Ic 2021

ESC GUIDELINES
European Heart Journal (2021)

00,1 128
doi:10.1093/eurheartj/ehab368
2021 ESC Guidelines for the diagnosis and treatment
2021
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of acute and chronic heart failure
Developed by the Task Force for the diagnosis and treatment of acute and
chronic heart failure of the European Society of Cardiology (ESC)
With the special contribution of the Heart Failure Association (HFA) of the ESC
Authors/Task Force Members: Theresa A. McDonagh* (Chairperson) (United Kingdom), Marco

Metra * (Chairperson) (Italy), Marianna Adamo (Task Force Coordinator) (Italy), Roy S.
Gardner (Task Force Coordinator) (United Kingdom), Andreas Baumbach (United Kingdom),
Michael Bo¨hm (Germany), Haran Burri (Switzerland), Javed Butler (United States of America),
Jelena Celutkien e_ (Lithuania), Ovidiu Chioncel (Romania), John G.F. Cleland (United
Kingdom), Andrew J.S. Coats (United Kingdom), Maria G. Crespo-Leiro (Spain), Dimitrios
Farmakis (Greece), Martine Gilard (France), Stephane Heymans
* Corresponding authors: The two chairpersons contributed equally to the document.

Theresa McDonagh, Cardiology Department, King’s College Hospital, Denmark Hill, London, SE5 9RS, United Kingdom. Tel: þ44 203 299 325,
E-mail: theresa.mcdonagh@kcl.ac.uk;
Marco Metra, Institute of Cardiology, ASST Spedali Civili di Brescia and Department of Medical and Surgical Specialties, Radiological Sciences and Public Health, University of
Brescia, Brescia, Italy. Tel: þ39 303 07221, E-mail: metramarco@libero.it
Author/Task Force Member affiliations: listed in Author information.
ESC Clinical Practice Guidelines Committee (CPG): listed in the Appendix.
ESC subspecialty communities having participated in the development of this document:
Associations: Association for Acute CardioVascular Care (ACVC), 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 of Cardio-Oncology, Council on Basic Cardiovascular Science, Council on Valvular Heart Disease.
Working Groups: Adult Congenital Heart Disease, Cardiovascular Pharmacotherapy, Cardiovascular Regenerative and Reparative Medicine, Cardiovascular Surgery, e-Cardiology,
Myocardial and Pericardial Diseases, Myocardial Function.
Patient Forum
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
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 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.
This article has been co-published with permission in the European Heart Journal and European Journal of Heart Failure. VC the European Society of Cardiology 2021. All rights
reserved. 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.
2 ESC Guidelines
(Netherlands), Arno W. Hoes (Netherlands), Tiny Jaarsma (Sweden), Ewa A. Jankowska (Poland),
Mitja Lainscak (Slovenia), Carolyn S.P. Lam (Singapore), Alexander R. Lyon (United Kingdom), John
J.V. McMurray (United Kingdom), Alex Mebazaa (France), Richard Mindham (United Kingdom),
Claudio Muneretto (Italy), Massimo Francesco Piepoli (Italy), Susanna Price (United Kingdom),
Giuseppe M.C. Rosano (United Kingdom), Frank Ruschitzka (Switzerland), Anne Kathrine
2021
Skibelund (Denmark), ESC Scientific Document Group
Document Reviewers: Rudolf A. de Boer (CPG Review Coordinator) (Netherlands), P. Christian Schulze
(CPG Review Coordinator) (Germany), Magdy Abdelhamid (Egypt), Victor Aboyans (France),
Stamatis Adamopoulos (Greece), Stefan D. Anker (Germany), Elena Arbelo (Spain), Riccardo Asteggiano
(Italy), Johann Bauersachs (Germany), Antoni Bayes-Genis (Spain), Michael A. Borger (Germany),
Werner Budts (Belgium), Maja Cikes (Croatia), Kevin Damman (Netherlands), Victoria Delgado
(Netherlands), Paul Dendale (Belgium), Polychronis Dilaveris (Greece), Heinz Drexel (Austria),
Justin Ezekowitz (Canada), Volkmar Falk (Germany), Laurent Fauchier (France), Gerasimos Filippatos
(Greece), Alan Fraser (United Kingdom), Norbert Frey (Germany), Chris P. Gale (United Kingdom),
Finn Gustafsson (Denmark), Julie Harris (United Kingdom), Bernard Iung (France), Stefan Janssens
(Belgium), Mariell Jessup (United States of America), Aleksandra Konradi (Russia), Dipak Kotecha (United
Kingdom), Ekaterini Lambrinou (Cyprus), Patrizio Lancellotti (Belgium), Ulf Landmesser (Germany),
Christophe Leclercq (France), Basil S. Lewis (Israel), Francisco Leyva (United Kingdom), Ales Linhart
(Czech Republic), Maja-Lisa Løchen (Norway), Lars H. Lund (Sweden), Donna Mancini (United States of
America), Josep Masip (Spain), Davor Milicic (Croatia), Christian Mueller (Switzerland), Holger Nef
(Germany), Jens-Cosedis Nielsen (Denmark), Lis Neubeck (United Kingdom), Michel Noutsias (Germany),
Steffen E. Petersen (United Kingdom), Anna Sonia Petronio (Italy), Piotr Ponikowski (Poland),
Eva Prescott (Denmark), Amina Rakisheva (Kazakhstan), Dimitrios J. Richter (Greece), Evgeny Schlyakhto
(Russia), Petar Seferovic (Serbia), Michele Senni (Italy), Marta Sitges (Spain), Miguel Sousa-Uva (Portugal),
Carlo G. Tocchetti (Italy), Rhian M. Touyz (United Kingdom), Carsten Tschoepe (Germany),
Johannes Waltenberger (Germany)
All experts involved in the development of these guidelines have submitted declarations of interest. These have been compiled in
a report and published in a supplementary document simultaneously to the guidelines. The report is also 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 European Heart Journal online
...................................................................................................................................................................................................
Keywords Guidelines • heart failure • natriuretic peptides • ejection fraction • diagnosis • pharmacotherapy • neuro-
hormonal antagonists • cardiac resynchronization therapy • mechanical circulatory support •
transplantation • arrhythmias • comorbidities • hospitalization • multidisciplinary management •
advanced heart failure • acute heart failure
1 Preamble . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ....................... 3.2.4 Terminology related to the symptomatic severity

............. 9 of heart failure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
.
. . . . . . . . . . . . . . . 15
. . . . . . . . . . . 11
3.3 Epidemiology and natural history of heart
2.1 What is new . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . failure . . . . . . . . . . . . . . 15
. . . . . . . . . . . 11
3.3.1 Incidence and prevalence. . . . . . . . . . . . . . . . . . . . . . . . . .
3 Definition, epidemiology and . . . . . . . 15
prognosis . . . . . . . . . . . . . . . . . . . . . . . . . . . 14
3.3.2 Aetiology of heart failure .......................
3.1 Definition of heart failure .................... . . . . . . . . . 16
. . . . . . . . . . . . . . . . 14
3.3.3 Natural history and prognosis . . . . . . . . . . . . . . . . . . . . . .
3.2 Terminology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
. . . . . . 16
. . . . . . . . . . 143.2.1 Heart failure with preserved, mildly
reduced, and reduced ejection fraction . . . . . . . . . . . . . . . . 4 Chronic heart failure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
ESC Guidelines 3
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14 . . . . . . . . . . . . 16
4.1 Key steps in the diagnosis of chronic heart failure
. . . . . . . . . . . . . 16
Table of contents ...... 3.2.23.2.3 Right ventricular
dysfunction . . . . . . . . . . . . . . . . . . . . . . . . . . . . .Other common terminology used in heart failure . . . . . . . . . 1515
4.2 Natriuretic 8 Heart failure with
peptides . . . . . . . . . . . preserved ejection
................... fraction . . . . . . . . . . . . .
. . . . . . . . . . . 18 . . . . . . . . 32
4.2.1 Use in the 8.1 The
non-acute setting . background to heart
................ failure with preserved
. . . . . . . . . . . . 19 ejection
4.3 Investigations fraction . . . . . . . . . . . .
to determine the ...................
...................
underlying
. . . . . . . 32
aetiology of
8.2 Clinical
chronic heart
characteristics of
failure . . . . . . . . . .
patients with heart
................
failure with preserved
................
ejection
. . . 19
fraction . . . . . . . . . . . .
5 Heart failure
...................
with reduced ejection
fraction . . . . . . . . . . . . . . . . . . . . . 32
. . . . . . . . . 21 8.3 The diagnosis
5.1 The diagnosis of heart failure with
of heart failure with preserved ejection
reduced ejection fraction . . . . . . . . . . . .
...................
fraction . . . 21 5.2
...................
Pharmacological
treatments for
.............................................................................................................. . . . . . . . 32
patients with heart

