 Strategies to control plasma .. ple treated with various agents that reduce serum TGs (fibrates, nia-
cholesterol ..
. cin, and n-3 PUFAs) and reported a 12% reduction in CV

Recommendations for pharmacological low-density lipoprotein cholesterol lowering

Recommendations Classa Levelb

It is recommended that a high-intensity statin is prescribed up to the highest tolerated dose to reach the goals set for the
I A
specific level of risk.32,34,38
If the goalsc are not achieved with the maximum tolerated dose of a statin, combination with ezetimibe is
I B
recommended.33
For primary prevention patients at very-high risk, but without FH, if the LDL-C goal is not achieved on a maximum toler-
IIb C
ated dose of a statin and ezetimibe, a combination with a PCSK9 inhibitor may be considered.
For secondary prevention, patients at very-high risk not achieving their goalc on a maximum tolerated dose of a statin and
I A
ezetimibe, a combination with a PCSK9 inhibitor is recommended.119,120
For very-high-risk FH patients (that is, with ASCVD or with another major risk factor) who do not achieve their goalc on
I C
a maximum tolerated dose of a statin and ezetimibe, a combination with a PCSK9 inhibitor is recommended.
If a statin-based regimen is not tolerated at any dosage (even after rechallenge), ezetimibe should be considered.197,265,353 IIa C
If a statin-based regimen is not tolerated at any dosage (even after rechallenge), a PCSK9 inhibitor added to ezetimibe
IIb C
may also be considered.197,265,353
If the goalc is not achieved, statin combination with a bile acid sequestrant may be considered. IIb C

ASCVD = atherosclerotic cardiovascular disease; FH = familial hypercholesterolaemia; LDL-C = low-density lipoprotein cholesterol; PCSK9 = proprotein convertase subtilisin/
kexin type 9.
a
Class of recommendation.
b
Level of evidence.
c
For definitions see Table 7.
36 ESC/EAS Guidelines

Intensity of lipid lowering treatment


Treatment Average LDL-C reduction
Moderate intensity statin ≈ 30%

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High intensity statin ≈ 50%
High intensity statin plus ≈ 65%
ezetimibe
PCSK9 inhibitor ≈ 60%
PCSK9 inhibitor plus high intensity statin ≈ 75%
PCSK9 inhibitor plus high intensity statin ≈ 85%
plus ezetimibe

% reduction LDL-C Baseline LDL-C

Absolute reduction LDL-C

Relative risk reduction Baseline risk

©ESC 2019
Absolute risk reduction

Figure 3 Expected clinical benefits of low-density lipoprotein cholesterol-lowering therapies. The expected clinical benefits of treatment to lower low-
density lipoprotein cholesterol for any person can be estimated; it depends on the intensity of therapy, the baseline low-density lipoprotein cholesterol
level, the expected absolute achieved reduction in low-density lipoprotein cholesterol, and the baseline estimated risk of atherosclerotic cardiovascular
disease. The intensity of therapy should be selected to achieve the recommended proportional reduction in low-density lipoprotein cholesterol based on
the person’s estimated risk of atherosclerotic cardiovascular disease. Multiplying the proportional reduction in low-density lipoprotein cholesterol by a
person’s baseline low-density lipoprotein cholesterol level estimates the expected absolute reduction in low-density lipoprotein cholesterol that is likely
to be achieved with that therapy. Because each 1.0 mmol/L absolute reduction in low-density lipoprotein cholesterol is associated with a 20% reduction in
the risk of cardiovascular events, larger absolute reductions in low-density lipoprotein cholesterol lead to larger proportional reductions in risk.
Multiplying the proportional reduction in risk expected for the achieved absolute reduction in low-density lipoprotein cholesterol by a person’s estimated
baseline risk of atherosclerotic cardiovascular disease determines the expected absolute risk reduction for that person. LDL-C = low-density lipoprotein
cholesterol; PCSK9 = proprotein convertase subtilisin/kexin type 9.
ESC/EAS Guidelines 37

A Total CV risk assessment


See Table 4

In selected low- and moderate-risk patients Baseline LDL-C levels

Risk modifiers
imaging (subclinical atherosclerosis)
Risk Reclassification?

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Indication for drug therapy?
See Table 5

Y N
Define treatment goal Lifestyle advice /
See Table 7 Lifestyle intervention

High potency statin at highest


recommended /
tolerable dose to reach the goal

LDL-C goal reached?

Y N
Follow-up
Annually, or more frequently Add ezetimibe
if indicated

LDL-C goal reached?

Y N
• Secondary prevention (very-high-risk)
Follow-up
• Primary prevention: patients with
Annually, or more frequently Add PCSK9 inhibitor
FH and another major risk factor
if indicated
(very-high risk)

• Primary prevention: patients at


Consider adding
very-high risk but without FH
PCSK9 inhibitor
(see Table 4)

B Treatment goal
for LDL-C • SCORE <1%
• SCORE ≥1% and <5%
• Young patients (T1DM <35 years;
T2DM <50 years) with DM duration
3.0 mmol/L
(116 mg/dL)
Low <10 years without other risk factors

• SCORE ≥5% and <10%


2.6 mmol/L • Markedly elevated single risk factors, in
(100 mg/dL) Moderate particular TC >8 mmol/L (310 mg/dL) or
LDL-C >4.9 mmol/L (190 mg/dL) or
BP ≥180/110 mmHg
• FH without other major risk factors
• Moderate CKD (eGFR 30–59 mL/min)
• DM w/o target organ damage, with DM
duration ≥10 years or other additional risk factor

1.8 mmol/L
(70 mg/dL)
High • ASCVD (clinical/imaging)
• SCORE ≥10%
& ≥50% • FH with ASCVD or with another
reduction major risk factor
• Severe CKD (eGFR <30 mL/min)
from • DM & target organ damage: ≥3
1.4 mmol/L
baseline Very High major risk factors; or early onset of
(55 mg/dL) T1DM of long duration (>20 years)
©ESC 2019

Low Moderate High Very high CV Risk

Figure 4 (A) Treatment algorithm for pharmacological low-density lipoprotein cholesterol lowering. (B) Treatment goals for low-density lipoprotein
cholesterol across categories of total cardiovascular disease risk. ASCVD = atherosclerotic cardiovascular disease; BP = blood pressure; CKD = chronic
kidney disease; CV = cardiovascular; DM = diabetes mellitus; eGFR = estimated glomerular filtration rate; FH = familial hypercholesterolaemia; LDL-C =
low-density lipoprotein cholesterol; PCSK9 = proprotein convertase subtilisin/kexin type 9; SCORE = Systematic Coronary Risk Estimation; T1DM =
type 1 DM; T2DM = type 2 DM; TC = total cholesterol.
38 ESC/EAS Guidelines

..
outcomes.354 Recently, the REDUCE-IT trial194 demonstrated that in .. among these, FH is the most common and is strongly related to CVD
statin-treated patients with high CV risk with fasting TG levels .. (Table 11). In general, in a patient with dyslipidaemia, the pattern of
..
between 135499 mg/dL (1.521.63 mmol/L), high-dose icosapent .. inheritance commonly does not suggest that there is a major single
ethyl, a highly purified and stable EPA (2 g) taken b.i.d., significantly .. gene (monogenic) disorder causing the abnormality; rather, it stems
..
reduced the risk of ischaemic events, including CV death, by about .. from the inheritance of more than one gene variant affecting lipopro-
one-quarter over a median follow-up of 4.9 years. In addition, the .. tein metabolism that, on its own, might have relatively little effect, but
..
VITAL trial showed that n-3 fatty acids at the lower dose of 1 g/day .. in combination with another or others has a greater influence on TC,

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were not effective for primary prevention of CV or cancer events .. TGs, or HDL-C. The pattern of inheritance is polygenic.357 It is com-
..
among healthy middle-aged men and women over 5 years of follow- .. mon to find that high LDL-C, high TG, or low HDL-C levels affect
up.333 Recommendations for the treatment of HTG are shown .. several family members.
..
below. ..
..
..
.. 9.1.1 Familial combined hyperlipidaemia
.. Familial combined hyperlipidaemia (FCH) is a highly prevalent mixed
Recommendations for drug treatment of patients with ..
hypertriglyceridaemia
.. dyslipidaemia (1:100200) characterized by elevated levels of LDL-
..
.. C, TGs, or both, and is an important cause of premature CAD. FCH
Recommendations Classa Levelb .. is a complex disease, and the phenotype is determined by the interac-
..
Statin treatment is recommended as the first
.. tion of multiple susceptibility genes and the environment. It has con-
.. siderable overlap with the dyslipidaemic phenotypes of T2DM and
drug of choice to reduce CVD risk in high-risk ..
individuals with hypertriglyceridaemia [TG lev-
I B .. MetS. Even within a family, the phenotype shows high inter- and intra-
.. personal variability based on lipid values (TGs, LDL-C, HDL-C, and
els >2.3 mmol/L (>200 mg/dL)].355 ..
.. ApoB). FCH has no monogenic component and is not linked to a sin-
In high-risk (or above) patients with TG levels .. gle genetic cause, but the phenotype is high LDL-C and/or high
between 1.55.6 mmol/L (135499 mg/dL) ..
.. TGs.358,359 Therefore, the diagnosis is commonly missed in clinical
despite statin treatment, n-3 PUFAs (icosapent IIa B .. practice; the combination of ApoB >120 mg/dL and TGs >1.5 mmol/
ethyl 22 g/day) should be considered in ..
.. L (>133 mg/dL) with a family history of premature CVD can be used
combination with a statin.194 ..
.. to identify people who most probably have FCH.360
In primary prevention patients who are at .. The concept of mixed dyslipidaemia is also valuable clinically in
LDL-C goal with TG levels >2.3 mmol/L .. assessing CV risk. It emphasizes both the importance of considering
(>200 mg/dL), fenofibrate or bezafibrate may IIb B
..
.. family history in deciding how rigorously to treat dyslipidaemia and
be considered in combination with .. that elevated LDL-C levels portend a higher risk when HTG is also
statins.305307,356
..
.. present. Statin treatment decreases CV risk by the same relative
In high-risk patients who are at LDL-C goal .. amount in people with HTG as in those without. Because the abso-
..
with TG levels >2.3 mmol/L (>200 mg/dL),
IIb C
.. lute risk is often greater in those with HTG, they may therefore bene-
fenofibrate or bezafibrate may be considered .. fit greatly from LDL-lowering therapy.
..
in combination with statins.305307,356 ..
..
CVD = cardiovascular disease; LDL-C = low-density lipoprotein cholesterol; ..
PUFA = polyunsaturated fatty acids; TG = triglyceride. .. 9.1.2 Familial hypercholesterolaemia
a
Class of recommendation. ..
b
Level of evidence.
.. 9.1.2.1 Heterozygous familial hypercholesterolaemia. FH is a common
.. codominant monogenic dyslipidaemia causing premature CVD due
..
.. to lifelong elevation of plasma levels of LDL-C. If left untreated, men
.. and women with HeFH typically develop early CAD before the ages
..
.. of 55 and 60 years respectively. The risk of CHD among individuals
9 Management of dyslipidaemias .. with definite or probable HeFH is estimated to be increased at least
..
in different clinical settings .. 10-fold. However, early diagnosis and appropriate treatment can dra-
.. matically reduce the risk for CAD.
..
9.1 Familial dyslipidaemias .. The prevalence of HeFH in the population is estimated to be
Plasma lipid levels are, to a very large extent, determined by genetic .. 1/200250,361 translating to a total number of cases between 1434
..
factors. In its more extreme forms this is manifested as familial dyslipi- .. million worldwide.362,363 Only a minor fraction of these cases is iden-
daemias. A number of monogenic lipid disorders have been identified; .. tified and properly treated.
ESC/EAS Guidelines 39

Table 11 Genetic disorders of lipoprotein metabolism


Disorder Prevalence Gene(s) Effect on lipoproteins
HeFH 1 in 200250 LDLR "LDL-C
APO B
PCSK9
HoFH 1 in 160 000320 000 LDLR ""LDL-C

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APO B
PCSK9
FCH 1 in 100/200 USF1 þ modifying genes "LDL-C "VLDL-C "ApoB
Familial dysbetalipoproteinaemia 1 in 5000 APO E ""IDL and chylomicron remnants (bVLDL)
Familial lipoprotein lipase deficiency 2 in 106 LPL ""chylomicrons and VLDL-C
(familial chylomicron syndrome) APO C2
ApoAV, GPIHBP1
LMF1
Tangier disease (analphalipoproteinaemia) 1 in 106 ABCA1 ##HDL-C
6
Familial LCAT deficiency 1 in 10 LCAT #HDL-C
Apo = apolipoprotein; FCH = familial combined hyperlipidaemia; HDL-C = high-density lipoprotein cholesterol; HeFH = heterozygous familial hypercholesterolaemia; HoFH =
homozygous familial hypercholesterolaemia; IDL = intermediate-density lipoprotein; LCAT = lecithin cholesterol acyltransferase; LDL-C = low-density lipoprotein cholesterol;
VLDL = very low-density lipoprotein cholesterol.

Table 12 Dutch Lipid Clinic Network diagnostic criteria for familial hypercholesterolaemia
Criteria Points
1) Family history
First-degree relative with known premature (men aged <55 years; women <60 years) coronary or vascular disease, 1
or first-degree relative with known LDL-C above the 95th percentile
First-degree relative with tendinous xanthomata and/or arcus cornealis, or children aged <18 years with LDL-C above the 95th percentile 2
2) Clinical history
Patient with premature (men aged <55 years; women <60 years) CAD 2
Patient with premature (men aged <55 years; women <60 years) cerebral or peripheral vascular disease 1
a
3) Physical examination
Tendinous xanthomata 6
Arcus cornealis before age 45 years 4
4) LDL-C levels (without treatment)
LDL-C >_8.5 mmol/L (>_325 mg/dL) 8
LDL-C 6.58.4 mmol/L (251325 mg/dL) 5
LDL-C 5.06.4 mmol/L (191250 mg/dL) 3
LDL-C 4.04.9 mmol/L (155190 mg/dL) 1
5) DNA analysis
Functional mutation in the LDLR, apoB, or PCSK9 genes 8
Choose only one score per group, the highest applicable; diagnosis is based on the total number of points obtained
A ‘definite’ FH diagnosis requires >8 points
A ‘probable’ FH diagnosis requires 68 points
A ‘possible’ FH diagnosis requires 35 points
CAD = coronary artery disease; FH = familial hypercholesterolaemia; LDL-C = low-density lipoprotein cholesterol; PCSK9 = proprotein convertase subtilisin/kexin type 9.
a
Exclusive of each other (i.e. maximum 6 points if both are present).
40 ESC/EAS Guidelines

FH is a monogenic disease caused by loss-of-function mutations in Recommendations for the detection and treatment of
the LDLR or apoB genes, or a gain-of-function mutation in the PCSK9 patients with heterozygous familial hypercholesterolaemia
gene; around 95% of FH cases are caused by mutations in LDLR. More
Recommendations Classa Levelb
than 1000 different mutations that cause FH have been identified in
LDLR. The different mutations cause reduced function or complete It is recommended that a diagnosis of FH is
loss-of-function, the latter being associated with more severe hyper- considered in patients with CHD aged <55
cholesterolaemia and CVD. years for men and <60 years for women, in

