Download Choosing the right drug to fit the patient when selecting oral

Review
doi: 10.1111/joim.12360
Choosing the right drug to fit the patient when selecting oral
anticoagulation for stroke prevention in atrial fibrillation
A. M. Shields1 & G. Y. H. Lip2,3
From the 1Acute Medicine Directorate, Croydon University Hospital, London; 2University of Birmingham Centre for Cardiovascular Sciences,
City Hospital, Birmingham, UK; and 3Aalborg Thrombosis Research Unit, Department of Clinical Medicine, Faculty of Health, Aalborg
University, Aalborg, Denmark
Abstract. Shields AM, Lip GYH (Croydon University
Hospital, London; University of Birmingham
Centre for Cardiovascular Sciences, City Hospital,
Birmingham, UK; and Aalborg University, Aalborg,
Denmark). Choosing the right drug to fit the
patient when selecting oral anticoagulation for
stroke prevention in atrial fibrillation. (Review). J
Intern Med 2015; 278: 1–18.
Atrial fibrillation (AF) is the most common cardiac
arrhythmia worldwide and is a growing health
problem that is associated with a significantly
increased risk of stroke and thromboembolism.
Oral anticoagulant (OAC) therapy reduces the risk
of stroke and all-cause mortality in patients with
AF. OAC therapy is commonly given as a wellcontrolled vitamin K antagonist (VKA; e.g. warfarin)
and can reduce the risk of stroke in AF patients by
almost two-thirds. However, the widespread use of
VKAs has been hampered by the unpredictable
Introduction
Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia, and it is estimated that
1% of the population suffer from AF worldwide [1].
The prevalence of AF, the associated disease burden and the healthcare costs are all rising, commensurate with the ageing population [2, 3]. AF
may be caused by valvular, typically rheumatic,
disease, but the vast majority of cases are of
nonvalvular aetiology. In this review, we will focus
on nonvalvular AF.
The morbidity and mortality associated with AF
are considerable. Through mechanisms dependent on left atrial stasis and the associated
endothelial dysfunction and dysregulation of
coagulation, AF increases the risk of ischaemic
stroke almost fivefold and is the major cardiovascular morbidity with an independent effect on
stroke incidence [4]. The risk of stroke secondary
pharmacokinetic and pharmacodynamic properties of the drugs and justifiable concerns about the
consequent risk of haemorrhage. The non-VKA
OACs (NOACs) have revolutionized thromboprophylaxis in AF by providing therapeutic options
with predictable pharmacodynamic and pharmacokinetic properties that are as efficacious as
warfarin in the prevention of stroke and thromboembolism but are more convenient to use. In this
review, we provide a patient-centred framework to
assist clinicians in recommending the right OAC
therapy to fit the individual patient with AF,
including methods for stratifying the risk of stroke
and haemorrhage and the chances of achieving
tight control of VKA anticoagulation, and we discuss the properties of the NOACs that favour their
use in particular patient cohorts.
Keywords: anticoagulation, atrial fibrillation, NOAC,
stroke, warfarin.
to either paroxysmal or permanent AF is the same
and, from the perspective of thromboprophylaxis,
should be treated in the same manner [5]. The
consequences of AF are particularly pronounced
in older individuals. Indeed, AF is believed to be
responsible for 15% of ischaemic strokes overall,
rising to 25% in the elderly population [6] Furthermore, AF is also an independent risk factor for
myocardial infarction [7], cognitive decline [8],
congestive cardiac failure [9] and all-cause
mortality [10].
Thromboprophylaxis is critical for the prevention
of strokes in patients with AF. Until recently,
vitamin K antagonists (VKAs; e.g. warfarin) and
aspirin have been widely used to manage the risk
of ischaemic stroke in patients with AF. Aspirin
remains in widespread use for primary stroke
prevention in patients with AF, despite overwhelming evidence that oral anticoagulation is
superior in most clinical situations and that
ª 2015 The Association for the Publication of the Journal of Internal Medicine
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A. M. Shields & G. Y. H. Lip
aspirin is only minimally effective and confers a
major bleeding risk that is similar to that of wellcontrolled warfarin [11–14]. This evidence is
reflected in the most recent National Institute for
Health and Care Excellence (NICE) [15] and
European Society of Cardiology guidelines [16].
The VKAs are remarkably effective in stroke
prevention; for example, well-controlled warfarin
treatment can reduce the risk of ischaemic stroke
and systemic embolism by up to two-thirds and is
associated with a 26% relative risk reduction in
all-cause mortality in patients with nonvalvular
AF [12, 14, 17].