............................................................... 8.4 Treatment of
heart failure with
failure with reduced
preserved ejection
ejection fraction
fraction . . . . 33 9
............
Multidisciplinary team
. . . . . . . . . . . . . . . . 21
management for the
5.2.1 Goals of
prevention and
pharmacothera
treatment of chronic
py for patients
with heart heart failure
failure with .............
reduced ...................
ejection fraction . . 35
.............. 9.1 Prevention of heart
............ failure ....
21 .................
. . . . . . . . . . . . . . 35
5.2.2 General
9.2 Multidisciplinary
principles of
management of
pharmacothera chronic heart
py for heart failure . . . . . . . . .
failure with 35
reduced 9.2.1 Models of care
ejection fraction .................
.............. .................
............ . . . . . . . . 35 9.2.2
21 Characteristics and
5.3 Drugs components of a
4 ESC Guidelines
recommended in heart failure
all patients with management
heart failure with programme . . . . . . .
reduced ejection .................
fraction . . . . . . . . . . . . . . . . . . . . . . 35
................ 9.3 Patient education,
............... self-care and
22 lifestyle advice . . . .
5.1.1 Angiotensin- . . . . . . . . . . . . 35
converting enzyme 9.4 Exercise
inhibitors . . . . . . . . . . . . rehabilitation . . . . .
. . . . 23 .................
5.1.2 Beta- .................
blockers . . . . . . . . . . . . . 38
..................... 9.5 Follow-up of
. . . . . . . . . 23 chronic heart
5.1.3 Mineralocorti failure . . . . . . . . . . .
coid receptor .................
antagonists ... 38
. . . . . . . . . . . . . . . 23 9.5.1General
5.1.4 Angiotensin follow-
receptor-neprilysin up . . . . . . . . . .
inhibitor . . . . . . . . . . . . . .............
. . . . 23 .............
. . . 38
5.1.5 Sodium-
9.5.2Monitoring
glucose co-transporter 2
with
inhibitors . . . . . . . . . . . . biomarkers . . .
. . 24 5.4 Other drugs .............
recommended or to be .............
considered in selected 38
9.6 Telemonitoring . . .
patients with heart
...................
failure with reduced ...................
ejection fraction . . . . . 38
............ 10 Advanced heart
..................... failure . . . . . . . . . . . . .
...................
. . . . . . . . . . . . . . . 24
. . . . . . . . . . 39
5.4.1 Diuretics . . . .
10.1Epidemiology,
.................
diagnosis, and
.................
prognosis . . . . . . .
. . . . . . . . . . 25
...............
5.4.2 Angiotensin II 39
type I receptor 10.2Management . . . .
blockers ... ................
................ ................
25 . . . . . . . . . . . 41
5.4.3 If-channel 10.2.1 Phar
inhibitor ... macological therapy
................. and renal
................. replacement . . . . . .
. 25 . . . 41
5.4.4 Combination 10.2.2 Mec
of hydralazine and hanical circulatory
isosorbide dinitrate support . . . . . . . . . .
. . . . . . 25 . . . . . . . . . . . . . . . 41
5.4.5 Digoxin . . . . .
10.2.3 Hear
................. t transplantation
................. .............
. . . . . . . . . . 255.4.6 .................
Recently reported . . . . 45
advances from 10.2.4 Sym
ptom control and
trials in heart end-of-life care . . . .
failure with . . . . . . . . . . . . . . . 46
ESC Guidelines 5
reduced ejection 11 Acute heart failure . . .
fraction . . . . . . . . . . ...................
...................
................
. . . . . 46
26
11.1Epidemiology,
5.5 Strategic diagnosis and
phenotypic prognosis ....
overview of the ................
management of . . 46
heart failure with 11.2Clinical
reduced ejection presentations . . .
................
fraction . . . . . . . . .
................
.............. . . . . 48
26
11.2.1 Acut
6 Cardiac ely decompensated
rhythm management heart failure
for heart failure with .............
reduced ejection . . . . . . 48
fraction . . . . . . . . . . . . . . 11.2.2 Acut
e pulmonary
.....................
oedema . . . . . . . . . .
. . . . . . . . . . . . . . . . 26 .................
6.1 Implantable . . . 49
cardioverter- 11.2.3 Isola
defibrillator . . . . . . . . ted right ventricular
................. failure . . . . . . . . . . .
27 . . . . . . . . . . . . . . 49
6.1.1 Secondary 11.2.4 Card
prevention of sudden iogenic
cardiac death shock . . . . . . . . . . . .
........... .................
28 . . . . . . . . 49
6.1.2 Primary 11.3Management . . . .
prevention of sudden ................
cardiac death . . . . . . . . . ................
. . . . . . . . . . . 51
. . . . . 28 6.1.3 Patient
11.3.1 Gen
selection for eral aspects . . . . . . .
implantable .................
cardioverterdefibrillator ................
51
therapy ............
11.3.2 Oxy
..................... gen therapy and/or
. . . . . . . . . 28 ventilatory support .
6.1.4 Implantable . . . . . . . . . . . . 52
cardioverter- 11.3.3 Diur
etics . . . . . . . . . . . . .
defibrillator .................
programming . . . . . ................
. . 28 6.1.5 54
Subcutaneous and 11.3.4 Vas
odilators . . . . . . . . .
wearable .................
implantable .................
cardioverter- 56
defibrillators. . . . . . . . . . 11.3.5 Inot
..................... ropes . . . . . . . . . . . .
. . . . . 28 .................
6.2 Cardiac .................
resynchronization 57
therapy . . . . . . . . . . . . 11.3.6 Vas
. . . . . . . . . . . . . . . 29 opressors . . . . . . . . .
6.3 Devices under .................
evaluation . . . . . . . . . ................
................... 57
. . . . . . . . 30 11.3.7 Opia
6 ESC Guidelines
7 Heart failure tes . . . . . . . . . . . . . .
with mildly reduced .................
ejection fraction .................
............ 57
. . . . 30 11.3.8 Digo
7.1 The diagnosis xin . . . . . . . . . . . . . .
of heart failure with .................
.................
mildly reduced
58
ejection
11.3.9 Thro
fraction . . . . . . . . . . . .
mboembolism
................... prophylaxis ....
................... .................
. . . . . . . 30 . . . 58
7.2 Clinical 11.3.10 Shor
characteristics of t-term mechanical
patients with heart circulatory support
failure with mildly ............
reduced ejection 58 11.3.11 Pre-
fraction . . . . . . . . . . . . discharge
................. assessment and
31 post-discharge
7.3 Treatments management
for patients with planning . . . . . . . . . .
heart failure with
mildly .................
reduced ejection . . . . . . . . . . . . . . 59
fraction . . . . . . . . . . . . 12 Cardiovascular
................... comorbidities . . . . . . .
. . . . . . . . . 31 ...................
7.3.1 Angiotensin- . . . . . . . . . 59
converting enzyme 12.1Arrhythmias and
inhibitors . . . . . . . . . . . . conduction
. . . . 31 disturbances . . . .
7.3.2 Angiotensin ...............
receptor II type 1 59
receptor blockers 12.1.1 Atri
. . . . . . . . . 31 al
7.3.3 Beta- fibrillation . . . . . . . .
blockers . . . . . . . . . . . . . .................
..................... . . . . . . . . . . . . . . . 59
. . . . . . . . . 31 12.1.2 Vent
7.3.4 Mineralocorti ricular arrhythmias
coid receptor
.............
antagonists ...
. . . . . . . . . . . . . . . 31 .................
7.3.5 Angiotensin . . 62 12.1.3
receptor-neprilysin Symptomatic
inhibitor . . . . . . . . . . . . .
bradycardia, pauses
. . . . 31
and atrio-
7.3.6 Other drugs
............ ventricular block
..................... .............
. . . . . . . . . . . 32 .................
7.3.7 Devices . . . . .
.................
.....................
..................... . . . . . . . . . 62
. . 32 12.2Chronic coronary
syndromes . . . . . .
................
. . . . . . . . . 62
12.2.1 Med
ical therapy . . . . . . .
.................
................
63
2021
7
Myo
.................
revascularization . .
. . . . . . . . . 64
cardial
12.2.2
ESC Guidelines
8 ESC Guidelines
12.3 Valvular heart .............................................................................................................................. Recommenda
disease . . . . . . . . . . . tions for
. . . . . . . . . . . . . . . . . . ............................................... specialized
. . . . . . . . . 64
diagnostic
12.3.1 Aortic
tests for
stenosis . . . . . .
.............. selected
.............. patients with
. . . . . . . 64 chronic heart
12.3.2 Aortic failure to
regurgitation . . detect
.............. reversible/trea
.............. table causes of
. . . . . . 66
heart failure . .
12.3.3 Mitral
.............
regurgitation . .
.............. .............
.............. .............
. . . . . . . 66 . . . . . 20
12.3.4 Tricuspid Pharmacologic
regurgitation . . al treatments
.............. indicated in
.............. patients with
. . . 68 (NYHA class
12.4 Hypertension IIIV) heart
................ failure with
................ reduced
.............. ejection
68 fraction
12.5 Stroke . . . . . . (LVEF <_40%) .
................ .............
................ .............
............... .............
68
.............
13 Non-
. 22 Other
cardiovascular
comorbidities pharmacologic
............... al treatments
............... indicated in
68 selected
13.1 Diabetes . patients with
.................. NYHA class IIIV
..................
heart failure
. . . . . . . . . . . . . . 68
with reduced
13.2 Thyroid
disorders . . . . . . . . . ejection
.................. fraction (LVEF
. . . . . . . . . . . . . . . 69 <_40%) . . . . . .
13.3 Obesity . . .............
.................. .............
.................. .............
. . . . . . . . . . . . . . 70
. 24
13.4 Frailty,
Recommenda
cachexia, sarcopenia
.................. tions for an
. . . . . . . . . . . . . . . 70 implantable
13.5 Iron cardioverter-
deficiency and defibrillator in
anaemia . . . . . . . . . . patients with
.................. heart failure . .
. . . . . 70
.............
13.6 Kidney
.............
dysfunction . . . . . . . ............
.................. 27
................ Recommenda
71 13.7 Electrolyte tions for
ESC Guidelines 9
disorders: cardiac
hypokalaemia, resynchroniza
hyperkalaemia, tion therapy
hyponatraemia, implantation
hypochloraemia . . . in patients
with heart
.................. failure . . . . . . .
. . . . . . . . . . . . 72 .............
13.8 Lung . . . . . . . 29
disease, Pharmacol
sleep- ogical
disordered treatment
breathing . .
........... s to be
. . . . . . . 73 considere
13.9 Hyperlipida d in
emia and patients
lipid- with
modifying
(NYHA
therapy . . . .
........... class IIIV)
. . 73 heart
13.10Gout and failure
arthritis . . . . with
........... mildly
...........
reduced
...........
. . . . 74 ejection
13.11Erectile fraction . . . . . .
dysfunction .............
........... .............
........... .............
........... .............
. . . . . . 74
. 31
13.12Depression .
........... Recommenda
........... tions for the
........... treatment of
........... patients with
. . 74 heart failure
13.13Cancer . . . . with
...........
preserved
...........
........... ejection
........... fraction . . . . . .
. . . 74 .............
13.14Infection . . . .............
........... . . . . 34
...........
Recommenda
...........
........... tions for the
. . . 77 primary
14 Special prevention of
conditions . . . . . . heart failure in
............... patients with
............... risk factors for
. . . . . . . . . . 77
its
14.1 Pregnancy
development
.........
.................. ....
.................. .............
. . . . 77 . . . . . . 34
14.1.1Pregnanc Multidisciplina
y in pre- ry
existing interventions
heart
recommended
failure . .
for the
10 ESC Guidelines
........ management
........ of chronic
. 77 heart failure . .
14.1.2New .............
heart
.............
failure
presentin .............
g during . . . . 35
pregnanc Recommenda
y....... tions for
. . . 77 exercise
14.2 Cardiomy rehabilitation
opathies . . . . . . . . .
in patients
..................
. . . . . . . . . . . . . . 79 with
14.2.1Epidemio chronic heart
logy and failure . . . . . . .
diagnosis .............
........ .............
........ .............
........ . 38
. . . . . 79
Recommenda
14.2.2Treatme
tions for
nt . . . . . .
........ telemonitoring
........ .............
........ .............
........ . . . . 39
....... Recommenda
79
tions for the
14.3 Left
treatment of
ventricular non-
patients with
compaction . . . . . . .
.................. advanced
. . . 83 heart failure . .
14.4 Atrial .............
disease . . . . . . . . . . . .............
.................. .............
.................. .............
84
. 45
14.4.1Definitio
n....... Recommenda
........ tions for the
........ initial
........ treatment of
........ acute heart
....... failure . . . . .
84
57
14.4.2Diagnosis
Recommenda
........
........ use of short-
........ term
........ mechanical
. . . . . . 84 circulatory
14.4.3Manage support in
ment . . .
patients with
........
........ cardiogenic
........ shock . . . . . . .
........ .............
........ . . . . . . 58
84 Recommenda
14.5 Myocardi tions for pre-
tis . . . . . . . . . . . . . . .
discharge and
..................
. . . . . . . . . . . . . . . 84 early post-
14.5.1Epidemio discharge
ESC Guidelines 11
logy and follow-up of
diagnosis patients
........ hospitalized
........
for acute heart
........
. . . . . 84 failure . . . . . . .
14.5.2Treatme . . . . . . 59
nt . . . . . . Recommenda
........ treatment of
........ atrial
........ fibrillation in
.......
patients with
84
14.6 Amyloidos heart failure . .
is . . . . . . . . . . . . . . . . .............
.................. .............
. . . . . . . . . . . . . . 84 .............
14.6.1Epidemio . 62
logy and
Recommenda
diagnosis
........ tions for
........ myocardial
........ revascularizati
. . . . . 84 on in patients
14.6.2Therapy with heart
of failure with
amyloido
reduced
sis and
heart ejection
failure fraction . . . .
........ .............
........ . . . 64
87
Recommenda
14.7 Iron
tions for the
overload
cardiomyopathy . . . management
.................. of valvular
. . . . . . . . . 87 heart
14.8 Adult disease in
congenital heart patients with
disease . . . . . . . . . heart failure . .
.................. .............
. . . 88 15 Key .............
messages . . . . . . . . . . . . . 67
Recommenda
..................
tions for the
..................
treatment of
. . . . . 90 16 Gaps in
diabetes in
evidence . . . . . . . . . .
heart failure . .
.................. . . . 69
.................. Recommenda
. 91 17 ‘What to do’ tions for the
and ‘what not to do’ management
messages from the of anaemia
guidelines . . . and iron
92 deficiency in
18 Quality patients with
indicators . . . . . . . . . heart failure . .
................. .............
................. .............
. . . 95
............
19 Suppleme 71
ntary data Recommenda
......... tions for the
12 ESC Guidelines
................. management
................. of patients
. 96 20 Author with cancer
information . . . . . . . and heart
failure . . . . . . .
.................
.............
.................
.............
. . . . 96
.............
21 Appendix . . . . . . . . . . . . 77
...............
Recommenda
...............
............... tions for the
. . 96 treatment of
22 References . . . . . transthyretin
............... amyloidosis-
............... cardiac
............... amyloidosis . .
. . . 97 .............
.............
. . . . . . . . 88
List of
List of
recommenda
tables
tions
Table 1
Recommended Classes of
diagnostic tests recommendati
in all patients ons . . . . . . . . .
with suspected .............
chronic heart . . . . . . . . . 10
failure . . . . . . . . .
Table 2 Levels
...............
of
.............
19 evidence . . . . .
.............
.............
. . . . . . . . . . 10
Table 3
Definition of
heart failure
with reduced
ejection
fraction,
mildly reduced
ejection
fraction and
preserved
ejection
fraction . . . . .
15 Table 4
New York
Heart
Association
functional
classification
based on
severity of
symptoms and
physical
activity . . . . . .
...........
16 Table 5
Causes of
heart failure,
common
ESC Guidelines 13
modes of
presentation
and specific
investigations .
.............
.............
.............
. . 18 Table 6
Symptoms and
signs typical of
2021
heart failure . .
.............
. . . 19
14 ESC Guidelines
Table 7 Causes ........................................................................................................................ Table 37 Main European