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The diagnosis of FH is usually based on clinical presentation. The people with relatives with premature fatal or
commonly used criteria from the Dutch Lipid Clinic Network are non-fatal CVD, in people with relatives who
I C
shown in Table 12. Other criteria are the Simon Broome register or have tendon xanthomas, in people with
the WHO criteria.364,365 severely elevated LDL-C [in adults >5 mmol/L
The diagnosis can be verified by showing causative mutations in (>190 mg/dL), in children >4 mmol/L (>150
the pathogenic genes. However, in most studies, the frequency of mg/dL)], and in first-degree relatives of FH
detectable mutations in patients with a clinically definite or probable patients.
HeFH is between 6080%. This suggests that a considerable propor- It is recommended that FH should be diag-
tion of patients with FH have either a polygenic cause of the disease nosed using clinical criteria and confirmed, I C
or that other genes, yet to be identified, are involved. when possible, via DNA analysis.
Genetic testing and cascade screening. Probands (index cases) should Once the index case is diagnosed, family cas-
be identified according to the following criteria: I C
cade screening is recommended.
• TC >_8 mmol/L (>_310 mg/dL) without treatment in an adult or It is recommended that FH patients with
adult family member (or >95th percentile by age and gender for ASCVD or who have another major risk fac-
country); tor are treated as very-high-risk, and that I C
• Premature CHD in the patient or a family member; those with no prior ASCVD or other risk fac-
• Tendon xanthomas in the patient or a family member; or tors are treated as high-risk.
• Sudden premature cardiac death in a family member. For FH patients with ASCVD who are at very-
Cascade screening of family members of a known index case high risk, treatment to achieve a >_50% reduc-
allows for the efficient identification of new cases. Cascade screening tion from baseline and an LDL-C <1.4 mmol/L
I C
is best performed by a lipid clinic. In most families, the cases may be (<55 mg/dL) is recommended. If goals cannot
identified with TC or LDL-C analysis; however, genetic testing is rec- be achieved, a drug combination is
ommended when the causative mutation is known. recommended.
Cholesterol-lowering treatment should be initiated as soon as pos- In primary prevention, for individuals with FH
sible after a diagnosis has been made. To improve risk assessment, at very-high risk, an LDL-C reduction of >_50%
IIa C
the use of imaging techniques to detect asymptomatic atherosclerosis from baseline and an LDL-C goal of <1.4
is recommended. The concept of cumulative cholesterol burden mmol/L (<55 mg/dL) should be considered.
illustrates the importance of early treatment (for children, see Treatment with a PCSK9 inhibitor is recom-
below). Treatment should be initiated with high-intensity statin ther- mended in very-high-risk FH patients if the
I C
apy, in most cases in combination with ezetimibe. In FH patients at treatment goal is not achieved on maximal tol-
very-high risk of ASCVD due to a prior history of ASCVD or another erated statin plus ezetimibe.
major risk factor, LDL-C goals are a >_50% reduction of LDL-C from In children, testing for FH is recommended
baseline and an LDL-C <1.4 mmol/L (<55 mg/dL). In the absence of from the age of 5 years, or earlier if HoFH is I C
ASCVD or another major risk factor, patients with FH are catego- suspected.
rized as high-risk, and LDL-C goals are a >_50% reduction of LDL-C Children with FH should be educated to adopt
from baseline and an LDL-C <1.8 mmol/L (<70 mg/dL). a proper diet and treated with a statin from
PCSK9 inhibitors lower LDL-C levels by up to 60% on top of sta- 810 years of age. Goals for treatment should IIa C
tins. Two RCTs have reported a beneficial effect on clinical endpoints be LDL-C <3.5 mmol/L (<135 mg/dL) at >10
in ASCVD patients without FH.119,120 PCSK9 inhibitors are recom- years of age.
mended in very-high-risk patients with FH if the treatment goal is not
ASCVD = atherosclerotic cardiovascular disease; CHD = coronary heart disease;
achieved on maximal tolerated statin plus ezetimibe. PCSK9 inhibi-
CVD = cardiovascular disease; FH = familial hypercholesterolaemia; HoFH =
tors are also recommended in FH patients who cannot tolerate homozygous FH; LDL-C = low-density lipoprotein cholesterol; PCSK9 = propro-
statins.366,367 tein convertase subtilisin/kexin type 9.
a
Class of recommendation.
Recommendations for the detection and treatment of patients b
Level of evidence.
with HeFH are shown below.
ESC/EAS Guidelines 41

9.1.2.2 Homozygous familial hypercholesterolaemia. HoFH is a rare and


..
.. The detection of ApoE2 homozygosity in a dyslipidaemic patient is
life-threatening disease. The clinical picture is characterized by exten- .. diagnostic and analysis of ApoE isoforms is now available in most
..
sive xanthomas, marked premature and progressive CVD, and TC .. clinical laboratories. The presence of cholesterol remnants charac-
>13 mmol/L (>500 mg/dL). Most patients develop CAD and aortic .. teristic of familial dysbetalipoproteinaemia can be reliably predicted
..
stenosis before the age of 20 years and die before 30 years of age. .. on the basis of plasma levels of cholesterol, TGs, and ApoB.376 If sus-
The frequency of HoFH is estimated to be 1/160 0001/320 000. .. picion is confirmed, ApoE genotyping can be performed. In older
..
The early identification of these children and prompt referral to a .. patients with xanthomata resembling those of familial dysbetalipo-

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specialized clinic is crucial. The patients should be treated with inten- .. proteinaemia who prove not to be homozygous for ApoE2, a para-
..
sive LDL-lowering drug therapy and, when available, with lipoprotein .. protein should be sought. The treatment of familial
apheresis. This treatment (every 12 weeks) can decrease plasma .. dysbetalipoproteinaemia should be undertaken in a specialist clinic.
..
LDL-C levels by 5570%. The procedure frequency may be adjusted .. Most cases respond well to treatment with a statin or, if dominated
for each patient as lipid levels, symptoms, and other disease-related .. by high TGs, a fibrate; often a combination of a statin and a fibrate
..
parameters change. Maximally tolerated pharmacological therapy .. may be needed.
must be maintained.368 For a more detailed discussion on HoFH, see ..
..
the EAS consensus statements.366,368 ..
.. 9.1.4 Genetic causes of hypertriglyceridaemia
..
9.1.2.3 Familial hypercholesterolaemia in children. FH is diagnosed in .. Although the genetic aetiology for HTG seems to be very complex,
children based on phenotypic criteria including elevated LDL-C plus a
..
.. recent data have extended our genetic understanding of HTG, in par-
family history of elevated LDL-C, premature CAD, and/or positive .. ticular that of chylomicronaemia.37,226,377 Moderate elevation of TG
genetic testing.369 Testing during childhood is optimal to discriminate
..
.. levels (between 2.010.0 mmol/L) is caused by the polygenic effect
between FH and non-FH using LDL-C. In children with a family history .. of multiple genes influencing both VLDL production and removal.
of high cholesterol or premature CHD, an accepted cut-off is >_4.0
..
.. Monogenic severe HTG causes chylomicronaemia, pancreatitis, and
mmol/L (>_160 mg/dL). If a parent has a known genetic defect, the diag- .. lipid deposits. Thus far, mutations in six genes (LPL, apoC2, apoA5,
..
nostic level for the child is >_3.5 mmol/L (>_130 mg/dL). If possible, .. LMF1, GPIHBP1, and GPD1) with monogenic effects have been recog-
genetic testing of the child is suggested. .. nized to lead to severe elevation of serum TGs due to disruption of
..
Although there have been no placebo-controlled trials in children, .. the chylomicron removal pathways. These mutations are inherited as
observational studies have suggested that early treatment can reduce .. autosomal recessive traits and are rare. The profound defect in the
..
LDL-C burden, improve endothelial function, substantially attenuate .. catabolism of chylomicrons and VLDL results in chylomicronaemia
the development of atherosclerosis, and improve coronary out- .. and TG levels >11.2 mmol/L (>1000 mg/dL), with turbid and milky
..
comes.369371 Treatment of children with FH includes a healthy life- .. serum. Severe HTG is seen in patients who are homozygous or com-
style and statin treatment. A heart-healthy diet should be adopted .. pound heterozygous for mutations of the enzyme LPL, and in other
..
early in life and statin treatment should be considered at 610 years .. genes linked to the catabolism of TG-rich lipoproteins.
of age. Statin treatment should be started with low doses and the .. Heterozygous carriers of these same gene mutations commonly
..
dose should be increased to reach goals.372 The goal in children >10 .. express moderate elevations of serum TG levels that expose them
years of age is an LDL-C <3.5 mmol/L (<135 mg/dL) and at younger .. to increased CVD risk.378 Recently, gene therapy for LPL deficiency
..
ages a >_50% reduction of LDL-C. .. has been developed and tested in clinical trials,379 and the alipogene
.. tiparvovec was approved by the EMA in 2013. However, this therapy
..
.. is no longer available. A gain-of-function mutation in apoC3 that leads
9.1.3 Familial dysbetalipoproteinaemia
.. to high ApoC-III levels can also cause severe HTG by inhibiting the
..
Familial dysbetalipoproteinaemia (i.e. type III hyperlipoproteinaemia; .. activity of LPL, whereas loss-of-function mutations are associated
..
remnant removal disease) is rare and is generally inherited as an auto- .. with a favourable lipid profile with low TG levels.380 These findings
somal recessive disorder with variable penetrance. Familial dysbetali- .. have raised the possibility of ApoC-III being a novel lipid drug target.
..
poproteinaemia produces a characteristic clinical syndrome in which ..
both TC and TGs are elevated before treatment, usually both in the .. 9.1.4.1 Action to prevent acute pancreatitis in severe hypertriglyceridae-
..
range of 710 mmol/L. In severe cases, patients develop tuberoerup- .. mia. The risk of pancreatitis is clinically significant if TGs are >10 mmol/L
tive xanthomas, particularly over the elbows and knees, and palmar .. (880 mg/dL), particularly when occurring in association with familial chy-
..
xanthomata in the skin creases of the hands and wrists. The risk of .. lomicronaemia, and actions to prevent acute pancreatitis are manda-
CAD is very high, and accelerated atherosclerosis of the femoral and .. tory.381,382 Notably, HTG is the cause of 10% of all cases with
..
tibial arteries is also prevalent. The syndrome is usually not expressed .. pancreatitis, and patients can develop pancreatitis even when their TG
at a young age or in women before menopause. The majority of cases .. concentration is 510 mmol/L (440880 mg/dL). Recent data from a
..
are homozygous for the E2 isoform of ApoE. ApoE is important for .. prospective cohort study reported that the risk of acute pancreatitis
the hepatic clearance of chylomicron remnants and IDL. ApoE2 binds .. increased significantly over the quartiles of serum TGs, highlighting the
..
less readily than the E3 and E4 isoforms to hepatic receptors. .. fact that, as a risk factor, serum TGs may have been underestimated.383
However, without some coincidental cause of dyslipidaemia such as .. Any factor that increases VLDL production can aggravate the risk of pan-
..
dyslipidaemia associated with HTG, DM, obesity, or hypo- .. creatitis, with alcohol consumption being the most common contributing
thyroidism,373375 ApoE2 homozygosity does not generally cause
.. factor. Either a patient should be admitted to hospital if symptomatic, or
..
familial dysbetalipoproteinaemia. . careful and close follow-up of the patient’s TG values should be
42 ESC/EAS Guidelines

..
undertaken. Restriction of calories and fat content (1015% recom- .. vascular events, major coronary events, coronary revascularization,
mended) in the diet, and alcohol abstinence are obligatory. Fibrate ther- .. and stroke were similar in women and men.35
..
apy (fenofibrate) should be initiated, with n-3 fatty acids (24 g/day) as ..
adjunct therapy. Lomitapide may also be considered in severe cases.37 In
..
.. 9.2.2 Non-statin lipid-lowering drugs
patients with DM, insulin therapy should be initiated to achieve good gly- ..
caemic control. In general, a sharp decrease of TG values is seen within
.. Definitive evidence of the cardioprotective effects of non-statin drugs
.. that lower LDL-C is now available, and the beneficial effects are simi-
25 days. In the acute setting, plasmapheresis is able to rapidly lower ..

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TG levels.384 Volanesorsen has been recently approved by the EMA as
.. lar in both women and men. In the IMPROVE-IT study,33 the relative
.. benefit of adding ezetimibe to simvastatin was similar in women and
an adjunct to diet in adult patients with genetically confirmed FCS who ..
are at high-risk for pancreatitis.
.. men.33 In the ACCORD lipid study, there was no evidence that feno-
.. fibrate added to the effects of simvastatin in patients with T2DM,306
..
.. but an analysis of the FIELD study showed consistent CV event
9.1.5 Other genetic disorders of lipoprotein metabolism .. reduction in both women and men.389 Several outcome trials assess-
Sometimes patients are encountered with extremely low levels of ... ing the effects of adding a PCSK9 inhibitor to high-intensity statin
..
LDL-C or HDL-C. The most common form of genetic hypolipidae- .. therapy have now been reported, with similar proportional reduc-
mia is hypobetalipoproteinaemia, which is dominantly inherited and ..
.. tions in major vascular events in women and men.120,286,290
often due to truncation of ApoB. Serum LDL-C is typically between ..
0.51.5 mmol/L (2060 mg/dL). A more profound deficiency of ..
..
ApoB occurs in abetalipoproteinaemia when steatorrhoea, and neu- .. 9.2.3 Hormone therapy
rological or other complications require specialist treatment. Almost .. Currently prescribed third-generation, low-dose oestrogenprogestin
..
absent levels of HDL-C occur in Tangier disease (analphalipoprotei- .. oral contraceptives do not appear to increase adverse coronary
naemia) and very low levels of HDL-C occur in lecithin cholesterol .. events390 and can be used, after baseline lipid profile assessment, in
..
acyltransferase (LCAT) deficiency. Both these conditions are associ- .. women with acceptable TC levels. In contrast, alternative contracep-
ated with distinct clinical syndromes and require specialist investiga-
.. tive measures should be recommended in women with hypercholes-
..
tion. Very high levels of HDL-C are detected in patients with CETP .. terolaemia [LDL-C >4 mmol/L (>160 mg/dL)] or with multiple risk
deficiency. In the heterozygous form, levels of 2.02.3 mmol/L
.. factors, and in those at high-risk of thrombotic events.391 Oestrogen
..
(8090 mg/dL) are typically observed, and levels >_5 mmol/L (>_200 .. replacement therapy, despite some favourable effects on lipid profiles,
mg/dL) are observed in homozygotes. This is not associated with
.. has not been demonstrated to reduce CV risk and cannot be recom-
..
atherosclerotic disease and may be associated with reduced risk. .. mended for CVD prevention in women.392 No lipid-lowering drugs
Lysosomal acid lipase deficiency or cholesterol ester storage dis-
.. should be administered during pregnancy and the period of breastfeed-
..
ease (in children with Wolman disease) is a rare cause (recessive .. ing because data on possible adverse effects are lacking. However, bile
.. acid sequestrants may be considered.
transmission) of elevated LDL-C and low HDL-C, accompanied by ..
hepatomegaly and microvesicular hepatosteatosis. Statin treatment .. Box 6 lists the main measures in the management of dyslipidaemia
.. in women.
does decrease LDL-C levels and could therefore prevent ASCVD in
these patients, but it cannot stop the progression of liver damage.
Treatment with a PCSK9 inhibitor may lead to an even greater over- Box 6 Management of dyslipidaemia in women
load of lysosomes.385 Enzyme replacement therapy with sebelipase
Statin treatment is recommended for primary prevention of ASCVD in
alfa might offer a treatment solution in the near future.386
high-risk women.34,35
Statins are recommended for secondary prevention in women with the
9.2 Women same indications and goals as in men.34,35
Few randomized trials of statin therapy have reported independently Lipid-lowering drugs should not be given when pregnancy is planned, dur-
significant CV benefits in women,387,389 chiefly because women have
ing pregnancy, or during the breastfeeding period. However, for severe
not been adequately represented in statin trials. FH patients, bile acid sequestrants (which are not absorbed) and/or LDL
apheresis may be considered.
9.2.1 Effects of statins in primary and secondary ASCVD = atherosclerotic cardiovascular disease; FH = familial hypercholestero-
prevention laemia; LDL = low-density lipoprotein.
There has previously been controversy over whether statins are
effective for primary prevention in women. Using published data, a
2013 Cochrane analysis showed that statin therapy reduced all-cause
mortality, vascular events, and revascularizations in primary preven- 9.3 Older people
tion, and the proportional effects in women were similar to those in The proportion of older people (defined herein as those aged >65
men.213 The CTT collaboration has provided a more complete years) in society is increasing and, as a consequence, >80% of individ-
assessment of the evidence through a comprehensive analysis of IPD uals who die from CVD are >65 years of age. The proportion of
from 22 trials of statins vs. control and five trials of more- vs. less- patients with MI >85 years of age has increased several-fold.393
intensive statin therapy.35 Overall, 46 675 (27%) of 174 149 partici- A meta-analysis of observational studies has shown that higher TC
pants were women, and after adjustment for non-gender differences, is associated with increased CAD mortality at all ages.62,394
the proportional reductions per mmol/L reduction in LDL-C in major However, since the absolute risk of CAD is higher in older persons,
ESC/EAS Guidelines 43

the associated absolute increase in risk for a given increment in TC is .. 9.4 Diabetes and metabolic syndrome
..
larger with increasing age.217 .. The number of people with DM will increase from 415 million
..
.. today up to 550 million by 2030, but the situation may get even
9.3.1 Effects of statins in primary and secondary
.. worse.399 Despite significant advantages in the management strat-
..
prevention .. egies that lessen atherosclerotic CVD risk factors, CVD has remained
The use of statin therapy declines with increasing age, reflecting dif-
.. the leading cause of morbidity and mortality in patients with T2DM.
..
ferences in both prescription and compliance.395,396 This trend is .. The good news is that fatal CVD outcomes have declined significantly

