Europace (2011) 13, 723–746 EHRA POSITION PAPER

doi:10.1093/europace/eur126

Bleeding risk assessment and management

in atrial fibrillation patients: a position document
from the European Heart Rhythm Association,
endorsed by the European Society of Cardiology

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Working Group on Thrombosis
Gregory Y.H. Lip (Chair) 1*†, Felicita Andreotti 2†‡, Laurent Fauchier 3†, Kurt Huber 4*†,
Elaine Hylek 5†, Eve Knight 6†, Deirdre A. Lane 1†, Marcel Levi 7†, Francisco Marin 8†,
Gualtiero Palareti9†, and Paulus Kirchhof (Co-chair)10†
Document reviewers: Jean-Philippe Collet 11, Andrea Rubboli 12, Daniela Poli 13, and John Camm 14

1
University of Birmingham Centre for Cardiovascular Sciences, City Hospital, Birmingham B18 7QH, UK; 2Department of Cardiovascular Medicine, ‘A. Gemelli’ University Hospital,
Rome, Italy; 3Cardiologie B, Centre Hospitalier Universitaire Trousseau et Université François Rabelais, Tours, France; 43rd Department of Medicine, Cardiology and Emergency
Medicine, Wilhelminenhospital, A-1160 Vienna, Austria; 5Department of Medicine, Research Unit-Section of General Internal Medicine, Boston University Medical Center, Boston, MA
02118, USA; 6AntiCoagulation, Europe; 7Department of Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands; 8Department of Cardiology,
Hospital Universitario Virgen de la Arrixaca, Murcia, Spain; 9Department of Angiology and Blood Coagulation, University Hospital S. Orsola-Malpighi, Bologna, Italy; 10Department of
Cardiology and Angiology, Universitätsklinikum Münster, D-48149 Münster, Germany; 11Groupe Hopitalier Pitie-Salpetriere, Paris, France; 12Maggiore Hospital, Bologna, Italy;
13
Department of Heart and Vessels, Thrombosis Center, Florence, Italy; and 14Division of Cardiac and Vascular Sciences, St.George’s University of London, London, UK

Despite the clear net clinical benefit of oral anticoagulation (OAC) in atrial fibrillation (AF) patients at risk for stroke, major bleeding events
(especially intra-cranial bleeds) may be devastating events when they do occur. The decision for OAC is often based on a careful assessment
of both stroke risk and bleeding risk, but clinical scores for bleeding risk estimation are much less well validated than stroke risk scales. Also,
the estimation of bleeding risk is rendered difficult since many of the known factors that increase bleeding risk overlap with stroke risk
factors. As well as this, many factors that increase bleeding risk are transient, such as variable international normalized ratio values, oper-
ations, vascular procedures, or drug –drug and food –drug interactions.
In this Position Document, we comprehensively review the published evidence and propose a consensus on bleeding risk assessments
in AF patients, with a view to summarizing ‘best practice’ when approaching antithrombotic therapy in AF patients. We address the epide-
miology and size of the problem of bleeding risk in AF and review established bleeding risk factors. We also summarize definitions of bleeding
in the published literature. Patient values and preferences balancing the risk of bleeding against thrombo-embolism is reviewed, and the prog-
nostic implications of bleeding are discussed. We also review bleeding risk stratification and currently published bleeding risk schema. A brief
discussion of special situations [e.g. peri-ablation, peri-devices (implantable cardioverter-defibrillator, pacemakers) and presentation with
acute coronary syndromes and/or requiring percutaneous coronary interventions/stents and bridging therapy], as well as a discussion of pre-
vention of bleeds and managing bleeding complications, is made. Finally, this document also puts forwards consensus statements that may
help to define evidence gaps and assist in everyday clinical practice.
Bleeding risk is almost inevitably lower than stroke risk in patients with atrial fibrillation. Nonetheless, identification of patients at high risk of bleed-
ing and delineation of conditions and situations associated with bleeding risk can help to refine antithrombotic therapy to minimize bleeding risk.
-----------------------------------------------------------------------------------------------------------------------------------------------------------
Keywords Bleeding † Oral anticoagulation † Atrial fibrillation † Risk assessment † Stroke prevention † Antithrombotic
therapy † Triple therapy

* Corresponding author. Tel: +44 121 5075080; Fax: +44 121 507 4907; Email: g.y.h.lip@bham.ac.uk
†
Task Force Members.
‡
Representing the ESC Working Group on Thrombosis.
Published on behalf of the European Society of Cardiology. All rights reserved. & The Author 2011. For permissions please email: journals.permissions@oup.com.
724
Introduction and scope
Prevention of stroke and thrombo-embolism is one of the main
therapeutic goals in atrial fibrillation (AF).1,2 Oral anticoagulation
(OAC) is highly effective in preventing ischaemic strokes in patients
with AF and conveys a clear net clinical benefit despite a potential
risk for major bleeding events.3
Currently, anticoagulation therapy manily consists of vitamin K
antagonists (VKAs), often warfarin or acenocoumarol or phenpro-
coumon, which are dose adjusted to achieve an international nor-
malized ratio (INR) of 2.0 –3.0.2 The VKAs have many limitations,
including a significant inter- and intra-patient variability of effective
dose, and various food and drug interactions. Thus, regular antic-
oagulation monitoring is required in all patients to keep the INR
within the narrow therapeutic range of 2.0 –3.0. Furthermore,
this variability causes many patients to spend significant amounts
of time outside the therapeutic INR window, and an important
proportion of patients discontinue OAC therapy.4 New OACs,
broadly divided into two categories, the oral direct thrombin
inhibitors and the oral direct factor Xa inhibitors, are in advanced
clinical development, and may offer alternative therapies to
patients who suffer from the limitations and dis-utility associated
with VKAs.5 Indeed, indirect comparisons show how well these
new OACs may perform relative to VKA, aspirin–clopidogrel
combination therapy, aspirin monotherapy or placebo.6
Anticoagulant therapy with VKAs carries a risk for bleeding,
including severe bleeding events, but the clinical benefit of OAC
clearly outweighs the risk of OAC therapy, especially in patients
at high risk for stroke: bleeding events are five to eight times
less likely than ischaemic strokes reported among AF patients
from trials and registry data.7
Estimation of the stroke risk in an individual patient with AF can
be achieved using easily applicable clinical stroke risk estimators
such as the CHADS2 score8 and an increasingly more refined
score that considers additional stroke risk factors, the
CHA2DS2 –VASC [congestive heart failure, hypertension, age
≥75 (doubled), diabetes, previous stroke (doubled)–vascular
disease, age 65– 74, sex category] score.2,9 Patients at moder-
ate–high risk for stroke are increasingly being considered
candidates for OAC based on both an old and a new evidence
base.2,10
Despite the clear net clinical benefit of OAC to AF patients at risk
for stroke, major bleeding events, especially intra-cranial bleeds, may
be devastating when they do occur.3,11 The decision for OAC should
therefore be based on a careful assessment of both stroke risk and
bleeding risk. Unfortunately, clinical scores for bleeding risk estimation
are much less well validated than stroke risk scales. Moreover, the
estimation of bleeding risk is rendered difficult by other factors:
(i) many of the known factors that increase bleeding risk overlap
with stroke risk factors;
(ii) many factors that increase bleeding risk are transient, such as
variable INR values, operations, vascular procedures, and
drug –drug or food –drug interactions.
In recognizing this problem, the European Heart Rhythm Associ-
ation (EHRA) and the European Society of Cardiology (ESC)
Working Group on Thrombosis convened a Task Force, which
G.Y.H. Lip et al.
aimed to review the published evidence and to propose a consensus
on bleeding risk assessment in AF patients, with a view to
summarizing ‘best practice’. The present document summarizes
the available evidence and put forwards consensus statements that
may help to define evidence gaps and assist in everyday clinical
practice.
The ultimate judgement regarding care of a particular patient
must be made by the healthcare provider and the patient in light
of all of the circumstances presented by that patient.
Literature searches were conducted in the following databases:
PubMed/MEDLINE and the Cochrane Library (including the
Cochrane Database of Systematic Reviews and the Cochrane Con-
trolled Trials Registry). Searches focused on English-language
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sources and studies in human subjects. Articles related to animal
experimentation were only cited when the information was impor-
tant for understanding pathophysiological concepts pertinent to
patient management and comparable data were not available
from human studies. Additional information was requested from
the authors where necessary.
Systematic review of evidence/
data
Epidemiology and size of the problem
of bleeding risk in atrial fibrillation
The risk of stroke attributable to AF increases with age. For
example, among individuals aged 50–59 years old, 1.5% of
strokes are attributable to AF compared with 23.5% of strokes
among individuals aged 80–89 years.12 Oral anticoagulation
therapy greatly reduces the risk of stroke in AF, and the clinical
dilemma faced by physicians and patients is anticoagulant-related
haemorrhage, which also increases with age. It is of note that the
rate of intra-cranial haemorrhage has quintupled in recent years,
due to the expanded use of anticoagulants and antiplatelet
therapy in older adults.13 Perceived bleeding risk and older age
are potent negative predictors of receiving warfarin and partly
explain the reported low rates of warfarin use in clinical prac-
tice.14,15 It is worth remembering that the risk of both haemorrhage
and stroke are highest when AF is newly diagnosed and during the
initiation of anticoagulant medication.16 Nonetheless, one recent
study does not suggest that OAC naı̈ve status conferred a disadvan-
tage in relation to efficacy and bleeding endpoints.17,18
Reported rates of major bleeding among individuals with AF
taking oral VKAs vary widely ranging from 1.3 to 7.2% per year
(Table 1). These disparate rates reflect the variability in patient
population characteristics studied and the methodology employed.
The early trials in AF that established the efficacy of warfarin
excluded almost 90% of individuals screened. To establish drug
efficacy, efforts to minimize trial drop-out and cross-over are
imperative. Trial participants, therefore, are often selected based
on a lower bleeding risk profile and higher likelihood of adherence.
For these reasons, bleeding rates reported from randomized trials
will often be lower than in clinical practice. Randomized controlled
trials designed to evaluate the safety and efficacy of new
anti-thrombotic agents should also include substantial numbers
Bleeding risk assessment and management in atrial fibrillation patients 725

Table 1 Annual rates of major haemorrhage among patients taking warfarin

Study Year published Population (n) Major haemorrhage, ICH % per year New to Age, mean
% per year warfarin, %
...............................................................................................................................................................................
Randomised trials
AFI18 1994 AF (n ¼ 3691) 1.3 0.3 100 69
SPAF II19 (2 age strata) 1994 AF (n ¼ 715) 1.7 0.5 100 NR
AF (n ¼ 385) 4.2 1.8 100 80
AFFIRM20 2002 AF (n ¼ 4060) 2.0 0.6 NR 70
SPORTIF III21 2003 AF (n ¼ 3407) 2.2 0.4 27 70
SPORTIF V22 2005 AF (n ¼ 3422) 3.4 0.1 15 72
ACTIVE W23 2006 AF (n ¼ 6706) 2.2 NR 23 71