of elevated Society of Cardiology
concentrations ..................................................... Quality Indicators for the
of natriuretic
evaluation of care and
peptides . . .
outcomes for patient
............ with heart failure . . . . 95
............
............
............ List of figures
. . . . . . . 20 Figure 1 The diagnostic
Table 8 algorithm for heart
Evidence- failure . . . . . . . . . . . . . . . .
based doses . . . 17 Figure 2
of disease- Therapeutic algorithm of
modifying Class I Therapy
drugs in key Indications for a patient
randomized with heart failure with
trials in reduced ejection
patients with fraction . . . . . . . . . . . . .
heart failure 22 Figure 3 Central
with reduced illustration Strategic
ejection phenotypic overview of
fraction . . . the management of heart
.......... failure with reduced
.......... ejection fraction . . . . . . . .
.......... . . 26 Figure 4 Algorithm
.......... for the treatment of
. . . . . . . . 23 patients with advanced
Table 9 heart
Objective failure . . . . . . . . . . . . . . . .
evidence of ......................
. . . . . . . . . . . . . . . . . 42
cardiac
Figure 5 Triage of
structural,
patients with advanced
functional
heart failure and
and
serological appropriate timing of
abnormaliti referral . . . . . . . . . . . . . . .
......................
es
. 43 Figure 6 Diagnostic
consistent
workup of new onset
with the
acute heart failure . . . . . .
presence of
. . . 47 Figure 7
left
Management of acute
ventricular
decompensated heart
diastolic
failure . . . . . . . . . 50
dysfunction
Figure 8 Management of
/raised left
pulmonary oedema . . . . .
ventricular
. . . . . . . . . . . . . . . . . . . 51
filling
pressures . .
right ventricular failure . .
..........
. . . . . . . . . . . . . . . . . . . 52
..........
..........
cardiogenic
..........
shock . . . . . . . . . . . . . . . . .
..........
. . . . . . . 53 Figure 11
. . . . . 33
Stages of management of
Table 10
patients with acute
Risk factors
heart
for the
failure . . . . . . . . . . . . . . . .
developme
......................
ESC Guidelines 15
nt of heart . . . . . . . . . . . . . . . . . 54
failure and Figure 12 Initial
potential management of acute
corrective heart failure .....
actions . . . . . . . . . . . . . . . . . 55 Figure
.......... 13 Diuretic therapy
.......... (furosemide) in acute
.......... heart failure . . . . . . . . 56
. . . . . . 34 Figure 14 Management of
Table 11 atrial fibrillation in
Important patients with heart
characteris failure . . . . . . . . . . . . . . . .
tics and ......................
component ......................
s in a heart . 60 Figure 15 Algorithm
failure for the medical
manageme treatment of chronic
nt coronary syndrome in
programme patients with heart
.. failure with reduced
.......... ejection fraction . . . . . . . .
.......... ......................
.......... .....................
. . . 36 Table 63 Figure 16
12 Patient Management of patients
education with severe low-flow
and self- low-gradient aortic
care . . . . . . stenosis and heart failure
.......... .............
.......... . . . . . . . . . . 65 Figure 17
. . 36 Table Management of
13 Criteria secondary mitral
for regurgitation in patients
definition with heart failure and
of reduced ejection
advanced fraction . . . . . . . . . . . . . . .
. . . . . . 66 Figure 18
heart
Management of patients
failure . . . .
with cancer and heart
.........
failure . . . . . . 76 Figure
40
19 Management of
Table 14
Interagency patients with heart
Registry for failure before and during
Mechanically pregnancy . . . . . . . . . . . . .
Assisted ......................
Circulatory . . . . . . . . . . . . . . . 78
Support Figure 20 Management of
profile patients with heart
description failure and acute
s of myocarditis .....
patients ......................
with ......................
advanced . . . . . . 86 Figure 21
heart Diagnosis and treatment
failure . . . . of cardiac amyloidosis in
.......... heart failure patients . . . .
.......... ......................
.......... .....................
..........
16 ESC Guidelines
.......... 89
. 40 Table
15 Terms
describing Abbreviations
various
indications
and acronyms
for 6MWT 6-minute walk
test
mechanical
99m Tc-PYP
circulatory Technetium-
support . . . . . . labelled
............. pyrophosph
............. ate
............. AATAC
. . . 44 Table 16 Amiodarone for
Patients Treatment of
potentially At
ria
eligible for
l
implantation
Fi
of a left
br
ventricular ill
assist device . . ati
............. on
............. in
............. Pa
. . . 44 Table 17 tie
Heart nt
transplantatio s
n: indications W
it
and
h
contraindicatio
Congestive Heart
ns . . . . . . . . . . .
Failure and an
............. Implanted
............. ICD/CRTD (trial)
............. AC
45 Table 18 cardiomyopathy
Patients with ACE
heart failure in converting enzyme
whom end-of- ACE-I
life care converting enzyme
should be inhibitor
considered . . . ACHD
.............
............. Adult
.............
congenital
. . . . 46 Table
heart disease
19 Key
ACS
components of
palliative care
service in Acute
patients coronary
with syndrome
advanced ADHF
heart decompensated heart
failure .. failure
.......... AF Atrial fibrillation
.......... AF-CHF
.......... Congestive Heart
46 Table 20 Fa
Diagnostic
ilu
re
tests in
ESC Guidelines 17
patients (tr
with acute ial
heart )
failure . . . .
. . . . . 48
Table 21
Clinical
presentatio
ns of acute
heart
failure . . . .
..........
. . 49 Table
22
Inotropes
and/or
vasopressor
s used to
treat acute
heart
failure . . . .
..........
..........
..........
..........
..........
. . . . . . . 57
Table 23
Cancer
drugs
causing
heart
failure . . . .
..........
..........
. 75 Table
24
Infections
in patients
with heart
failure . . . .
..........
. . . . . . . 77
Table 25
Possible
causes and
disease
modifiers of
most
frequent
cardiomyop
athies ..
..........
..........
..........
..........
. . . . . . . 80
Table 26
Initial
18 ESC Guidelines
diagnostic
assessment
in patients
with
suspected
cardiomyop
athy . . . . . .
..........
..........
..........
..........
. . . . . 80
Table 27
Dilated
cardiomyop
athy or
hypokinetic
non-dilated
cardiomyopath
y: specific
aspects of
diagnosis and
treatment . . . .
. . . . . 81 Table
28
Hypertrophic
cardiomyopath
y: specific
aspects of
diagnosis
and
treatment. .
..........
..........
..........
..........
. 82 Table
29
Arrhythmog
enic
cardiomyop
athy:
specific
aspects of
diagnosis
and
Treatment .
..........
..........
..........
..........
. . 83 Table
30
Aetiologies
to be
considered
triggering
acute
myocarditis
ESC Guidelines 19
....
.............
.............
.............
............
84 Table 31
Diagnostic
workup in
suspected
acute
myocarditis . . .
. . . . . . 85
Table 32
Endomyocardi
al biopsy in
patients with
suspected
myocarditis
...
............
............
............
............
. . . . 86 Table
33 Cardiac
magnetic
resonance in
patients with
suspected
myocarditis
...
............
............
............
............
. . . . 87 Table
34 Treatment
and follow-up
of acute
myocarditis . .
...........
87 Table 35
“Red flags”
for most
common
forms of
cardiac
amyloidosis
..
..........
..........
..........
..........
..........
. . . 88 Table
36
Treatment
of adult
congenital
heart
2021
ESC Guidelines
disease and
..........
..........
..........
centres . . .
specialized
. . . . . . . 90
failure in
heart
20
ESC Guidelines 21
AFFIRM Atrial Fibrillation .................................................................................................... CHARM
Candesarta
Follow-up n in Heart
.......................................................................
AFFIRM- Investigation of CHF Failure -
AHF Rhythm CI Assessment
Management (trial) CKD of
A Randomized, CMP moRtality
Double-blind CMR and
Placebocontrolled CMV Morbidity
Trial Comparing COAPT
(trial)
AHF the Effect of Chronic
AL Intravenous Ferric heart
AL-CA Carboxymaltose failure
on Hospitalizations COC Confidence
AMICA and Mortality in interval
Irondeficient COMMANDChronic
ANCA Subjects Admitted ER-HF kidney
ARB for Acute Heart disease
ARNI Failure (trial) Cardiomyo
ARVC Acute heart failure pathy
Light Cardiac
ATTR magnetic
chain
AV resonance
immun
b.i.d. oglobuli COMPASS Cytomegalo
BAG3 virus
n Light Cardiovasc
BiVAD
chain ular
BMI COPD
immun
BNP
oglobuli CORONA Outcomes
BP Assessment
b.p.m. n
COVID-19 of the
BTB cardiac MitraClip
CR
BTC amyloid
CREDENCE Percutaneo
BTD osis us Therapy
BTR Atrial Fibrillation for HF
B Management in
CRT patients
T Congestive
CRT-D with
T Heart Failure With
functional
Ablation (trial)
Antineutrophil CRT-P mitral
C CSA regurgitatio
cytoplasmic
A CT n
antibody
Angiotensin- CTCA (trial)
CABANA receptor blocker Cardio-
Angiotensin CV Oncology
CABG receptor-neprilysin DAPA-HF Council
CAD inhibitor (part of the
CANVAS-R Arrhythmogenic DCM European
DECL Society of
right ventricular
CARE-HF ARET Cardiology)
cardiomyopathy
CASTLE- IMI A Study to
Transthyretin
AF 58 Assess the
amyloidosis
Effectivene
Atrio-ventricular
Bis in die (twice DIAMOND ss and
CCB daily) Safety of
CCS Bcl2-associated Rivaroxaba
CHA2DS2- athanogene 3 n in
VASc Biventricular assist DIG Reducing
device DNA the Risk of
Body mass index DOAC Death,
B-type natriuretic DPD Myocardial
peptide Infarction
CHAMPIT Blood pressure or Stroke in
Beats per minute
Participants
B
With Heart
r
22 ESC Guidelines
i Failure and
d Coronary
g Artery
e Disease
Following
an
t Episode of
o Decompens
ated Heart
b Failure
r (trial)
i Rivaroxaba
d n for the
Prevention
g
of Major
e
Cardiovasc
ular Events
B in Coronary
r or
i Peripheral
d Artery
g Disease
e (trial)
Chronic
obstructive
t pulmonary
o disease
COntrolled
c ROsuvastati
a n
n multiNAtio
nal
d
(trial)
i
Coronaviru
d
s disease
a 2019
c Controlled
y release
Bridge to decision Canagliflozi
Bridge to recovery n and Renal
Bridg Endpoints
e to in
trans Diabetes
plant with
ation Established
Cardi Nephropat
hy
ac
Clinical
amyl
Evaluation
oidos (trial)
is (or Cardiac
amyl resynchro
oid nization
cardi therapy
omy Cardiac
opat resynchro
hy) nization
Catheter ABlation therapy
vs. ANti-arrhythmic with
drug therapy for defibrillat
Atrial fibrillation or
(trial) Cardiac
Coronary artery resynchroni
bypass graft zation
ESC Guidelines 23
Coronary artery therapy
disease pacemaker
CANagliflozin Central
cardioVascular sleep
Assessment apnoea
Study - Renal Computed
CArdiac tomograph
REsynchronization y
in Heart Failure Computed
Catheter Ablation tomograph
versus Standard y coronary
conventional angiograph
Treatment in y
patients with LEft Cardiovasc
ventricular and ular
Atrial Fibrillation Dapagliflozi
(trial) n And
Calcium channel Prevention
blocker of
Chronic coronary Adverseout
syndrome comes in
Congestive heart Heart
failure or left Failure
ventricular (trial)
dysfunction, Dilated
Hypertension, Age cardiomyop
>_75 athy
(doubled), Dapagliflozi
Diabetes, Stroke n Effect on
Cardiovasc
(doubled)Vascular
uLAR
disease, Age 6574, Events
Sex category (Thromboly
(female) (score) sis in
Acute Coronary Myocardial
syndrome/Hyperten Infarction)
sion (trial)
emergency/Arrhyth Patiromer
mia/acute for the
Mechanical Manageme
nt of
cause/Pulmonary
Hyperkale
embolism/Infection
mia in
s/
Subjects
Tamponade Receiving
RAASi
Medication
s for the
Treatment
of Heart
Failure
(trial)
Digitalis
Investigatio
n Group
(trial)
Deoxyribon
ucleic acid
Direct-
acting oral
anticoagula
nt
3,3-
diphosphon
2021
ESC Guidelines
propanodic
arboxylic
o-1,2-
acid
.
24
ESC Guidelines 25
DPP-4 Dipeptidyl .......................................................................................................... HCM Hypertrophi
DSC2 peptidase-4 HEART c
Desmocollin
................................................................. cardiomyop
DSG2 HER2
DSP 2 HF athy
DT Desmoglein HFA Heart
2
E/e0 (ratio) HFA-PEFF Failure
Desmoplaki Revascularis
n ation Trial
Destination Human
EACVI
therapy epidermal
E/e0 (ratio) growth
factor
EAST-AFNET = early receptor 2
4 filling
Heart failure
velocity on HF-MP Heart
ECG transmitral HFmrEF Failure
EchoCRT Doppler/e Association
arly HFpEF Heart
ECLS relaxation HFrEF Failure
ECMO HHV
velocity on Association
E HIV
tissue HLA-DR of ESC
F
Doppler HMDP diagnostic
European HR algorithm, P
e Association H Initial
G of T Workup
F Cardiovascu
R (Step 1:
lar
H Pretest
Imaging
(part of the T Assessment)
E
European M ,E-
H
Society of i.v. Diagnostic
R
Cardiology) IABP Workup
A ICCU
Early (Step 2:
EMA ICD
Treatment Echocardiog
EMB ICU
of Atrial raphic and
EMPA-REG IHD
Fibrillation Natriuretic
OUTCOME for INR
Peptide
Stroke INTERMAC
EMPEROR Prevention S score), F1
Reduced Trial 4 (trial) Advanced
Electrocardi INTrEPID Workup
EROA ogram (Step 3:
ESC Echocardiog Functional
EU raphy IOCM testing in
EuroSCORE Guided IPD Case of
II Cardiac I-
Resynchroni Uncertainty)
PRESERVE
FDA zation , F2
FDG Therapy KCNH2 Aetiological
FiO2 (trial) Workup
FLN Extracorpor KCNQ1 (Step 4:
FLNC eal life Final
GGT support Aetiology)
LA
GISSI-HF Extracorpor Heart failure
LAE
eal managemen
LBBB
membrane t
LDB3
oxygenation
GLP-1 LFT programme
Ejection
GUIDE- LGE Heart failure
fraction
HF LMNA with mildly
Estimated
LMWH reduced
glomerular
h LUS ejection
filtration
LV fraction
rate
LVAD Heart failure
H European
with
26 ESC Guidelines
2 Heart preserved
F Rhythm ejection
P Association fraction
European Heart failure
E
Medicines with
F Agency reduced
Endomyoca ejection
rdial biopsy fraction
Empagliflozi Human
n herpes virus
Cardiovascu Human
lar Outcome immunodefi
Event Trial ciency virus
HbA1c in Type 2 Human
Diabetes leukocyte
Mellitus antigen-DR
Patients isotype
(trial) Hydroxyl-
EMPagliflozi methylene-
n outcomE diphosphon
tRial in ate
Patients Hazard ratio
With Heart
chrOnic transplantati
heaRt on
Failure With Home
Reduced telemonitori
Ejection ng
Fraction Intravenous
(trial) Intra-aortic
Effective balloon
regurgitant pump
orifice area Intensive
European coronary
Society of care unit
Cardiology Implantable
European cardioverter
Union -defibrillator
European Intensive
System for care unit
Cardiac Ischaemic
Operative heart
Risk disease
Evaluation II Internationa
(score) l normalized
Food and ratio
Drug Interagency
Administrati Registry for
on Mechanicall
Fluorodeoxy y
glucose Assisted
Fraction of Circulatory
inspired Support
oxygen Investigatio
Filamin n of
Filamin C Nontranspla
Gamma- nt-Eligible
glutamyl Patients
transferase Who Are
Gruppo Inotrope
Italiano per Dependent
lo Studio (trial)
della Iron
Streptochin overload
asi cardiomyop
ESC Guidelines 27
nell’Infarto athy
Miocardico Individual
Heart patient data
Failure Irbesartan in
(trial) Patients
Glucagon- with Heart
like peptide- Failure and
1 PRESERVEd
Hemodyna Ejection
2021
mic-GUIDEd Fraction
Manageme (trial)
nt of Potassium
Heart voltage-
Failure gated
(trial) channel
Hour/hours subfamily
Heavy H member 2
(BMI>30 Potassium
kg/m2), voltage-
Hypertensiv gated
e (use of channel
>_2 subfamily
antihyperte Q member 1
nsive Left
medications atrium/atrial
), atrial Left atrial
Fibrillation enlargement
(paroxysmal Left bundle
or branch
persistent), block
Pulmonary LIM domain
hypertensio binding 3
n (Doppler Liver
Echocardiog function test
raphic Late
estimated gadolinium
Pulmonary enhanceme
Artery nt
Systolic Lamin A/C
Pressure Low-
>35 mmHg), molecular-
Elderly weight
(age >60 heparin
years), Lung
Filling ultrasound
pressure Left
(Doppler ventricular/
Echocardiog ventricle
raphic E/e0 Left
>9) (score) ventricular
Glycated assist device
haemoglobi
n
.
28 ESC Guidelines
LVEDP Left .................................................................................................... PLN Phospholamban
LVEF ventricular PPCM Peripartum
end-diastolic
.......................................................................
LVESD PREVEND cardiomyopathy
LVH pressure Prevention of
LVNC Left PV REnal and Vascular
LVOT ventricular PVC ENd-stage
LVOTO ejection PVI Disease (trial)
MADIT-CRT fraction p Pulmonary vein
Left V Premature
ventricular ventricular
O
MADIT-II end-systolic 2
contraction
diameter Pulmonary vein
MADIT-RIT Left isolation
ventricular Q Peak exercise
hypertrophy I oxygen
Left QOL consumption
MAGGIC
ventricular QRS Quality indicator
non- RAAS Quality of life
MCS compaction RACE II Q, R, and S waves
MEK Left on an ECG
MI ventricular Renin-angiotensin-
MITRA-FR outflow tract
RAFT aldosterone
Left system
ventricular RASi Rate Control
MMR outflow tract RATE-AF Efficacy in
MR obstruction Permanent Atrial
MRA Multicenter
RBM20 Fibrillation: a
MRI Automatic
RCT Comparison
mRNA Defibrillator
REMATCH between Lenient
MR-proANP Implantation
M versus Strict Rate
Trial with
T Cardiac Control II (trial)
Resynchroniz REVERSE Resynchronization
ation /Defibrillation for
M
Therapy Ambulatory Heart
V REVIVED Failure Trial (trial)
(trial)
Multicenter Renin-angiotensin
m Automatic RNA system inhibitor
W Defibrillator RRT Rate Control
H Implantation RV Therapy
O RVAD Evaluation in
Trial II (trial)
MYPC RVEDP Permanent Atrial
Multicenter
NICM SARS-CoV- Fibrillation (trial)
Automatic
NKX2-5 2 Ribonucleic acid
Defibrillator
NP binding motif 20
Implantation
NSAID SAVR Randomized
Trial Reduce
NSVT SBP controlled trial
Inappropriat
NT- SCORED Randomized
e
proBNP Evaluation of
Therapy Mechanical
NYHA (trial) Assistance for the
o.d Meta-
SCN5a Treatment of
OMT Analysis
SENIORS Congestive
OSA Global Group Heart Failure (trial)
PA in Chronic REsynchronizati
PaO2 Heart Failure
on reVErses
PARADIGM- Mechanical SERVE-HF
Remodeling in
HF circulatory
support Systolic left
Mitogen- vEntricular
activated dysfunction
pCO2 S
protein (trial)
PCI G
kinase REVascularization
PCR L
Myocardial for Ischaemic
PCWP T
infarction VEntricular
2 Dysfunction (trial)
Percutaneou
ESC Guidelines 29
PEP-CHF s Repair with S- Ribonucleic acid
the MitraClip IC Renal replacement
PET Device for D therapy
PKP2 Severe Right
Functional/S SMR ventricular/ventric
econdary SPECT le
Mitral Right ventricular
Regurgitatio assist device
n (trial) Right ventricular
Mismatch end-diastolic
repair pressure Severe
Mitral acute respiratory
regurgitation syndrome
Mineralocor
coronavirus 2
ticoid
Surgical aortic
receptor
valve replacement
antagonist
Systolic blood
Magnetic
pressure
resonance
Effect of
imaging
Sotagliflozin on
Messenger
Cardiovascular and
ribonucleic
Renal Events in
acid
Patients with Type
Mid-regional
2
pro-atrial
Diabetes and
natriuretic
Moderate Renal
peptide
Impairment
Medical
Who Are at
therapy
Cardiovascular
Mitral valve
Risk (trial)
Modified
Sodium channel
World
alpha subunit 5
Health
Study of the
Organization
Effects of
Myosin-
binding Nebivolol
protein C Intervention on
Non- Outcomes and
ischaemic Rehospitalizations
cardiomyopa in
thy Seniors with Heart
NK2 Failure (trial)
transcription Treatment of
factor Sleep-Disordered
related, Breathing with
locus 5 Predominant
Natriuretic
Central Sleep
peptide
Apnea by Adaptive
Non-
Servo Ventilation
steroidal
anti- in Patients with
inflammator Heart Failure (trial)
y drug Sodium-glucose
Non- co-transporter 2
sustained Subcutaneous
ventricular implantable
tachycardia cardioverterdefibri
N-terminal llator
pro-B-type Secondary mitral
natriuretic regurgitation
peptide Single-photon
New York emission
Heart computed
Association tomography
Omne in die
30 ESC Guidelines
(once daily)
Optimal
medical
therapy
O
b
st
ru
c
ti
v
e
sl
e
e
p
a
p
n
o
e
a
P
ul
m
o
n
ar
y
ar
te
ry
Partial
pressure of
oxygen
Prospecti
ve
comparis
on of
ARNI
with ACEI
to
Determin
e Impact
on Global
Mortality
and
morbidit
y in
Heart
Failure
(trial)
Partial
pressure
of carbon
dioxide
Percutaneou
s coronary
intervention
Polymerase
chain
ESC Guidelines 31
reaction
Pulmonary
capillary
wedge
pressure
Perindopril
in Elderly
People with
Chronic
2021
Heart Failure
(trial)
Positron
emission
tomography
Plakophilin 2
.
32 ESC Guidelines
SpO2 Transcutan ..................................................................................................................... societies and
SR eous organizations.
STEMI oxygen
........................................................
Because of their
STICH saturation impact on clinical
Sinus
practice, quality
STICHES rhythm
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ST-
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STS-PROM
myocardial guidelines have
infarction been established
SZC
T2DM Surgical in order to make
T Treatment all decisions
A for transparent to the
Ischemic user. The
V
Heart recommendations
I
Failure
for formulating
(trial)
T and issuing ESC
Extended
F follow-up Guidelines can be
T of patients found on the ESC
t.i.d. from the website
TKI STICH trial (https://www.esca
TMEM43 Society rdio.org/
TNNT of Guidelines). The
TR Thoracic ESC Guidelines
TRPM4 Surgeons represent the
Predicted official position of
TSAT Risk of the ESC on a given
TSH Mortality topic and are
TTN Sodium regularly updated.
TTR zirconium In addition to
UK cyclosilicat
US the publication of
e
VAD Clinical Practice
Type 2
Val-HeFT diabetes guidelines, the
VEGF mellitus ESC carries out the
VERTIS-CV Transcathe EURObservational
ter aortic Research
valve Programme of
implantati international
VEST on registries of
Thyroid cardiovascular
VKA function (CV) diseases and
V test interventions
O Ter in die
which are
(three
2 essential to assess
times a
day) diagnostic/therap
V eutic processes,
Tyrosine
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kinase
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Transmem
VV interval
brane registries aim at
WARCEF
protein 43 providing a better
Troponin-T understanding of
wtTTR-CA Tricuspid medical practice
XL regurgitati in Europe and
on
around the world,
Transient
based on high-
receptor
quality data
potential
collected during
cation
routine clinical
channel
practice.
subfamily
ESC Guidelines 33
M Furthermore,
member 4 the ESC has
Transferrin developed and
saturation embedded in this
Thyroid- document a set of
stimulating quality indicators
hormone (QIs), which are
Titin
tools to evaluate
Transthyre
the level of
tin
implementation of
United
Kingdom the guidelines and
United may be used by
States the ESC, hospitals,
Ventricular healthcare
assist providers and
device professionals to
Valsartan measure clinical
Heart practice as well as
Failure used in
Trial (trial) educational
Vascular
programmes,
endothelia
alongside the key
l growth
factor messages from
Cardiovasc the guidelines, to
ular improve quality of
Outcomes care and clinical
Following outcomes.
Ertugliflozi The Members
n of this Task Force
Treatment were selected by
in Type 2 the ESC, including
Diabetes
representation
Mellitus
from its relevant
Participant
s With ESC sub-specialty
Vascular groups, in order to
Disease represent
(trial) professionals
Vest involved with the
Prevention medical care of
of Early patients with this
Sudden pathology.
Death Trial Selected experts
(trial)
in the field
Vitamin K
undertook a
antagonist
Oxygen comprehensive
consumpti review of the
on published
Ventricular evidence for
premature management of a
beat given condition
Versus according to ESC
Interventri Clinical Practice
cular delay
Guidelines (CPG)
interval
Committee policy.
Warfarin
and A critical
Aspirin in evaluation of
Reduced diagnostic and
Cardiac therapeutic
Ejection procedures was
Fraction
34 ESC Guidelines
(trial) performed,
Wild-type including
transthyre assessment of the
tin cardiac riskbenefit ratio.
amyloidosi The level of
s
evidence and the
Extended
strength of the
release
recommendation
1 Preamble of particular
Guidelines management
summarize and options were
evaluate available weighed and
evidence with the graded according
aim of assisting to predefined
health scales, as outlined
professionals in below.
proposing the best The experts of
management the writing and
strategies for an reviewing panels
individual patient provided
with a given declaration of
condition. interest forms for
Guidelines and all relationships
their that might be
recommendations perceived as real
should facilitate or potential
decision making of sources of
health conflicts of
professionals in interest. Their
their daily practice. declarations of
However, the final
interest were
decisions
reviewed
concerning an
according to the
individual patient
ESC declaration of
must be made by
interest rules and
the responsible
can be found on
health
the ESC website
professional(s) in
(http://www.escar
consultation with
dio.org/
the patient and
guidelines) and
caregiver as
have been
appropriate.
A great number of compiled in a
guidelines have been report and
issued in recent years published in a
by the European supplementary
Society of Cardiology document
(ESC), as well as by simultaneously to
other the guidelines.
This process
ensures
transparency and
prevents potential
biases in the
development and
review processes.
Any changes in
declarations of
interest that arise
during the writing
ESC Guidelines 35
period were
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.
The Committee is
also responsible
for the
endorsement
process of these
Guidelines. The
ESC Guidelines
undergo extensive
review by the CPG
and external
experts. After
appropriate
revisions the
guidelines are
signed-off by all
the experts
involved in the
Task Force. The
finalized
document is
signed-off by the
CPG for
publication in the
European Heart
Journal. The
guidelines were
developed after
careful
consideration of
the scientific and
medical
knowledge and
the evidence
available at the
time of their
dating.
The task of
developing ESC
Guidelines also
includes the
creation of
educational tools
and
implementation
programmes for
36 ESC Guidelines
the
recommendations
including
condensed pocket
guideline versions,
summary slides,
summary cards for
non-specialists
and an electronic
version for digital
2021
ESC Guidelines 37
Table 1 Classes of recommendations
2021
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 2021
evidence C retrospective studies, registries.
applications (smartphones, etc.). These versions are