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even more prominent among older patients who do not have evi-
.. in both T1DM and T2DM between 1998 and 2014.400 DM itself is an
..
dence of occlusive vascular disease.396 One explanation for this pat- .. independent risk factor for CVD and is associated with a higher risk
.. of CVD, even more so in women. The difference in CVD risk
tern may be uncertainty about the effects of statins in older people ..
due to the relatively small number of people aged >75 years who .. between individuals with and without DM has narrowed substantially
.. over the last few decades,401 and there are strong associations
have been included in statin trials.233,397,398 The CTT collaboration ..
recently provided a comprehensive assessment of the randomized .. between DM and vascular outcomes.402,403 Recent data indicate that
.. DM per se increases CVD risk about two-fold on average, but the risk
evidence on the effects of statin therapy at different ages.217 Among ..
186 854 participants in 28 trials, 14 483 (8%) were aged >75 years at .. is subject to wide variation depending on the population and current
.. aggressive prophylactic therapy.401,404 Importantly, those with DM
randomization. Overall, statin therapy produced a 21% relative ..
reduction in major vascular events (relative risk 0.79, 95% CI ... and CAD are at substantially higher CVD risk for future events. In
0.770.81) per 1.0 mmol/L reduction in LDL-C, and there was direct .. T2DM, the risk of ASCVD is strongly determined by the presence of
.. target organ damage—including nephropathy (microalbuminuria),
evidence of benefit among those aged >75 years. The relative reduc- ..
tion in major vascular events was similar, irrespective of age, among .. neuropathy, or retinopathy—with the risks increasing in relation to
..
patients with pre-existing vascular disease, but appeared smaller .. the number of conditions present.405 Hypertension, dyslipidaemia,
among older individuals not known to have vascular disease. .. abdominal obesity, and non-alcoholic fatty liver disease (NAFLD)
..
Therefore, the available evidence from trials indicates that statin ther- .. commonly coexist with T2DM and further aggravate the risk, which
apy produces significant reductions in major vascular events irrespec- .. is highest in people with T2DM and multiple cardiometabolic risk
..
tive of age. However, there is less direct evidence of benefit among .. factors.406408 Importantly, DM confers excess mortality risk follow-
patients aged >75 years who do not already have evidence of occlu-
.. ing ACS despite modern therapies, highlighting the poor prognosis of
..
sive vascular disease, and this limitation is currently being addressed .. coronary patients with T2DM and the need for intensive therapy.409
by the STAtin therapy for Reducing Events in the Elderly (STAREE)
.. How to capture the extra risk beyond the traditional risk factors in
..
trial in Australia. .. clinical practice is a debated issue. A practical approach is that if one
.. component is identified, a systematic search should be made for the
..
.. others.410
9.3.2 Adverse effects, interactions, and adherence ..
The safety and adverse effects of statins are a matter of special con- ..
..
cern in older adults because they often have comorbidities, take mul- .. 9.4.1 Specific features of dyslipidaemia in insulin
tiple medications, and have altered pharmacokinetics and .. resistance and type 2 diabetes mellitus
..
pharmacodynamics. Statindrug interactions are a concern, primarily .. Diabetic dyslipidaemia is a cluster of plasma lipid and lipoprotein
because of their potential to increase muscle-related statin-associ- .. abnormalities that are metabolically interrelated. The increase in
..
ated adverse effects such as myalgia without CK elevation, myopathy .. large VLDL particles in T2DM initiates a sequence of events that
with CK elevation, and the rare but serious rhabdomyolysis. It is rec- .. generates atherogenic remnants, small dense LDL, and small TG-
..
ommended that a statin is started at a low dose if there is significant .. rich dense HDL particles.411 These components are not isolated
renal impairment and/or the potential for drug interactions, and then .. abnormalities but are closely linked to each other. Both LDL and
..
titrated upwards to achieve LDL-C treatment goals. .. HDL particles show variable compositional changes that are
The recommendations for the treatment of dyslipidaemias in older
.. reflected in their functions. Notably, ApoC-III levels are increased
..
people are shown below. . in people with T2DM.412 High ApoC-III concentrations prevent

Recommendations for the treatment of dyslipidaemias in older people (aged >65 years)

Recommendations Classa Levelb

Treatment with statins is recommended for older people with ASCVD in the same way as for younger patients.217 I A
217
Treatment with statins is recommended for primary prevention, according to the level of risk, in older people aged <_75 years. I A
Initiation of statin treatment for primary prevention in older people aged >75 years may be considered, if at high-risk or above.217 IIb B
It is recommended that the statin is started at a low dose if there is significant renal impairment and/or the potential for drug
I C
interactions, and then titrated upwards to achieve LDL-C treatment goals.

ASCVD = atherosclerotic cardiovascular disease; LDL-C = low-density lipoprotein cholesterol.


a
Class of recommendation.
b
Level of evidence.
44 ESC/EAS Guidelines

..
the clearance of both TRLs and remnants, resulting in prolonged .. Ezetimibe lowers LDL-C by 24% and, when added to statin ther-
residence times of these particles in the circulation.413,414 In fact, .. apy, decreases the risk of major vascular events.33 The relative risk
..
the defective catabolism of TRLs seems to be a more important .. reduction in major vascular events is proportional to the absolute
contributor to the elevation of plasma TGs than the increased .. degree of LDL-C lowering and consistent with the relationship seen
..
production rate leading to an excess of remnant particles. .. for statins. The subset of patients with DM in IMPROVE-IT had, as
Together, TRL remnants, small dense LDL, and small dense HDL .. expected, a higher rate of major vascular events than patients with-
..
comprise the atherogenic lipid profile, which is also characterized .. out DM (46 vs. 31% 7 year KaplanMeier rate in the placebo arm).

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by an increase in ApoB concentration due to an increased number .. Ezetimibe appeared particularly efficacious in patients with DM, with
..
of ApoB-containing particles. Importantly, TRLs—including chylo- .. a relative risk reduction of 15% (95% CI 622%) and an absolute risk
microns, VLDL, and their remnants—carry a single ApoB mole- .. reduction of 5.5%.299
..
cule, also like LDL particles. Therefore, the malignant nature of .. The mAb PCSK9 inhibitors evolocumab and alirocumab lower
diabetic dyslipidaemia is not always revealed by the lipid measures .. LDL-C levels by 60% and, when added to statin therapy, decrease
..
used in clinical practice, as LDL-C levels may remain within the .. the risk of major vascular events.119 In the FOURIER study, the rela-
normal range. It may be better revealed by non-HDL-C levels.415 .. tive risk reduction for major vascular events was similar in patients
..
Elevation of TGs or low HDL-C levels in the fasting or post-pran- .. with and without DM; however, given the higher baseline risk in
dial state is seen in about one-half of all people with T2DM,416,417
.. patients with DM, the absolute risk reductions tended to be greater
..
and is also often present in people with abdominal adiposity, insu- .. in patients with DM (2.7% absolute decrease in major vascular events
lin resistance or impaired glucose tolerance.413
.. over 3 years).297 Of note, the achieved LDL-C in the evolocumab
..
Box 7 summarizes dyslipidaemia in MetS and T2DM. .. arm was 0.8 mmol/L. The same benefits were also recently demon-
.. strated for diabetic patients after ACS in the ODYSSEY trial.420
..
Box 7 Summary of dyslipidaemia in metabolic syndrome
.. Recent studies have suggested an increased incidence of DM in
..
and type 2 diabetes mellitus .. patients treated with statins.247 These observations have been seen
.. in Mendelian randomization studies and in clinical trials, although the
Dyslipidaemia represents a cluster of lipid and lipoprotein abnormalities, ..
.. effect appears greatest in patients already at high risk for DM (e.g.
including elevation of both fasting and post-prandial TG, ApoB, and small .. those with pre-diabetes). These observations should not lessen our
dense LDL, and low HDL-C and ApoA1 levels. ..
.. attention to the treatment of patients, as the overall benefits in CV
Non-HDL-C or ApoB are good markers of TRLs and remnants, and are a .. event reduction remain and greatly outweigh the increased incidence
secondary objective of therapy. Non-HDL-C <2.6 mmol/L (<100 mg/dL) ..
.. of DM. In RCTs, neither ezetimibe nor the PCSK9 inhibitors have
and ApoB <80 mg/dL are desirable in those at high-risk, and non-HDL-C .. been reported to increase the risk of DM.297
<2.2 mmol/L (<85 mg/dL) and ApoB <65 mg/dL in those at very high-
..
..
risk. For those at very high-risk with recurrent ASCVD events, a goal of .. 9.4.2.2 Triglycerides and high-density lipoprotein cholesterol. Lifestyle
non-HDL-C <1.8 mmol/L (<70 mg/dL) and ApoB <55 mg/dL may be
..
.. modification provides the first option to improve atherogenic dyslipi-
considered. .. daemia due to its multifaceted effects. Weight loss is, in most cases,
..
Atherogenic dyslipidaemia is one of the major risk factors for CVD in .. the most effective measure since it is associated with very pro-
people with type 2 diabetes, and in people with abdominal obesity and .. nounced effects on plasma TG and HDL levels, together with a mod-
..
insulin resistance or impaired glucose tolerance. .. est decrease in TC and LDL-C levels. Moderate-to-heavy aerobic
Apo = apolipoprotein; ASCVD = atherosclerotic cardiovascular disease; CVD =
.. exercise is also associated with improvement of the plasma lipid pro-
..
cardiovascular disease; HDL-C = high-density lipoprotein cholesterol; LDL-C = .. file by reducing TG levels and increasing HDL-C concentrations. In
low-density lipoprotein cholesterol; TG = triglyceride; TRLs = triglyceride-rich .. relation to diet composition, besides the need to eliminate trans fat,
lipoproteins. ..
.. the available evidence supports the reduction of saturated fat intake
.. and its substitution with unsaturated fat, as well as the replacement
..
.. of a major proportion of refined starchy foods and simple sugars with
9.4.2 Evidence for lipid-lowering therapy
.. fibre-rich foods like fruits, vegetables, and wholegrains.179
..
9.4.2.1 Low-density lipoprotein cholesterol. LDL-C is the primary target .. The clinical benefits achieved by the treatment of high TG and low
of lipid-lowering therapy in patients with DM. Trials specifically per-
..
.. HDL-C levels (frequently seen with DM) are still a matter of debate,
formed in people with T2DM, as well as subsets of individuals with .. as the effects of fenofibrate therapy on the major outcome (MACE)
DM in major statin trials, have consistently demonstrated significant
..
.. remained negative in both the FIELD and the ACCORD studies per-
benefits of statin therapy on CVD events in people with T2DM.418 .. formed in T2DM cohorts.306,307 In a post hoc analysis of the FIELD
Statin therapy reduces the 5 year incidence of major CVD events by
..
.. study, fenofibrate reduced CVD events by 27% in those with elevated
23% per 1 mmol/L reduction in LDL-C, regardless of the initial LDL- .. TGs [2.3 mmol/L (200 mg/dL)] and increased HDL-C levels (NNT
..
C level or other baseline characteristics based on meta-analysis.418 .. = 23).416 The ACCORD trial confirmed the following: patients who
The CTT meta-analysis further indicates that people with T2DM will .. had both TG levels in the higher third [2.3 mmol/L (200 mg/dL)]
..
have a relative risk reduction that is comparable to that seen in non- .. and an HDL-C level in the lower third [<_0.4 mmol/L (<_34 mg/dL)],
diabetic patients; however, being at higher absolute risk, the absolute .. representing 17% of all participants, appeared to benefit from the
..
benefit will be greater, resulting in a lower number needed to treat .. addition of fenofibrate to simvastatin.306
(NNT). Thus, statin therapy is the first-line treatment for LDL-C low- .. Recently, post-trial follow-up of the ACCORD lipid trial partici-
..
ering and for the reduction of CVD burden.419 . pants reported the beneficial effect of fenofibrate in people with
ESC/EAS Guidelines 45

HTG and low HDL-C levels at baseline.421 Consistent with these


.. benefits were seen in patients with T1DM and T2DM. In diabetic
..
findings, a meta-analysis of fibrates in the prevention of CVD in .. patients with ACS, intensive statin treatment led to a reduction in
11 590 people with T2DM showed that fibrates significantly reduced
.. all-cause mortality and CV death, and contributed to a reduction
..
the risk of non-fatal MI by 21%, but had no effect on the risk of overall .. in atheroma progression.432
..
mortality or coronary mortality.422 In CV outcome trials of fibrates, ..
the risk reduction has appeared to simply be proportional to the ..
..
degree of non-HDL-C lowering.50 ..