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RE-LY24 2009 AF (n ¼ 18006) 3.4 0.74 51 72
ROCKET-AF25 Presented 2010 AF (n ¼ 14264) 3.5 0.7 37 73
Inception cohort
Landefeld and Goldman26 1989 All (n ¼ 565) 7.4 1.3 100 61
Steffensen et al. 27 1997 All (n ¼ 682) 6.0 1.3 100 59F/66M
Beyth et al. 28 1998 All (n ¼ 264) 5.0 0.9 100 60
Pengo et al. 29 2001 AF (n ¼ 433) Age ≥ 75: 5.1 NA 100 68
Age , 75: 1.0
Hylek et al. 30 2007 AF (n ¼ 472) 7.2 2.5 100 77
Non-inception cohort (prevalent warfarin use)
Van der Meeret al. 31 1993 All (n ¼ 6814) 2.7 1.3 NR 66
Fihn et al. 32 1996 All (n ¼ 928) 1.0 1.3 NR 58
ATRIA33 2003 AF (n ¼ 6320) 1.52 0.46 NR 71
Poli et al. 34 2009 AF (n ¼ 783) 1.4 2.5 NR 75
Rose et al. 35 2009 AF (n ¼ 3396) 1.9 NA 5 74

of patients without prior exposure to anticoagulation since these
individuals are at the highest risk for bleeding and
thrombo-embolism.17 Observational studies are also subject to
selection bias and methodological differences.
Thus, to more fully interpret bleeding rates from real-world
observational cohorts of AF patients, it is important to know the
proportion of patients within the defined AF population taking
warfarin. This proportion reflects individual physician judgement
of VKA candidacy or eligibility, which is often subjective. Prospec-
tive registries that require written informed consent for partici-
pation are less likely to enroll the more acutely ill, medically
complex, or frail individuals, and thus will also underestimate the
bleeding that occurs in routine care. Indeed, rates reported from
these studies are significantly lower than rates of haemorrhage
from recent studies that have enrolled older individuals and
more first-time takers of warfarin (warfarin naı̈ve).34 – 38
Available data suggest that strokes in AF patients are more
severe than other types of stroke, and more often result in perma-
nent disability or death than in non-AF stroke.39 Given the severity
of these presumably ischaemic strokes, determination of a bleeding
risk threshold that would justify withholding anticoagulant therapy
is difficult.
Definitions of bleeding
The incidence of bleeding with OAC varies widely in published
studies. Differences in study design, patient populations, and
quality of monitoring seem to have the most important roles in
explaining such differences. At least in part, the difference in
reported rates, however, can also be attributed to the diverse
classification of bleeding events (major, life-threatening, and
minor) adopted in each study. For example, large differences are
found in the various definitions as regards the decrease in haemo-
globin level required for a bleed to be considered as ‘major’.40
The various definitions appear to have different validities
depending on the clinical situation in which the antithrombotic
drug is being used, complicating the formulation of a single univer-
sal bleeding definition. This is particularly true now that several
trials have incorporated the rate of major bleeding as a component
of the primary study endpoints.
Heterogeneous definitions are frequently observed in the trials
assessing the benefits of antithrombotic drugs in acute coronary
syndromes (ACS), with the TIMI (thrombolysis in myocardial
infarction) and GUSTO being the two bleeding definitions most
commonly used in trials on ACS.41,42 Different definitions are
also used in studies on patients with other clinical conditions
(Table 2). The Academic Research Consortium has defined bleed-
ing clinical endpoints in Coronary Stent Trials, as shown in
Table 2.55 However, most studies focusing on bleeding events in
AF patients have used broadly similar definitions for major bleed-
ing, as follows: fatal bleeding, bleeding requiring hospitalization or
transfusion of ≥2 units of packed red blood cells, or bleeding
with involvement of a critical site (i.e. intra-cranial, retroperitoneal,
726 G.Y.H. Lip et al.

Table 2 Major bleeding definitions in clinical trials

Study or author, year Reference Definition of major bleeding

...............................................................................................................................................................................
(a) Acute coronary syndrome (ACS) trials
TIMI, 1987 41 Fatal, intra-cranial, bleeding associated with a decrease in Hb of at least 5 g/dL, transfusions are factored in 1
unit¼1 g/dL Hb, and cardiac tamponade
GUSTO, 1993 42 Intra-cerebral, bleeding associated with blood transfusion, or bleeding resulting in haemodynamic compromise
requiring treatment
ASSENT-3, 2001 43 Bleeding associated with blood transfusion and bleeding resulting in haemodynamic compromise
CURE, 2001 44 Major bleeding was subclassified as life threatening if it was fatal, resulted in a drop in haemoglobin
concentration of at least 5 g/dL, caused significant hypotension requiring intra-venous inotropes or surgical
intervention, resulted in symptomatic intra-cranial haemorrhage, or if four or more units of blood were
transfused

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ACUITY, 2004 45 Intracranial or intra-ocular, drop in Hb of at least 4 g/dL without an overt source of bleeding, or of at least 3 g/dL
with an overt source of bleeding. Bleeding associated with blood transfusion. Haematoma ≥5 cm in
diameter, bleeding requiring re-operation, or access site haemorrhage requiring intervention
OASIS-5, 2006 46 Clinically overt bleeding that is fatal. Symptomatic intra-cranial, retroperitoneal, or intra-ocular. Overt bleeding
with a drop in haemoglobin of at least 3 g/dL. Overt bleeding associated with transfusion of 2 units of red
blood cells
PLATO, 2009 47 Fatal bleeding, intra-cranial bleeding, intra-peri-cardial bleeding with cardiac tamponade, hypovolemic shock or
severe hypotension due to bleeding, bleeding requiring pressors or surgery, bleeding associated with a drop
in haemoglobin of at least 5 g/dL or more, or associated with transfusion of 4 units of blood; or bleeding
either associated with a drop in haemoglobin of 3– 5 g/dL, bleeding associated with transfusion of 2– 3 units
of red cells. Intraocular bleeding with permanent vision loss
(b) Major bleeding definition in other conditions
Landefeld and Goldman, 26 Fatal, life threatening, potentially life threatening, leading to severe blood loss, to surgical treatment or to
1989 moderate blood loss (acute or subacute) not explained by trauma or surgery
Palareti, 1996 73 Fatal intra-cranial (documented by imaging); ocular (with blindness); articular; retroperitoneal; if surgery or
angiographic intervention are necessary to stop bleeding; haemoglobin drop of 2 g/dL or need for transfusion
of ≥2 blood units
Beyth et al., 1998 28 Overt bleeding leading to a drop in haemoglobin of 2 g/dL in 7 days or less, or life threatening
Kuijer et al., 1999 49 Clinically overt and associated with a decline in haemoglobin concentration of at least 2 g/dL, transfusion of 2
units or more of red blood cells, retroperitoneal or intra-cranial, warranted permanent discontinuation of
treatment
Wells et al., 2003 48 Loss of 2 units of blood in a 7-day period or bleeding otherwise life threatening
ISTH, 2005 58 Fall in haemoglobin of 2 g/dL or transfusion of 2 or more units of blood, bleeding that is symptomatic in a critical
organ (intra-cranial, intra-spinal, intra-ocular, retroperitoneal, intra-articular or peri-cardial, or intra-muscular
with compartment syndrome) or fatal
Aspinall et al., 2005 51 Haemodynamic instability, association with transfusion of blood, intra-cranial haemorrhage, or death (e.g. a
gastrointestinal bleed in a hypotensive patient, subdural haematoma)
Gage et al., 2006 52 International classification of disease-9th version codes for bleed in any location
Shireman et al., 2006 53 Hospitalization for ‘major acute bleeding’ (including gastrointestinal haemorrhage or intra-cranial haemorrhage
Ruiz-Gimenez et al., 54 Overt, requiring a transfusion of 2 or more units of blood, retroperitoneal, spinal, intra-cranial, fatal
2008
Poli et al., 2009 34 Fatal, intra-cranial (documented by imaging), ocular causing blindness, articular, or retroperitoneal; when
surgery or transfusion of more than two blood units were required or with haemoglobin drop of 2 g/dL or
more
(c) BARC (Bleeding Academic Research Consortium) bleeding definitions 55
Type 0 No bleeding
Type 1 Bleeding that is not actionable and does not cause the patient to seek unscheduled performance of studies, hospitalization, or
treatment by a health care professional
Type 2 (minor) Any overt sign of haemorrhage (e.g. more bleeding than would be expected for a clinical circumstance; including bleeding
found by imaging alone) that does not meet criteria for Type 3 BARC bleeding, Type 4 BARC bleeding (CABG-related), or
Type 5 BARC bleeding (fatal bleeding) that is actionable
Type 3 (major) a. BARC Type 3a bleeding
Intracranial haemorrhage (does not include microbleeds; does include intra-spinal). Subcategories; confirmed by autopsy or
imaging or LP
Intra-ocular compromising vision (even temporarily)
Overt bleeding plus haemoglobin drop .5 g/dL (provided haemoglobin drop is related to bleed)

Continued
Bleeding risk assessment and management in atrial fibrillation patients 727

Table 2 Continued

Study or author, year Reference Definition of major bleeding

...............................................................................................................................................................................
Tamponade
Bleeding requiring surgical or percutaneous intervention for control (exclude dental/nose/skin/haemorrhoids) or inotropes
b. BARC Type 3b bleeding
Any transfusion with overt bleeding
Overt bleeding plus haemoglobin drop 3 to 5 g/dL
Type 4 (CABG) BARC CABG-related bleeding definitions must include the same criteria for fatal bleeding, intra-cranial haemorrhage, need for
intervention to control bleeding and the number of transfusions as for BARC non-CABG related bleeding
Type 5 (Fatal) Fatal bleeding is bleeding that directly causes death with no other explainable cause. BARC fatal bleeding is categorized as
either definite or probable

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CABG, coronary artery bypass graft surgery; PLATO, PLATelet inhibition and clinical Outcomes.