abridged and thus, for more detailed information, the
user should always access to the full text version of the judgment, as well as in the determination and the
guidelines, which is freely available via the ESC website implementation of preventive, diagnostic, or
and hosted on the EHJ website. The National Cardiac therapeutic medical strategies. However, the ESC
Societies of the ESC are encouraged to endorse, adopt, Guidelines do not override in any way whatsoever the
individual responsibility of health professionals to
translate and implement all ESC Guidelines. ..............................
make appropriate and accurate decisions in
Implementation programmes are needed because it
consideration of each patient’s health condition and in
has been shown that the outcome of disease may be consultation with that patient or the patient’s
favourably influenced by the thorough application of caregiver where appropriate and/or necessary. It is
clinical recommendations. also the health professional’s responsibility to verify
Health professionals are encouraged to take the ESC the rules and regulations applicable in each country to
Guidelines fully into account when exercising their clinical drugs and devices at the time of prescription.
Introduction .
2 ... New recommendations
Recommendations Class
Recommendations for the diagnosis of HF

38 ESC Guidelines
Right heart catheterization should be considered in patients
the experts consulted in its development.ESC CPG Committee. As such, where HF is thought to be due to constrictive pericarditis, it
is a consensus/majority opinion ofForce (including two patient restrictive cardiomyopathy, congenital heart disease, and IIa
representatives), the reviewers, and theguideline provides practical, high output states.
evidence-based recommendations.The aim of this ESC Guideline is to
Right heart catheterization may be considered in selected
help health professionals managepeople with heart failure (HF) IIb
patients with HFpEF to confirm the diagnosis.
according to the best available evi-dence. Fortunately, we now have a
Recommendations for treatment of chronic HF
wealth of clinical trials to help usselect the best management to
improve the outcomes for peoplewith HF; for many, it is now both HFrEF
preventable and treatable. ThisIn addition to the recommendations Dapagliflozin or empagliflozin are recommended for
2021
patients with HFrEF to reduce the risk of HF hospitalization I
listed below, the following tableGuidelines2.1lists some new concepts and death.
compared with the 2016 version.tion the treatment effect supported by
the class and level of evidenceand are presented in tables. For HF with Vericiguat may be considered in patients in NYHA class IIIV
who have had worsening HF despite treatment with an ACE-
reduced ejection fraction(bidity outcomes. Where there are
I IIb
symptomatic benefits, these arehighlighted in the text and/or in the
(or ARNI), a beta-blocker and an MRA to reduce the risk of
web appendices. Detailed sum-maries of the trials underpinning the
CV mortality or HF hospitalization.
recommendations are availablein the web appendices. For diagnostic
indications, we have suggestedinvestigations that all patients with HF HFmrEF
should receive, and investiga-tions that can be targeted to specific An ACE-I may be considered for patients with HFmrEF to
IIb
circumstances. As diagnostictests have rarely been subject to reduce the risk of HF hospitalization and death.
randomized controlled trials(tion (AF), and asymptomatic left An ARB may be considered for patients with HFmrEF to
IIb
ventricular (LV) systolic dysfunction]However, that does not mean that reduce the risk of HF hospitalization and death.
there A beta-blocker may be considered for patients with HFmrEF
IIb
has to reduce the risk of HF hospitalization and death.
A change of the term ‘heart failure with mid-range ejection fraction’
to ‘heart failure with mildly reduced ejection fraction’ (HFmrEF). not An MRA may be considered for patients with HFmrEF to
IIb
been reduce the risk of HF hospitalization and death.
A new simplified treatment algorithm for HFrEF.
Sacubitril/valsartan may be considered for patients with
The addition of a treatment algorithm for HFrEF according to IIb
phenotypes. HFmrEF to reduce the risk of HF hospitalization and death.
Modified classification for acute HF. HFpEF
Updated treatments for most non-cardiovascular comorbidities Screening for, and treatment of, aetiologies, and CV and
including diabetes, hyperkalaemia, iron deficiency, and cancer. nonCV comorbidities are recommended in patients with I
HFpEF (see relevant sections of this document).
ESC 2021
Updates on cardiomyopathies including the role of genetic testing

and new treatments. Prevention and monitoring
The addition of key quality indicators. Self-management strategies are recommended to reduce
I
appropriatetreatment of HF, not on its prevention. Management of CV the risk of HF hospitalization and mortality.
risk andmany CV diseases [especially systemic hypertension, diabetes Either home-based and/or clinic-based programmes
melli-tus, coronary artery disease, myocardial infarction (MI), atrial improve outcomes and are recommended to reduce the risk I
of HF hospitalization and mortality.
fibrilla-will reduce the risk of developing HF, which is addressed by
manyother ESC Guidelines and inrigorous evaluation of diagnostic Influenza and pneumococcal vaccinations should be
IIa
tests.its diagnosis and management. The therapy recommendations considered in order to prevent HF hospitalizations.
men-HFrEF), the tabular recommendations focus on mortality and A supervised, exercise-based, cardiac rehabilitation
morRCTs), most of the evidence would be regarded as level C.New programme should be considered in patients with more IIa
conceptsThis guideline is the result of a collaboration between the severe disease, frailty, or with comorbidities.
TaskWe have revised the format of the previous 2016 ESC HFIn this Non-invasive HTM may be considered for patients with HF
in order to reduce the risk of recurrent CV and HF
guideline, we have decided to focus on the diagnosis and What is IIb
hospitalizations and CV death.
new1 to make each phenotype of HF stand-alone in terms ofsection
Recommendations for management of patients with advanced
9.1 of the current guideline.27 - HF
.......................................................................................
Patients being considered for long-term MCS must have
...
...................................... good compliance, appropriate capacity for device handling I
and psychosocial support.
ESC Guidelines 39
Heart transplantation is recommended for patients with
.....
advanced HF, refractory to medical/device therapy and I .....
who do not have absolute contraindications.
.....
Continuous inotropes and/or vasopressors may be .....
considered in patients with low cardiac output and evidence
of organ hypoperfusion as bridge to MCS or heart
IIb ..
transplantation.
Recommendations for management of patients after HF hospitalization
It is recommended that patients hospitalized for HF be

carefully evaluated to exclude persistent signs of congestion I
before discharge and to optimize oral treatment.
It is recommended that evidence-based oral medical
I
treatment be administered before discharge.
An early follow-up visit is recommended at 12 weeks after
discharge to assess signs of congestion, drug tolerance, and I
start and/or uptitrate evidence-based therapy.
Recommendations for management of patients with HF and atrial