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9.4.4 Management of dyslipidaemia for pregnant women
Overall, available data indicate that diabetic patients with athero- ..
.. with diabetes
genic dyslipidaemia may derive clinical benefits from TG-lowering .. In both T1DM and young-onset T2DM patients, there is a paucity of
therapy as an add-on to statin treatment.354 The ongoing ..
.. evidence to indicate the age at which statin therapy should be initi-
PROMINENT trial is exploring the efficacy of pemafibrate, a new .. ated. To guide an approach, statins are not indicated in pregnancy,433
selective PPAR-a modulator, in reducing CVD outcomes in 10 000 ..
.. and should be avoided in both T1DM and T2DM individuals who are
diabetic patients with atherogenic dyslipidaemia on a statin.317,423 .. planning pregnancy. If diabetic individuals aged <_30 years have no evi-
There are limited data on the impacts on CVD of adding omega-3 ..
.. dence of vascular damage and, in particular, microalbuminuria, it
fatty acids to statin therapy in patients with high plasma TG levels .. seems reasonable to delay statin therapy in asymptomatic patients
who are treated with statins. The REDUCE-IT trial examined the ..
.. until the age of 30. Below this age, statin therapy should be managed
effects of icosapent ethyl 2 g b.i.d. on CV events in 8179 high-risk .. on a case-by-case basis, taking into account the presence of microal-
patients with HTG who were taking a statin. Over a median of 4.9 ..
.. buminuria, end organ damage, and ambient LDL-C levels.
years, there was a significant (P < 0.001) 25% reduction in the compo- .. Recommendations for the treatment of dyslipidaemias in DM are
site primary outcome of CV death, non-fatal MI, non-fatal stroke, cor-
..
. shown in the table below.
onary revascularization, or unstable angina, corresponding with an
absolute reduction of 4.8%, which was offset by a 1% increased abso-
lute risk of hospitalization for atrial fibrillation or flutter.194 The
Recommendations for the treatment of dyslipidaemias
STRENGTH trial is investigating the effect of omega-3 fatty acids, in in diabetes mellitus
addition to a statin, in individuals with HTG and low HDL-C levels
who are at high-risk for CVD. The ASCEND trial was a randomized Recommendations Classa Levelb
22 factorial design study of aspirin and omega-3 fatty acid supple-
In patients with T2DM at very-high riskc, an
ments for the primary prevention of CV events in people with DM,
LDL-C reduction of >_50% from baseline and
but not specifically with HTG. Among 15 480 people randomized to I A
an LDL-C goal of <1.4 mmol/L (<55 mg/dL) is
omega-3 fatty acid supplements vs. placebo over a mean follow-up of
recommended.34,418,432
7.4 years, there was no significant effect (HR 0.97, 95% CI 0.871.08)
In patients with T2DM at high risk,c an LDL-C
on serious vascular events [non-fatal MI, non-fatal stroke, transient
reduction of >_50% from baseline and an LDL-
ischaemic attack (TIA), or vascular death].329,424426 I A
C goal of <1.8 mmol/L (<70 mg/dL) is
recommended.418
9.4.3 Type 1 diabetes mellitus Statins are recommended in patients with
I A
T1DM is associated with high CVD risk, in particular in patients with T1DM who are at high or very-high risk.c 427
microalbuminuria and renal disease.427 Conclusive evidence supports Intensification of statin therapy should be con-
the proposition that hyperglycaemia accelerates atherosclerosis. sidered before the introduction of combina- IIa C
Emerging evidence highlights the frequent coexistence of MetS with tion therapy.
T1DM, resulting in the so-called double diabetes increasing CVD risk.428 If the goal is not reached, statin combination
The lipid profile in T1DM patients with good glycaemic control is IIa B
with ezetimibe should be considered.33,299
‘supernormal’, and is characterized by subnormal TG and LDL-C lev- Statin therapy is not recommended in pre-
els, whereas HDL-C levels are usually within the upper normal range menopausal patients with diabetes who are
or slightly elevated. This is explained by subcutaneous administration III C
considering pregnancy or are not using
of insulin that increases LPL activity in adipose tissue and skeletal adequate contraception.
muscle, and consequently the turnover rate of VLDL particles.429
Statin therapy may be considered in both
However, there are potentially atherogenic changes in the composi-
T1DM and T2DM patients aged <_30 years
tions of both HDL and LDL particles.
with evidence of end organ damage and/or an IIb C
Consistent data have demonstrated the efficacy of statins in
LDL-C level >2.5 mmol/L, as long as preg-
preventing CV events and reducing CV mortality in patients with
nancy is not being planned.
DM, with no evidence of sex differences.430,431 A meta-analysis
including 18 686 patients with DM demonstrated that a statin- LDL-C = low-density lipoprotein cholesterol; T1DM = type 1 diabetes mellitus;
T2DM = type 2 diabetes mellitus.
induced reduction of LDL-C yielded a 9% reduction in all-cause a
Class of recommendation.
mortality and a 21% reduction in the incidence of major CV events b
Level of evidence.
per 1.0 mmol/L (40mg/dL) lower LDL cholesterol.418 Similar
c
See Table 6.
46 ESC/EAS Guidelines

..
9.5 Patients with acute coronary .. pronounced (46% relative risk reduction) in a post hoc analysis includ-
.. ing 865 ST-elevation MI (STEMI) patients undergoing reperfusion by
syndromes and patients undergoing ..
.. primary PCI.443 Based on current evidence, we recommend the initia-
percutaneous coronary intervention .. tion of high-intensity statin therapy during the first 14 days of hospi-
Patients who present with ACS are at increased risk of experiencing ..
.. talization for the index ACS.438442 Moreover, pre-treatment (or
recurrent CV events. For these patients, lipid management should be .. loading dose for patients already on a statin) with a high-intensity sta-
undertaken in the context of a comprehensive global risk reduction ..
.. tin should be considered in ACS patients with planned invasive

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strategy including lifestyle adaptations, risk factor management, and .. management.443
the implementation of cardioprotective drug strategies. Ideally, ..
..
patients should be signed up to cardiac rehabilitation programmes to .. 9.5.1.2 Ezetimibe. In the IMPROVE-IT trial, the addition of ezetimibe
enhance the control of lipid levels434 and improve overall survival fol- ..
.. to simvastatin therapy provided an additional benefit (6.4% relative
lowing ACS.435 Despite the acknowledged clinical benefits of lower- ..
.. risk reduction in the composite clinical endpoint) to post-ACS
ing LDL-C in patients with ACS,436 attainment of LDL-C target .. patients.33 The clinical benefit of adding ezetimibe was consistent
values remains suboptimal in this very high-risk setting.437 .. across patient subgroups299,444 and also led to a reduction of total
..
.. CV events,445 stroke,446 and rehospitalizations.447 Patients at higher
9.5.1 Lipid-lowering therapy in patients with acute
.. atherothrombotic risk [as assessed by the TIMI (Thrombolysis In
..
coronary syndromes .. Myocardial Infarction) risk score for secondary prevention] benefit-
.. ted the most from the addition of ezetimibe.448 In another random-
LDL-C levels tend to decrease during the first days of ACS and there- ..
fore a lipid profile should be obtained as soon as possible after admis- .. ized, open-label trial including 1734 patients with ACS, the addition
..
sion for ACS. Patients do not have to be fasting as this has little .. of ezetimibe to moderate-intensity statin (pitavastatin 2 mg) therapy
impact on LDL-C levels.100 Lipid-lowering treatment should be initi- .. failed to improve outcomes overall, but did reduce the composite
..
ated as early as possible to increase patient adherence after dis- .. primary endpoint (death, MI, stroke, unstable angina, and ischaemia-
charge. Lipid levels should be re-evaluated 46 weeks after ACS to .. driven revascularization) during 3.9-year follow-up in patients with
..
determine whether treatment goals have been achieved and to check .. increased intestinal absorption of cholesterol (as assessed by ele-
for any safety issues; the therapeutic regimen can then be adapted .. vated levels of sitosterol)449; however, this finding requires further
..
accordingly. .. confirmation.
..
..
9.5.1.1 Statins. Data from RCTs and meta-analyses indicate that rou- .. 9.5.1.3 Proprotein convertase subtilisin/kexin type 9 inhibitors. In the
tine early use of high-intensity statin therapy is associated with rapid .. FOURIER trial, which included 27 564 patients with atherosclerotic
..
and sustained clinical benefits.438442 We recommend the initiation .. CV disease, the addition of evolocumab to statin therapy (69% high-
of high-intensity statin therapy in all statin-naı̈ve ACS patients with no .. intensity therapy) resulted in a 15% relative risk reduction of the
..
contraindication, regardless of initial LDL-C values; the treatment .. composite primary endpoint throughout a 2.2 year follow-up.
goal is to reach a 50% LDL-C reduction from baseline and an LDL-C
.. Results were consistent in the subgroup of patients with a history of
..
goal of <1.4 mmol/L (<55 mg/dL). In those with recurrent events .. MI (81% of all patients).119,450 A subanalysis of the FOURIER trial
within 2 years while taking maximally tolerated statin therapy, a goal
.. showed that patients who achieved the lowest LDL-C values under
..
of <1.0 mmol/L (<40 mg/dL) for LDL-C should be considered. The .. PCSK9 treatment also had the lowest risk of future MACE.451 In the
intensity of statin therapy should be increased in those patients
.. ODYSSEY Outcomes trial, which included 18 924 patients with
..
receiving low- or moderate-intensity statin treatment at presenta- .. recent ACS (112 months prior to enrolment, median 2.6 months),
tion, unless there is a definite history of intolerance to high-intensity
.. alirocumab added to statin therapy (89% high-intensity therapy) also
..
statin therapy. The use of lower-intensity statin therapy should be .. resulted in a 15% relative risk reduction in the primary composite
.. endpoint and was associated with a 15% relative reduction in all-
considered in patients at increased risk of adverse effects with high- ..
intensity statin therapy, such as in the elderly, patients diagnosed with .. cause mortality throughout a 2.8 year follow-up.120 No serious side
..
hepatic or renal impairment, or in the case of a potential risk of .. effects or safety concerns were reported in these two large trials.
drugdrug interactions with other essential concomitant therapies. .. The optimal timing of initiating PCSK9 inhibition after ACS and its
..
Regarding the timing of statin treatment initiation, the Statins .. impact on clinical outcomes remain to be determined. Regarding the
Evaluation in Coronary Procedures and Revascularization (SECURE- .. timing of PCSK9 inhibitor treatment initiation, post hoc analyses from
..
PCI) randomized, placebo-controlled trial recently assessed the .. the FOURIER trial have shown that the closer to the event this is
impact of peri-procedural loading with atorvastatin [two loading .. done, the better. Treatment initiation with PCSK9 inhibitors during
..
doses of 80 mg, before and 24 h after the planned percutaneous cor- .. the acute phase of ACS is under investigation in the EVOlocumab for
onary intervention (PCI)] on MACE at 30 days in 4191 patients with .. Early Reduction of LDL-cholesterol Levels in Patients With Acute
..
ACS and planned invasive management.443 All patients received ator- .. Coronary Syndromes (EVOPACS) trial.452 Based on current evi-
vastatin 40 mg per day starting 24 h after the second loading dose. .. dence, we recommend the initiation of treatment with PCSK9 inhibi-
..
The authors found no significant treatment benefit in the overall .. tors in patients with ACS who do not reach their respective LDL-C
study population. In a pre-specified analysis, a significant 28% relative
.. goals (as outlined in Table 7) after 46 weeks of maximum tolerated
..
risk reduction in MACE was observed among patients who under- .. statin and ezetimibe therapy. In patients who present with an ACS
went PCI (65% of all patients). The benefit was even more
.. and whose LDL-C levels are not at goal, despite already taking a
ESC/EAS Guidelines 47

maximally tolerated statin dose and ezetimibe prior to the event, Recommendations for lipid-lowering therapy in very-
the addition of a PCSK9 inhibitor early after the event (during high-risk patients with acute coronary syndromes
the hospitalization for the ACS event if possible) should be
Recommendations Classa Levelb
considered.
In all ACS patients without any contraindica-
9.5.1.4 n-3 polyunsaturated fatty acids. Oral supplementation with tion or definite history of intolerance, it is rec-
highly purified n-3 PUFAs reduced mortality in survivors of MI in one ommended that high-dose statin therapy is I A

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study [Gruppo Italiano per lo Studio della Sopravvivenza nell’Infarto initiated or continued as early as possible,
Miocardico-Prevenzione (GISSI-P)] but failed to affect clinical out- regardless of initial LDL-C values.438,440,442
comes in subsequent trials using contemporary secondary preven- Lipid levels should be re-evaluated 46 weeks
tion therapies. A recent meta-analysis of available RCTs showed no after ACS to determine whether a reduction
reduction in mortality, MI, or major vascular events associated with of >_50% from baseline and goal levels of LDL-
n-3 PUFAs, including the subgroup of patients with known CAD.453 C <1.4 mmol/L (<55 mg/dL) have been IIa C
Therefore, routine treatment with n-3 PUFAs cannot be achieved. Safety issues need to be assessed at
recommended. this time and statin treatment doses adapted
accordingly.
9.5.1.5 Cholesteryl ester transfer protein inhibitors. In 2007, a large pro- If the LDL-C goal is not achieved after 46
spective study using the CETP inhibitor torcetrapib failed to show weeks with the maximally tolerated statin
any clinical benefit in more than 15 000 high-risk patients, and was I B
dose, combination with ezetimibe is
potentially harmful.336 The CETP inhibitors dalcetrapib (in >30 000 recommended.33
patients with recent ACS65) and evacetrapib (in >12 000 high-risk If the LDL-C goal is not achieved after 46
patients63) were investigated in 2012 and 2017, respectively. Neither weeks despite maximal tolerated statin ther-
clinical study was able to show any clinical benefit associated with I B
apy and ezetimibe, the addition of a PCSK9
CETP inhibitors.65 More recently, the REVEAL study investigated inhibitor is recommended.119,120
anacetrapib in >30 000 patients with atherosclerotic vascular disease
In patients with confirmed statin intolerance
and resulted in a lower incidence of MACE compared with placebo
or in patients in whom a statin is contraindi- IIa C
after 4 years, with no safety concerns.64 However, this compound
cated, ezetimibe should be considered.
was not filed for marketing authorization.
For patients who present with an ACS and
whose LDL-C levels are not at goal, despite
9.5.2 Lipid-lowering therapy in patients undergoing already taking a maximally tolerated statin
percutaneous coronary intervention dose and ezetimibe, the addition of a PCSK9 IIa C
In a meta-analysis of 13 randomized studies including 3341 inhibitor early after the event (during hospital-
patients who were planned to undergo PCI, pre-treatment with a ization for the ACS event if possible) should
high-dose statin (statin-naı̈ve patients, 11 studies) or a high- be considered.
dose statin loading dose reduced the risk of MACE (death, MI, or ACS = acute coronary syndrome; LDL-C = low-density lipoprotein cholesterol;
target vessel revascularization) by 44% both for peri-procedural PCSK9 = proprotein convertase subtilisin/kexin type 9.
a
MI and MACE at 30 days.454 In all but one study, PCI was b
Class of recommendation.
Level of evidence.
performed in the setting of stable angina or in a non-emergency
setting in non-ST elevation ACS (NSTE-ACS). One of the studies
that was included in the meta-analysis showed an improvement in Recommendations for lipid-lowering therapy in very-
high-risk patients undergoing percutaneous coronary
coronary flow when primary PCI was used for the treatment
intervention
of STEMI.455 A routine strategy of either short pre-treatment
or loading (on the background of pre-existing therapy) with a Recommendations Classa Levelb
high-dose statin before PCI should be considered in elective
PCI or NSTE-ACS.454,456,457 Routine pre-treatment or loading (on a back-
In addition, pre-treatment with a statin has also been shown to ground of chronic therapy) with a high-dose
IIa B
reduce the risk of contrast-induced acute kidney injury after coronary statin should be considered in patients under-
angiography or intervention.458 going PCI for an ACS or elective PCI.443,454,456
Recommendations for lipid-lowering therapy in patients with ACS ACS = acute coronary syndrome; PCI = percutaneous coronary intervention.
a
and patients undergoing PCI are summarized below. Class of recommendation.
b
Level of evidence.
48 ESC/EAS Guidelines

..
9.6 Stroke .. hospitalizations,218,471 as well as a small reduction in MI, was
Stroke has a heterogeneous aetiology, including cardiac throm-
.. observed in a pooled analysis of the Controlled Rosuvastatin
..
boembolism [often associated with atrial fibrillation, but also of .. Multinational Trial in Heart Failure (CORONA) and GISSI-HF tri-
.. als.472 Based on current evidence, routine administration of statins in
uncertain source (embolic stroke of undetermined source)], carotid ..
artery and proximal aortic atherosclerosis and thromboembolism, .. patients with HF without other indications for their use (e.g. CAD) is
.. not recommended. Because there is no evidence of harm in patients
small-vessel CVD, and intracranial haemorrhage (including intracere- ..
bral and subarachnoid haemorrhage). Dyslipidaemia may play a varia- .. on statin treatment after the occurrence of HF, there is no need for