The risk of ischaemic stroke associated with AF is
not homogenous and is dependent on a plethora of
stroke risk factors [18]. Moreover, anticoagulation
itself is not without risk, most notably of major
haemorrhage. The risk of these two extremes of
clinical outcome, thromboembolism and haemorrhage, may be amplified by poorly controlled
anticoagulation [19]. As such, a variety of scoring
systems have been developed to evaluate the risks
of thrombosis and bleeding, thus aiding clinical
decision-making when initiating anticoagulation
[18, 20] (Table 1).
The non-VKA oral anticoagulants (NOACs) have
changed the landscape of thromboprophylaxis for
ischaemic stroke by offering physicians and
patients the opportunity to use effective anticoagulants with predictable pharmacokinetic profiles, wide therapeutic windows and fewer drug–
drug and drug–food interactions without the need
for intensive therapeutic drug monitoring. Individually, the NOACs have been shown to be
noninferior to warfarin for the prevention of
stroke and systemic embolism in patients with
AF, although each has various properties that
may favour use in particular patients, allowing
physicians to fit the drug to the patient profile
(and vice versa) [21–24].
As the therapeutic armamentarium for the management of ischaemic stroke risk in AF has
expanded, clinical decision-making in terms of
anticoagulant choice has become more complex.
In this review, we first discuss the evidence
supporting the use of the different anticoagulant
drugs in different patient cohorts and conclude by
advocating an individualized patient-centred
approach to oral anticoagulant choice for patients
with AF.
2
ª 2015 The Association for the Publication of the Journal of Internal Medicine
Journal of Internal Medicine, 2015, 278; 1–18
Review: Stroke prevention in atrial fibrillation
Anticoagulants for treatment of AF
Until 2010, the VKAs such as warfarin were the only
available oral anticoagulants to protect against
stroke in patients with AF. Although warfarin is
efficacious in stroke prevention in the context of AF
[17], its use is limited by certain practicalities. Slow
onset, drug–drug and drug–food interactions [25],
genetic polymorphisms in CYP2C9 [26] and the
vitamin K epoxide reductase complex subunit [27]
and patient factors including comorbidities all affect
the pharmacokinetic properties, dosing requirements and anticoagulant effect of warfarin, making
it an unpredictable drug requiring regular, sometimes intensive, monitoring of the international
normalized ratio (INR) to achieve maximum therapeutic effect and minimum risk of harm to the
patient. Even when tight control of anticoagulation
is achieved, adverse haemorrhagic events can still
occur in patients treated with VKAs.
The NOACs (previously referred to as new or novel
oral anticoagulants [28]) were developed to provide
efficacious anticoagulant drugs with rapid onset, a
favourable side effect profile and predictable pharmacokinetic properties obviating the need for
therapeutic drug monitoring [29, 30] (Table 2).
Two classes of NOACs have been developed, and
three drugs are currently licensed for use as
anticoagulants in nonvalvular AF [31]: the direct
thrombin inhibitors (dabigatran [21]) and the direct
factor Xa inhibitors (rivaroxaban [22] and apixaban
[24]). A further direct factor Xa inhibitor, edoxaban
[23], has completed Phase III clinical trials and is
licensed in Japan for use as thromboprophylaxis
following lower limb orthopaedic surgery, for prevention of stroke and systemic embolism in nonvalvular AF and for the treatment and prevention of
recurrent venous thromboembolism. Licence applications are in progress in Europe and North
America for the use of edoxaban, particularly
for stroke prevention and treatment of venous
thromboembolism.