fibrillation
Long-term treatment with an oral anticoagulant should be HF = heart failure. ..................
considered for stroke prevention in AF patients with a IIa Continued
CHA2DS2-VASc score of 1 in men or 2 in women.
.............................SGLT2 inhibitors (dapagliflozin, empagliflozin, and
Recommendations for management of patients with HF and sotagliflo-zin) are recommended in patients with T2DM and HFrEF toreduce
CCS hospitalizations for HF and CV death.The DPP-4 inhibitor saxagliptin is not
CABG should be considered as the first-choice recommended inRecommendations for management of patients with HF
revascularization strategy, in patients suitable for surgery, anddiabetesSGLT2 inhibitors (canagliflozin, dapagliflozin,
IIa
especially if they have diabetes and for those with empagliflozin,ertugliflozin, sotagliflozin) are recommended in patients withT2DM at
multivessel disease. risk of CV events to reduce hospitalizations for HF,major CV events, end-stage renal
In LVAD candidates needing coronary revascularization, dysfunction, and CV death. II
IIa
CABG should be avoided, if possible.
Coronary revascularization may be considered to improve
outcomes in patients with HFrEF, CCS, and coronary
anatomy suitable for revascularization, after careful
evaluation of the individual risk to benefit ratio, including
IIb
coronary anatomy (i.e. proximal stenosis >90% of large
vessels, stenosis of left main or proximal
LAD), comorbidities, life expectancy, and patient’s
perspectives.
PCI may be considered as alternative to CABG, based on
Heart Team evaluation, considering coronary anatomy, IIb
comorbidities, and surgical risk.
Recommendations for management of patients with HF and valvular

heart disease
Aortic valve intervention, TAVI or SAVR is recommended in
patients with HF and severe high-gradient aortic stenosis to I
reduce mortality and improve symptoms.
It is recommended that the choice between TAVI and SAVR

be made by the Heart Team, according to individual patient
preference and features including age, surgical risk, clinical, I
............................Recommendations for management of patients with HF
anatomical and procedural aspects, weighing the risks and andpatients with HF.iron deficiencyIt is recommended that all patients with HF are
benefits of each approach. periodicallyscreened for anaemia and iron deficiency with a full bloodcount, serum
ferritin concentration, and TSAT.should be considered in symptomatic HF patients
Percutaneous edge-to-edge mitral valve repair should be recently hospi-Intravenous iron supplementation with ferric carboxymaltosetalized
considered in carefully selected patients with secondary for HF and with LVEF <_50% and iron deficiency, defined IIaIIII
mitral regurgitation, not eligible for surgery and not needing
IIa
coronary revascularization, who are symptomatic despite
OMT and who fulfil criteria to achieve a reduction in HF
hospitalizations.
Percutaneous edge-to-edge mitral valve repair may be
considered to improve symptoms in carefully selected
patients with secondary mitral regurgitation, not eligible for
surgery and not needing coronary revascularization, who IIb
are highly symptomatic despite OMT and who do not fulfil
criteria for reducing HF hospitalization.
40 ESC Guidelines
...........as serum ferritin <100 ng/mL or serum ferritin 100with TSAT <20%, to
reduce the risk of HF hospitalization.Treatment of anaemia in HF with erythropoietin stimulating299 ng/mL
Downloaded from https://academic.oup.com/eurheartj/advance-article/doi/10.1093/eurheartj/ehab368/6358045 by guest on 27 August 2021

... agents is not recommended in the absence of other indica- III
ESC 2021
..................................................................................Tafamidis is recommended in patients
with wtTTR-CA andtalization and mortality.NYHA class I or II symptoms to reduce symptoms, CV hospi-tions for this therapy.ven hereditary hTTR-CMP and
NYHA class I or II symptoms toamyloidosisTafamidis is recommended in patients with genetic testing pro-reduce symptoms, CV hospitalization and mortality.A
baseline CV risk assessment should be considered in allcancer patients scheduled to receive a cancer treatment withthe potential to cause
HF.Recommendations for treatment of patients with HF andcancerIt is recommended that cancer patients at increased risk for cardi-otoxicity, defined by a
history or risk factors of CV disease, pre-vious cardiotoxicity or exposure to cardiotoxic agents, undergoCV evaluation before scheduled anticancer therapy,
preferably bya cardiologist with experience/interest in Cardio-Oncology.Treatment with an ACE-I and a beta-blocker (preferably carvedi-lol) should be
considered in cancer patients developing LV systolicRecommendations for management of patients with HF andvalue lower than 50%, during anthracycline
chemotherapy.dysfunction, defined as a 10% or more decrease in LVEF and to a gestive heart failure or left ventricular dysfunction, Hypertension, Age >_75artery bypass
graft; CCS = chronic coronary syndrome; CHAblocker;ACE-I = angiotensin-convertingARNI = angiotensinreceptor-neprilysinenzymeinhibitor; inhibitor;ARB = angiotensin-
receptorCABG = coronary2DS2-VASc = conIIaIIaIII -
ESC Guidelines 41
................... ing; hTTR = hereditary transthyretin; LAD = left anterior descending artery; LV
=reduced ejection fraction; HFpEF = heart failure with preserved ejection fraction;dipeptidyl peptidase-4; HF = heart failure; HFmrEF = heart failure with mildlygory(tion fraction;
MCS = mechanical circulatory support; MRA = mineralocorticoidleft ventricular; LVAD = left ventricular assist device; LVEF = left ventricular ejec-HFrEF = heart failure with reduced
ejection fraction; HTM = home telemonitor-doubled), Diabetes, Stroke (doubled)-Vascular disease, Age(female)(score); CMP = cardiomyopathy; CV = cardiovascular;6574, Sex
cateDPP-4 =-
......medicalreceptor therapy;antagonist;PCI = percutaneousNYHA = New YorkcoronaryHeart

intervention;Association; SAVR = surgicalOMT = optimal
Continued aortic valve replacement; SGLT2 = sodium-glucose co-transporter 2; T2DM = type 2

diabetes mellitus; TAVI = transcatheter aortic valve implantation; TSAT =
transferrin saturation; wtTTR-CA = wild-type transthyretin cardiac amyloidosis.
42 ESC Guidelines
Changes in recommendations
2021 Class 2016 Class
Recommendations for diagnosis of HF

Invasive coronary angiography may be considered in Invasive coronary angiography should be considered in
patients with HFrEF with an intermediate to high pre-test patients with HF and intermediate to high pre-test
probability of CAD and the presence of ischaemia in probability of CAD and the presence of ischaemia in non-
noninvasive stress tests. IIb invasive stress tests (who are considered suitable for IIa
potential coronary revascularization) in order to establish
2021
the diagnosis of CAD and its severity.
CTCA should be considered in patients with a low to Cardiac CT may be considered in patients with HF and
intermediate pre-test probability of CAD or those with low to intermediate pre-test probability of CAD or those
equivocal non-invasive stress tests in order to rule out IIa with equivocal non-invasive stress tests in order to rule IIb
coronary artery stenosis. out coronary artery stenosis.
Right heart catheterization may be considered in patients Right heart catheterization with a pulmonary artery
with probable pulmonary hypertension, assessed by echo catheter should be considered in patients with probable
in order to confirm the diagnosis and assess its pulmonary hypertension assessed by echocardiography in
IIb IIa
reversibility before the correction of valve/structural order to confirm pulmonary hypertension and its
heart disease. reversibility before the correction of valve/structural
heart disease.
Recommendations for device therapy in HFrEF
An ICD should be considered to reduce the risk of Primary prevention
sudden death and all-cause mortality in patients with An ICD is recommended to reduce the risk of sudden
symptomatic HF (NYHA class IIIII) of a non-ischaemic death and all-cause mortality in patients with
aetiology, and an LVEF <_35% despite >_3 months of symptomatic HF (NYHA class IIIII), and an LVEF <_35%
IIa I
OMT, provided they are expected to survive despite >_3 months of OMT, provided they are expected
substantially longer than 1 year with good functional to survive substantially longer than 1 year with good
status. functional status, and they have DCM.
CRT should be considered for symptomatic patients with CRT is recommended for symptomatic patients with HF
HF in sinus rhythm with a QRS duration of 130149 ms and in sinus rhythm with a QRS duration of 130149 ms and
LBBB QRS morphology and with LVEF <_35% despite OMT IIa LBBB QRS morphology and with LVEF <_35% despite I
in order to improve symptoms and reduce morbidity and OMT in order to improve symptoms and reduce
mortality. morbidity and mortality.
Patients with an LVEF <_35% who have received a Patients with HFrEF who have received a conventional
conventional pacemaker or an ICD and subsequently pacemaker or an ICD and subsequently develop
develop worsening HF despite OMT and who have a IIa worsening HF despite OMT and who have a high IIb
significant proportion of RV pacing should be considered proportion of RV pacing may be considered for upgrade
for ‘upgrade’ to CRT. to CRT. This does not apply to patients with stable HF.
Recommendations for management of patients with acute HF

Combination of a loop diuretic with thiazide-type Combination of loop diuretic with either thiazide-type
diuretic should be considered in patients with resistant diuretic or spironolactone may be considered in patients with
oedema who do not respond to an increase in loop IIa resistant oedema or insufficient symptomatic response. IIb
diuretic doses.
In patients with AHF and SBP >110 mmHg, i.v. vasodilators In patients with hypertensive AHF, i.v. vasodilators should
may be considered as initial therapy to improve symptoms IIb be considered as initial therapy to improve symptoms and IIa
and reduce congestion. reduce congestion.
Routine use of opiates is not recommended, unless in Opiates may be considered for cautious use to relieve
selected patients with severe/intractable pain or anxiety. III dyspnoea and anxiety in patients with severe dyspnoea IIb
but nausea and hypopnea may occur.
Short-term MCS should be considered in patients with Short-term MCS may be considered in refractory cardiogenic
cardiogenic shock as a BTR, BTD, BTB. Further indications shock depending on patient age, comorbidities, and
include treatment of the cause of cardiogenic shock or IIa neurological function. IIb
long-term MCS or transplantation.
Continued
ESC Guidelines 43
2021
AF = atrial fibrillation; AHF = acute heart failure; AV = atrio-ventricular; BTB = bridge to bridge; BTD = bridge to decision; BTR = bridge to cardiac recovery; CAD = coronary
artery disease; CCS = chronic coronary syndrome; CHA 2DS2-VASc = congestive heart failure or left ventricular dysfunction, Hypertension, Age >_75 (doubled), Diabetes,
Stroke (doubled)-Vascular disease, Age 6574, Sex category (female) (score); CRT = cardiac resynchronization therapy; CT = computed tomography; CTCA = computed
tomography coronary angiography; CV = cardiovascular; DCM = dilated cardiomyopathy; DOAC = direct oral anticoagulant; HF = heart failure; HFrEF = heart failure with
reduced ejection fraction; ICD = implantable cardioverter-defibrillator; LBBB = left bundle branch block; LVEF = left ventricular ejection fraction; MCS = mechanical circulatory
support; NOAC = non-vitamin K antagonist oral anticoagulant; NYHA = New York Heart Association; OMT = optimal medical therapy; QRS = Q, R, and S waves (combination of
three of the graphical deflections); RV = right ventricular/ventricle; SBP = systolic blood pressure; SGLT2 = sodium-glucose co-transporter 2; T2DM = type 2 diabetes mellitus;
VKA = vitamin K antagonist.
3 Definition, .........................................................3.2 Terminology

3.2.1 Heart failure with preserved, mildly
epidemiology and prognosis reduced, and reduced ejection fraction
Traditionally, HF has been divided into
3.1 Definition of heart failure
distinct phenotypes based on the
Heart failure is not a single pathological
measurement of left ventricular ejection
diagnosis, but a clinical syndrome consisting
fraction (LVEF) (Table 3). The rationale
of cardinal symptoms (e.g. breathlessness,
ankle swelling, and fatigue) that may be behind this relates to the original
accompanied by signs (e.g. elevated jugular treatment trials in HF that demonstrated
venous pressure, pulmonary crackles, and substantially improved outcomes in
peripheral oedema). It is due to a structural patients with LVEF <_40%. However, HF
and/or functional abnormality of the heart spans the entire range of LVEF (a normally
that results in elevated intracardiac pressures distributed variable), and measurement
and/or inadequate cardiac output at rest by echocardiography is subject to
and/or during exercise. substantial variability. We have decided
Identification of the aetiology of the on the following classification of HF (Table
underlying cardiac dysfunction is mandatory 3):
in the diagnosis of HF as the specific
pathology can determine subsequent • Reduced LVEF is defined as <_40%, i.e.
treatment. Most commonly, HF is due to those with a significant reduction in LV
myocardial dysfunction: either systolic, systolic function. This is designated as
diastolic, or both. However, pathology of the HFrEF.
44 ESC Guidelines
valves, pericardium, and endocardium, and • Patients with a LVEF between 41% and
abnormalities of heart rhythm and 49% have mildly reduced LV systolic
conduction can also cause or contribute to
function, i.e. HFmrEF. Retrospective
HF.
analyses from RCTs in HFrEF or HF
with preserved ejection fraction
(HFpEF) that have included patients
with ejection fractions in the
4050% range suggest that th
2021
benefit from similar
Table 3 Definition of heart failure with reduced ejection fraction, mildly reduced ejection fraction and preserved ejection fraction
Type of HF HFrEF HFmrEF HFpEF
a a a
1 Symptoms ± Signs Symptoms ± Signs Symptoms ± Signs
CRITERIA
b
2 LVEF <_40% LVEF 41 49% LVEF >_50%
3 Objective evidence of cardiac structural and/or functional
ESC 2021
abnormalities consistent with the presence of LV diastolic
c
dysfunction/raised LV filling pressures, including raised natriuretic peptides
HF = heart failure; HFmrEF = heart failure with mildly reduced ejection fraction; HFpEF = heart failure with preserved ejection fraction; HFrEF = heart failure with reduced
ejection fraction; LV = left ventricle; LVEF = left ventricular ejection fraction.
a
Signs may not be present in the early stages of HF (especially in HFpEF) and in optimally treated patients.
b
For the diagnosis of HFmrEF, the presence of other evidence of structural heart disease (e.g. increased left atrial size, LV hypertrophy or echocardiographic measures of
impaired LV filling) makes the diagnosis more likely.
c
For the diagnosis of HFpEF, the greater the number of abnormalities present, the higher the likelihood of HFpEF.
.
renaming of HFmrEF from ‘heart failure with mid-range ejection
fraction’ to ‘heart failure with mildly reduced ejection fraction’. 14
• Those with symptoms and signs of HF, with evidence of

structural and/or functional cardiac abnormalities and/or raised
natriuretic peptides (NPs), and with an LVEF >_50%, have HFpEF.
The diagnosis of HFrEF, HFmrEF, and HFpEF is covered in more
detail in their respective sections (sections 5, 7, and 8, respectively).
These definitions are consistent with a recent report on the
Universal Definition of Heart Failure.15
Patients with non-CV disease, e.g. anaemia, pulmonary, renal, thy-
roid, or hepatic disease may have symptoms and signs very similar to
those of HF, but in the absence of cardiac dysfunction, they do not
fulfil the criteria for HF. However, these pathologies can coexist with
HF and exacerbate the HF syndrome.
3.2.2 Right ventricular dysfunction
Heart failure can also be a result of right ventricular (RV) dysfunc-
therapies to those with LVEF <_40%.813 This supports the