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.. statin discontinuation for patients already on treatment.
ble role in the pathogenesis of stroke according to the particular ..
aetiology. The relationship between dyslipidaemia and atherothrom- .. There is no evidence regarding the effect of PCSK9 inhibition in
.. patients with chronic HF. In the recent PCSK9 clinical outcomes tri-
botic events, including ischaemic stroke and TIA, is well recognized, ..
while the association of dyslipidaemia with other types of stroke is .. als, FOURIER119 and ODYSSEY Outcomes,120 PCSK9 inhibition in
.. patients with atherosclerotic CVD or after an ACS did not reduce
uncertain. Notwithstanding, concomitant control of other aetiologi- ..
cal factors, such as hypertension, is of paramount importance. .. the risk of HF hospitalization. In the BIOlogy Study to TAilored
.. Treatment in Chronic Heart Failure (BIOSTAT-CHF) study of 2174
Following ischaemic stroke or TIA, patients are at risk not only of ..
recurrent cerebrovascular events, but also of other major CV events, .. patients with worsening HF, multivariable analysis revealed a positive
.. linear association between PCSK9 levels and the risk of mortality,
including MI. Secondary prevention therapy with statins reduces the ..
risk of recurrent stroke (by 12% per mmol/L reduction in LDL cho- .. and the composite of mortality and unplanned HF hospitalization.473
.. Similarly, there was a negative association between LDLR levels and
lesterol), MI, and vascular death.459,460 Statin pre-treatment at TIA ..
onset was associated with reduced recurrent early stroke risk in
.. mortality, indicating a potential relationship between the
.. PCSK9LDLR axis and outcomes among patients with HF that
patients with carotid stenosis in a pooled data analysis, supporting as- ..
early-as-possible initiation of statins after stroke.460462 Statin ther-
.. requires further investigation.473,474
..
apy may yield a small increase in the risk of haemorrhagic stroke, but .. Treatment with n-3 PUFAs 1 g o.d. may confer a small benefit in
the evidence regarding this risk is uncertain.34,36,251,252
.. patients with chronic HF, as shown by a significant 9% relative risk
..
.. reduction for mortality in the GISSI-HF RCT.475
..
Recommendations for lipid-lowering therapy for the ..
prevention of atherosclerotic cardiovascular disease .. 9.7.3 Valvular heart diseases
events in patients with prior ischaemic stroke .. Aortic stenosis increases the risk of CV events and mortality, and fre-
..
.. quently coexists with atherosclerotic CVD. Life-long high levels of
Recommendations Classa Levelb .. LDL-C476 and Lp(a)477 have been associated with incident aortic
..
Patients with a history of ischaemic stroke or .. valve stenosis and aortic valve calcification in genetic Mendelian ran-
.. domization studies. Observational studies have suggested possible
TIA are at very high-risk of ASCVD, particu- ..
larly recurrent ischaemic stroke, so it is rec- I A .. beneficial effects of intensive lipid lowering in slowing the progression
.. of native valve aortic stenosis.478 However, this has not been con-
ommended that they receive intensive LDL-C- ..
lowering therapy.459,460 .. firmed in RCTs,266,479481 or in meta-analyses of observational and
.. randomized trials.482,483 Three modestly sized trials479481 and one
..
ASCVD = atherosclerotic cardiovascular disease; LDL-C = low-density lipopro- .. large randomized trial (SEAS, which included 1873 patients treated
tein cholesterol; TIA = transient ischaemic attack. .. with simvastatin 40 mg plus ezetimibe 10 mg or placebo)266 failed to
a
Class of recommendation. ..
b
Level of evidence. .. show a reduction in the clinical progression of aortic stenosis in
.. patients with mild-to-moderate native valve aortic stenosis. In a post
..
.. hoc analysis of the SEAS trial, the efficacy of lipid-lowering therapy in
9.7 Heart failure and valvular diseases ..
.. impeding the progression of aortic stenosis increased with higher
9.7.1 Prevention of incident heart failure in coronary .. pre-treatment LDL-C levels and lower peak aortic jet velocity (i.e.
..
artery disease patients .. milder stenosis at baseline).484 Similarly, a post hoc analysis of three
Cholesterol lowering with statins reduces the incidence of HF in .. RCTs, including patients without known aortic valve stenosis at base-
patients with CAD (stable CAD or a history of ACS) without previous
..
.. line [Treating to New Targets (TNT), Incremental Decrease In End-
HF; this has been shown consistently in RCTs that have compared sta- .. points Through Aggressive Lipid-lowering (IDEAL), and Stroke
tin vs. no statin treatment463,464 as well as more-intensive vs. less-
..
.. Prevention by Aggressive Reduction in Cholesterol Levels
intensive statin therapy.465468 A large-scale meta-analysis of primary .. (SPARCL)] showed no impact of high-dose vs. usual-dose statin ther-
..
and secondary prevention RCTs with statins showed a modest (10%) .. apy on the incidence of aortic valve stenosis.485 In patients who
reduction in first non-fatal HF hospitalizations with statin treatment, .. underwent transcatheter aortic valve replacement, statin therapy
..
with no effect on HF death within the limited RCT period.469 There is .. was associated with improved outcomes in a small observational
no evidence that statins can prevent HF of non-ischaemic origin. .. study.486
..
.. Aortic valve sclerosis (calcification of the aortic leaflets without sig-
9.7.2 Chronic heart failure .. nificant transvalvular pressure gradient) is associated with an increased
..
Two large RCTs466,470 (mainly including patients with systolic HF), as .. risk of CAD even in the absence of increased risk profiles. Whether or
well as a meta-analysis of 24 RCTs, have shown no benefit of statin
.. not statins may be useful both for aortic valve disease and CAD pro-
..
treatment on CV mortality or stroke;471 a reduction in HF . gression in such patients warrants further investigation.487
ESC/EAS Guidelines 49

..
Recommendations for lipid-lowering therapy in patients with HF .. whether statin therapy is effective in more advanced CKD, particularly
and valvular diseases are shown below. .. dialysis patients. By combining data from the three CKD trials with
..
.. other trials in the existing database, the CTT investigators found that,
Recommendations for the treatment of dyslipidaemias .. even after adjusting for the smaller LDL-C reductions achieved among
in chronic heart failure or valvular heart diseases ..
.. patients with more advanced CKD and for differences in outcome defi-
.. nitions between dialysis trials, there was a trend towards smaller relative
Recommendations Classa Levelb ..
.. reductions per mmol/L reduction in LDL-C in major atherosclerotic

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Initiation of lipid-lowering therapy is not rec- .. events as estimated GFR (eGFR) declines (with little evidence of benefit
..
ommended in patients with HF in the absence III A .. among dialysis patients).214 This diminution in relative risk reduction as
of other indications for their use.466,470
.. GFR declines implies that, at least in non-dialysis patients, more intensive
..
Initiation of lipid-lowering treatment in .. LDL-lowering regimens are required to achieve the same benefit.
..
patients with aortic valvular stenosis without ..
CAD to slow progression of aortic valve III A .. 9.8.3 Safety of lipid management in patients with chronic
.. kidney disease
stenosis in the absence of other indications for ..
their use is not recommended.266,479481 .. Safety issues and dose adjustments are important in advanced stages
..
CAD = coronary artery disease; HF = heart failure.
.. of CKD (stages 35), as adverse events are commonly dose-related
a
Class of recommendation.
.. and due to increased blood concentrations of compounds. Although
b
..
Level of evidence. .. it has been suggested that preference should be given to regimens
.. and doses that have been shown to be beneficial in RCTs conducted
..
.. specifically in such patients,494 the CTT meta-analysis makes clear
9.8 Chronic kidney disease .. that the goal—as in patients without CKD—should be to achieve the
CKD is defined as abnormalities of kidney structure or function, present
..
.. largest possible absolute reduction in LDL-C safely. Although there
for >3 months, with implications for health. CKD is classified on the .. were no specific safety concerns raised by the 4D, AURORA, or
basis of the cause, GFR category, and category of albuminuria.488 In the
..
.. SHARP trials, statins metabolized via CYP3A4 may result in adverse
adult population, decreasing GFR is associated with increased CVD risk, .. effects due to drugdrug interactions and caution is required.
independent of other CV risk factors.489492 There is an increased risk
..
.. Based on the evidence for lipid management in patients with CKD,
of both atherosclerotic vascular disease and structural heart disease.492 .. the Kidney Disease: Improving Global Outcomes (KDIGO) organiza-
Patients with CKD and established CVD have a much higher mortality
..
.. tion has developed an updated clinical practice guideline for lipid
rate compared with patients with CVD and normal renal function.493 .. management in CKD.494 In line with this, but with a focus on those
..
Therefore, patients with CKD are considered to be at high (stage 3 .. patients at high or very-high risk for developing CVD, recommenda-
CKD) or very-high risk (stage 45 CKD or on dialysis) of CVD, and .. tions are summarized below.
there is no need to use risk estimation models in these patients.

Recommendations for lipid management in patients


9.8.1 Lipoprotein profile in chronic kidney disease
with moderate-to-severe (Kidney Disease Outcomes
In the initial stages of CKD, TG levels are specifically elevated and Quality Initiative stages 35) chronic kidney disease
HDL-C levels are lowered. LDL subclasses display a shift to an excess
of small dense LDL particles. Studies suggest that the kidney has a Recommendations Classa Levelb
role in Lp(a) catabolism and that Lp(a) levels are increased in associa-
It is recommended that patients with Kidney
tion with kidney disease. Such acquired abnormalities can be reversed
Disease Outcomes Quality Initiative stage 35c
by kidney transplantation or remission of nephrosis. I A
CKD are considered to be at high or very-high risk
of ASCVD.489493
9.8.2 Evidence for risk reduction through statin-based
The use of statins or statin/ezetimibe combina-
therapy in patients with chronic kidney disease
tion is recommended in patients with non-dialy- I A
In the Die Deutsche Diabetes Dialyse Studie (4D) trial, which involved
sis-dependent stage 35 CKD.214,222,495,496
1200 patients with diabetes on haemodialysis, atorvastatin had no sig-
In patients already on statins, ezetimibe, or a sta-
nificant effect on risk of CVD.220 Similar results were obtained in the
tin/ezetimibe combination at the time of dialysis
AURORA (A study to evaluate the Use of Rosuvastatin in subjects IIa C
initiation, continuation of these drugs should be
On Regular haemodialysis: an Assessment of survival and cardiovascu-
considered, particularly in patients with ASCVD.
lar events) trial, which involved 2776 patients on haemodialysis.221
In the SHARP study,222 simvastatin and ezetimibe combination ther- In patients with dialysis-dependent CKD who
apy reduced the risk for major atherosclerotic events (coronary death, are free of ASCVD, commencement of statin III A
MI, non-haemorrhagic stroke, or any revascularization) compared with therapy is not recommended.220,221
placebo in persons with CKD stage 3A5. The trial did not have suffi- ASCVD = atherosclerotic cardiovascular disease; CKD = chronic kidney disease;
cient power to separately assess the effects on the primary outcome in eGFR = estimated glomerular filtration rate.
a
Class of recommendation.
dialysis and non-dialysis patients. Although statin-based therapy is clearly b
Level of evidence.
effective in mild-to-moderate CKD, a major controversy that remained c
Defined as eGFR < 60ml/min/1.73m2 on two measurements more than 3 months
after the publication of the 4D, AURORA, and SHARP studies was apart.
50 ESC/EAS Guidelines

9.9 Transplantation Recommendations for low-density lipoprotein lowering


in solid organ transplant patients
Dyslipidaemias are very common in patients who have undergone
heart, lung, liver, kidney, or allogenic haematopoietic stem cell trans- Recommendations Classa Levelb
plantation, and predispose such patients to an increased risk of devel-
oping ASCVD and transplant arterial vasculopathy.497501 In patients Statins should be considered as first-line agents in
with CKD undergoing renal transplantation, the risk of ASCVD may transplant patients. Initiation should be at low
be determined, at least in part, by the increased risk resulting from doses with careful uptitration and with caution IIa B

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CKD itself. regarding potential drugdrug interactions, partic-
Immunosuppressive drug regimens may have adverse effects on ularly for patients on ciclosporin.507
lipid metabolism leading to increases in TC, VLDL, and TGs, and in In patients who are intolerant of statins or those
the size and density of LDL particles. These effects vary with different with significant dyslipidaemia despite maximally
IIb C
immunosuppressive drugs.497,498,502506 tolerated statin treatment, alternative or addi-
The management of dyslipidaemias in transplant recipients is com- tional therapy with ezetimibe may be considered.
parable to what is recommended for patients at high or very high a
Class of recommendation.
ASCVD risk, although more attention is needed regarding the causes b
Level of evidence.
of the lipid disturbances and possible side effects due to drugdrug
interactions (see Recommendations for low-density lipoprotein in solid ..
.. 9.10 Peripheral arterial disease
organ transplant patients below). .. PAD encompasses all vascular sites, including carotid, vertebral, upper
The clinical effectiveness of statins in renal transplant patients ..
.. extremity, mesenteric, renal, and lower extremity arteries. The aorta
is uncertain owing to a lack of randomized trials in this population. .. is often included in the term.510 PAD is a common manifestation of
A systematic review of the benefits and harms of statins in ..
.. atherosclerosis and such patients are at elevated risk of coronary
patients with a functioning kidney transplant included 3465 .. events, with PAD representing an independent risk factor for MI and
patients, free of CHD, from 22 studies. Although the authors con- ..
.. CV death.510,511 Patients with PAD are at very-high risk and should be
cluded that statins may reduce CV events, they also suggested a ..
need for additional studies.253 However, in patients with a function- .. managed according to the recommendations in Table 7. Elevated CV
.. risk has led to the inclusion of PAD among the list of ‘risk equivalent’
ing renal transplant at increased risk of CVD, it may be appropriate ..
to extrapolate from the clear evidence of benefit from statin ther-
.. conditions, and therapeutic strategies of secondary prevention should
.. be implemented [see Recommendations for lipid-lowering drugs in patients
apy, without safety concerns, in people with moderate reductions ..
in GFR.214
.. with peripheral arterial disease (including carotid artery disease) below].
.. Yet, despite the high CV morbidity and mortality risk, PAD patients
Several potential drug interactions must also be considered, espe- ..
cially with ciclosporin, which is metabolized through CYP3A4, and
.. are usually inadequately managed compared with CAD patients.511
..
may increase systemic statin exposure and the risk of myopathy. ... 9.10.1 Lower extremity arterial disease
Ciclosporin increases the blood levels of all statins. .. A low ABI (0.90) is diagnostic for lower extremity arterial disease
Fluvastatin, pravastatin, pitavastatin, and rosuvastatin are metabo-
..
.. (LEAD). Either a low (0.90) or high (1.40, related to stiffened arteries)
lized through different CYP enzymes than the others and have less .. ABI is predictive of CV morbidity and mortality. Lowering LDL-C lev-
..
potential for interaction.507 .. els reduces the risk of ischaemic CV events and worsening of claudi-
Tacrolimus is also metabolized by CYP3A4, but appears to have .. cation, while it also improves walking performance. As for cardiac
..
less potential for harmful interaction with statins than ciclosporin. .. events, a systematic review of 18 trials including 10 000 patients, with
Other drugs that influence CYP3A4 activity should be avoided if pos- ..
.. cholesterol levels ranging from normal to elevated, reported that
sible, and used with extreme caution in patients receiving both calci- .. lipid-lowering therapy in people affected by atherosclerosis of the
neurin inhibitors and statins. ..
.. lower limbs was associated with a 20% reduction in total CV events,
For transplant patients with dyslipidaemia, ezetimibe could be con- .. together with a non-significant 14% reduction of all-cause mortal-
sidered as an alternative for patients unable to take a statin or added ..
.. ity.512 In the Heart Protection Study, the need for non-coronary
to the highest tolerated statin dose.507509 No outcome data are .. revascularization was reduced by 16% with statin therapy.513
available for this drug, which should generally be reserved for ..
.. In addition to statins, PSCK9 inhibitors have also been shown to
second-line use. Ciclosporin can induce a 212-fold increase in the .. reduce CV events in PAD patients. In a pre-specified subgroup analy-
ezetimibe level. ..
.. sis of the FOURIER trial, evolocumab significantly reduced the pri-
Care is required with the use of fibrates, as they can decrease .. mary endpoint in patients with PAD.514 PAD had larger absolute risk
ciclosporin levels and have the potential to cause myopathy. ..
.. reductions for the primary endpoint (3.5% with PAD and 1.6% with-
Extreme caution is required if fibrate therapy is planned in combi- .. out PAD). Evolocumab also reduced the risk of major adverse limb
nation with a statin. Cholestyramine is not effective as monother-
..
.. events by 42% in patients, with consistent effects in those with and
apy in heart transplant patients and has the potential to reduce .. without known PAD. In the FIELD trial, fenofibrate reduced the risk
absorption of immunosuppressants; this potential is minimized by
..
.. of amputations, particularly minor amputations without known large-
separate administration. .. vessel disease, probably through non-lipid mechanisms.515
ESC/EAS Guidelines 51