intra-spinal, intra-ocular, peri-cardial, or atraumatic intra-articular
haemorrhage).56,57
The subcommittee on control of anticoagulation of the Scientific
and Standardization Committee of the International Society of
Thrombosis and Haemostasis (ISTH) proposed a definition of
bleeding complications in non-surgical patients that was recently
revisited.50,58 Most of the contemporary AF studies have been per-
formed according to this standardized definition. Although the
adoption of a single standardized definition would facilitate com-
parison of bleeding events across studies, it remains to be estab-
lished whether the proposed ISTH definition is more reliable
than other existing definitions for identifying clinically relevant
bleeding episodes. Even the ISTH definition suffers from the
inclusion of a wide range of events with variable clinical relevance
to the patient, ranging from death or severely life-threatening
events to ‘laboratory indices of bleeding’ (2 g/dL Hb drop),
which may well be a normal variant, for example, in well-hydrated
ACS patients undergoing percutaneous coronary interventions
(PCI) with a small access site haematoma.
How to interpret major bleeding rates in clinical practice
Clearly, there is a need to record major bleeds in order to assess
the safety of a new antithrombotic therapy. Especially prior to
regulatory approval, counting major bleeds will allow to detect
a signal for enhanced bleeding risk early during the course of
clinical development of a new antithrombotic regime. On the
other hand, many of the events that are counted as major
bleeds in large trials are clinically less significant: in addition to
life-threatening bleeds, events that cause permanent organ
damage, and bleeds requiring acute intervention or operation
to stabilize the patient, major bleeds also comprise asymptomatic
haemoglobin drop of 2 or 3 g/dL combined with a small access
site or nasal bleed. Furthermore, modern management of gastro-
intestinal bleeds has helped to contain long-term consequences
of such bleeds for patients. For decision making in clinical prac-
tice, it may therefore be helpful to distinguish major bleeding
events into clinically relevant major bleeds and clinically less rel-
evant major bleeds. The former would include life-threatening
events, symptomatic intra-cerebral bleeds and other bleeding
events resulting in permanent organ damage and bleeds that
require an acute operation to stabilize the patients. Clinically
less relevant major bleeds would be less acute events, e.g. an
asymptomatic haemoglobin drop and bleeding events that result
in a temporary cessation of antithrombotic therapy. From a clini-
cal perspective, many bleeding events appear minor, as evidenced
by continuous antithrombotic therapy. Clinical decision making
may be made easier if such subgroups of major bleeding events
were reported in clinical trials.
Prognostic implications of bleeding
Despite the varying clinical impact of different subtypes of ‘major’
bleeds, major bleeding events are associated with a several-fold
risk of death for up to 1 year compared with non-bleeders, at
least in patients with acute coronary syndromes.59 – 66
Although extensive information regarding the prognostic
impact of bleeding in patients with AF is lacking, the mechanisms
underlying the adverse prognosis associated with bleeding are
likely to be similar (at least in part) to those observed among
ACS patients who develop a major bleed. Severe bleeding
events may be a marker of adverse outcomes, as well as a
cause of poor outcomes.
The short-term adverse prognosis of patients with bleeding
events compared with patients without such events may stem
not only from the critical location of blood loss (intra-cranial, peri-
cardial, and haemothorax) or the development of haemorrhagic
shock, but also from the negative impact of transfusions67 and
from the frequent discontinuation of antithrombotic therapy,
with the ensuing enhanced risk of thrombo-embolic events.68
Additionally, in the short term, reduced tissue oxygenation
through declining haemoglobin concentrations, increased cardiac
work, haemodynamic compromise, and activation of sympathetic,
vasoconstrictive and prothrombotic mechanisms may all concur
to produce adverse outcomes (Table 3).
Importantly, both the short- and long-term prognoses of patients
with bleeding events (even of those who develop minor bleeding
events)69 may relate to an unfavourable cluster of baseline charac-
teristics, typical of ‘high-risk’ patients; indeed, patients with bleeding
events are older and with more co-morbidities (e.g. renal failure,
hypertension, history of prior bleed, or stroke) compared with non-
bleeders.69 In fact, the CHADS2 score is a valid indicator not only
for stroke risk, but also for bleeding risk, and sums the known
728
Table 3 Factors by which bleeding may negatively
impact short- and long-term outcome
Short-, mid- and long-term prognosis
† Accumulation of risk factors for cardiovascular events in patients
with bleeding events
Short- and mid-term prognosis
† Critical location, e.g. intra-cranial, peri-cardial, haemothorax
† Impaired tissue perfusion, e.g. by hypotension, shock, hypoxemia
† Withdrawal of antithrombotic agents, with resultant increased risk
of ischaemic complications
† Activation of sympathetic, vasoconstrictive, and prothrombotic
mechanisms
† Increased cardiac work through increased heart rate and output
† Negative impact of transfusions, especially of older blood
† Prolonged hospitalisation and bed rest, with increased risk of venous
thrombo-embolism
Table 4 Factors affecting bleeding risk when using oral
anticoagulant therapy
Intensity of anticoagulation
Management modality
† Usual care vs. dedicated anticoagulation clinic or increased
monitoring frequency or self management
Patient characteristics
† Age
† Genetics (may also be assessed by the INR response in the initial
period of VKA therapy initiation)
† Prior stroke
† History of bleeding
† Anaemia
† Co-morbidity (hypertension, renal insufficiency, liver disease)
Use of concomitant medication or alcohol
† Antiplatelet agents
† NSAIDs
† Medication that affects the intensity of anticoagulation
† Alcohol abuse
risk factors for cardiovascular events. Thus, the occurrence of any
bleeding event identifies individuals as belonging to a high-risk
subset. Not surprisingly, the baseline features of patients who
bleed largely overlap with those of individuals at high risk of
thrombo-embolic events,70 thereby denoting a general condition
of vascular frailty. Intra-cranial and spontaneous bleeds carry
worse prognosis than procedure-related or extracranial bleeds.71
The Task Force recognizes that there is a need to better under-
stand the causes of adverse outcomes in patients who bleed during
OAC (Table 4). This may be approached by analysing existing data-
bases and by prospective ‘real-world’ registries of patients who bleed.
Established bleeding risk factors
Intensity of anticoagulation, management modality, and patient
characteristics constitute an important determinant of bleeding
G.Y.H. Lip et al.
risk (Table 4). Drug compliance and maintenance of a therapeutic
INR range are other considerations.
Age
Older age, in the majority of studies, has been shown to increase
the risk of major haemorrhage. Elderly patients have a two-fold
increased risk of bleeding36 and the relative risk of intra-cranial
haemorrhage (in particular at higher INRs) was 2.5 (95% CI 2.3 –
9.4) in patients .85 years old compared with patients 70– 74
years old.37 In the AFFIRM trial (Atrial Fibrillation Follow-up Inves-
tigation of Rhythm Management), the risk of major bleeding
increased by 5% per year of age.20
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International normalized ratio range
The most important risk factor for haemorrhage is the intensity of
the anticoagulant effect (Table 4).38 Studies indicate that with a
target INR of .3.0 the incidence of major bleeding is twofold
greater compared to those with a target INR of 2.0–3.0, at least in
some patient groups.72,73 In studies of patients with prosthetic
heart valves, a lower INR target range resulted in a lower frequency
of major bleeding and intra-cranial haemorrhage with a similar antith-
rombotic efficacy.74 One retrospective analysis of outpatients using
warfarin who presented with intra-cranial haemorrhage demon-
strated that the risk of this complication doubled for each 1 unit
increment of the INR.75 Not only the target INR but also the
actual individual INR is strongly associated with the risk of bleeding.76
Time spent in the therapeutic range (TTR) is also a marker of
risk. Among individuals randomized to warfarin in the SPORTIF
(Stroke Prevention Using an Oral Direct Thrombin Inhibitor in
Atrial Fibrillation) trials, those with TTR ,60% experienced
higher rates of major haemorrhage compared with those with
TTR .75%, 3.85%/year vs. 1.58%/year, P , 0.01.77 A similar
trend was found in the ACTIVE W (Atrial Fibrillation Clopidogrel
Trial with Irbesartan for Prevention of Vascular Events).78 It is likely
that this association reflects the increased bleeding risk during
times spent with supra-therapeutic INR values.
It has been clearly shown that structured and well-organized
management of anticoagulant treatment, e.g. by specialized antic-
oagulation clinics, results in higher proportions of patients in the
therapeutic target range.79 Point of care testing as well as patient
self-management has also been shown to improve TTR compared
with conventional care in older studies, but not in a more recent
large trial.80 Careful INR monitoring by experienced personnel,
e.g. in anticoagulation clinics, results in similar rates of bleeding
and thrombosis as self-monitoring.80,81
Genetic factors affecting vitamin K antagonists
metabolism and their antithrombotic effect
Recently, genetic factors have been identified that may affect the risk
of bleeding. Common polymorphisms in the cytochrome P450 2C9
gene were found to be associated with slow metabolism of VKAs
and (possibly) a higher risk of bleeding.82 Other genetic factors
that may influence the requirement of VKAs are variants in the
vitamin K epoxide reductase complex subunit 1 gene (VKORC1).83
Indeed, the combined analysis of VKORC1, CYP2C9 SNPs, and
age may account for .50% of the individual variability in the war-
farin maintenance dosage, and based on this, prediction models of
Bleeding risk assessment and management in atrial fibrillation patients
warfarin maintenance dosage taking into account these individual
parameters have been developed.84 While available data from
trials suggest that patients carrying such variants require a lower
daily dose of VKAs to achieve therapeutic INR values, the clinical
relevance of these genetic polymorphisms is still controversial.
Co-morbidities including uncontrolled hypertension,
hepatic, and renal insufficiency
History of bleeding and anaemia are risk factors for subsequent
bleeding,56,57 being part of various bleeding risk prediction
models (see later). Also, anaemia is frequent in patients with
renal failure, who are at high risk of bleeding complications when
anticoagulated.85
Prior stroke is a potent risk factor for thrombo-embolic stroke
in AF, but it is also a risk factor for intra-cerebral haemorrhage.56,57
Other co-morbidities, such as hypertension, renal, or hepatic insuf-
ficiency, also significantly increase the risk of bleeding. A systolic
blood pressure of 140 mmHg or greater has been shown to
increase the risk of both haemorrhagic and ischaemic stroke
among patients with AF56,57 A case-control study in 1986 patients
on VKAs showed that renal impairment and hepatic disease each
independently more than doubled the risk of bleeding.86 These
associations were confirmed in the AFFIRM study, in which
hepatic or renal disease conferred a two-fold increase in risk
(hazard ratio, 1.93; 95% CI, 1.27–2.93).
The AFFIRM investigators also found that heart failure and dia-
betes increase bleeding risk, with hazard ratios of 1.43 and 1.44,
respectively.20 However, diabetes has been a less consistent risk
factor for bleeding in other overviews.56,57
Concomitant medications
Another critically important determinant of bleeding risk is the use
of concomitant medications, especially antiplatelet drugs. Two
meta-analyses, comprising 6 trials with a total of 3874 patients
and 10 trials with a total of 5938 patients, found a relative risk
of major bleeding when VKAs were combined with aspirin of 2.4
(95% CI 1.2 –4.8) and 2.5 (95% CI 1.7– 3.7), respectively.87,88
A population-based case-control study confirmed the high risk of
upper gastro-intestinal bleeding in patients using VKAs in combi-
nation with aspirin and/or clopidogrel.89,90
Non-steroidal anti-inflammatory drugs (NSAIDs) and alcohol
abuse are also associated with an enhanced risk of gastro-intestinal
bleeding. The combined use of VKAs and NSAIDs may result in an
11-fold higher risk of hospitalization for gastro-intestinal bleeding as
compared with the general population.90 – 92 This risk is not signifi-
cantly lower when using selective inhibitors of cyclo-oxygenase 2.91,92
Clearly, frailty is an important consideration and biological age
rather than calendar age is perhaps a better marker of bleeding
risk. Falls may be overstated as a risk factor for bleeding, and
based on a decision analysis model, a patient with AF would
need to fall 295 times per year for the benefits of stroke preven-
tion with warfarin to be outweighed by the risk of intra-cranial
haemorrhage.93
Implications for clinical practice
The assessment of the absolute risk of bleeding in an individual
patient may be difficult when using data from published clinical
729
studies. In six pivotal trials that demonstrated the superiority of
warfarin over placebo in the prevention of thrombo-embolic com-
plications in patients with AF, 28 787 patients were screened but
only 12.6% of these patients were included in the study.94 In a case-
control study in 993 patients on VKAs with major bleeding and 993
non-bleeding controls, ,70% of patients using VKAs would have
been eligible for the clinical trials.94 In the group of patients that
presented with haemorrhage, the proportion with any exclusion
criteria was considerably greater (40%; 95% CI 37 –43%) than in
the control group (23%; 95% CI 21 –26%). Bleeding risk increased
sharply with the number of exclusion criteria: two vs. none
increased the risk four-fold (odds ratio, 3.8; 95% CI 2.7 –5.2) and
three or more vs. none increased the risk 15-fold (odds ratio,
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14.9; 95% CI 4.7 –46). The fact that many patients were not
included in the clinical trials may have a major impact on the exter-
nal validity of these trials, in particular regarding safety.94
Recent trials of stroke prevention in AF have reported rates of
major haemorrhage of 3%/year among patients randomized to
warfarin.22,24 Bleeding rates did not differ markedly between
open and double-blind trials.94 Rates as high as 7% have been
reported in the first year of warfarin therapy among unselected
patients with AF in routine practice.29 Hence, in patients not fulfill-
ing the criteria for randomized controlled trials, a more individua-
lized approach may be necessary to weigh the expected risks and
benefits of VKA therapy. Furthermore, warfarin-naive patients may
carry a higher risk for severe bleeding events than other patients.
Taken together, clear risk factors for bleeding in patients using
VKAs can be identified. Systematic reviews56,57 have concluded
that the following patient characteristics had supporting evidence
for being risk factors for anticoagulation-related bleeding compli-
cations in AF patients: advanced age, uncontrolled hypertension,
history of myocardial infarction or ischaemic heart disease, cer-
ebrovascular disease, anaemia or a history of bleeding, and the
concomitant use of other drugs such as antiplatelet agents. The
presence of diabetes mellitus, controlled hypertension, and
gender were not identified as significant risk factors.
Appreciation of bleeding risk factors will help to inform decision
making and will also identify higher risk patients for whom manage-
ment strategies to mitigate bleeding risk should be implemented.
Bleeding risk stratification and current
published bleeding risk schema
Several distinctive clinical prediction rules have been proposed for
the assessment of the individual risk for bleeding during OAC in
patients with AF, based on a combination of treatment- and
person-associated factors.56,57 These prediction rules may help
physicians stratify patients into categories of increasing risk of
bleeding so as to evaluate the individual risk/benefit ratio of an
oral anticoagulant, either prior to starting or during treatment.
The characteristics of the available clinical prediction rules specifi-
cally addressing AF patients are reported in Table 5.
The modified Outpatient Bleeding Risk Index (mOBRI)28 has
been prospectively derived and validated28,48 in patients with
different indications for OAC, including AF patients.51 Another
strength of the mOBRI schema was the blinded outcome assess-
ment of bleeding.28 In addition, the settings of the anticoagulation
 730
Table 5 Published bleeding risk prediction schemas for patients with atrial fibrillation

Schema, acronym, Reference Population Designa, n b, mean Definition of major Calculation of risk score Bleeding risk classification Major bleeding events by Validated in
author (SD) age, % male; indication for bleeding event n (%) patients in each risk risk category in validation other cohorts
anticoagulationc; length of adjudication category cohort, n (%)
follow-upd
.............................................................................................................................................................................................................................................