................................................................................................................. patients with mild symptoms may still have a
high risk of hospitaliza-tion and death.appears to be 1advanced HF to guide selection of cardiac transplantation and devicetherapies. This
will be covered in detail in the section on advancedHF (diuretic therapy in the outpatient setting. In addition, HF can presentmore acutely.
Both of these are considered in the section on AHF(Takotsubotomanydence of HF in Europe is about 3/1000 person-years (all age-groups)or
about 5/1000 person-years in adults.tachycardiomyopathy]. Other patients with LV systolic dysfunctionmay show a substantial or even
ESC Guidelines 45
complete recovery of LV systolicfunction after receiving drug and device therapy.3.2.4heart failureThe simplest terminology used to describe
the severity of HF is the(Newslowly, the episode may be described as ‘decompensated’ HF. Thiscan result in a hospital admission or
treatment with intravenous (i.v.)3.3.1In developed countries, the age-adjusted incidence of HF may be fall-ing, presumably reflecting better
management of CV disease, but dueto ageing, the overall incidence is increasing. heart failure3.3recognized/diagnosed HF cases, the
true prevalence is likely to behigher.those aged <55 years to >10% in those aged 70 years or over.section 11Table Some individuals with HF
may recover completely [e.g. those duesection 10alcohol-induced Incidence and prevalenceEpidemiology and natural history
ofTerminology related to the symptomatic severity of 32
York4other) . However, this relies solely on symptoms and there areThe prevalence
increases with age: from around 1% for ). syndrome, Heartbetter). 202 % of adults.Predicting outcome is particularly important in
Associationprognosticcardiomyopathy peripartum21,27 (indicatorsNYHA31 cardiomyopathyAs studies only usually include (25CMP),), 2621
functional The prevalence of HFin24 HF.Currently, the inci-viral19 (classificationImportantly,myocarditis,PPCM),33 36or It
tion. RV mechanics and function are altered in the setting of either
pressure or volume overload.16 Although the main aetiology of
chronic RV failure is LV dysfunction-induced pulmonary hyperten-
sion, there are a number of other causes of RV dysfunction [e.g.
MI, arrhythmogenic right ventricular cardiomyopathy (ARVC), or
valve disease].17 The diagnosis is determined by a quantitative
assessment of global RV function, most commonly by echocar-
diography, using at least one of the following measurements: frac-
tional area change (FAC); tricuspid annular plane systolic
excursion (TAPSE); and Doppler tissue imaging-derived systolic S 0
velocity of the tricuspid annulus. The diagnosis and management
of RV dysfunction is covered comprehensively in a recent Heart
Failure Association (HFA) position paper.18
3.2.3 Othercommon terminology used inheart failure
Heart failure is usually divided into two presentations: chronic heart
failure (CHF) and acute heart failure (AHF). CHF describes those
who have had an established diagnosis of HF or who have a more
gradual onset of symptoms. If CHF deteriorates, either suddenly or
those who remain stable or transition to a higher ejection

fraction category.4852
Table 4 New York Heart Association functional classification .........
HFpEF is generally considered to confer a better survival than
based on severity of symptoms and physical activity . HFrEF, but most observational studies show that this difference
is
.
in the 1990s, and then

is generally declined.54,55*,5860
believed that, of However, in a recent
those with HF, ................................................................................................................study of incident HF
about 50% have conducted between
HFrEF and 50%
46 ESC Guidelines
have 1998 and 2017 in the

HFpEF/HFmrEF, United Kingdom (UK),
mainly based on age-adjusted rates of
studies in first hospitalizations
hospitalized increased by 28% for
patients.32,35,37,38 both all-cause and HF
The ESC Long- admissions, and by 42%
Term Registry, in for non-CV
61
the outpatient admissions. These
setting, reports increases were higher
that 60% have in women, perhaps
HFrEF, 24% have related to higher
HFmrEF, and 16% comorbidity rates. The
have risk of HF
HFpEF.39 Somewhat hospitalization is 1.5
more than 50% of HF times higher in patients
patients are with diabetes
female.21,40,41 compared to controls.
AF, a higher body mass
3.3.2 Aetiologyof index (BMI), and higher
heart failure glycated haemoglobin
The most common (HbA1c), as well as a
causes (as well as low estimated
some key glomerular filtration
investigations) of rate (eGFR) are strong
HF are shown in predictors of HF
Table 5. The hospitalizations. 29
aetiology of HF Due to population

varies according growth, ageing, and the
to geography. In increasing prevalence
Western-type and of comorbidities, the
developed absolute number of
countries, hospital admissions for
coronary artery HF is expected to
disease (CAD) and increase considerably in
hypertension are the future, perhaps by
as much as 50% in the
predominant
next 25 years.24,62
factors.27
With regard to
ischaemic aetiology,
HFmrEF resembles
HFrEF, with a higher 4 Chronic
frequency of heart failure
underlying CAD
compared to those 4.1 Key steps in
with the diagnosis of
HFpEF.38,42,43 chronic heart
failure
3.3.3 Natural history The diagnosis of CHF
andprognosis requires the presence
The prognosis of of symptoms and/or
patients with HF signs of HF and
has improved objective evidence of
considerably since cardiac dysfunction
the publication of (Figure 1). Typical
the first treatment
symptoms include
trials a few
breathlessness, fatigue,
decades ago.
ESC Guidelines 47
However, it and ankle swelling
remains poor, and (Table 6). Symptoms
quality of life and signs lack sufficient
(QOL) is also accuracy to be used
markedly reduced. alone to make the
The improvement diagnosis of HF.6366
in prognosis has
The diagnosis of CHF
been confined to
is made more likely in
those with HFrEF.
patients with a history
Mortality rates
of MI, arterial
are higher in
hypertension, CAD,
observational diabetes mellitus,
studies than in alcohol misuse, chronic
clinical trials.44 In kidney disease (CKD),
the Olmsted cardiotoxic
County cohort, 1- chemotherapy, and in
year and 5-year those with a family
mortality rates history of CMP or
sudden death.
after diagnosis, for
The following
all types of HF
diagnostic tests are
patients, were recommended for the
20% and 53%, assessment of patients
respectively, with suspected chronic
between 2000 and HF:
2010.45 A study
(1) Electrocardiogram
combining the (ECG). A normal
Framingham Heart ECG makes the
Study (FHS) and diagnosis of HF
unlikely.63 The ECG
Cardiovascular
may reveal
Health Study abnormalities such
(CHS) cohorts as AF, Q waves, LV
reported a 67% hypertrophy (LVH),
and a widened QRS
mortality rate
complex (Table 7)
within 5 years that increase the
following likelihood of a
diagnosis.46 diagnosis of HF and
also may guide
Despite receiving therapy.
less evidence-
based treatment,
women have a
better survival
47
than men.
Overall
prognosis is better
in HFmrEF
compared to
HFrEF.39 Of note,
transition in
ejection fraction
over time is
common, and
patients who
progress from
HFmrEF to HFrEF
have a worse
prognosis than
48 ESC Guidelines
Class I No limitation of physical activity. Ordinary physical activity ..................................... tion in the Olmsted County cohort was 1.3 per
person-year.Interestingly, the majority (63%) of hospitalizations were related tonon-CV causes.cluded that the adjusted
mortality risk for patients with HFpEF wasconsiderably lower than in patients with HFrEF.2000year on
average.negligible.United States (US) have shown that HF hospitalization rates peakedHowever, this positive trend may
have levelled off since then.After the initial diagnosis, HF patients are hospitalized once everyStudies from several countries
2021
ESC 2021
have shown that between 1980 andsurvival 45,46 In contrast, the large MAGGIC meta-analysis con- 45in54Studies from several
European countries and theFrom 2000 to 2010, the mean rate of hospitaliza-HF patients has improved 53 markedly.4541,5457
does not cause undue breathlessness, fatigue, or palpitations.
Class II Slight limitation of physical activity. Comfortable at rest,

but ordinary physical activity results in undue
breathlessness, fatigue, or palpitations.
Class III Marked limitation of physical activity. Comfortable at rest,
but less than ordinary activity results undue
breathlessness, fatigue, or palpitations.
Class IV Unable to carry on any physical activity without discom-
fort. Symptoms at rest can be present. If any physical
activity is undertaken, discomfort is increased.
ESC Guidelines 49
2021
Figure 1 The diagnostic algorithm for heart failure. BNP = B-type natriuretic peptide; ECG = electrocardiogram; HFmrEF = heart failure with mildly
reduced ejection fraction; HFpEF= heart failure with preserved ejection fraction; HFrEF= heart failure with reduced ejection fraction; LVEF= left
ventricular ejection fraction; NT-proBNP = N-terminal pro-B type natriuretic peptide. The abnormal echocardiographic findings are described in
more detail in the respective sections on HFrEF (section 5), HFmrEF (section 7), and HFpEF (section 8).
Table 5 Causes of heart failure, common modes of presentation and specific investigations
50 ESC Guidelines
Symptoms Signs
Typical More specific
Breathlessness Elevated jugular venous pressure
Orthopnoea Hepatojugular reflux
Paroxysmal nocturnal dyspnoea Third heart sound (gallop
Reduced exercise tolerance rhythm)
Fatigue, tiredness, increased Laterally displaced apical impulse
time to recover after exercise
Ankle swelling
Less typical Less specific

Nocturnal cough Weight gain (>2 kg/week)
Wheezing Weight loss (in advanced HF)
Bloated feeling Tissue wasting (cachexia)
Loss of appetite Cardiac murmur
Confusion (especially in the Peripheral oedema (ankle,
elderly) sacral, scrotal)
Depression Pulmonary crepitations
Palpitation Pleural effusion
Dizziness Tachycardia
Syncope Irregular pulse
5-HIAA = 5-hydroxyindoleacetic acid; ACE = angiotensin-converting enzyme; ANA = anti-nuclear antibody; ANCA = anti-nuclear cytoplasmic antibody; ARVC = arrhythmogenic
Bendopneaa CMR = cardiac magnetic resonance;
right ventricular cardiomyopathy; BP = blood pressure; CAD = coronary artery disease; CMP = cardiomyopathy; Tachypnoea CK = creatinine kinase; CT
= computed tomography; ECG = electrocardiogram; Echo = echocardiography; EMB = endomyocardial biopsy; FDG = fluorodeoxyglucose; GGT =respiration
Cheyne-Stokes gamma-glutamyl
transferase; HIV = human immunodeficiency virus; h = hour; LFT = liver function test; LGE = late gadolinium enhancement; MEK = mitogen-activated protein kinase; PET =
(2) Measurement of NPsTFTare recommended, if available. Hepatomegaly
positron emission tomography; = thyroid function test; VEGF = vascular A plasma growth factor.
endothelial
concentration of B-type natriuretic peptide (BNP) <35 pg/mL, .....Table 6 Symptoms and signs typical of heart failure
Ascites
The diagnostic value of NPs, in addition
Cold extremities
BNP = B-type natriuretic peptide; ECG = electrocardiogram;
to signs Oliguria
and symptoms and other
HbA1c = glycated haemoglobin; NT-proBNP = N-terminal pro- ......................................................
B-type natriuretic peptide; TSAT = transferrin saturation. diagnosticNarrow
tests, pulse
suchpressure
as an ECG, has
ESC Guidelines 51
been assessed in several studies in the
primary care setting.68,7680 The aim of
these studies was to either exclude or
establish a diagnosis of HF. The Task
Force considered studies of adequate
quality that included NP cut-off points
in their diagnostic algorithms, below
a
which the probability of having HF was
Class of recommendation.
b
Level of evidence.
extremely low. The upper limits of
c
References are listed in normal in the non-acute setting are 35
section 4.2 for this item. pg/mL for BNP, and 125 pg/mL for NT-
proBNP. In these studies, the negative
predictive values of NP concentrations
below these thresholds range from 0.94
4.2 Natriuretic peptides to 0.98.7678 Fewer data are available for
Plasma concentrations of NPs are recommended MR-proANP in CHF than in AHF. A
as initial diagnostic tests in patients with concentration of <40 pmol/L can be
symptoms suggestive of HF to rule out the used to rule out HF.68
diagnosis. Elevated concentrations support a
diagnosis of HF, are useful for prognostication, 72
and may guide further cardiac investigation. 73 4.3 Investigations to
However, it should be noted that there are many determine the
causes of an elevated NP—both CV and non-CV—
that might reduce their diagnostic accuracy (Table underlying aetiology of
7). These causes include AF, increasing age, and chronic heart failure
acute or chronic kidney disease. 74 Conversely, NP Recommended tests to determine the
concentrations may be disproportionately low in underlying aetiology of CHF are
obese patients.75 summarized in Table 5.
.
mL, or mid-regional pro-atrial natriuretic peptide (MR-proANP) <40 pmol/L make a diagnosis of HF unlikely. These will be discussed in more
detail in section 4.2.
(3) Basic investigations such as serum urea and electrolytes, creatinine, full blood count, liver and thyroid function tests are recommended to
differentiate HF from other conditions, to provide prognostic information, and to guide potential therapy.
(4) Echocardiography is recommended as the key investigation for the assessment of cardiac function. As well as the determination of the
2021
Downloaded from https://academic.oup.com/eurheartj/advance-article/doi/10.1093/eurheartj/eha
LVEF, echocardiography also provides information on other parameters such as chamber size, eccentric or concentric LVH, regional wall
motion abnormalities (that may suggest underlying CAD, Takotsubo syndrome, or myocarditis), RV function, pulmonary hypertension,
valvular function, and markers of diastolic function.
(5) A chest X-ray is recommended to investigate other potential causes of breathlessness (e.g. pulmonary disease). It may also provide
supportive evidence of HF (e.g. pulmonary congestion or cardiomegaly).
2021
ESC
N-terminal pro-B-type natriuretic peptide (NT-proBNP) <125 pg/ 16,716869,70

....................................................................................................forward. HF = heart failure.This symptom of advanced HF corresponds
a
to shortness of breath when leaning67

68/6358045 by guest on 27 August
52 ESC Guidelines
Recommended diagnostic tests in all patients with suspected chronic heart failure
a b
Recommendations Class Level
c
BNP/NT-proBNP I B
12-lead ECG I C
Transthoracic echocardiography I C
Chest radiography (X-ray) I C
2021
Routine blood tests for comorbidities, including
full blood count, urea and electrolytes, thyroid
ESC 2021
I C
function, fasting glucose and HbA1c, lipids, iron
status (TSAT and ferritin) ..... 4.2.1 Usein thenon-acute setting
Table 7 Causes of elevated concentrations of natriuretic Computed tomography coronary angiography (CTCA) may be
peptides considered in patients with a low to intermediate pre-test
probability of CAD, or those with equivocal non-invasive stress
tests in order to exclude the diagnosis of CAD.
Single-photon emission CT (SPECT) can also be used to assess
myocardial ischaemia and viability, myocardial inflammation or
infiltration. Scintigraphy with technetium (Tc)-labelled
bisphosphonate has shown high sensitivity and specificity for
imaging cardiac transthyretin amyloid.
Recommendations for specialized diagnostic tests for selected
patients with chronic heart failure to detect reversible/treatable
causes of heart failure
Recommendations Classa Levelb
CMR
CMR is recommended for the assessment of
myocardial structure and function in those with I C
poor echocardiogram acoustic windows.
CMR is recommended for the characterization

of myocardial tissue in suspected infiltrative
disease, Fabry disease, inflammatory disease I C
(myocarditis), LV non-compaction, amyloid,
sarcoidosis, iron overload/haemochromatosis.
CMR with LGE should be considered in DCM to

distinguish between ischaemic and non- IIa C
ischaemic myocardial damage.
Invasive coronary angiography (in those who are considered eligible

for potential coronary revascularization)
ACS = acute coronary syndrome; COPD = chronic obstructive pulmonary disease;
ICD = implantable cardioverter-defibrillator.
Invasive coronary angiography is recommended
in patients with angina despite pharmacological I B
therapy or symptomatic ventricular arrhythmias.5
Invasive coronary angiography may be