..
9.10.2 Carotid artery disease .. 9.11 Other special populations at risk of
While there are currently no randomized studies that have assessed ..
.. atherosclerotic cardiovascular disease
whether lipid-lowering treatments reduce the incidence of CV events .. In general, the effects of lowering LDL-C are determined by the abso-
in patients enrolled on the basis of carotid atherosclerotic disease ..
.. lute risk of ASCVD and the achieved reduction in LDL-C, so it is
and without previous CV events, lipid-lowering therapy had .. important to identify and treat all those at increased risk of ASCVD.
reduced stroke in numerous studies. In a meta-analysis of RCTs ..
.. There are a few specific groups of patients in whom an underlying dis-
enrolling >90 000 patients, statin therapy did lead to a 21% reduction .. ease confers such increased risk, and in addition in whom the stand-

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in the incidence of all strokes in different populations; this effect was ..
.. ard treatments may themselves cause dyslipidaemia that may
mainly driven by the extent of LDL-C reduction.460 .. contribute to the risk of ASCVD. These include: (i) chronic immune-
..
.. mediated inflammatory disease, (ii) patients with human immunodefi-
9.10.3 Retinal vascular disease
.. ciency virus (HIV), and (iii) patients with severe mental illness. The
..
Atherosclerotic changes of retinal arteries correlate with TC, LDL-C, .. management principles are the same in these patient groups, but their
TG, and apoB levels and also with CAD.516 Fenofibrate reduces the
.. management may need to address specific issues related to individual
..
progression of diabetic retinopathy.517,518 .. dyslipidaemias and drug safety. Details are provided in the
..
.. Supplementary Data document.
..
9.10.4 Secondary prevention in patients with abdominal ..
aortic aneurysm ..
.. 10 Inflammation
The presence of an abdominal aortic aneurysm represents a risk- ..
equivalent condition for CAD and is associated with age, male gender, ..
.. Recent advances in basic science have established a fundamental role
personal history of atherosclerotic CVD, smoking, hypertension, and .. for low-degree chronic inflammation in mediating all stages of athero-
dyslipidaemia;519 in contrast, diabetic patients are at decreased risk. ..
.. sclerosis, from initiation through progression and, ultimately, to the
There are currently no available clinical trials on the reduction of CV .. rupture of plaque and ensuing thrombotic complications of atheroscle-
risk with lipid-lowering therapy in patients affected by this condition. ..
.. rosis. The cellular and molecular interactions involved during athero-
Systematic reviews,520 mostly based on retrospective non-randomized .. genesis are fundamentally not different from those in chronic
studies, have reported that there is still inconclusive evidence that sta- ..
.. inflammatoryfibroproliferative diseases, such as rheumatoid arthritis
tin therapy reduces peri-operative CV morbidity and mortality. In an .. (RA), glomerulosclerosis, or pulmonary fibrosis.525 Almost all cell types
RCT comparing atorvastatin 20 mg with placebo, the composite end-
..
.. of the immuno-inflammatory system, such as macrophages, and T- and
point of cardiac death, MI, stroke, and unstable angina was significantly .. B-cells, as well as many pro- and anti-inflammatory cytokines and che-
reduced in 100 patients undergoing vascular non-cardiac surgery,
..
.. mokines, have been identified during the process of atherosclerosis.526
including abdominal aortic aneurysm repair.521 In another double-blind, .. Interestingly, cholesterol accumulation in cells triggers the inflam-
placebo-controlled trial in 497 patients undergoing vascular surgery,
..
.. masome response and results in the production of inflammatory
peri-operative fluvastatin therapy (80 mg/day) was associated with an .. mediators such as interleukin (IL)-1b. Numerous animal studies, using
improvement in post-operative cardiac outcome.522
..
.. the knockout model, have demonstrated that inflammation and the
.. immune system both play crucial roles during atherogenesis.527
..
9.10.5 Renovascular atherosclerosis .. During inflammatory processes, large numbers of acute-phase
.. proteins have been identified, and several clinical studies have
Lipid-lowering therapy has never been tested in an RCT in patients ..
affected by renovascular atherosclerosis; however, a recent non- .. reported C-reactive protein528 to be the most useful serum marker
.. of inflammation, even though it has poor specificity for any particular
randomized population-based study showed that in patients older ..
than 65 years of age with atherosclerotic renovascular disease raised .. inflammation process, including atherosclerosis. The high-sensitivity
..
the hypothesis that such treatment may yield cardiorenal benefits; .. C-reactive protein diagnostic test was developed to detect very low
the risk of a major cardiorenal composite endpoint (MI, stroke, HF, .. levels of C-reactive protein, and thereby enable a more accurate and
..
acute renal failure, dialysis, and death) was significantly lower in statin .. precise measure of chronic inflammation compared with standard C-
users than in non-users.523 .. reactive protein.529 This diagnostic tool differs only in the range of C-
..
.. reactive protein levels that it can detect. Several studies have found
Recommendations for lipid-lowering drugs in patients .. that elevated levels of high-sensitivity C-reactive protein in the blood
with peripheral arterial disease (including carotid artery ..
disease) .. are associated with an increased risk of CV events and could be used
.. to predict clinical outcomes independently of cholesterol lev-
..
Recommendations Classa Levelb .. els.530,531 Other studies have not been able to show any relationship
.. between low-grade chronic inflammation, as indicated by high-sensi-
In patients with PAD, lipid-lowering therapy, ..
.. tivity C-reactive protein levels, and increased risk of CV.532535
including a maximum tolerated dose of statin, .. Finally, genetic studies of large population cohorts have not demon-
plus ezetimibe or a combination with a PCSK9 I A ..
.. strated that chronic elevated high-sensitivity C-reactive protein
inhibitor if needed, is recommended to reduce .. increases the risk of atherosclerotic events.536 Nevertheless, in some
the risk of ASCVD events.512,524
..
.. guidelines, high-sensitivity C-reactive protein has been added to tradi-
.. tional risk factors for prognostic information, especially for patients
ASCVD = atherosclerotic cardiovascular disease; PAD = peripheral arterial dis- ..
ease; PCSK9 = proprotein convertase subtilisin/kexin type 9.
a
. at intermediate risk.537,538
Class of recommendation.
b
Level of evidence.
52 ESC/EAS Guidelines

..
Statins have been shown to reduce C-reactive protein secretion .. applies to tests of possible toxicity, such as ALT and CK.
by hepatocytes,539 and a series of clinical trials and post hoc analyses .. Recommendations stem from consensus rather than evidence-based
..
have found that beneficial outcomes after statin therapy relate both .. medicine.
to a reduction in cholesterol levels and reduced inflammation.540544 .. Response to therapy can be assessed at 68 weeks from initiation
..
The Justification for the Use of Statins in Prevention: an Intervention .. of therapy, but response to lifestyle may take longer. Standard prac-
Trial Evaluating Rosuvastatin (JUPITER) trial542 demonstrated that in .. tice for subsequent follow-up monitoring is 612 months, but such
..
primary prevention for individuals with chronically elevated C-reac- .. monitoring intervals are arbitrary. As a minimum, LDL-C should be

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tive protein (>2 mg/L), statin treatment markedly reduced CV .. assessed whenever available, but better management decisions will
..
events.545 It is of note that other lipid-lowering agents, such as ezeti- .. probably occur if a full lipid profile is performed, including HDL-C
mibe and more recently the anti-PCSK9 mAbs, do not influence high- .. and TGs. Non-HDL-C or ApoB should also be analysed, and used as
..
sensitivity C-reactive protein levels,546,547 but lead to further signifi- .. a secondary treatment target. A separate issue is the impact of regu-
cant reductions in CV events when added to statin therapy. .. lar lipid monitoring in promoting patient adherence to lifestyle
..
Specific anti-inflammatory treatment was tested in the .. changes or drug regimens that impact positively on their health, as
Canakinumab Antiinflammatory Thrombosis Outcome Study .. found in a range of studies. It is unclear whether only the process of
..
(CANTOS) trial.548 In patients with previous MI and chronic elevated .. monitoring is critical in achieving this or whether a combination of
high-sensitivity C-reactive protein levels, all on optimal medical treat-
.. education, regular contact, and adherence assessment is required.
..
ment, including statins, the anti-IL-1b mAb canakinumab dose- .. Where pharmacological lipid-lowering therapy is implemented,
dependently reduced high-sensitivity C-reactive protein and signifi-
.. safety blood tests are advised, including ALT and CK at baseline, to
..
cantly lowered the rate of recurrent CV events compared with pla- .. identify the limited number of patients where treatment is contraindi-
cebo, independently of the level of lipid lowering. Not surprisingly,
.. cated. CK should be checked in patients at high-risk for myopathy,
..
there was a slight increase in the risk of severe and fatal infections asso- .. such as the very elderly with comorbidities, patients with antecedents
..
ciated with canakinumab. This study was the first to highlight the posi- .. of muscle symptoms, or patients receiving interacting drugs. A mild
tive correlation between high-sensitivity C-reactive protein and CV .. and typically transient elevation of ALT is seen in about 2% of patients
..
events, where lower achieved high-sensitivity C-reactive protein values .. and normalization is seen with continuing therapy.240,244,552 Recent
were directly correlated with a lower risk of future CV events.548 .. reviews are encouraging regarding the safety of long-term statin ther-
..
Nevertheless, the FDA declined to approve canakinumab for CV risk .. apy and statin-induced liver injury is reported to be very
reduction on the strength of data from the CANTOS study. As canaki- .. uncommon.243,244,553555 ALT is recommended before the start of
..
numab treatment has not been tested against anti-PCSK9 mAb and/or .. statin therapy; routine control of ALT during treatment is not recom-
ezetimibe added to statin therapy, the question of residual risk remains .. mended but should be performed, if indicated, based on clinical
..
for patients with elevated high-sensitivity C-reactive protein despite .. observations. During fibrate therapy, regular ALT control is still rec-
achieving very low (below goal) LDL-C values, and whether patients .. ommended. In patients whose liver function tests increase to above
..
with very low LDL-C would benefit from anti-IL-1b treatment or .. three times the ULN, explanations such as alcohol ingestion or
other anti-inflammatory agents. In addition, all currently recommended .. NAFLD should be sought, and the levels monitored. If levels remain
..
lipid-lowering drugs, including anti-PCSK9 mAbs, have demonstrated .. elevated then lipid-lowering therapy should be stopped, but may be
beneficial effects on atherosclerotic plaque composition as well as pla- .. cautiously reintroduced under monitoring after levels have returned
..
que volume regression; such results are still missing for anti- .. to normal.
inflammatory treatment. Another anti-inflammatory approach using
.. There is no predictive value of routine repeat CK testing for rhab-
..
methotrexate was tested in the Cardiovascular Inflammation .. domyolysis since the level can increase for many reasons, including
Reduction Trial (CIRT).549 Very low-dose methotrexate (10 mg
.. muscle injury or excess muscular exercise. However, CK must be
..
weekly), a proven anti-inflammatory regimen that reduces tumour .. assessed immediately in patients who present with muscle pain and
necrosis factor (TNF), IL-6, and C-reactive protein levels and is widely
.. weakness, and especially in the elderly, and treatment stopped if CK
..
used in the treatment of RA, was allocated vs. placebo to 7000 stable .. rises to >10 times the ULN. Strategies to handle CK elevations are
CAD patients. This study was stopped prematurely due to futility.
.. given in Table 13.
..
Interestingly, this regimen of methotrexate had no effect on either IL-6 .. Due to the increased frequency of DM during statin treat-
..
or high-sensitivity C-reactive protein blood levels in this population, .. ment,247,249,556,557 regular checks of HbA1c should be considered in
which could explain the neutral results of this trial.550 Based on the cur- .. patients at high-risk of developing DM and under high-dose statin
..
rent level of evidence, no further recommendations on the use of anti- .. treatment. Groups to be considered for glucose control are the eld-
inflammatory agents can be made.551 .. erly or those with MetS, obesity, or signs of insulin resistance.
..
..
..
..
11 Monitoring of lipids and .. 12 Cost-effectiveness of
..
..
enzymes in patients on .. cardiovascular disease prevention
..
lipid-lowering therapy .. by lipid modification
..
Evidence concerning which tests should be carried out to monitor
.. In 2015, there were >85 million people in Europe living with CVD.558
..
lipids in patients on treatment is limited. Similar limited evidence . Aging populations,559 unhealthy diets, smoking, sedentary lifestyles,
ESC/EAS Guidelines 53

Table 13 Summary of recommendations for monitoring lipids and enzymes in patients, before and on lipid-lowering
therapy

Testing lipids
How often should lipids be tested?
•Before starting lipid-lowering drug treatment, at least two measurements should be made, with an interval of 112 weeks, with the exception of condi-
tions where prompt drug treatment is suggested, such as ACS and very high-risk patients.

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How often should a patient’s lipids be tested after starting lipid-lowering treatment?
• After starting treatment: 8 (±4) weeks.
• After adjustment of treatment: 8 (±4) weeks until the goal is achieved.
How often should lipids be tested once a patient has achieved the target or optimal lipid level?
• Annually (unless there are adherence problems or other specific reasons for more frequent reviews).
Monitoring liver and muscle enzymes
How often should liver enzymes (ALT) be routinely measured in patients on lipid-lowering drugs?
• Before treatment.
• Once, 812 weeks after starting a drug treatment or after dose increase.
• Routine control of ALT thereafter is not recommended during statin treatment, unless symptoms suggesting liver disease evolve. During treatment with
fibrates, control of ALT is still recommended.
What if liver enzymes become elevated in a person taking lipid-lowering drugs?
If ALT <3 ULN:
• Continue therapy.
• Recheck liver enzymes in 46 weeks.
If ALT rises to >_3 ULN
• Stop lipid-lowering therapy or reduce dose and recheck liver enzymes within 46 weeks.
• Cautious reintroduction of therapy may be considered after ALT has returned to normal.
• If ALT remains elevated check for the other reasons.
How often should CK be measured in patients taking lipid-lowering drugs?
Pre-treatment
• Before starting therapy.
• If baseline CK is >4 ULN, do not start drug therapy; recheck.
Monitoring:
• Routine monitoring of CK is not necessary.
• Check CK if patient develops myalgia.
Be alert regarding myopathy and CK elevation in patients at risk, such as: elderly patients, those on concomitant interfering therapy, multiple medications,
liver or renal disease, or athletes.
What if CK becomes elevated in a person taking lipid-lowering drugs?
Re-evaluate indication for statin treatment.
If >_4 ULN:
• If CK >10 ULN: stop treatment, check renal function, and monitor CK every 2 weeks.
• If CK <10 ULN: if no symptoms, continue lipid-lowering therapy while monitoring CK between 2 and 6 weeks.
• If CK <10 ULN: if symptoms present, stop statin and monitor normalization of CK, before rechallenge with a lower statin dose.
• Consider the possibility of transient CK elevation for other reasons such as exertion.
• Consider myopathy if CK remains elevated.
• Consider combination therapy or an alternative drug.
If <4 ULN:
• If no muscle symptoms, continue statin (patient should be alerted to report symptoms; check CK).
• If muscle symptoms, monitor symptoms and CK regularly.
• If symptoms persist, stop statin and re-evaluate symptoms after 6 weeks; re-evaluate indication for statin treatment.
• Consider rechallenge with the same or another statin.
• Consider low-dose statin, alternate day or once/twice weekly dosing regimen, or combination therapy.
For details on CK elevation and treatment of muscular symptoms during statin treatment see algorithm in Supplementary Figure 4.
In which patients should HbA1c or blood glucose be checked?
• Regular checks of HbA1c or glucose should be considered in patients at high-risk of developing diabetes, and on high-dose statin treatment.
• Groups to be considered for glucose control are the elderly and patients with metabolic syndrome, obesity, or other signs of insulin resistance.