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mOBRI Beyth et al. 28 Prospective inception cohorta
1998
Derivation-n ¼ 556, 61 (14); 46.6%b
Validation—n ¼ 264, 60 (16); 47.3%
Derivation—Post-operative cardiac
surgery, mitral valve disease, AF,
stroke, TIA, PE, DVT, or other
thrombo-embolismc
Validation—VTE and cardiac surgery
4 yearsd
HEMORR2HAGES 52 Retrospective analysis of NRAF
Gage et al. 2006 cohorta
Validation—n ¼ 3971, 80.2e; 43%b
AFc
3138 patient yearsd
Bleeding risk factors for schema
identified by adaptation of 3
existing bleeding risk schema
(mOBRI, SBRPS, plus bleeding risk
factors identified in literature: Beyth
et al.28 Gage et al-Pub Med search)
Overt bleeding that resulted Age ≥65 years, previous stroke, GI bleed Low: 0 Cumulative incidence of Aspinall
in the loss of ≥2.0 units in in last 2 weeks, ≥1 of the following major bleeding (95% CI) at et al.200551
≤7 days, or was otherwise comorbidities (recent MI, haematocrit 3/12/48 months
life threatening ,30%, creatinine .1.5mg/dL, or
diabetes mellitus) with 1 point for
presence of each risk factor and 0 if
absent
Intermediate: 1–2
High: ≥3
Derivation
Blinded event adjudication, Low: 186 (33.5%) Low: 1 (0–4)/3 (0– 8)/3 (0 –8)
unaware of bleeding risk
factors
Intermediate: 336 (60.4%) Intermediate: 5 (1–8)/8 (3–
12)/12 (5–19)
High: 34 (6.1) High: 6 (0 –17)/30 (0 –62)/53
(11 –97)
Validation
Low: 80 (30.3)
Intermediate: 166 (62.9)
High: 18 (6.8)
ICD-9-CM codes for major Hepatic or renal disease, ethanol abuse, Low: 0– 1 Low: 15 (2.1%)
bleeds except those malignancy, older (aged .75), reduced
unrelated to platelet count, re-bleeding risk,
antithrombotic therapye uncontrolled hypertension, anaemia,
genetic factors (CYP 2C9 single
nucleotide polymorphisms), excessive
fall risk, previous stroke/TIA, 1 point for
each risk factor present, and 2 points for
previous bleed
Intermediate: 2–3
High: ≥ 4 Intermediate: 35 (5.0%)
Among those on warfarin High: 17 (8.8%)
(n ¼ 1604)
Low: 717 (44.7%)
Intermediate: 694 (43.3%)

G.Y.H. Lip et al.

High: 193 (12.0%)
 Bleeding risk assessment and management in atrial fibrillation patients
Shireman et al. 2006 53 Retrospective chart review of NRAF Hospitalisation within 90 days (0.49×age ≥ 70) + (0.32×female Low: ≤1.07 Low: 35 (0.9%)
cohort and Medicare dataa of hospital discharge gender)+ (0.58×remote
following index AF for GI bleed)+(0.62×recent bleed)+
haemorrhage (0.71×alcohol/drug abuse)+
(diagnosis-related group (0.27×diabetes)+ (0.86×anaemia)+
code 174 or 175) or (0.32×antiplatelet) with 1 point for the
intra-cranial haemorrhage presence of each condition and 0 if

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e
(ICD-9 430 –432) absent
Derivation—n ¼ 19 875, ≥65 years; Intermediate: .1.07 to Intermediate: 48 (2.0%)
47.5%b ,2.19
Validation—n ¼ 6511, ≥65 years; High: ≥2.19 High: 12 (5.4%)
46.9%
AFc Low: 3889 (59.7%)
3 monthsd Intermediate: 2400 (36.9%)
High: 222 (3.4%)
HAS-BLED Pisters 95 Retrospective analysis of Euro Heart Requiring hospitalisation and/ Hypertension (uncontrolled SBP.160 mm Low: 0– 1 Low: 22 (1.1%)
et al. 2010 Survey cohorta or causing Hb ≥2g/L, Hg), Abnormal renal and/or liver
need for blood transfusion function, Stroke, bleeding history, Labile
that was not a INR, elderly (age . 65 years), drugs
e
haemorrhagic stroke (antiplatelets/NSAIDS)/concomitant
alcohol (≥8 units/week), with 1 point
for the presence of each risk factor
(maximum of 9 points)
Derivation—n ¼ 3978b Intermediate: 2 Intermediate: 14 (1.9%)
Validation—n ¼ 3071, 66.8 (12.8); High: ≥3 High: 12 (4.9%)
59% male
AF patientsc Low: 2084 (67.9%)
12 monthsd Intermediate: 744 (24.2%)
Bleeding risk factors drawn from Euro High: 243 (7.9%)
Heart Survey cohort and ‘historic’
bleeding risk factors (OAC, alcohol
use and hypertension)
e
Fang et al. 2010 (in 96 Retrospective analysis of the ATRIA Anaemia, severe renal disease (GFR Low: 0 to 3 Low: 0.8%
abstract form cohorta ,30 mL/min or dialysis dependent),
only) age ≥75 years, previous bleed,
hypertension, with 1 point each for
presence of previous bleed and
hypertension, 2 points for age≥75, and
3 points each for presence of anaemia
and renal disease
9186b,e Moderate: 4 Moderate: 2.6%
AF patientsc High: 5 –10 High: 5.8%
ed

AF, atrial fibrillation; ATRIA, AnTicoagulation and Risk factors In Atrial fibrillation; DVT, deep vein thrombosis; GFR, glomerular filtration rate; GI, gastrointestinal; HAS-BLED, Hypertension, Abnormal renal &/or liver function, Stroke, Bleeding
history, Labile INR, Elderly (age . 65 years), Drugs (antiplatelets/NSAIDS)/concomitant alcohol (≥8 units/week); Hb haemoglobin; HEMORR2HAGES Hepatic or renal disease, Ethanol abuse, Malignancy, Older (aged.75), Reduced platelet
count, Re-bleeding risk, uncontrolled Hypertension, Anaemia, Genetic factors (CYP 2C9 single nucleotide polymorphisms), Excessive fall risk, previous Stroke/TIA; ICD-9-CM, international classification of disease-9th version, clinical
modification; ICU, intensive/critical care stay; INR, international normalised ratio; MI, myocardial infarction; mOBRI, modified Outpatient Bleeding Risk Index; NRAF, National Registry of Atrial Fibrillation; NSAIDs, non-steroidal
anti-inflammatory drugs; OAC, oral anticoagulation; OBRI, Outpatient Bleeding Risk Index; PE, pulmonary embolism; RCT, randomised controlled trial; SBP, systolic blood pressure; TIA, transient ischaemic attack; VTE, venous
thrombo-embolism.
e
Not reported.

731
732
control were the primary care physician28 or a pharmacist-run
anticoagulation clinic,51 demonstrating derivation and validation in
‘real-life’ AF patients.
All the clinical prediction rules include age as a risk factor for
bleeding, but each schema employs a different cut-off. In the
mOBRI, age ≥ 65 years scores one point. Given the advanced age
of most AF patients, the majority of the evaluated patients would
be assigned at least to the intermediate-risk classification (1–2
points) using the mOBRI, which in the validation cohort28 was associ-
ated with an incidence of major bleeding of 5, 8, and 12% after 3, 12,
and 48 months of treatment, respectively. In the independent vali-
dation of the mOBRI among elderly AF patients by Aspinall et al.,51
the mOBRI discriminated significantly (P , 0.001) between those
in the intermediate- and high-risk categories for major bleeding.
The remaining prediction schemas have a retrospective design,
based on the review of data from the National Registry of Atrial
Fibrillation,52 the same Registry plus Medicare data,53 the Euro
Heart Survey cohort,95 and the AnTicoagulation and Risk factors
in Atrial fibrillation (ATRIA) study.96 The retrospective design
may represent a limitation of the validity of these schemas since
a potential loss of patients with complications in the early phase
of treatment cannot be excluded.
The HEMORR2HAGES (Hepatic or renal disease, Ethanol abuse,
Malignancy, Older (aged .75), Reduced platelet count, Re-bleeding
risk, uncontrolled Hypertension, Anaemia, Genetic factors (CYP
2C9 single nucleotide polymorphisms), Excessive fall risk, previous
Stroke/TIA) score,52 which considers age . 75 years as a condition
at risk, includes factors such as CYP2C9 single nucleotide poly-
morphism, which is rarely investigated, and reduced platelet count
and anaemia that are not easily available, whereas important
factors such as antiplatelet treatment or other co-medications are
not included. The rate of patients at high risk of bleeding was
12.0%. The cumulative incidence of major bleeding by risk category
in the validation cohort was 2.1, 5.0, and 8.8% patient-years in the
low, intermediate, and high risk categories, respectively.
The schema by Shireman et al.53 incorporates eight risk factors
for bleeding, including female gender and an antiplatelet treatment,
as well as age. There was a relatively short (90 days) follow-up
period and the rate of patients at a high risk was very low
(3.4%). This schema requires a complex mathematical calculation
to derive the individual patient bleeding risk score, thereby limiting
its applicability. In general, some important factors related to
bleeding risk, such as poor quality anticoagulation control and
the presence of NSAIDs as concomitant medication,56,57 have
not been included in four30,52,53,96 of the aforementioned
schemas. Reliable ascertainment of aspirin therapy given its non-
prescription status is problematic. Moreover, no blinded
outcome assessment was conducted and no indication of the
setting of anticoagulation control was provided in either the
HEMORR2HAGES52 or Shireman et al.53 studies.
More recently, a new clinical prediction rule for bleeding risk
evaluation in AF patients, HAS-BLED (Hypertension, Abnormal
renal/liver function, Stroke, Bleeding history or pre-disposition,
Labile INR, Elderly (.65), Drugs/alcohol concomitantly), has
been proposed by Pisters et al.56,57,95 The HAS-BLED score
demonstrated a good predictive accuracy in the overall cohort
(c-statistic 0.72) but performed particularly well in predicting
G.Y.H. Lip et al.
bleeding risk when only antiplatelet therapy (c-statistic 0.91) or
no antithrombotic therapy at all (c-statistic 0.85) were used. In
the SPORTIF III and V cohorts, the HAS-BLED score was a good
predictor of bleeding events among warfarin-naı̈ve patients at base-
line (c-statistic 0.66) and those patients receiving warfarin plus
aspirin (c-statistic 0.60).97 The HAS-BLED score has been incor-
porated into the 2010 ESC guidelines for the management of
AF2 and the Canadian guidelines.98
Preliminary data on a bleeding score from the ATRIA study have
been presented in abstract form.96 This is a weighted score con-
taining elements already contained within the HAS-BLED score,
and gives 3 points for anaemia, 3 points for severe renal disease,
2 points for age ≥ 75, and 1 point each for prior bleeding and
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hypertension; essentially including similar components as the
scores discussed above, but assigning a weight to the various risk
factors (thus making it more complicated). The c-statistic for the
continuous risk score was 0.74, but on collapsing points into a
three-category risk index, the annual major haemorrhage rate
was 0.8% in the low-risk group (0–3 points), 2.6% in medium
risk (4 points), and 5.8% in high risk (5–10 points).
In summary, the four available published bleeding risk prediction
rules demonstrate wide variation in the proportions of patients
determined to be at low, intermediate, and high risk of bleeding,
due to differences in the risk factors comprising each schema.
Further, the four published schemas do not share a common defi-
nition of major bleeding and the length of follow-up of the cohorts
differs between studies, which affects the event rate (but this can
be easily corrected for). Despite the limitations of the available
bleeding risk schema, they do offer a starting point for physicians
to consider bleeding when initiating and/or continuing long-term
OAC in AF patients, and to think about potentially correctable
risk factors, for example, in the case of the HAS-BLED score, by
treating uncontrolled blood pressure, improving anticoagulation
control labile INRs (if on VKAs) or stopping concomitant aspirin
use.
Bleeding risk stratification should be considered as an integral
part of anticoagulation treatment decision making, and this group
recommends the use of the HAS-BLED score, in keeping with
international guideline recommendations.2,98
Patient values and preferences
Patients’ beliefs about their health, the medications and healthcare
they receive are important determinants of whether or not they
accept recommended treatments and adhere to therapy. Patients
often have perceptions about VKAs, including the inconvenience
of dosing adjustments, the need for daily medication and regular
blood tests to monitor INR levels, reduction/abstinence from
alcohol, dietary restrictions, the risk of minor and major bleeding,
and under-appreciation or lack of knowledge regarding the risk of
stroke that may influence their acceptance of warfarin and their
ability to maintain good INR control.99 – 101 On the other hand,
patients may feel protected by taking VKAs. Thus, patients’ prefer-
ences and their beliefs about their health are fundamental in deter-
mining whether anticoagulant treatment, particularly with warfarin,
is adopted in the first place and maintained long term. Changes in
health-care policy emphasize the need to achieve, and benefits of,
patient involvement in the management of their own health102 and
Bleeding risk assessment and management in atrial fibrillation patients 733