Exercise or pharmacological stress echocardiography may be considered in patients with HFrEF with an
used for the assessment of inducible ischaemia in those who are intermediate to high pre-test probability of CAD IIb B
considered suitable for coronary revascularization. In patients and the presence of ischaemia in non-invasive
stress tests.89
with HFpEF, valve disease, or unexplained dyspnoea, stress
echocardiography might help clarify the diagnosis. Non-invasive testing
Cardiac magnetic resonance (CMR) imaging with late CTCA should be considered in patients with a
gadolinium enhancement (LGE), T1 mapping and extracellular low to intermediate pre-test probability of CAD
or those with equivocal non-invasive stress tests IIa C
volume will identify myocardial fibrosis/scar, which are typically
in order to rule out coronary artery stenosis.
subendocardial for patients with ischaemic heart disease (IHD) in
contrast to the mid-wall scar typical of dilated cardiomyopathy Non-invasive stress imaging (CMR, stress
(DCM). In addition, CMR allows myocardial characterization in, echocardiography, SPECT, PET) may be
considered for the assessment of myocardial
e.g. myocarditis, amyloidosis, sarcoidosis, Chagas disease, Fabry IIb B
ischaemia and viability in patients with CAD who
disease, LV non-compaction CMP, haemochromatosis, and are considered suitable for coronary
arrhythmogenic cardiomyopathy (AC). revascularization.9093
ESC Guidelines 53
Exercise testing may be considered to detect Cardiopulmonary exercise testing should be
reversible myocardial ischaemia and investigate IIb C considered to identify the cause of unexplained IIa C
the cause of dyspnoea.9496 dyspnoea and/or exercise intolerance.9496
Cardiopulmonary exercise testing Right heart catheterization

Cardiopulmonary exercise testing is Right heart catheterization is recommended in
recommended as a part of the evaluation for I C patients with severe HF being evaluated for I C
heart transplantation and/or MCS.9496 heart transplantation or MCS.
Continued
Cardiopulmonary exercise testing should be
considered to optimize prescription of exercise IIa C
training.9496
CAD = coronary artery
disease; CMR = cardiac
................................................................................................... the reduction of mortality
magnetic resonance; . (either all-cause or CV). The
CTCA = computed recommendations for each
tomography coronary treatment are summarized
angiography; DCM =
below.
dilated cardiomyopathy;
EMB = endomyocardial
biopsy; HF = heart failure;
HFpEF = heart failure with
preserved ejection
5.2.2 General principles
fraction; HFrEF = heart of pharmacotherapy for
failure with reduced heart failure with reduced
ejection fraction; LGE =
ejection fraction
late gadolinium
enhancement; LV = left Modulation of the renin-
ventricular; MCS = angiotensin-aldosterone
mechanical circulatory
support; PET = positron
(RAAS) and sympathetic
emission tomography; nervous systems with
SPECT = single-photon angiotensin-converting
emission computed
tomography. aClass of enzyme inhibitors (ACE-I) or
recommendation. bLevel an angiotensin receptor-
of evidence. neprilysin inhibitor (ARNI),
beta-blockers, and
mineralocorticoid receptor
Coronary antagonists (MRA) has been
angiography is shown to improve survival,
recommended in reduce the risk of HF
patients with HF, who hospitalizations, and reduce
have angina pectoris or symptoms in patients with
an ‘angina equivalent’
HFrEF. These drugs serve as
despite
the foundations of
pharmacological
pharmacotherapy for
therapy, in order to
patients with HFrEF. The
establish the diagnosis
triad of an ACE-I/ARNI, a
of CAD and its severity.
beta-blocker, and an MRA is
Coronary angiography
recommended as
may also be considered
cornerstone therapies for
in patients with HFrEF
these patients, unless the
who have an
drugs are contraindicated or
intermediate to high
not tolerated.103105 They
pre-test probability of
should be uptitrated to the
CAD and who are
doses used in the clinical
considered potentially
trials (or to maximally
suitable for coronary
tolerated doses if that is not
revascularization.5
possible). This guideline still
recommends the use of ARNI
as a replacement for ACE-I in
5 Heart suitable patients who remain
symptomatic on ACE-I, beta-
failure with blocker, and MRA therapies;
reduced however, an ARNI may be
54 ESC Guidelines
ejection
Right heart catheterization should be considered
fraction
in patients where HF is thought to be due to considered as a first-line
constrictive pericarditis, restrictive cardiomyop- IIa C therapy instead of an ACE-
5.1 athy,
Thecongenital
diagnosisheart disease, and high output I.106,107 The recommended
of heart
states. failure doses of these drugs are
withRight
reduced
heart catheterization should be considered given in Table 8. Angiotensin-
ejection fraction
in patients with probable pulmonary hyperten- receptor blockers (ARBs) still
The sion,
diagnosis of by
assessed HFrEF
echo in order to confirm the IIa C have a role in those who are
2021
requires the presence
diagnosis and assess its reversibility before the intolerant to ACE-I or ARNI.
of symptoms and/or
correction of valve/structural heart disease. The sodium-glucose co-
signs of HF and a
Right heart catheterization may be considered in transporter 2 (SGLT2)
reduced ejection
selected patients with HFpEF to confirm the IIb C inhibitors dapagliflozin and
fraction (LVEF <_40%).
This diagnosis.
is most usually empagliflozin added to
EMB
obtained by therapy with
echocardiography.
EMB should be considered in patients with rap- ACE-I/ARNI/betablocker/MR
Details about HFthe
idly progressive despite standard therapy A reduced the risk of CV
quality standards that
when there is a probability of a specific diagnosis, IIa C death and worsening HF in
ESC 2021
should
whichbecan
adhered to only in myocardial
be confirmed patients with HFrEF. 108,109
whensamples.
determining
97,98 the Unless contraindicated or
presence of reduced LV
not tolerated, dapagliflozin
systolic function by
echocardiography can or empagliflozin are
be found in the recommended for all
European Association patients with HFrEF already
of Cardiovascular treated with an ACE-I/ARNI,
Imaging (EACVI)
a beta-blocker, and an MRA,
position paper.99 If
assessment of EF is not regardless of whether they
possible by have diabetes or not.
echocardiography, Other drugs may be used
then CMR or rarely, for selected patients with
nuclear techniques can HFrEF. These are discussed in
be employed. section 5.4.
............................................................for patients with symptomatic HFrEF is given indrugs and devices in patients with HFrEF, for
Class I indications foralongside non-pharmacological interventions.tional capacity, and QOL.due to worsening HF, and (iii) improvement in
ESC Guidelines 55
clinical status, func-5.2(patients with heart failure with reducedejection fraction 5.2.1failure with reduced ejection
fractionPharmacotherapy is the cornerstone of treatment for HFrEF andshould be implemented before considering device therapy, andthe
investigation of the underlying aetiology, please refer toi) reduction in mortality, (ii) prevention of recurrent hospitalizationsFigureThe key
evidence supporting the recommendations in this sectionThere are three major goals of treatment for patients with HFrEF:An algorithm for
56 ESC Guidelines
the diagnosis of HFrEF is depicted inPharmacological treatments forGoals of pharmacotherapy for patients with heart2 depicts
the algorithm for the treatment strategy, including 100102Supplementary Table 1FigureTable1. For5. .
ESC Guidelines 57
Table 8 Evidence-based doses of disease-modifying drugs in key Practical guidance on how to use ACE-Is is given in
randomized trials in patients with heart failure with reduced ejection Supplementary Table 2.
fraction
............
ACE-I = angiotensin-converting enzyme inhibitor; HF = heart failure; HFrEF = heart failure with reduced ejection fraction; LVEF = left ventricular ejection fraction; MRA =
mineralocorticoid receptor antagonist; NYHA = New York Heart Association.
a
Class of recommendation.
b
Level of evidence.
ACE-I = angiotensin-converting enzyme inhibitor;
ARNI = angiotensin receptorneprilysin inhibitor;
.............................................................. Practical guidance on how to use MRAs
is given in Supplementary Table 4.
58 ESC Guidelines
b.i.d. = bis in die (twice daily); CR = controlled 5.3.4 Angiotensin receptor-neprilysin
release; CV = cardiovascular; MRA = inhibitor
mineralocorticoid receptor antagonist; o.d. =
In the PARADIGM-HF trial,
omne in die (once daily); SGLT2 = sodium-glucose
co-transporter 2; t.i.d. = ter in die (three times a sacubitril/valsartan, an ARNI, was shown
day); XL = extended release. to be superior to enalapril in reducing
a hospitalizations for worsening HF, CV
Indicates an ACE-I where the dosing target is
derived from post-myocardial infarction trials. b
mortality, and all-cause mortality in
Indicates drugs where a higher dose has been patients with ambulatory HFrEF with LVEF
shown to reduce morbidity/mortality compared <_40% (changed to <_35% during the
with a lower dose of the same drug, but there is study). Patients in the trial had elevated
no substantive randomized, placebo-controlled
plasma NP concentrations, an eGFR >_30
trial and the optimum dose is uncertain.
c mL/ min/1.73 m2 and were able to
Sacubitril/valsartan may have an optional lower tolerate enalapril and then sacubitril/
starting dose of 24/26 mg b.i.d.
for those with a history of symptomatic hypotension. valsartan during the run-in period. 105
d Additional benefits of sacubitril/ valsartan
Indicates a treatment not shown to reduce CV or all-
included an improvement in symptoms
cause mortality in patients with heart failure (or
shown to be non-inferior to a treatment that does). and QOL,105 a reduction in the incidence of
e diabetes requiring insulin treatment,126
A maximum dose of 50 mg twice daily can be
administered to patients weighing over 85 kg.
and a reduction in the decline in eGFR, 127
f as well as a reduced rate of
Spironolactone has an optional starting dose of 12.5
hyperkalaemia.128 Additionally, the use of
mg in patients where renal status or hyperkalaemia
warrant caution. sacubitril/valsartan may allow a reduction
in loop diuretic requirement. 129
Symptomatic hypotension was reported
5.3.1 Angiotensin-converting enzyme more commonly in patients treated with
inhibitors sacubitril/valsartan as compared to
ACE-Is were the first class of drugs shown enalapril, but despite developing
to reduce mortality and morbidity in hypotension, these patients also gained
patients with HFrEF. 110113 They have also clinical benefits from sacubitril/valsartan
been shown to improve symptoms. 111 therapy.128,130
They are recommended in all patients
unless contraindicated or not tolerated.
They should be uptitrated to the
maximum tolerated recommended
doses.
ESC Guidelines 59
................................................................................................... symptoms.maximum tolerated dose. In patients
2021
admitted with AHF, beta-blocker trials in HFrEF has shown no benefit
on hospital admissionseuvolaemic, patients at a low dose and
gradually uptitrated to theand mortality in the subgroup of patients with HFrEF with AF.blockers should be cautiously initiated in hospital,
60 ESC Guidelines
once the patient ishaemodynamically stabilized.mortality and the risk of HF hospitalization.However, since this is a retrospective subgroup
analysis, and becausebeta-blockers did not increase risk, the guideline committee decidednot to make a separate recommendation according
to heart rhythm.to an ACE-I and a beta-blocker, in all patients with HFrEF to reduceMRAs (spironolactone or eplerenone) are recommended,
in addition5.3.3Supplementary Table 3roid and androgen) receptors. Eplerenone is more specific for aldos-terone blockade and, therefore,
ESC Guidelines 61
causes less gynaecomastia.impaired renal function and in those with serum potassium concen-trations >5.0 mmol/L.different degrees of
affinity, other steroid hormones (e.g. corticoste-that ACE-I and beta-blockers can be commenced together as soonas the diagnosis of
symptomatic HFrEF is established. There is no evi-dence favouring the initiation of a beta-blocker before an ACE-I andvice versa.Beta-
blockers have been shown to reduce mortality and morbidity inpatients with HFrEF, in addition to treatment with an ACE-I and diu-
62 ESC Guidelines
retic.5.3.2An individual patient data (IPD) meta-analysis of all major beta-PracticalCaution should be exercised when MRAs are used in
patients with114Mineralocorticoid receptor antagonistsBeta-blockers 120124121guidance onThey also improve symptoms.MRAs block receptors
that bind aldosterone and, withBeta-blockers should be initiated in clinically stable,. how to use beta-
blockers121123,122There is consensusThey also improveisgiven 125in