All four agents have been found to be individually
noninferior to warfarin for the prevention of stroke
and systemic embolism in large, international
randomized control trials [21–24]. In the most
recent meta-analysis, including data from Phase
III trials of all four agents, the NOACs significantly
reduced stroke and systemic embolism compared
to warfarin [relative risk (RR) 0.81, 95% confidence
interval (CI) 0.73–0.91; P < 0.0001], intracranial
A. M. Shields & G. Y. H. Lip
Review: Stroke prevention in atrial fibrillation
Table 1 Recommended risk assessment tools for stroke risk, bleeding risk and successful vitamin K antagonist-based
anticoagulation in patients with atrial fibrillation
Criteria
Points
Notes
Congestive heart failure
1
Moderate to severe systolic left ventricular [LV] dysfunction, defined
Hypertension
1
Patient on antihypertensives or two concurrent readings >140 systolic
Age > 75
2
Diabetes
1
1) The CHA2DS2VASc score
arbitrarily as left ventricular ejection fraction [LVEF] <40%
and/or >90 diastolic
Fasting blood glucose >7 mmol L
1
or patient on antihyperglycaemic
drugs
Stroke/TIA/thromboembolism
2
Vascular disease
1
Prior MI, angina,PCI, CABG, intermittent claudication, previous surgery or
percutaneous intervention on the abdominal aorta or the lower extremity
vessels, abdominal or thoracic surgery, aterial and venous thrombosis
Age 65–74
1
Sex – female
1
Total
9
2) The HAS-BLED Score
Hypertension
1
Patient on antihypertensives or two concurrent readings >140 systolic
Abnormal liver and/or renal
1 (each)
Dialysis, transplant, creatinine >200 lmol L
and/or >90 diastolic
, cirrhosis, bilirubin >29
upper limit of normal, AST/ALT/ALP >39 upper limit of normal
function
Stroke
1
1
Bleeding
1
Previous major haemorrhage, anaemia
Labile INRs
1
TTR<60%
Elderly
1
Age >65 or frail condition
Drugs/Alcohol
1 (each)
e.g. NSAIDs, >8 units week
Total
9
1
3) The SAMeTT2R2 Score
Sex – female
1
Age <60
1
Medical history (>2
1
comorbidities)
Treatment (interacting drugs)
1
e.g. amiodarone
Tobacco use
2
Any current smoking
Race (ethnic minority)
2
Total
8
TIA, transient ischaemic attack; LV, left ventricular; LVEF, left ventricular ejection fraction; MI, myocardial infarction;
PCI, percutaneous coronary intervention; CABG, coronary artery bypass grafting; INR, international normalized ratio;
AST, aspartate aminotransferase; ALT, alanine transaminase; ALP, alkaline phosphatase; TTR, time in therapeutic range;
NSAID, nonsteroidal anti-inflammatory drug.
ª 2015 The Association for the Publication of the Journal of Internal Medicine
Journal of Internal Medicine, 2015, 278; 1–18
3
A. M. Shields & G. Y. H. Lip
Review: Stroke prevention in atrial fibrillation
Table 2 The pharmacokinetic and pharmacodynamic properties of warfarin and the nonwarfarin oral anticoagulants
Molecular target
Warfarin
Dabigatran
Rivaroxaban
Apixaban
Edoxaban
Vitamin K
Thrombin
Factor Xa
Factor Xa
Factor Xa
dependent
clotting factors
Dosing in AF
Once daily
Twice daily
Once daily
Twice daily
Once daily
Time to peak
240.00
85–150
30–180
30–120
30–60
96–120
2
2–3
1–2
1–2
40.00
14–17
5–9 (increased to
8–15
9–11
plasma
concentration
(mins)
Time to peak
effect (h)
Half life (h)
11–13 in elderly)
Renal clearance
<1%
80%
30%
27%
0.35
Food and drug
Foods rich in
Strong P-gp
Strong CYP3A4
Strong inhibitors
Strong P-gp
interactions
vitamin K,
inhibitors and
inducers, strong
and inducers of
inhibitors
Substrates of
inducers
inhibitors of both
CYP3A4 and P-gp
CYP2C9, CYP3A4
CYP3A4 and P-gp
and CYP1A2
Creatine clearance
n/a
<30 mL min
1
<15 mL min
1
<15 mL min
1
<30 mL min
1
(Japan)
below which drug
is contraindicated
AF, atrial fibrillation; n/a, not applicable; P-gp, permeability glycoprotein.
haemorrhage (RR 0.48, 95% CI 0.39–0.59;
P < 0.0001) and all-cause mortality (RR 0.90,
95% CI 0.85–0.95; P = 0.0003) but increased the
risk of gastrointestinal bleeding (RR 1.25, 95% CI
1.01–1.55; P = 0.04) in patients with AF [32].
Relative risk reductions in major haemorrhage
rates were greatest in centres in which the mean
time in therapeutic range (TTR) (i.e. mean time
spent by patients with an INR between 2.0 and 3.0)
was <66%, suggesting that NOACs have an advantage in healthcare systems where adequate control
of anticoagulation cannot be achieved [32].