incorporation of patients’ preferences for anti-thrombotic therapy
should be considered in the decision-making process.
To date, 15 studies have examined patient preferences for antith-
rombotic therapy in AF patients103 – 113 and in patients at high risk of
developing AF,114 – 118 although one study is yet to report its
results118 (Table 6). A variety of decision aids, such as audio-
booklets,108,112,116,117 decision boards105,108,109,114,115,117 (see
Figure 1) and interactive videos/computer programs,103,104,106,113,117
have been designed to enable patients to participate in the decision-
making process with regard to their antithrombotic therapy, to
ensure that treatment choices are consistent with their personal
preferences, values, and beliefs. These decision aids provide
written, visual, and verbal information on the likelihood of clinically
achieve this, although this may represent a lack of patient understand-
ing of the disability associated with major bleeding, particularly intra-
cranial haemorrhage. However, other studies suggest that the
decision to accept OAC is attenuated by inclusion of information
on intra-cranial haemorrhage risk, indicating that some patients
place a greater importance on avoiding an event caused by
anti-thrombotic therapy (i.e. major bleed) than a stroke caused by
choosing not to take such therapy.110,115 Presenting patients with
decision aids makes them more likely to be able to make a decision
regarding antithrombotic therapy and improves their knowledge of
AF and the need for such therapy.105,108,113,116,117 However, research
suggests that the use of decision aids results in fewer patients choos-
ing to take OAC108 – 110,113,115,117 and that incorporating patient

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important outcomes, such as stroke and major haemorrhage associ-
ated with antithrombotic therapy, present the treatment options
(currently warfarin, aspirin, or no antithrombotic therapy), and ask
patients to indicate their treatment choice.
Patients appear to trade-off the risks associated with antithrombo-
tic treatment in order to avoid death.117,119 Overall, these studies
appear to suggest that patients place greater emphasis on avoidance
of stroke and are willing to accept a higher risk of bleeding to
preferences would lead to fewer patients choosing to take oral
anticoagulants than the current guidelines would recommend.110,113
It is hard to draw firm conclusions from the available
studies as the sample sizes are often small, typically ≤100
patients,103 – 106,109 – 111,114,115,117 and there is significant heterogen-
eity between the studies (methods employed to elicit preferences,
patients’ education, risks employed; inclusion of AF patients and
those without AF, etc.). It is important to distinguish between

Table 6 Patients’ preferences for antithrombotic therapy among atrial fibrillation patients and those at high risk of
developing atrial fibrillation

Author, year, Study population. Study design Method of eliciting patient Outcomes
country Number participants, preferences
mean (SD) age, years
...............................................................................................................................................................................
Studies in patients with atrial fibrillation
Gage et al. 1995, n ¼ 57; 70a Cross-sectional, Interviews, computer-based TTO † High utility for daily aspirin (0.998) or
USA103 Markov decision warfarin (0.988)
model † Disutility associated with severe stroke
(0.39) or extra-cranial haemorrhage
(0.76)
Gage et al. 1996, n ¼ 70; 70.1 (7.3) Cross-sectional, Interviews, computer-based TTO † High utility for daily aspirin (1.0) or
USA104 longitudinal warfarin (0.997)
† Disutility associated with
moderate-to-severe stroke (0.07 and
0.0, respectively)
Man Son Hing et al. n ¼ 64; 68.9 (9.0) RCT Interviews, PTOT † 52% willing to take warfarin for
1996, USA105 absolute risk reduction ≤1/100
Gage 1998, USA106 n ¼ 69; 70a Cross-sectional, Interviews, computer-based TTO † Disutility associated with strokeb
Markov decision
model
Sudlow et al. 1998, n ¼ 176; ≥50 yearsa Cross-sectional Questionnaire and interview † 89% willing to take warfarin to prevent
UK107 stroke
Man Son Hing et al. n ¼ 287; control 67, RCT PTOT vs. usual care † Proportion choosing warfarin greater
1999, USA108 intervention 65a in control group
† PTOT  ability to make decision
choice
Howitt and n ¼ 56a Cross-sectional ‘Qualitative’ interview, PTOT † 20 choose not to take warfarin despite
Armstrong knowledge of stroke risk
1999, UK109
Protheroe et al. n ¼ 97; 77 (3.9) Observational, Individualised decision analysis † 61% preferred warfarin based on
2000, UK110 Markov decision individualised stroke risk
model

Continued
734 G.Y.H. Lip et al.

Table 6 Continued

Author, year, Study population. Study design Method of eliciting patient Outcomes
country Number participants, preferences
mean (SD) age, years
...............................................................................................................................................................................
Thomson et al. n ¼ 57; 73a Cross-sectional, Interview, standard gamble † High utility for daily warfarin (0.94)
2000, UK111 Markov decision † Disutility associated with severe stroke
model (0.19)
McAlister et al. n ¼ 434; 72a Cluster randomised Self-administered, PTOT † PTOT  patient ability to choose
2005, USA112 trial ‘appropriate’ antithrombotic therapy
in short-term only
Thomson et al. n ¼ 109; 73 (6) RCT Computerised decision aid vs. † Computerised decision aid led to
2007, UK113 guideline evidence significantly fewer patients choosing

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warfarin
Studies in patients at high risk of developing AF but without AF
Devereaux et al. n ¼ 61; aged 40– 74 Prospective Interview, PTOT † 74% willing to take warfarin if just one
2001, Canada114 yearsa observational stroke in 100 patients were prevented
over 2 years
† 57% willing to accept 22 extra bleeds
in 100 patients over a 2-year period
on warfarin
† Most patients willing to take aspirin if it
prevented just 1 stroke in 100 patients
over 2 years
Fuller et al. 2004, n ¼ 81; 81a Cross-sectional Qualitative interview and † Avoidance of stroke paramount
UK115 questionnaire, PTOT † .50% would decline warfarin when
presented with stroke risk
information plus increasing ICH risk
† Need for daily tablets, regular blood
tests, and restrictions on alcohol,
reduced number willing to take
warfarin slightly
Man Son Hing et al. n ¼ 198; 71 (7) RCT Qualitative vs. quantitative, PTOT † Patients more likely to choose aspirin
2002, Canada116 † Patients at moderate-stroke risk more
likely to choose warfarin
† No significant difference in treatment
choice between groups
Holbrook et al. n ¼ 98; 73.6 (6.1) RCT Interview, decision board vs. † When treatment names were blinded,
2007, Canada117 decision booklet with 40% chose warfarin, 42% chose
audiotape vs. interactive aspirin and 18% no treatment
computer program † Unblinding of treatment led to fewer
people choosing warfarin or no
treatment
† Most people chose aspirin
Alonso-Coello n≥96; ≥60 years Cross-sectional Interview, PTOT and visual † Ongoing study data not yet available
et al. 2008, analogue scale
Spain118

AF, atrial fibrillation; SD, standard deviation; UK, United Kingdom; USA, United States of America; ICH, intra-cranial haemorrhage; PTOT, probability trade-off technique; RCT,
randomised controlled trial; TTO, time-trade off; , increased; , decreased.
a
Not reported.
b
Based on data from only 14 patients.