ESC Guidelines 63
Table 5.
5.3.5 Sodium-glucose co-transporter 2 inhibitors

The DAPA-HF trial investigated the long-term effects of dapagliflozin (SGLT2 inhibitor) compared to placebo in addition to optimal medical
therapy (OMT), on morbidity and mortality in patients with ambulatory HFrEF. Patients participated in the trial if they were in NYHA class
IIIV, and had an LVEF <_40% despite OMT. Patients were also required to have an elevated plasma NT-proBNP and an eGFR >_30
mL/min/1.73 m .
Therapy with dapagliflozin resulted in a 26% reduction in the primary endpoint: a composite of worsening HF (hospitalization or an urgent
visit resulting in i.v. therapy for HF) or CV death. Both of these components were significantly reduced. Moreover, dapagliflozin reduced all-
cause mortality, alleviated HF symptoms, improved physical function and QOL in patients with symptomatic HFrEF. Benefits were seen early
after the initiation of dapagliflozin, and the absolute risk reduction was large. Survival benefits were seen to the same extent in patients with
HFrEF with and without diabetes, and across the whole spectrum of HbA1c values.
Therefore, it is recommended that an ACE-I or ARB is

replaced by sacubitril/valsartan in ambulatory patients is expected and is reversible and should not lead to
with HFrEF, who remain symptomatic despite optimal .............................premature discontinuation of the drug.
treatment outlined above. Two studies have examined Practical guidance on how to use the SGLT2
the use of ARNI in hospitalized patients, some of whom inhibitors dapagliflozin and empagliflozin are given in
had not been previously treated with ACE-I. Initiation Supplementary Table 6.
in this setting appears safe and reduces subsequent CV
death or HF hospitalizations by 42% compared to
enalapril.106,107,131 As such, initiation of 5.4 Other drugs recommended or to be
sacubitril/valsartan in ACE-I naive (i.e. de novo) considered in selected patients with
patients with HFrEF may be considered (class of
recommendation IIb, level of evidence B). Patients heart failure with reduced ejection
being commenced on sacubitril/valsartan should have fraction
an adequate blood pressure (BP), and an eGFR >_30 Other pharmacological treatments indicated in
mL/min/1.73 m2. A washout period of at least 36 h selected patients with NYHA class II–IV heart failure
after ACE-I therapy is required in order to minimize the with reduced ejection fraction (LVEF 40%)
risk of angioedema. ............
Practical guidance on how to use ARNI is given in135108 2 2108108109 133 134108 136
Supplementary132
.................................................................................................................................... Continued
64 ESC Guidelines
Subsequently, the EMPEROR-Reduced trial found that empagliflozin reduced the combined primary endpoint of CV death or HF
hospitalization by 25% in patients with NYHA class IIIV symptoms, and an LVEF <_40% despite OMT. This trial included patients with an eGFR
>20 mL/min/1.73 m and there was also a reduction in the decline in eGFR in individuals receiving empagliflozin. It was also associated with
an improvement in QOL. Although there was not a significant reduction in CV mortality in the EMPEROR-Reduced trial, a recent meta-
analysis of the DAPA-HF and EMPEROR-Reduced trials found no heterogeneity in CV mortality.
Therefore, dapagliflozin or empagliflozin are recommended, in addition to OMT with an ACE-I/ARNI, a beta-blocker and an MRA, for
patients with HFrEF regardless of diabetes status. The diuretic/ natriuretic properties of SGLT2 inhibitors may offer additional benefits in
reducing congestion and may allow a reduction in loop diuretic requirement.
The combined SGLT-1 and 2 inhibitor, sotagliflozin, has also been studied in patients with diabetes who were hospitalized with HF. The
2021
drug reduced CV death and hospitalization for HF. It is discussed further in the AHF and comorbidity sections.
Recommendations Classa Levelb
Loop diuretics
Diuretics are recommended in patients with

HFrEF with signs and/or symptoms of congestion
to alleviate HF symptoms, improve exercise I C
capacity, and reduce HF hospitalizations. 137
ARB
An ARBc is recommended to reduce the risk of HF

hospitalization and CV death in symptomatic
patients unable to tolerate an ACE-I or ARNI I B
(patients should also receive a beta-blocker and
an MRA).138
If-channel inhibitor
Ivabradine should be considered in symptomatic

patients with LVEF <_35%, in SR and a resting
heart rate >_70 b.p.m. despite treatment with
an evidence-based dose of beta-blocker (or IIa B
maximum tolerated dose below that), ACE-I/(or
ARNI), and an MRA, to reduce the risk of HF
hospitalization and CV death.139
Ivabradine should be considered in symptomatic
patients with LVEF <_35%, in SR and a resting
heart rate >_70 b.p.m. who are unable to
tolerate or have contraindications for a beta-
IIa C
blocker to reduce the risk of HF hospitalization
and CV death. Patients should also receive an
ACE-I (or
ARNI) and an MRA.140
Soluble guanylate cyclase receptor stimulator
Vericiguat may be considered in patients in

NYHA class IIIV who have had worsening HF
despite treatment with an ACE-I (or ARNI), a beta- IIb B
blocker and an MRA to reduce the risk of
CV mortality or HF hospitalization.141
Hydralazine and isosorbide dinitrate
Hydralazine and isosorbide dinitrate should be

considered in self-identified black patients with
LVEF <_35% or with an LVEF <45% combined
with a dilated left ventricle in NYHA class IIIIV IIa B
despite treatment with an ACE-I (or ARNI), a
beta-blocker and an MRA to reduce the risk of
HF hospitalization and death.142
ESC Guidelines 65
blocker; ARNI = uptitrate beta-
angiotensin receptor-
blocker therapy to
neprilysin inhibitor;
b.p.m. = beats per guideline
minute; CV = recommended/maxi
cardiovascular; HF = mally tolerated doses
heart failure; HFrEF =
heart failure with
prior to considering
reduced ejection ivabradine.
fraction; LVEF = left Practical guidance
ventricular ejection
on how
fraction; MRA =
mineralocorticoid
useivabradine is
receptor antagonist; given in
NYHA = New York Heart Supplementary Table
Association; SR = sinus 8.
a
rhythm. Class of
recommendation.
b
Level of evidence. 5.4.4
c
The ARBs with evidence in hydralazine and
HFrEF are candesartan, isosorbide
losartan, and valsartan. dinitrate
There is no clear
evidence to suggest
5.4.1 Diuretics
Loop diuretics are the use of this fixed-
recommended to dose combination
reduce the signs therapy in all patients
and/or symptoms of with HFrEF. A small
congestion in RCT conducted in
patients with HFrEF. self-identified black
The quality of the patients showed that
evidence regarding an addition of the
diuretics is poor and combination of
their effects on .............................................................................................................. hydralazine and
morbidity and isosorbide dinitrate
.................... to conventional
mortality have not
been studied in RCTs. therapy (an ACE-I, a
However, it should beta-blocker, and an
also be remembered MRA) reduced
that the major mortality and HF
disease-modifying hospitalizations in
treatment trials for patients with HFrEF
HFrEF were and NYHA classes
conducted with a IIIIV.142 These results
high background use are difficult to
of loop diuretic translate to patients
therapy. One meta- of other racial or
analysis has shown ethnic origins.
that in patients with Additionally, a
HFrEF, loop and combination of
thiazide diuretics
hydralazine and
appear to reduce the
isosorbide dinitrate
risk of death and
may be considered in
worsening HF
symptomatic patients
compared with a
with HFrEF who
placebo, and
cannot tolerate any
compared with an
of an ACE-I, ARNI, or
active control, diuretics
an ARB (or if they are
improve exercise
capacity. 137 contraindicated) to
reduce mortality.
Loop diuretics
However, this
produce a more
recommendation is
intense and shorter
based on the results
diuresis than
of the relatively small
66 ESC Guidelines
thiazides, although Veterans
they act Administration
synergistically Cooperative Study,
(sequential nephron which included only
blockade) and the male patients with
combination may be symptomatic HFrEF
used to treat diuretic who were treated
resistance. However, with digoxin and
adverse effects are diuretics.143
more likely, and
these combinations
5.4.5 Digoxin
should only be used Digoxin may be
with care. Of note,
considered in
ARNI, MRAs, and
patients with HFrEF in
SGLT2
SR to reduce the risk
inhibitors may also
possess diuretic of hospitalization,144
properties.129,145 although its effect on
The aim of diuretic those routinely
therapy is to achieve treated with beta-
and maintain blockers has not been
euvolaemia with the tested. In the DIG
lowest diuretic dose. trial, the overall
In some effect on mortality
euvolaemic/hypovola with digoxin was
emic patients, the use neutral.
of a diuretic drug The effects of
might be reduced or digoxin in patients
discontinued.146 with HFrEF and AF
Patients should be have not been
trained to self-adjust studied in RCTs.
their diuretic dose Some studies have
based on monitoring suggested a
of symptoms/signs of potentially higher risk
congestion and daily of events in patients
weight with AF receiving
measurements. digoxin,149,150 whereas
Practical guidance on another meta-
how to use analysis concluded,
diuretics is given on the basis of non-
in RCTs, that digoxin has
Supplementary Table 7.
no deleterious effect
on mortality in
5.4.2 Angiotensin II type I patients with AF and
receptor blockers HF, most of whom
The place of ARBs in had HFrEF.151
the management of Therefore, in patients
HFrEF has changed with symptomatic HF
over the last few and AF, digoxin may
years. They are now be useful for the
recommended for
treatment of patients
patients who cannot
tolerate ACE-I or with HFrEF and AF
ARNI because of with rapid ventricular
serious side effects. rate, when other
Candesartan in the therapeutic options
CHARM-Alternative cannot be
study reduced CV pursued.150,152155
deaths and HF
hospitalizations in Digoxin has a
ESC Guidelines 67
patients who were narrow therapeutic
notHydralazine
receiving and isosorbide dinitrate may be con-
an ACE-I window and so levels
duesideredto in previous
patients with symptomatic HFrEF who should be checked
138
intolerance.
cannot tolerate any of an ACE-I, an ARB, or IIb B aiming for a serum
Valsartan, in addition
ARNI (or they are contraindicated) to reduce digoxin concentration
to theusual therapy,
risk of death.143 <1.2 ng/mL.156,157
including
Digoxin ACE-I, Caution should also
reduced HF be exercised when
Digoxin may be considered in patients with
hospitalizations in the using it in females,
symptomatic HFrEF147
trial. in sinus rhythm despite
2021
Val-HeFT the elderly, frail,
However, no ARBanhas
treatment with ACE-I (or ARNI), a beta-
IIb B hypokalaemic, and
blocker and all-cause
reduced an MRA, to reduce the risk of hospi- malnourished
ESC 2021
talization
mortality in(both all-cause and HF
any trial. subjects. In patients
144
hospitalizations). with reduced renal
function, digitoxin
ACE-I = angiotensin-converting enzyme inhibitor; ARB = angiotensin-receptor
could be considered.
Digitoxin use in HF
and SR is currently
being investigated.158
Therapy with SGLT2 inhibitors may increase the risk of recurrent genital fungal infections. A small reduction in eGFR following initiation
...........................................
ivabradine conferred a survival benefitand in SR with a resting heart rate >_75 b.p.m., because in this
groupmendation is based on the heart rate of >_70 b.p.m. used in the SHIFTtrial. However, the European Medicines Agency (EMA)
approvedivabradine for use in Europe in patients with HFrEF with LVEF <_35%5.4.3Ivabradine slows heart rate by inhibition of the Inode and
is therefore only effective in patients in SR. Ivabradinereduced the combined endpoint of CV mortality and HF hospitaliza-tion in patients
with symptomatic HFrEF with an LVEF <_35%, with HFheart rate >_70 b.p.m. who were on evidence-based therapy includingan ACE-I (or
ARB), a beta-blocker, and an MRA.hospitalization in recent 12 months, in sinus rhythm (SR) and with asubgroup analysis. Every effort should
be made to commence andIf-channel inhibitor 148 based on a retrospectivef channel in the sinus139,140 Our recom-
68 ESC Guidelines
2021
Figure 3 Central illustration. Strategic phenotypic overview of the management of heart failure with reduced ejection fraction. ACE-I= angiotensin-
converting enzyme inhibitor; ARB= angiotensin receptor blocker; ARNI= angiotensin receptor-neprilysin inhibitor; BB= beta-blocker; b.p.m.=beats
per minute; BTC =bridge to candidacy; BTT=bridge to transplantation; CABG=coronary artery bypass graft; CRT-D= cardiac resynchronization therapy
with defibrillator; CRT-P= cardiac resynchronization therapy with pacemaker; DT= destination therapy; HF= heart failure; HFrEF=heart failure with
reduced ejection fraction; ICD=implantable cardioverter-defibrillator; ISDN= isosorbide dinitrate; LBBB= left bundle branch block; MCS= mechanical
circulatory support; MRA=mineralocorticoid receptor antagonist; MV= mitral valve; PVI=pulmonary vein isolation; QOL= quality of life; SAVR=surgical
aortic valve replacement; SGLT2i= sodium-glucose co-transporter 2 inhibitor; SR= sinus rhythm; TAVI= transcatheter aortic valve replacement; TEE=
transcatheter edge to edge. Colour code for classes of recommendation: Green for Class of recommendation I; Yellow for Class of recommendation
IIa (see Table 1 for further details on classes of recommendation). The Figure shows management options with Class I and IIa recommendations. See
the specific Tables for those with Class IIb recommendations.

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ESC GUIDELINES

European Heart Journal (2021)

2021 ESC Guidelines for the diagnosis and treatment

Authors/Task Force Members: Theresa A. McDonagh* (Chairperson) (United Kingdom), Marco

* Corresponding authors: The two chairpersons contributed equally to the document.

1 Preamble . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ....................... 3.2.4 Terminology related to the symptomatic severity

patients with heart

Table 7 Causes ........................................................................................................................ Table 37 Main European

Level of Data derived from multiple randomized clinical trials

Level of Data derived from a single randomized clinical trial

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

evidence C retrospective studies, registries.

applications (smartphones, etc.). These versions are

Recommendations for the diagnosis of HF

Modified classification for acute HF. HFpEF

Updates on cardiomyopathies including the role of genetic testing

It is recommended that patients hospitalized for HF be

Recommendations for management of patients with HF and atrial

Recommendations for management of patients with HF and valvular

It is recommended that the choice between TAVI and SAVR

Downloaded from https://academic.oup.com/eurheartj/advance-article/doi/10.1093/eurheartj/ehab368/6358045 by guest on 27 August 2021

......medicalreceptor therapy;antagonist;PCI = percutaneousNYHA = New YorkcoronaryHeart

Continued aortic valve replacement; SGLT2 = sodium-glucose co-transporter 2; T2DM = type 2

2021 Class 2016 Class

Recommendations for diagnosis of HF

Recommendations for management of patients with acute HF

3 Definition, .........................................................3.2 Terminology

fraction’ to ‘heart failure with mildly reduced ejection fraction’. 14

• Those with symptoms and signs of HF, with evidence of

natriuretic peptides (NPs), and with an LVEF >_50%, have HFpEF.

The diagnosis of HFrEF, HFmrEF, and HFpEF is covered in more

detail in their respective sections (sections 5, 7, and 8, respectively).

These definitions are consistent with a recent report on the

Universal Definition of Heart Failure.15

Patients with non-CV disease, e.g. anaemia, pulmonary, renal, thy-

those of HF, but in the absence of cardiac dysfunction, they do not

HF and exacerbate the HF syndrome.

3.2.2 Right ventricular dysfunction

Heart failure can also be a result of right ventricular (RV) dysfunc-

therapies to those with LVEF <_40%.813 This supports the

tion. RV mechanics and function are altered in the setting of either

pressure or volume overload.16 Although the main aetiology of

chronic RV failure is LV dysfunction-induced pulmonary hyperten-

sion, there are a number of other causes of RV dysfunction [e.g.

MI, arrhythmogenic right ventricular cardiomyopathy (ARVC), or

valve disease].17 The diagnosis is determined by a quantitative

assessment of global RV function, most commonly by echocar-

diography, using at least one of the following measurements: frac-

tional area change (FAC); tricuspid annular plane systolic

excursion (TAPSE); and Doppler tissue imaging-derived systolic S 0

velocity of the tricuspid annulus. The diagnosis and management

of RV dysfunction is covered comprehensively in a recent Heart

Failure Association (HFA) position paper.18

3.2.3 Othercommon terminology used inheart failure

Heart failure is usually divided into two presentations: chronic heart

who have had an established diagnosis of HF or who have a more

gradual onset of symptoms. If CHF deteriorates, either suddenly or

those who remain stable or transition to a higher ejection

in the 1990s, and then

have 1998 and 2017 in the

aetiology of HF Due to population

does not cause undue breathlessness, fatigue, or palpitations.

Class II Slight limitation of physical activity. Comfortable at rest,