ACS = acute coronary syndrome; ALT = alanine aminotransferase; CK = creatine kinase; ULN = upper limit of normal.
54 ESC/EAS Guidelines

..
increasing obesity, and diabetes560563 are the main contributors. .. in CV risk factors, primarily reductions in plasma cholesterol, BP
CVD cost the European Union about e210 billion in 2015, one-half .. levels, and smoking.560563,567 Lifestyle changes at the population
..
of which was in healthcare costs (8% of total healthcare expendi- .. level may be more cost-effective than lifestyle and drug interven-
ture), and the other half in productivity losses and informal care.558 .. tions at the individual level, particularly when targeted to popula-
..
In these Guidelines, the Joint Task Force recommends a range of .. tions at increased risk. Awareness and knowledge of how lifestyle
actions to reduce CVD by targeting plasma lipids, ranging from .. risk factors lead to CVD has increased in recent decades.
..
population-wide initiatives to promote healthy lifestyles to individual- .. Moreover, legislation promoting a healthy lifestyle, such as

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level interventions to reduce CVD risk factors, such as unhealthy
.. reduced salt intake and smoking bans, has been reported to be
..
diets and high lipid levels. Cost-effectiveness analysis can help target .. cost-effective in preventing CVD,568573 and initiatives to
resources for interventions where the net health gain is greatest in
.. improve infrastructure and promote physical activity have shown
..
relation to the net resources, and is increasingly required across .. promise.574,575 A number of structural strategies at international,
Europe.564 However, cost-effectiveness depends on available resour-
.. national, and regional levels combined can substantially reduce
..
ces, the costs of services, and disease risk in the population, and .. CVD morbidity and mortality.576,577 Individual-level interventions
results obtained in one country might not be valid in another.565 In
.. to improve diet,578,579 increase physical activity,580 and
..
addition, to fully capture the long-term effects of interventions, cost- .. stop smoking581 could also be cost-effective.582 However, subop-
..
effectiveness studies combining evidence from RCTs with modelling .. timal adherence limits benefits,583,584 and interventions to
and limitations in both could affect the reliability of findings. Here, the .. improve adherence, such as electronic device reminders to rein-
..
evidence for the cost-effectiveness of ASCVD preventive interven- .. force favourable health behaviours, are increasingly being
tions with respect to lipid modification is summarized; further scru- .. investigated.585
..
tiny in view of local circumstances is recommended. .. All statin regimens and ezetimibe are now generically available
The health impact pyramid summarizes the evidence on the rela- .. across Europe. There is strong evidence that lowering blood choles-
..
tive effort in relation to health impact (Figure 5), with interventions .. terol levels using low-cost statins is widely cost-effective586590 in
with the broadest impact on populations at the base and interven- .. many categories of patients. For secondary prevention of CVD, the
..
tions requiring considerable individual effort at the top.566 There is .. evidence suggests that statin treatments are highly cost-effec-
consensus that all the levels of the pyramid should be targeted but .. tive,586,590,591 and adding low-cost ezetimibe to high-intensity statin
..
that emphasis should be placed on the lower levels. This would .. therapy further reduces LDL-C and CVD risk cost-effectively.592 In
address the persistent socio-economic divide in CV health despite .. primary ASCVD prevention, the evidence indicates that generic
..
major improvements in ASCVD treatment.558 .. statin-based treatments are cost-effective for people at least down to
More than one-half of the reduction in CV mortality over the .. 1% annual total CVD risk and could be cost-effective at even lower
..
last three decades has been attributed to population-level changes .. risk,589 with the highest tolerated statin dose likely the most cost-
.. effective.591,593,594 Importantly, many patients on statin treatment fail
..
.. to take their medications adequately and/or to reach their therapeu-
Increasing Increasing .. tic goals,595 with clinical and economic consequences.596,597
population individual
..
.. Reinforcing measures aimed at improving adherence to treatment is
impact effort needed .. cost-effective.598600
..
Counseling .. Studies have shown that at mid-2018 prices PCSK9 inhibitors
and education .. were largely not cost-effective.601604 Their cost-effectiveness is
..
.. improved in selected high-risk patients, such as those with clinical
Clinical ..
interventions .. CVD or FH, other comorbidities, and high LDL-C levels.605,606
.. However, at lower prices, PCSK9 inhibitors would become cost-
..
Long-lasting protective .. effective in a wider range of high-risk patients; recent price reductions
interventions .. may therefore lead to increased use.607 Cost-effectiveness evidence
..
.. for other lipid-modifying therapies is lacking.
Changing the context to make .. Effective interventions to prevent ASCVD, including statins, typi-
individuals' default decisions healthy ..
.. cally exhibit similar relative risk reductions across categories of
.. patients, including by ASCVD risk; therefore, health benefits and
©ESC 2019

Socioeconomic factors ..
.. cost-effectiveness are greater among people at higher ASCVD risk
.. (Figure 6).36,233 Consequently, increased efforts and higher-intensity
..
.. interventions should be aimed at individuals and populations at higher
.. ASCVD risk.
Figure 5 Health impact pyramid.
..
..
ESC/EAS Guidelines 55

per 10,000 patients treated for 5 years


1,600 1440

Major vascular events avoided


1,400 1130
1,200

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730 1010
1,000 800
800 540
680
600 540
370 ≥30%
400
≥20%, <30%
200 170 250 310 5 year risk
≥10%, <20% of major
0
vascular event
1 ≥5%, <10%
1.5
2

©ESC 2019
LDL cholesterol reduction (mmol/L)
with statin treatment

Figure 6 Absolute reductions in major vascular events with statin therapy.233 LDL = low-density lipoprotein. Reproduced from The Lancet, 388/10059,
Collins et al., ‘Interpretation of the evidence for the efficacy and safety of statin therapy’, 2532-2561, 2016, with permission from Elsevier.

Box 8 lists the key messages regarding the cost-effectiveness of


CVD prevention by lipid modification, and Box 9 highlights gaps in the
evidence.

Box 8 Key messages

Prevention of CVD by lifestyle changes, medication, or both is cost-effective in many scenarios, including population-based approaches and actions directed
at individuals at increased CVD risk.
Cost-effectiveness depends on several factors, including baseline CVD risk and LDL levels, cost of treatment, and uptake of preventive strategies.
Interventions to prevent CVD are more cost-effective among individuals and populations at higher CVD risk.
Cost-effectiveness analyses are importantly informed by assumptions about long-term disease prognosis and treatment effects. Strengthening of the evidence
to inform these assumptions is encouraged.
CVD = cardiovascular disease; LDL = low-density lipoprotein.

Box 9 Gaps in the evidence

Cost-effectiveness requires evidence for effects of interventions on health and healthcare over a long time period; modelling techniques fill gaps. More data
are needed from RCTs and observational studies.
Direct evidence of effects of lipid-modifying treatments on overall mortality, particularly among people at low-to-moderate CVD risk, older people, and for
newer interventions, is lacking. Long-term post-trial follow-up in RCTs should be encouraged.
The cost-effectiveness of using lifetime CVD risk and more precise CVD risk scores to target interventions needs further investigation.
CVD = cardiovascular disease; RCT = randomized controlled trial.
56 ESC/EAS Guidelines

..
13 Strategies to encourage ..
..
(3) Use of cardiac imaging for risk stratification. CAC score
assessment with CT may be helpful in reaching decisions about
adoption of healthy lifestyle ..
.. treatment in people who are at moderate risk of ASCVD.
changes and adherence to lipid- .. Obtaining such a score may assist in discussions about treatment
..
modifying therapies .. strategies in patients where the LDL-C goal is not achieved with
.. lifestyle intervention alone and there is a question of whether to
..
Helping patients to change to healthier lifestyle habits is most effec- .. institute LDL-C-lowering treatment. Assessment of arterial (caro-

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tively achieved through formal programmes of preventive care, possi-
.. tid or femoral) plaque burden on ultrasonography may also be
..
bly because of the intensive follow-up and multidisciplinary expertise .. informative in these circumstances.
they provide.608 However, in everyday care, adherence to both
.. (4) Use of ApoB in risk stratification. ApoB may be a better
..
healthy lifestyle changes and medication regimens is a challenge to .. measure of an individual’s exposure to pro atherogenic lipopro-
.. teins, and hence its use may be particularly helpful for risk assess-
patients and professionals. ..
A comprehensive patient- and family-centred approach located in .. ment in people where measurement of LDL-C underestimates
.. this burden, such as those with high TG, DM, obesity, or very low
one healthcare setting is recommended rather than addressing single ..
risk factors with more than one intervention in different locations. .. LDL-C.
.. (5) Use of Lp(a) in risk stratification. A one-off measurement of
Box 10 includes some useful techniques when counselling patients for ..
behavioural change. .. Lp(a) may help to identify people with very high inherited Lp(a)
.. levels who may have a substantial lifetime risk of ASCVD. A high
..
Box 10 Methods for enhancing adherence to lifestyle .. Lp(a) plasma level may also be helpful in further risk stratification
.. of patients at high risk of ASCVD, in patients with a family history
changes ..
.. of premature CVD, and to determine treatment strategies in peo-
1. Explore motivation and identify ambivalence. Weigh pros and cons for .. ple whose estimated risk is on the border of risk categories.
change, assess and build self-efficacy and confidence, and avoid circular
..
.. (6) Intensification of treatment goals. It is important to ensure
discussion. ..
.. that treatment of the highest-risk patients achieves the largest
2. Offer support, and establish an alliance with the patient and his/her .. LDL-C reduction possible. These Guidelines aim to support this
family. ..
.. by setting both a minimum percentage LDL-C reduction (50%)
3. Involve the partner, other household members, or caregiver who may .. and an absolute LDL-C treatment goal of <1.4 mmol/L (<55 mg/
be influential in the lifestyle of the patient.
..
.. dL) for very-high-risk patients, and <1.8 mmol/L (<70 mg/dL) for
4. Use the OARS method (Open-ended questions, Affirmation, .. high-risk patients. It is recommended that FH patients with
..
Reflective listening, Summarising when discussing behaviour changes .. ASCVD or who have another major risk factor are treated as
(www.smartrecovery.org/wp-content/uploads/2017/03/UsingMIinSR.pdf). .. very-high-risk, and those with no prior ASCVD or other risk fac-
..
5. Tailor advice to an individual patient’s culture, habits, and situation. .. tors as high-risk.
6. Use SMART goal setting (negotiate goals for change that are Specific,
.. (7) Treatment of patients with recent ACS. New randomized
..
Measurable, Achievable, Realistic, and Timely). Follow-up on goals and .. trials support a strategy of intensification of LDL-C-lowering ther-
record progress on a shared record.
.. apy in very-high-risk patients with ACS (MI or unstable angina). If
..
.. the specified LDL-C treatment goal is not achieved after 46
.. weeks with the highest tolerated statin dose and ezetimibe, it is
A comprehensive approach to improving adherence to medication ..
is described in the Supplementary Data document.
.. appropriate to add a PCSK9 inhibitor.
.. (8) Safety of low LDL cholesterol concentrations. To date
..
.. there are no known adverse effects of very low LDL-C concentra-
.. tions [e.g. <1 mmol/L (40 mg/dL)].
14 Key messages ..
.. (9) Management of statin ‘intolerance’. While statins rarely
.. cause serious muscle damage (myopathy, or rhabdomyolysis in the
(1) Cholesterol and risk. Prospective studies, randomized trials, ..
and Mendelian randomization studies have all shown that raised .. most severe cases), there is much public concern that statins may
.. commonly cause less serious muscle symptoms. Such statin ‘intol-
LDL-C is a cause of ASCVD. Throughout the range of LDL-C lev- ..
els, ‘lower is better’ with no lower threshold, at least down to 1 .. erance’ is frequently encountered by practitioners and may be diffi-
..
mmol/L. Lowering LDL-C may yield worthwhile benefits in .. cult to manage. However, placebo-controlled randomized trials
patients with average or below average LDL-C who are already .. have shown very clearly that true statin intolerance is rare, and
..
receiving LDL-C-lowering treatment. The proportional reduction .. that it is generally possible to institute some form of statin therapy
in ASCVD risk achieved by lowering LDL-C (e.g. with a statin, eze- .. (e.g. by changing the statin or reducing the dose) in the over-
..
timibe, or PCSK9-inhibitor) depends on the absolute reduction in .. whelming majority of patients at risk of ASCVD.
LDL-C, with each 1 mmol/L reduction corresponding to a reduc- .. (10) Statin treatment for older people. A meta-analysis of
..
tion of about one-fifth in ASCVD. .. randomized trials has shown that the effects of statin therapy are
(2) PCSK-9 inhibitors. Large trials have shown that PCSK9 inhibi-
.. determined by the absolute reduction in LDL-C as well as the
..
tors further reduce ASCVD risk when given on top of statin-based .. baseline ASCVD risk, and are independent of all known risk fac-
therapy and their use may need to be restricted to those at the
.. tors, including age. Statin therapy in older people should therefore
..
highest risk for ASCVD. . be considered according to the estimated level of risk and baseline
ESC/EAS Guidelines 57

LDL-C, albeit with due regard to an individual’s underlying health


.. low dose if there is significant renal impairment and/or the poten-
..
status and the risk of drug interactions. There is less certainty .. tial for drug interactions, and then titrated upwards to achieve
about the effects of statins in individuals aged >75 years, particu-
.. LDL-C treatment goals.
..
larly in primary prevention. Statin therapy should be started at a .

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15 Gaps in the evidence

• Prospective studies are needed to investigate the incremental value of reclassifying total CV risk and defining eligibility for lipid-lowering therapy based on
CAC scores in individuals at moderate or high-risk.
• Outcome-based comparisons of CAC scores vs. assessment of arterial (carotid or femoral) plaque burden by ultrasonography for CV risk reclassification
in people at moderate or high-risk are needed.
• Although calibrated country-specific versions of the SCORE system are available for many European countries, risk charts based on country-specific
cohort data are missing for most countries. Regional total event charts (vs. mortality-only charts) are needed.
• Total CV risk estimation by means of the SCORE system and, accordingly, recommendations on eligibility for statins as well as treatment goals are based
on TC, whereas LDL-C is the primary lipid analysis method for screening, diagnosis, and management.
• There are no outcome-based comparisons of LDL-C vs. ApoB as primary measurement methods for screening, diagnosis, and management.
• Against a background of genetic and randomized clinical trial evidence showing no significant effect of increasing HDL levels on the risk of CVD events,
the clinical impact of therapies altering the function of HDL particles is unknown. More evidence is needed regarding the apparently adverse association
of extremely high levels of HDL-C with clinical outcomes.
• Dedicated studies assessing outcomes with specific Lp(a)-lowering therapies are warranted.
• More evidence is needed for PCSK9 inhibitors in specific populations, including patients with severe CKD and on dialysis, patients with HIV infection, in
children and adolescents with FH, after heart transplantation, and during pregnancy.
• The effects of PCSK9 inhibition on specific body compartments (as with siRNA or antisense) or only within plasma (as with monoclonal antibodies)
remain to be established.
• How early should a PCSK9 inhibitor be initiated in patients with ACS or stroke? In view of evidence of sustained clinical benefit associated with the early
initiation of statin treatment in the acute phase of ACS or stroke, the optimal timing of PCSK9 inhibitor treatment in ACS and stroke patients remains to
be addressed in outcome studies.
• Whether very low LDL-C levels achieved with the combination of statin, ezetimibe, and PCSK9 inhibitor reduce the need for further PCI remains to be
addressed in outcome studies.
• In patients with chronic HF, a small benefit of n-3 PUFAs has been shown in one RCT and merits further investigation.
• What is the optimal screening programme for detecting FH?
• In view of limited access to genetic testing in several environments, more evidence is needed regarding outcomes with only clinical vs. genetic screening
and diagnosis of FH.
• More RCT evidence is required to support the use of statin-based treatment in older people (aged >_75 years, but particularly in those aged >_80 years).
• More RCT evidence is needed for statin treatment in kidney transplant recipients.
• There are no data on the effects of statins, ezetimibe, or fibrates on CV events in dyslipidaemic HIV-infected patients.
• More evidence is needed regarding attainment of recommended LDL goals among very high-risk patients in real-world practice in the era of increasingly
prescribed combination therapies for LDL lowering.
58 ESC/EAS Guidelines