studies of patients with103 – 113 and without AF,114 – 118 as prefer-
ences may differ markedly between patients with AF who need to
decide about lifelong therapy and those in a hypothetical situation
who need to decide, if they had AF, which treatment they would
choose. Patients’ previous or current antithrombotic use and their
experiences (satisfaction with the antithrombotic regimen, adverse
events, etc.) may dramatically influence choice, since many studies
enrolled large proportions of people either currently taking warfarin
or aspirin103 – 106,108 – 110,112,113 or those with previous experience of
antithrombotic therapy. Patients tend to choose their current
therapy over other treatment choices to prevent cognitive disso-
nance (i.e. distress/conflict between preferences and actual treat-
ment choice).109,110,113,115 – 117 Further studies need to elicit
patient preferences for antithrombotic treatment in warfarin-naı̈ve
AF patients, with and without previous stroke, to remove these
potential biases. In addition, perceptions of risk can be altered by
the way in which information is presented—the effect of ‘framing’.
Positive framing, i.e. the chances of survival, is more effective in
Bleeding risk assessment and management in atrial fibrillation patients
Figure 1 Example of a probability trade-off decision aid (reproduced from Man Son Hing et al. JAMA 1999;282:738, with permission. Copy-
right & (1999) American Medical Association. All rights reserved).
persuading someone to take a ‘risky’ option, such as treatment, than
negative framing (i.e. the chances of death).120
There is also tremendous disparity in perceptions of the impact
of warfarin therapy on the lives of AF patients and this may influ-
ence the acceptance of such therapy, with many physicians tending
to underestimate the level of patients’ satisfaction,121 whereas
most patients report that warfarin did not precipitate any signifi-
cant changes in their day-to-day lives other than minor inconve-
niences (such as regular blood tests, adjusting warfarin dose, and
dietary restrictions) that they are willing to accept.
The novel OACs (direct thrombin inhibitors and factor Xa
inhibitors) that do not appear to require regular monitoring,
unlike VKA therapy, with few drug, food, and alcohol interactions,
suggest that OAC will be available to a wider range of people in the
future. It is conceivable that some patients will be more accepting
of new OACs but we do not currently have data on the impact of
such therapy on patients’ values and preferences.
In summary, patients’ preferences for antithrombotic treatment
are largely influenced by the type and format of information
735
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provided to the patient by the care provider (physician, nurse,
and other healthcare professionals), their level of education and
understanding of the consequences of such treatment, and their
previous experiences of antithrombotic therapy. Stroke is the
most feared complication that patients wish to avoid, but bleeding
risk with treatment attenuates the proportion of patients willing
to take antithrombotic therapy. Patients need clear, simple, and indi-
vidualized information (presented visually, verbally, and in writing)
on their need for antithrombotic therapy and the potential
complications.
Special situations with additional bleeding
risk considerations
Periablation
Catheter ablation carries a small but relevant risk of severe bleed-
ing, 0.5% in older series,122,123 associated with vascular access—
often with relatively large diameter sheaths and peri-interventional
anticoagulation, increasing when ablation is performed in the left
atrium or left ventricle. Interestingly, bleeding events do not
736
appear to be related to pre- and peri-procedural antithrombotic
therapy (aspirin, VKAs, or others). The available data suggest
that bleeding events during or shortly after catheter ablation pro-
cedures are largely due to mechanical factors such as vascular
access, transseptal puncture, and the ablation lesions themselves.
Catheter ablation also carries a risk for thrombotic events due
to the scars created in the endocardial walls. Furthermore, an
increasing number of patients undergoing catheter ablation are at
long-term risk for embolic stroke and therefore require continu-
ous OAC, e.g. most patients with AF or atrial flutter. Right-sided
ablation procedures carry a relatively low risk of peri-procedural
thrombotic events,122,124 and venous access required for such pro-
cedures appears to be securable without major bleeding risk when
anticoagulation is continued using VKAs, at least in a relatively small
series. Continuation of VKA therapy even demonstrated a trend
towards less minor bleeding events.123,125
Catheter ablation for AF combines the difficulties related to
bleeding (from transseptal puncture and requirement for anticoagu-
lation in many patients) and stroke risk (left atrial lesions, long
periods with foreign material in the left atrium, and often long endo-
cardial lesions in already diseased atria). The stroke and transient
ischaemic attack (TIA) rate is 1% in recent surveys, while bleeding
events occur at 1% for cardiac tamponade and 1 –2% for access
site bleeds.125 – 127 To avoid bleeding complications and to allow
rapid adaptation of antithrombotic regimens, a consensus document
from EHRA in 2008 recommended stopping warfarin 4– 5 days
before the ablation procedure and bridging with heparin.128
In a large population of 3052 patients with continuation of VKA
therapy at a therapeutic INR at the time of AF ablation without the
use of heparin [unfractionated heparin (UFH) or low molecular
weight heparin (LMWH)] for bridging, 1 patient had a haemorrha-
gic stroke but recovered completely and bleeding complications
occurred in 34 (1.11%) patients.129 Major haemorrhagic compli-
cations (tamponade, haematomas requiring intervention, and
necessity for transfusion) occurred in 10 (0.33%) patients.129 In a
case-control analysis, no significant difference in terms of vascular
events or bleeding was detected between patients with a thera-
peutic INR and the control group with normal INR.130 Thus, unin-
terrupted OAC is a potential alternative to strategies that use
bridging with heparin or LMWH. In summary, recent data
suggest that continuation of OAC during catheter ablation pro-
cedures for AF may be safe with respect to bleeding events and
may help to prevent peri-procedural strokes.
A higher complication rate has been reported in the elderly (.65
years old) than in young patients undergoing electrophysiological
study (2.2 vs. 0.5%) or radiofrequency ablation (6.1 vs. 2.0%).127
The incidence of vascular complications depends on the type of vas-
cular access (arterial, venous, or both), site of vascular access (i.e.
femoral vs. subclavian or jugular), number of introduced catheters,
length of the procedure, patient profile (i.e. obesity and baseline
coagulation parameters), type of anticoagulation used, management
of catheterization site during the procedure (i.e. flush) and after-
wards (immediate vs. delayed catheter removal, duration and
strength of compression, and the use of protamine), and operator
experience. The introduction of two sheaths through one puncture
site probably increases the risk of haematoma, as does the use of
wide-calibre sheaths for several simultaneous catheters.
G.Y.H. Lip et al.
The issue of bleeding with anticoagulation and catheter ablation
is increased for patients treated with intra-coronary stents and
with antiplatelet agents, such as clopidogrel and aspirin, which
cannot be antagonized. For the introduction and manoeuvring of
sheaths and catheters, the risk of peripheral bleeding or compli-
cations when using aspirin and clopidogrel is low. Additional use
of effective UFH adds to the risk of bleeding. There are no relevant
data in the literature on the specific question of the management of
cardiac tamponade when the patient is on aspirin and clopidogrel.
If life-threatening bleeding occurs, platelet transfusions may help.
The risk of perforation in catheter ablation is extremely low
except in the ablation of AF, which carries higher incidences of
tamponade, where tamponade is the cause of approximately half
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of the procedure-related deaths.123 It can be assumed that bleeding
is more severe and more difficult to be managed when the patient
is on aspirin and clopidogrel.
Most guidelines recommend continued anticoagulant therapy
for 2–3 months following an AF ablation in all patients regardless
of stroke risk factors.2 The optimal duration of this therapy has not
been clearly established. Owing to the risk of relapse, the EHRA
and ESC guidelines recommend that anticoagulation should be
continued long term as per the original indication in subjects
with stroke risk factors.2,128 This is in line with current recommen-
dations for AF and with the observation that AF tends to recur in
many patients, including late recurrences in patients after AF
ablation.131
Peri-devices (implantable cardioverter-defibrillator,
pacemakers)
It may be necessary to interrupt oral anticoagulant therapy for
elective implantation or replacement of a pacemaker or an implan-
table cardioverter defibrillator (ICD), although smaller procedures
can often be performed without interrupting anticoagulation. In
patients with mechanical prosthetic heart valves, it may be appro-
priate to substitute UFH or LMWH to prevent thrombosis.132 In
patients with AF who do not have mechanical valves, however,
based on extrapolation from the annual rate of thrombo-
embolism in patients with non-valvular AF, it was the consensus
of the Task Force for the 2010 ESC guidelines that anticoagulation
may be interrupted temporarily for procedures that carry a risk of
bleeding, such as ICD or pacemaker implantation, without substi-
tuting heparin.2 In high-risk patients (particularly those with prior
stroke, TIA, or systemic embolism), UFH or LMWH may be admi-
nistered. In the 2008 American College of Chest Physicians
(ACCP) guidelines,133 bridging is ‘suggested’ for patients with a
CHADS2 score of 3 or 4 (considered to be at moderate risk of
thrombo-embolism after interruption of antithrombotic therapy)
and ‘recommended’ for those with a CHADS2 score of 5 or 6
(considered at high risk, i.e. .10% risk per year). It is possible
that such operations can in part be performed without interrup-
tion of anticoagulation, as for vascular procedures.
The use of LMWH instead of UFH in patients with AF is based on
extrapolation from venous thrombo-embolic disease states and from
limited observational studies or trials.134 LMWH has several pharma-
cological advantages over UFH including a longer half-life, more pre-
dictable bioavailability, and a predictable antithrombotic response
based on body weight, which permits fixed-dose treatment
Bleeding risk assessment and management in atrial fibrillation patients
without laboratory monitoring, except under special circumstances
such as obesity, renal insufficiency, or pregnancy.135 Treatment
with LMWH is associated with a lower risk of heparin-induced
thrombocytopenia than treatment with UFH. The favourable prop-
erties of LMWH may simplify the treatment of AF in acute situations
and may shorten the need for hospitalization. However, excess
dosing of LMWH should be avoided in this vulnerable population
(elderly and with frequent subclinical kidney impairment).
Haematoma in the region of the generator pocket mainly occurs
in patients who are taking antiplatelet or anticoagulant medication.
Haematoma formation after implantation remains rare among
those who are anticoagulated with a rate that may be similar to
that in patients with a normal INR.136,137 Indeed, there are prob-
ably more patients with haematoma on dual-antiplatelet therapy
(incidence up to 20%) than on warfarin therapy (5–10%).
Pocket revision for evacuation may be needed in 20 –50% of
patients with this complication.136,138 In patients with non-valvular
AF, post-operative high-dose heparinization or post-operative
LMWH bridging substantially increases the haematoma rate (10 –
20 vs. 2 –8%) without reducing the rate of arterial embolism
within the first month after implantation.138 – 140
In a systematic review of the literature including eight studies on
the peri-operative management of anticoagulation in patients
having implantation of a pacemaker or ICD, a strategy involving
bridging anticoagulation with therapeutic-dose heparin was associ-
ated with an incidence of pocket haematoma of 12 –20%, while a
strategy involving peri-operative continuation of a coumarin was
associated with an incidence of pocket bleeding of 2–7%.141 The
incidence of thrombo-embolic events was 0 –1%, irrespective of
the peri-operative anticoagulation strategy used.141 In a recent pro-
spective randomized study including patients with high risk of
thrombo-embolic events in whom 80% had AF, implant of
devices while maintaining OAC was as safe as bridging with
heparin infusion and allowed a significant reduction of in-hospital
stay.142 When drainage systems are used, device implantation
appears to be safe and can be performed without significantly
increased risk of clinically relevant haematoma in patients on
continued dual-antiplatelet therapy.143
Thus, it has been recommended that for such implantations
treatment be interrupted pre-operatively and replaced by
heparin only if needed.2 If that is not feasible and implantation
must be performed under anticoagulant (whether maintaining
OAC or bridging with heparin) and/or antiplatelet therapy (see
the section Patients with ACS and/or requiring PCI/stents), the
procedure should be carried out by an experienced operator
who will pay close attention to haemostasis in the area of the gen-
erator pocket.144
Acute coronary syndromes and coronary angiography/
intervention
Several factors associated with coronary angiography or PCI bear
an increased bleeding risk in patients with a need for OAC (for
a detailed review see145). These include: ‘triple therapy’ using an
oral anticoagulant and dual platelet inhibition, most often aspirin
and clopidogrel; factors prolonging the duration of combined
antithrombotic therapy [e.g. use of drug-eluting stents (DES)];
OAC, when compared with non-anticoagulated patients; the
737
additional use of a GPIIb/IIIa inhibitor (GPI; e.g. in bailout situations
in elective patients or in very high-risk ACS patients); left main or
three-vessel disease; older age (e.g. .75 years); female gender;
smoking; chronic kidney disease; and high INR value (.2.6).
Some measures have been taken to reduce this increased bleed-
ing risk: radial instead of femoral access was associated with fewer
access site bleeding events in ‘all-comers’.146 The use of femoral
closure devices, although believed to reduce bleeding risk when
compared with manual compression, was not associated with
reduced bleeding events.147
Owing to the lack of prospective randomized investigations in
this field, a group of experts recently published recommen-
dations,145 which in the majority are level C, i.e. largely based on
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expert opinion (Table 7).
Our recommendations can be summarized as follows: (i) avoid
the use of DES for patients who require triple antithrombotic
therapy; (ii) when OAC is given in combination with clopidogrel
and/or low-dose aspirin, the intensity must be carefully regulated,
with a target INR of 2.0 –2.5;148,149 and (iii) in the case of combined
antithrombotic strategies, gastric protection is recommended at
least for the duration of combination therapy.150
In elective PCI for patients with chronic stable coronary disease,
DES, which require a more prolonged antithrombotic combination
therapy compared with bare metal stents (BMS),151 should be
avoided or strictly limited to those clinical and/or anatomical situ-
ations, such as long lesions, small vessels, diabetes, etc., where a
significant benefit is expected as compared with BMS. Triple
therapy (OAC, aspirin, and clopidogrel) should be given for the
duration and at the dosages shown in Table 7. After implantation
of a BMS, clopidogrel needs to be given in combination with
OAC plus aspirin only for 1 month after implantation, but at
least 3 months after the use of a ‘-limus’ (sirolimus, everolimus,
and tacrolimus) eluting stent and at least 6 months after a
paclitaxel-eluting stent. For OAC patients at moderate–high risk
of thrombo-embolism, an uninterrupted anticoagulation strategy
can be followed, and radial access can be used as the first choice
even during therapeutic anticoagulation (INR 2.0 –3.0).
In patients presenting with NSTE-ACS (including unstable angina
and non-ST elevation myocardial infarction [NSTEMI])
dual-antiplatelet therapy with aspirin plus clopidogrel (or other
P2Y12 receptor blockers) is recommended for 12 months. Those
with AF and a moderate–high risk of stroke should also receive
or continue anticoagulation therapy. The majority of these patients
will undergo cardiac catheterization and/or PCI with/without stent-
ing. Again DES should be avoided or be strictly limited to those clini-
cal and/or anatomical situations, such as long lesions, small vessels,
or diabetes. Given the risk of bleeding with combination antithrom-
botic therapies, it may be prudent to temporarily stop OAC, and
administer short-acting antithrombins or GPIs only if the INR is
≤2. However, in anticoagulated patients at very high risk of
thrombo-embolism, an uninterrupted strategy of OAC can be fol-
lowed and radial access can be used as the first choice even
during therapeutic anticoagulation (INR 2.0–3.0).
For longer-term management after an acute event, triple therapy
(OAC, aspirin, and clopidogrel) should be used in the mid-term
(3– 6 months), or longer in selected patients at low bleeding risk
(Table 7).
738 G.Y.H. Lip et al.

Table 7 Recommended antithrombotic strategies following coronary artery stenting in patients with atrial fibrillation at
moderate-to-high thrombo-embolic risk (in whom oral anticoagulation therapy is required)

Haemorrhagic risk Clinical setting Stent implanted Anticoagulation regime

...............................................................................................................................................................................
Low/intermediate risk
Elective Bare metal 1 month: triple therapy of VKA (INR 2.0–2.5)+aspirin ≤100 mg/
day+Clopidogrel 75 mg/day
Up to 12th month: combination of VKA (INR 2.0–2.5)+Clopidogrel 75 mg/
dayb (or aspirin ≤100 mg/day)
Lifelong: VKA (INR 2.0–20) alone
Elective Drug eluting 3 (-olimusa group) to 6 (paclitaxel) months: triple therapy of VKA (INR 2.0–
2.5)+aspirin ≤100 mg/day+Clopidogrel 75 mg/day
Up to 12th month: combination of VKA (INR 2.0–2.5)+Clopidogrel 75 mg/
dayb (or aspirin ≤100 mg/day)

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Lifelong: warfarin (INR 2.0–3.0) alone
ACS Bare metal/drug eluting 6 months: triple therapy of VKA (INR 2.0– 2.5)+aspirin ≤100 mg/
day+Clopidogrel 75 mg/day
Up to 12 th month: combination of VKA (INR 2.0–2.5)+Clopidogrel
75 mg/dayb (or aspirin ≤100 mg/day)
Lifelong: warfarin (INR 2.0–3.0) alone
High Elective Bare metalc 2– 4 weeks: triple therapy of VKA (INR 2.0– 2.5)+aspirin
≤100 mg/day+Clopidogrel 75 mg/day
Lifelong: VKA (INR 2.0–3.0) alone
ACS Bare metalc 4 weeks: triple therapy of VKA (INR 2.0– 2.5)+aspirin≤100 mg/
day+Clopidogrel 75 mg/day
Up to 12th month: combination of VKA (INR 2.0–2.5)+Clopidogrel 75 mg/
dayb (or aspirin ≤100 mg/day)
Lifelong: VKA (INR 2.0–3.0) alone

Gastric protection with a proton pump inhibitor (PPI) should be considered where necessary.
ACS, acute coronary syndrome; AF, atrial fibrillation; INR, international normalized ratio; VKA, vitamin K antagonist.
a
Srolimua everolimus, and tacrolimus.
b
Combination of VKA [INR 2.0 –3.0]+aspirin≤100 mg/day (with PPI, if indicated) may be considered as an alternative.
c
Drug-eluting stents should be avoided as far as possible, but, if used, consideration of more prolonged (3 –6 months) triple antithrombotic therapy is necessary.

Table 8 Resuming oral antiplatelet agents after invasive procedure

Initial therapy Treatment during Expected treatment immediately Practicalities during re-initiation of therapy
invasive procedure after invasive procedure
...............................................................................................................................................................................
Aspirin Aspirin Aspirin Aspirin same dosage
Aspirin None Aspirin Aspirin same dosage
Clopidogrel None Clopidogrel Clopidogrel 75 mg+300 mg
Clopidogrel Aspirin Aspirin Aspirin same dosage
Apirin + clopidogrel Aspirin Aspirin Aspirin same dosage+clopidogrel
75 mg+300 mg (major thrombotic risk)
Aspirin + clopidogrel None Aspirin Aspirin same dosage+clopidogrel
75 mg+300 mg (major thrombotic risk)
Aspirin+prasugrel Aspirin Aspirin Aspirin same dosage+prasugrel same dosage
Aspirin+ticagrelor Aspirin Aspirin Aspirin same dosage+ticagrelor same dosage

In patients with acute STEMI referred for primary PCI, usually
unfractionated heparin or bivalirudin is used as an anticoagulant
agent in combination with dual-antiplatelet therapy,152 but their
use, however, should be ideally limited to patients with a known
INR of ≤2. The use of more effective ADP receptor blockers in
this setting (prasugrel, ticagrelor) may further increase peri-
interventional bleeding rates. Accordingly, the additional use of
GPIs in patients on OAC should be considered only in rare
bailout situations and should not be part of a routine procedure.
Also, potent P2Y12 inhibitors (prasugrel and ticagrelor) should
not be used in combination with VKA until more data are available,
unless there is an urgent clinical need. Again, radial access for
primary PCI is probably the best option to avoid procedural bleed-
ing in patients on OAC, depending on operator expertise and
Bleeding risk assessment and management in atrial fibrillation patients
preference. The use of DES should be avoided. Long-term treat-
ment after primary PCI follows similar recommendations to
those in patients with NSTE-ACS (Table 7).
Surgical procedures and bridging therapy
Dual-antiplatelet therapy with aspirin and clopidogrel is a well-
established strategy to prevent thrombotic complications in
patients with high platelet reactivity following plaque rupture in
ACS or PCI.151 Current practice guidelines for antiplatelet
therapy advocate a 4 week dual-antiplatelet therapy in elective
procedures after BMS—PCI and a (6–) 12 months dual-antiplatelet
therapy after PCI in patients with ACS and/or the use of DES
PCI.151,152
Withdrawal of oral-antiplatelet drugs may cause a ‘rebound effect’
associated with the clustering of thrombotic events.153 Importantly,
patients requiring early surgery after coronary artery stenting face an
up to 30% incidence of in-hospital major adverse cardiac
events.154,155 Although oral-antiplatelet therapy is associated with
both short- and long-term clinical efficacy, platelet inhibition,
especially when combined with anticoagulant therapy, carries a sub-
stantial risk of in-hospital and long-term bleeding and may be a par-
ticular limitation in patients presenting for cardiac and non-cardiac
surgery.156 The risk of major bleeding has been demonstrated to
be particularly pronounced in ACS patients treated with prasugrel,
as compared with clopidogrel.157 Ticagrelor is an oral, reversible
and more potent P2Y antagonist than clopidogrel and has shown
better efficacy with a comparable bleeding risk including coronary
artery bypass graft surgery (CABG)-related bleeding; however,
similar to prasugrel, there was a statistically significant increase in
spontaneous severe bleeding rate.47
Patients on dual-antiplatelet therapy
Management of patients undergoing dual-antiplatelet therapy who are
referred for surgical procedures depends on the urgency of the situ-
ation and the thrombotic and bleeding risk of the individual
patient.156,158 Many surgical procedures are not immediately necess-
ary and should be delayed until combination antithrombotic treatment
is no longer necessary.158 If surgery, however, cannot be delayed, most
surgical procedures can be performed under dual-antiplatelet therapy
or at least under acetyl salicylic acid (ASA) alone with an acceptable
rate of bleeding; a multidisciplinary approach is required (cardiologist,
anesthesiologist, haematologist, and surgeon) to determine the
patient’s risk and choose the best method of treatment.
The assessment of these patients requires a balance between the
risk of thrombo-embolic events such as stent thrombosis or stroke,
and bleeding risk.159 – 161 Those at ‘high risk’ for thrombotic events
include those with any stent ,6 weeks; DES,6–12 months;
NSTEMI , 6 weeks; and STEMI , 12 months. Those at ‘moderate
risk’ include those with a BMS . 6 weeks, a DES . 12 months, and
those presenting with an ACS from 6 weeks to 1 year.
Patients on triple therapy
In patients taking triple therapy, it is even more important to choose
the right time point of surgery. For high-risk patients, OAC should
be stopped 3–5 days before surgery and replaced by LMWH or
UFH when the INR falls below the therapeutic range.
739
Practical approaches in patients taking dual-antiplatelet
therapy
In surgical procedures with high to very high bleeding risk:
(i) stop clopidogrel 5 days before surgery and stay on ASA,
unless very high bleeding risk surgery;
(ii) if prasugrel is used, therapy should be stopped 7 days before
surgery based on its prolonged and less unpredictable action
compared with clopidogrel;
(iii) the advantage of ticagrelor in patients referred for surgery
would be its fast offset of action after stopping intake.160 In
the PLATelet inhibition and clinical Outcomes (PLATO)
trial, ticagrelor was stopped 3–5 days before CABG and peri-
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operative bleeding rate was broadly similar to that seen with
clopidogrel.47
(iv) the substitution of combined antiplatelet therapy with LMWH
or UFH alone is ineffective;161
(v) restart clopidogrel (prasugrel and ticagrelor) as soon as poss-
ible with loading dose (if possible ,24 h after operation);
(vi) in very high-risk patients, in whom cessation of antiplatelet
therapy before surgery seems to be dangerous (e.g. shortly
after stent implantation), it has been suggested that to switch
from clopidogrel 5 days before surgery to a short half-life antipla-
telet agent, e.g. the GPIIb/IIIa-inhibitor tirofiban, and stop infusion
of these agents 4 h before surgery.162 This strategy has, however,
not been investigated in prospective randomized trials.
A summary of how to resume oral-antiplatelet drugs after an inva-
sive procedure is summarized in Table 8.
In surgical procedures with low to moderate bleeding risk:
consider operating on dual-antiplatelet therapy (ASA +
clopidogrel) if the specific type of surgery would allow.
Practical approaches in patients taking oral
anticoagulation
Tables 9 and 10 give an overview of bridging therapy in relation to
the choice of antithrombotic regimens and related dosage,
whereby the actual risk of developing a thrombotic complication
and the actual bleeding risk determine the respective therapeutic
approach.133,163 There may be evidence that continuation of
OAC with an INR of 2 is better for the prevention of
thrombo-embolism and bleeding events for PCI—but limited
data are available concerning surgery while on therapeutic OAC.
Managing bleeding complications
Management of bleeding consists of measures to preserve ade-
quate circulation, local control (e.g. endoscopic treatment or sur-
gical haemostasis), and proper transfusion procedures. If serious
bleeding occurs in a VKA user it may be necessary to reverse
the anticoagulant effect of the agent. When interrupting the admin-
istration of VKAs important differences in the half-lives of the
various agents (9 h for acenocoumarol, 36–42 h for warfarin,
and 90 h for phenprocoumon, respectively) need to be taken
into account.164 There is debate over the best management strat-
egy when a patient on VKA bleeds, given the competing concern
for thrombo-embolic risk. Adequacy of haemostasis and duration
of VKA interruption would vary with different patient scenarios.165
740 G.Y.H. Lip et al.

Table 9 A recommended approach to bridging therapy, in relation to risk of thrombo-embolism (adapted from ACCP8
guidelines, with permission133). Thrombo-embolic risk category of patient

Risk Indication for vitamin K antagonist therapy

stratum ..........................................................................................................................................................
Mechanical heart valve Atrial fibrillation VTE
...............................................................................................................................................................................
High Any mitral value prosthesis; older (caged-ball CHADS2, score: 5 or 6; recent Recent VTE (within 3 months); severe
or tilting-disc) aortic valve prosthesis; (within 3 months) stroke or thrombophilia: e.g. deficiency of protein C,
recent stroke or transient ischemic attack transient ischemic attack; protein S or antithrombin, antiphospholipid
(within 6 months) rheumatic valvular heart disease antibodies or multiple abnormalities
Moderate Bileaflet aortic valve prosthesis and one of the CHADS2, score: 3 or 4 VTE within the past 3–12 months: non-severe
following atrial fibrillation, prior stroke or thrombophilic conditions (e.g. heterozygous.
transient ischemic attack, hypertension, Factor V Leiden mutation or heterozygous.