16 ‘What to do’ and ‘what not to do’ messages from the Guidelines

Recommendations Classa Levelb

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CVD risk estimation
Total risk estimation using a risk estimation system such as SCORE is recommended for asymptomatic adults aged >40 years
I C
without evidence of CVD, DMCKD, FH, or LDL > 4.9 mmol/L (>190 mg/dL).
High- and very-high-risk individuals may be identified on the basis of documented CVD, DM, moderate-to-severe renal disease,
very high levels of individual risk factors, FH, or a high SCORE risk, and are a priority for advice and management of all risk I C
factors.
Risk scores developed for the general population are not recommended for CV risk assessment in patients with DM or FH. III C
Lipid analyses for CVD risk estimation
TC is to be used for the estimation of total CV risk by means of the SCORE system. I C
HDL-C analysis is recommended to further refine risk estimation using the online SCORE system. I C
LDL-C analysis is recommended as the primary lipid analysis method for screening, diagnosis, and management. I C
TG analysis is recommended as a part of the routine lipid analysis approach. I C
Non-HDL-C evaluation is recommended for risk assessment, particularly in people with high TG levels, DM, obesity, or very low
I C
LDL-C levels.
ApoB analysis is recommended for risk assessment, particularly in people with high TG levels, DM, obesity, or MetS, or very low
LDL-C levels. It can be used as an alternative to LDL-C, if available, as the primary measurement for screening, diagnosis, and I C
management, and may be preferred over non-HDL-C in people with high TG levels, DM, obesity, or very low LDL-C levels.
Treatment goals for LDL-C
In secondary prevention for patients at very-high risk, an LDL-C reduction of >_50% from baseline and an LDL-C goal of <1.4
I A
mmol/L (<55 mg/dL) are recommended.
In primary prevention for individuals at very-high risk, an LDL-C reduction of >_50% from baseline and an LDL-C goal of <1.4
I C
mmol/L (<55 mg/dL) are recommended.
In patients at high risk, an LDL-C reduction of >_50% from baseline and an LDL-C goal of <1.8 mmol/L (<70 mg/dL) are
I A
recommended.
Pharmacological LDL-C lowering
It is recommended that a high-intensity statin is prescribed up to the highest tolerated dose to reach the goals set for the specific
I A
level of risk.
If the goals are not achieved with the maximum tolerated dose of a statin, combination with ezetimibe is recommended. I B
For secondary prevention in patients at very-high risk not achieving their goal on a maximum tolerated dose of a statin and ezeti-
I A
mibe, a combination with a PCSK9 inhibitor is recommended.
For very-high-risk FH patients (that is, with ASCVD or with another major risk factor) who do not achieve their goal on a maxi-
I C
mum tolerated dose of a statin and ezetimibe, a combination with a PCSK9 inhibitor is recommended.
Drug treatment of patients with HTG
Statin treatment is recommended as the first drug of choice for reducing CVD risk in high-risk individuals with HTG [TGs >2.3
I B
mmol/L (>200 mg/dL)].
Management of patients with HeFH
It is recommended that a diagnosis of FH is considered in patients with CHD aged <55 years for men and <60 years for women,
in people with relatives with premature fatal or non-fatal CVD, in people with relatives having tendon xanthomas, in people with
I C
severely elevated LDL-C levels [in adults >5 mmol/L (>190 mg/dL), in children >4 mmol/L (>150 mg/dL)], and in first-degree rel-
atives of FH patients.
It is recommended that FH is diagnosed using clinical criteria and confirmed, when possible, with DNA analysis. I C
Once the index case is diagnosed, family cascade screening is recommended. I C
It is recommended that FH patients with ASCVD or who have another major risk factor are treated as very-high-risk, and those
I C
with no prior ASCVD or other risk factors as high-risk.
Continued
ESC/EAS Guidelines 59

For FH patients with ASCVD who are at very-high risk, treatment to achieve a >_50% reduction from baseline and an LDL-C
I C
<1.4 mmol/L (<55 mg/dL) is recommended. If goals cannot be achieved, a drug combination is recommended.
Treatment with a PCSK9 inhibitor is recommended in very-high risk FH patients if the treatment goal is not achieved on a maxi-
I C
mal tolerated statin plus ezetimibe.
In children, testing for FH is recommended from the age of 5 years, or earlier if HoFH is suspected. I C
Treatment of dyslipidaemias in older people

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Treatment with statins is recommended for older people with ASCVD in the same way as for younger patients. I A
Treatment with statins is recommended for primary prevention, according to the level of risk, in older people aged <_75 years. I A
It is recommended that the statin is started at a low dose if there is significant renal impairment and/or the potential for drug
I C
interactions, and then titrated upwards to achieve LDL-C treatment goals.
Treatment of dyslipidaemias in DM
In patients with T2DM at very-high risk,c an LDL-C reduction of >_50% from baseline and an LDL-C goal of <1.4 mmol/L
I A
(<55 mg/dL) is recommended.
In patients with T2DM at high risk,c an LDL-C reduction of >_50% from baseline and an LDL-C goal of <1.8 mmol/L (<70 mg/dL)
I A
is recommended.
Statins are recommended in patients with T1DM who are at high or very-high risk.c I A
Statin therapy is not recommended in pre-menopausal patients with or without DM who are considering pregnancy, or not using
III C
adequate contraception.
Management of patients with ACS
In all ACS patients without any contraindication or definite history of intolerance, it is recommended that high-dose statin therapy
I A
is initiated or continued as early as possible, regardless of initial LDL-C values.
If the LDL-C goal is not achieved after 46 weeks with the maximally tolerated statin dose, combination with ezetimibe is
I B
recommended.
If the LDL-C goal is not achieved after 46 weeks despite maximal tolerated statin therapy and ezetimibe, adding a PCSK9 inhibi-
I B
tor is recommended.
Lipid-lowering therapy for prevention of ASCVD events in patients with prior ischaemic stroke
Patients with a history of ischaemic stroke or TIA are at very-high risk of ASCVD, particularly recurrent ischaemic stroke, so it is
I A
recommended that they receive intensive LDL-C-lowering therapy.
Treatment of dyslipidaemias in chronic HF or valvular heart diseases
Initiation of lipid-lowering therapy is not recommended in patients with HF in the absence of other indications for their use. III A
Initiation of lipid-lowering treatment is not recommended in patients with aortic valvular stenosis without CAD to slow progres-
III A
sion of aortic valve stenosis in the absence of other indications for their use.
Lipid management in patients with moderate-to-severe (Kidney Disease Outcomes Quality Initiative stages 35) CKD
It is recommended that patients with stage 35 CKD are considered to be at high or very-high risk of ASCVD. I A
The use of statins or statin/ezetimibe combination is recommended in patients with non-dialysis-dependent stage 35 CKD. I A
In patients with dialysis-dependent CKD who are free of ASCVD, commencement of statin therapy is not recommended. III A
Lipid-lowering drugs in patients with PAD (including carotid artery disease)
In patients with PAD, lipid-lowering therapy—including a maximum tolerated dose of a statin, plus ezetimibe, or a combination
I A
with a PCSK9 inhibitor if needed—is recommended to reduce the risk of ASCVD events.
Lipid-lowering drugs in patients with CIID
The use of lipid-lowering drugs only on the basis of the presence of CIID is not recommended. III C
Lipid-lowering drugs in patients with SMI
It is recommended that SMIs are used as modifiers for estimating total ASCVD risk. I C
It is recommended that the same guidelines for the management of total ASCVD risk are used in patients with SMI as are used in
I C
patients without such disease.
It is recommended that in patients with SMI, intensified attention is paid to adherence to lifestyle changes and to compliance with
I C
drug treatment.

ACS = acute coronary syndrome(s); Apo = apolipoprotein; ASCVD = atherosclerotic cardiovascular disease; CAD = coronary artery disease; CHD = coronary heart disease;
CIID = chronic immune-mediated inflammatory diseases; CKD = chronic kidney disease; CV = cardiovascular; CVD = cardiovascular disease; DM = diabetes mellitus; FH = fam-
ilial hypercholesterolaemia; HDL-C = high-density lipoprotein cholesterol; HeFH = heterozygous FH; HF = heart failure; HoFH = homozygous FH; HTG = hypertriglyceridae-
mia; LDL-C = low-density lipoprotein cholesterol; MetS = metabolic syndrome; PAD = peripheral arterial disease; PCSK9 = proprotein convertase subtilisin/kexin type 9;
SCORE = Systematic Coronary Risk Estimation; SMI = severe mental illness; TC = total cholesterol; TG = triglycerides; TIA = transient ischaemic event; T1DM = type 1 DM;
T2DM = type 2 DM.
a
Class of recommendation.
b
Level of evidence.
60 ESC/EAS Guidelines

..
17 Supplementary data ..
..
Colin Baigent (United Kingdom), Jean-Philippe Collet (France),
Veronica Dean (France), Victoria Delgado (Netherlands), Donna
Supplementary Data with additional Supplementary Tables, Boxes,
..
.. Fitzsimons (United Kingdom), Chris P. Gale (United Kingdom),
and text complementing the full text—as well as sections on other .. Diederick E. Grobbee (Netherlands), Sigrun Halvorsen (Norway),
features of a healthy diet contributing to cardiovascular disease pre-
..
.. Gerhard Hindricks (Germany), Bernard Iung (France), Peter Jüni
vention, chronic immune-mediated inflammatory diseases, HIV .. (Canada), Hugo A. Katus (Germany), Ulf Landmesser (Germany),
..
patients, severe mental illness, and adhering to medications along .. Christophe Leclercq (France), Maddalena Lettino (Italy), Basil S.

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with the related references—are available on the European Heart .. Lewis (Israel), Bela Merkely (Hungary), Christian Mueller
..
Journal website and via the ESC website at www.escardio.org/ .. (Switzerland), Steffen Petersen (United Kingdom), Anna Sonia
guidelines. .. Petronio (Italy), Dimitrios J. Richter (Greece), Marco Roffi
..
.. (Switzerland), Evgeny Shlyakhto (Russian Federation), Iain A.
.. Simpson (United Kingdom), Miguel Sousa-Uva (Portugal), Rhian M.
..
18 Appendix .. Touyz (United Kingdom).
..
..
Author/Task Force Member Affiliations: .. ESC National Cardiac Societies actively involved in the review
Konstantinos C. Koskinas, Cardiology, Bern University Hospital
.. process of the 2019 ESC/EAS Guidelines for the management of dys-
..
(Inselspital), Bern, Switzerland; Manuela Casula, Epidemiology and .. lipidaemias: lipid modification to reduce cardiovascular risk.
..
Preventive Pharmacology Service (SEFAP), Department of ..
Pharmacological and Biomolecular Sciences (DiSFeB), University of .. Algeria: Algerian Society of Cardiology, Djamaleddine Nibouche;
.. Armenia: Armenian Cardiologists Association, Parounak H.
Milan, Milan, Italy and IRCCS MultiMedica, Sesto S. Giovanni (Milan), ..
Italy; Lina Badimon, Cardiovascular Program-ICCC and CiberCV, .. Zelveian; Austria: Austrian Society of Cardiology, Peter
.. Siostrzonek; Azerbaijan: Azerbaijan Society of Cardiology, Ruslan
IR-Hospital de la Santa Creu i Sant Pau, Barcelona, Spain; M. John ..
Chapman, National Institute for Health and Medical Research .. Najafov; Belgium: Belgian Society of Cardiology, Philippe van de
..
(INSERM), Paris, France; Sorbonne University, Paris, France; and .. Borne; Bosnia and Herzegovina: Association of Cardiologists of
Division of Endocrinology- Metabolism, Pitie-Salpetriere University .. Bosnia and Herzegovina, Belma Pojskic; Bulgaria: Bulgarian Society
..
Hospital, Paris, France; Guy G. De Backer, Public Health and .. of Cardiology, Arman Postadzhiyan; Cyprus: Cyprus Society of
Primary Care, Faculty of Medicine and Health Sciences, Ghent .. Cardiology, Lambros Kypris; Czech Republic: Czech Society
..
University, Ghent, Belgium; Victoria Delgado, Cardiology, Leiden .. of Cardiology, Jindrich Spinar; Denmark: Danish Society of
University Medical Center, Leiden, Netherlands; Brian A. Ference, .. Cardiology, Mogens Lytken Larsen; Egypt: Egyptian Society
..
Centre for Naturally Randomized Trials, Department of Public .. of Cardiology, Hesham Salah Eldin; Estonia: Estonian Society of
Health and Primary Care, University of Cambridge, Cambridge, .. Cardiology, Margus Viigimaa; Finland: Finnish Cardiac Society, Timo
..
United Kingdom; Ian M. Graham, Cardiology, Trinity College, .. E. Strandberg; France: French Society of Cardiology, Jean Ferrières;
Dublin, Ireland; Alison Halliday, Nuffield Department of Surgery,
.. Georgia: Georgian Society of Cardiology, Rusudan Agladze;
..
University of Oxford, Oxford, United Kingdom and NIHR Oxford .. Germany: German Cardiac Society, Ulrich Laufs; Greece: Hellenic
Biomedical Research Centre, Oxford, United Kingdom; Ulf
.. Society of Cardiology, Loukianos Rallidis; Hungary: Hungarian
..
Landmesser, Department of Cardiology, Charite .. Society of Cardiology, Laszl
o Bajnok; Iceland: Icelandic Society of
Universit€atsmedizin Berlin, Berlin, Germany; Berlin Institute of Health
.. Cardiology, Thorbjörn Gudj onsson; Ireland: Irish Cardiac Society,
..
(BIH), Berlin, Germany; and German Center of Cardiovascular .. Vincent Maher; Israel: Israel Heart Society, Yaakov Henkin; Italy:
Research (DZHK), Berlin, Germany; Borislava Mihaylova, Nuffield
.. Italian Federation of Cardiology, Michele Massimo Gulizia;
..
Department of Population Health and NIHR Oxford Biomedical .. Kazakhstan: Association of Cardiologists of Kazakhstan, Aisulu
.. Mussagaliyeva; Kosovo (Republic of): Kosovo Society of
Research Centre, University of Oxford, Oxford, United Kingdom and ..
Barts and The London School of Medicine and Dentistry, Queen Mary .. Cardiology, Gani Bajraktari; Kyrgyzstan: Kyrgyz Society
.. of Cardiology, Alina Kerimkulova; Latvia: Latvian Society of
University of London, London, United Kingdom; Terje R. Pedersen, ..
Preventive Cardiology, Oslo University Hospital, Aker, Oslo, Norway; .. Cardiology, Gustavs Latkovskis; Lebanon: Lebanese Society
..
Gabriele Riccardi, Clinical Medicine and Surgery, Federico II .. of Cardiology, Omar Hamoui; Lithuania: Lithuanian Society of
University, Naples, Italy; Dimitrios J. Richter, Cardiac Department, .. Cardiology, Rimvydas Slapikas; Luxembourg: Luxembourg Society
..
Euroclinic, Athens, Greece; Marc S. Sabatine, TIMI Study Group, .. of Cardiology, Laurent Visser; Malta: Maltese Cardiac Society, Philip
Division of Cardiovascular Medicine, Brigham and Women’s Hospital .. Dingli; Moldova (Republic of): Moldavian Society of Cardiology,
..
and Harvard Medical School, Boston, MA, United States of America; .. Victoria Ivanov; Montenegro: Montenegro Society of Cardiology,
Marja-Riitta Taskinen, Research Program for Clinical and Molecular .. Aneta Boskovic; Morocco: Moroccan Society of Cardiology,
..
Metabolism, University of Helsinki, Helsinki, Finland; Lale .. Mbarek Nazzi; Netherlands: Netherlands Society of Cardiology,
Tokgozoglu, Cardiology, Hacettepe University, Ankara, Turkey; .. Frank Visseren; North Macedonia: North Macedonian Society of
..
Olov Wiklund, Institute of Medicine, The Sahlgrenska Academy at .. Cardiology, Irena Mitevska; Norway: Norwegian Society of
University of Gothenburg, Gothenburg, Sweden. .. Cardiology, Kjetil Retterstøl; Poland: Polish Cardiac Society, Piotr
..
.. Jankowski; Portugal: Portuguese Society of Cardiology, Ricardo
ESC Committee for Practice Guidelines (CPG): Stephan
.. Fontes-Carvalho; Romania: Romanian Society of Cardiology, Dan
..
Windecker (Chairperson) (Switzerland), Victor Aboyans (France), . Gaita; Russian Federation: Russian Society of Cardiology, Marat

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