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diabetes, congestive heart failure or age Factor II mutation); recurrent VTE
.75 years
Active cancer (treated within 6 months or
palliative)
Low Bileaflet aortic valve prosthesis without atrial CHADS2; score. 0 –2 (and no prior Single VTE occurred .12 months ago and no
fibrillation and no other risk factors for stroke or transient ischaemic other risk factors
stroke attack)

Table 10 A recommended approach to bridging therapy, in relation to risk of thrombo-embolism (adapted from
ACCP8 guidelines, with permission133). Bridging anticoagulant therapy

Patient group Bridging recommendation Grade of

recommendation
...............................................................................................................................................................................

Patients with an MHV or NVAF or VTE at
high risk for thrombo-embolism
Patients with a MHV, NVAF, or VTE at
moderate risk for ‘thrombo-embolism’
Patients with MHV, NFAV, or VTE at low
risk for ‘thrombo-embolism’
Patients who are undergoing minor dental
procedures and are receiving VKAs
Patients who are undergoing cataract
removal and are receiving VKAs
Bridging anticoagulation with therapeutic-dose subcutaneous LMWH or Grade 1C
intra-venous UFH over no bridging during temporary interruption of
OAC
Bridging anticoagulation with therapeutic-dose subcutaneous LMWH, Grade 2C
therapeutic-dose intra-venous UFH, or low-dose subcutaneous LMWH
over no bridging curing. Temporary interruption of OAC (grade 2C)
Low-dose subcutaneous LMWH or no bridging over bridging with Grade 2C
therapeutic-dose subcutaneous LMWH or intra-venous UFH
Continuing VKAs at the lime of the procedure and co-administering an oral Grade 1E
prohaemostatic agent
Continuing VKAs at the time at the procedure Grade 1C

LMWH, low-molecular-weight heparin; MHV, mechanical heart value; NVAF, non-valvular artial fibrillation; OAC, oral anticoagulation; UFH, unfractionated heparin; VKA, vitamin
K antagonist; VTE, venous thrombo-embolism.

The most straightforward intervention to counteract the effect
of VKAs is the administration of vitamin K.164 – 167 There is some
debate on the need for vitamin K in the management of a
patient with a very high INR but with no signs of bleeding.
A recent randomized controlled trial did not find any difference in
bleeding or other complications in non-bleeding patients with INR
values of 4.5–10 who were treated with vitamin K or
placebo.168,169 In patients with clinically significant bleeding, adminis-
tration of vitamin K is crucial to reverse the anticoagulant effect of
VKAs. Vitamin K can be given orally and intravenously (iv), but the
parenteral route has the advantage of a more rapid onset of the
treatment.167 After the administration of iv vitamin K, the INR will
start to drop within 2 h and will be completely normalized within
12–16 h.168 After oral administration it will take up to 24 h to
normalize the INR.3 Intra-muscular injections of vitamin K should
be avoided in patients who are anticoagulated, and subcutaneous
administration of vitamin K results in a less predictable
bioavailability.164,169
When the INR is ,7, a dose range of 2.5– 5 mg vitamin K has
been advocated, whereas a dose of 5– 10 mg may be required
for correcting higher INRs. Higher doses of vitamin K are equally
effective but may lead to VKA resistance for more than a week,
which may hamper long-term management.169
In the case of very serious or even life-threatening bleeding,
immediate correction of the INR is essential and can be achieved
by the administration of vitamin K-dependent coagulation factors.
Theoretically, these factors are present in fresh frozen plasma;
however, the amount of plasma that is required for correcting
Bleeding risk assessment and management in atrial fibrillation patients
the INR is very large, carries the risk of fluid overload, and will
probably take hours to administer.170 Therefore, prothrombin
complex concentrates (PCCs), most of which contain all vitamin
K-dependent coagulation factors, are more useful, and individua-
lized dosing regimens based on INR at presentation and body
weight are more effective.171 – 174 The risk of disseminated intra-
vascular coagulation (DIC) due to traces of activated coagulation
factors in PCCs comes from the older literature and modern
PCCs seem not to be associated with precipating precipitating
DIC.175 However, PCCs do confer a small thrombotic risk, and
this needs to be weighed when considering their use.176
Left atrial appendage closure
A substantial number of patients eligible for OAC will suffer bleed-
ing complications that may be potentially life threatening. Patients
at high risk of embolic stroke, but with contraindications for
OAC are in need of an alternative strategy that is not associated
with long-term bleeding risk. This is particularly true for those
after an intra-cranial haemorrhage.
The high frequency of thrombus formation in the left ventricular
appendage (LAA) of patients with AF and its role as a source of
embolism have led to the hypothesis that resection or obliteration
of the LAA may reduce the risk of stroke. Surgical closure of the
LAA has been practiced, and indeed, current guidelines suggest
obliteration of the LAA during mitral valve surgery.177 Currently,
excision of the LAA at the time of mitral valve surgery is rec-
ommended for reduction of future stroke risk. Exclusion of the
LAA during coronary artery bypass graft surgery has also been
proposed, but with suboptimal results.177,178
A reasonable alternative may be the exclusion of the LAA cavity
from the circulation, using either surgical or percutaneous
catheter-based procedures. The percutaneous left atrial appendage
transcatheter occlusion device was the first to be successfully
deployed.179 The second device specifically designed for percuta-
neous transcatheter LAA exclusion is the WATCHMAN left
atrial appendage system. The WATCHMAN Left Atrial Appendage
System for Embolic PROTECTion in Patients With Atrial Fibrilla-
tion (PROTECT AF) study was designed to demonstrate the
safety, efficacy, and non-inferiority of the WATCHMAN device
compared to chronic warfarin therapy in those patients with non-
valvular AF who are eligible for long-term OAC.180 The rate of
ischaemic stroke was higher in the intervention group than in
the control group, whereas haemorrhagic strokes were less fre-
quent in the intervention group than in the control group. More-
over, an important risk of serious procedural complications was
observed (e.g., peri-cardial tamponade), perhaps related to a learn-
ing curve of device implantation. Several new devices, the
AMPLATZER and Coherex WaveCrest, are a novel alternative,
and initial results are encouraging.181 Major bleeding was higher
with warfarin (4.1%) compared with the WATCHMAN device
(3.5%).
Careful selection of patients and a meticulous technique are
required to improve the risk –benefit ratio. Further data are
required in order to recommend the use of LAA closure in our
high-risk patients.
741
A perspective on newer anticoagulants
At the time of writing of this summary, the direct thrombin inhibitor
dabigatran is approved for clinical use in the USA and in Canada, and
is close to approval in Europe. The pharmacokinetics of the drug and
its apparent safety compared with warfarin render dabigatran a
potentially attractive therapeutic option in patients in need of antic-
oagulation and at risk for bleeding; at the lower dose tested [110 mg
twice a day (bid)] the rate of intra-cerebral bleeding events was
higher in the VKA group in the RE-LY trial than in the dabigatran
group. At the higher tested dose (150 mg bid), dabigatran prevented
ischaemic strokes more effectively than VKAs. It is conceivable that
some of the other new anticoagulants may confer similar benefits,
Downloaded from https://academic.oup.com/europace/article/13/5/723/469556 by guest on 16 August 2021
but large trials in AF patients are not available as full publications
at the time of writing of this document. In addition to these long-
term benefits, the shorter half-life of direct thrombin or factor Xa
antagonists compared with VKAs suggests that the management of
bleeding complications and the antithrombotic regimen during oper-
ations and invasive procedures could become simpler with those
substances compared to VKAs. This assumption is supported by
the orthopaedic experience, e.g. with dabigatran 110 mg bid which
is often initiated 12–24 h after orthopedic surgery.
Consensus statements
General atrial fibrillation
populations1 – 3
(i) In most patients, thrombo-embolic rates without anticoagula-
tion are markedly (five- to eight-fold) higher than bleeding
rates. Therefore, most patients with AF—including the
majority of patients at high bleeding risk—are in need of
anticoagulant therapy.
(ii) For AF patients requiring permanent effective anticoagula-
tion, it is recommended that the 2010 ESC Guidelines for
the management of patients with AF be applied.
(iii) The bleeding risk with aspirin should be considered as similar
to that with VKA, especially in the elderly.
(iv) Most patients with a high CHA2DS2-VASC score would
benefit from OAC even if their bleeding risk is high. Only
in rare patients with a relatively low stroke risk and an extre-
mely increased risk of bleeding may the withholding of OAC
be considered.
(v) An assessment of the (long-term) risk of bleeding in the
general AF population is recommended.
(vi) In specific AF patient subsets (i.e. post-ablation, post-LAA
closure, post-percutaneous coronary intervention/acute cor-
onary syndrome, etc.), the assessment of bleeding risk is part
of overall management, balancing this risk against the risk of
thrombo-embolic complications.
(vii) The HAS-BLED score should be considered as a calculation
to assess bleeding risk, whereby a score of ≥3 indicates
‘high risk’ and some caution and regular review is needed, fol-
lowing the initiation of antithrombotic therapy, whether with
OAC or antiplatelet drugs.
742
Peri-ablation2,129
(i) Start OAC (e.g. VKA, such as warfarin INR 2.0 –3.0) for at
least 4 weeks prior to the ablation procedure.
(ii) In many cases, OAC can be continued throughout the abla-
tion procedure.
(iii) Where a bridging strategy is planned, stop VKA 2–5 days
before the ablation procedure and bridging therapy with
heparin (either LMWH or UFH) until the day before the abla-
tion procedure.
(iv) Peri-procedure anticoagulation: after sheath insertion and
transseptal puncture, administration of a bolus of intravenous
(IV) heparin (bolus dose empirically 5000–10 000 U or 50–
100 U/kg) followed by continuous infusion of 1000–1500 U/
h in order to achieve an ACT at least in excess of 300 s
that is checked every 30–45 min. On the completion of the
procedure, IV heparin is discontinued and sheaths removed
when the ACT is subtherapeutic (,160 s) or if high, reversed
by protamine. IV heparin to be resumed for 12–24 h at a
maintenance dose of 1000 U/h without a bolus that will main-
tain activated partical thromboplastin time at 60–80 s or at
least twice the baseline level. Oral anticoagulation to be
resumed on the day of the procedure.
(v) Replace IV heparin with subcutaneous LMWH after 12 –24 h
and reinitiate OAC. Stop LMWH when the target INR 2–3 is
reached.
(vi) Continue therapeutic warfarin for a minimum of 12 weeks
after the ablation procedure. Patients who have a CHA2DS2-
VASC score of ≥2 should continue OAC long term.
Peri-devices (implantable
cardioverter-defibrillator,
pacemakers)2,145
(i) Implant of devices maintaining OAC may be as safe as bridging
with heparin infusion and should allow a significant reduction
of in-hospital stay.
(ii) In some circumstances, anticoagulant treatment should be
interrupted pre-operatively and be replaced by heparin.
(iii) If implantation must be performed while on anticoagulant
(whether maintaining OAC or bridging with heparin infusion)
and/or antiplatelet therapy, the procedure should be carried
out by an experienced operator who will pay close attention
to haemostasis in the area of the generator pocket.
Presentation with ACS and/or requiring
PCI/stents2,146
(i) For antithrombotic therapy management in anticoagulated AF
patients presenting with an ACS and/or undergoing PCI/stent-
ing, the recommendations in the 2010 ESC Guidelines for the
management of patients with AF or the ESC thrombosis
working group consensus document should be applied.
The management of bleeding
complications
(i) Appropriate strategies should be implemented both in the long
term and peri-intervention, in order to prevent bleeding.
G.Y.H. Lip et al.
(ii) Bleeding risk assessment should be regularly performed, during
regular review of the patient. Correctable bleeding risk factors
should be managed.
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