In a Cochrane meta-analysis of direct thrombin
inhibitors, it was found that dabigatran 150 mg
twice daily was superior to warfarin in the prevention of vascular death and ischaemic events [odds
ratio (OR) 0.86, 95% CI 0.75–0.99] and direct
thrombin inhibitors were associated with significantly lower rates of fatal and nonfatal major
bleeding events, including haemorrhagic strokes
(OR 0.87, 95% CI 0.78–0.97) [33]. A meta-analysis
of the factor Xa inhibitors has also shown superi4
ª 2015 The Association for the Publication of the Journal of Internal Medicine
Journal of Internal Medicine, 2015, 278; 1–18
ority over warfarin in the prevention of ischaemic
and haemorrhagic stroke (OR 0.78, 95% CI 0.69–
0.89) and systemic embolic events (OR 0.53, 95%
CI 0.32–0.87), and a reduced incidence of intracranial haemorrhage (OR 0.56, 95% CI 0.45–0.70)
[34]. However, the evidence for a reduction in major
haemorrhages with the factor Xa inhibitors is less
robust due to heterogeneity within the studies
included in the review [34]; re-analysis with data
from the Effective Anticoagulation with Factor Xa
Next Generation in Atrial Fibrillation–Thrombolysis
in Myocardial Infarction 48 (ENGAGE AF-TIMI 48)
study may be beneficial.
To date, there is no evidence to suggest that any of
the NOACs are superior to the others for the
prevention of stroke in AF. Indirect comparison
between the NOACs is made difficult by subtle
differences between the patient cohorts enrolled in
the randomized trials [35]. For example, the Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for
Prevention of Stroke and Embolism Trial in Atrial
A. M. Shields & G. Y. H. Lip
NO
ANTITHROMBOTIC
THERAPY
REQUIRED
CHA2DS2VASc ≥ 2
(female)
or
CHA2DS2VASc ≥ 1
(male)
High risk of
haemorrhagic
complications
Modify bleeding risk where possible
e.g. uncontrolled hypertension, labile
INRs, concomitant aspirin/NSAID use,
alcohol excess
HAS-BLED ≥ 3
Determine
bleeding risk
with HAS-BLED
HAS-BLED < 3
Low risk ie.
CHA2DS2VASc = 0
(male) or = 1 (female)
STEP 1
Determine stroke
risk with
CHA2DS2VASc
Review: Stroke prevention in atrial fibrillation
Low risk of
haemorrhagic
complications
STEP 2
Decide on
VKA or
NOAC
Predict control
of warfarin
anticoagulation
using
SAMeTT2R2
NOAC
SAMeTT2R2 > 2
(consider patient
preferences &
individual drug
characteristics)
SAMeTT2R2 0-2
DOSE-ADJUSTED
VKA (INR 2.0–3.0)
with TTR >70%
(regularly review TTR and
consider patient
preferences)
Antiplatelet therapy with aspirin-clopidogrel or –
less effectively – aspirin monotherapy
(consider only in patients who unwilling/unable to
take any form of OAC whether VKA or NOAC
Fig. 1 An algorithm for the risk assessment of atrial fibrillation (AF) patients about to start anticoagulation treatment. The
assessment of risk of anticoagulation in patients with AF involves the use of the CHA2DS2VASc, HAS-BLED and SAMeTT2R
scores to evaluate stroke risk, bleeding risk and likelihood of successful warfarin therapy, respectively. Non-vitamin K
antagonist oral anticoagulants (NOACs) may be considered where the SAMeTT2R score predicts poor control of
anticoagulation with warfarin. VKA, vitamin K antagonist; INR, international normalized ratio; NSAID, nonsteroidal antiinflammatory drug; OAC, oral anticoagulant; TTR, time in therapeutic range.
Fibrillation (ROCKET-AF) trial included patients at
greater baseline risk of stroke, and patients in the
warfarin arm of this study spent a lower mean
percentage of time (mean centre time in therapeutic range (cTTR) 59%) in the therapeutic range
(2.0–3.0); by contrast, patients enrolled in the
Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY), Apixaban for Reduction in
Stroke and Other Thromboembolic Events in
Atrial Fibrillation (ARISTOTLE) and ENGAGE AFTIMI 48 trials all achieved a mean cTTR above 64%
[22]. Nevertheless, particular characteristics of
each agent, supported by evidence from clinical
trials, may favour its use in specific patient populations.
Choosing the right anticoagulant for the right patient
There are two major decisions that must be made
with respect to anticoagulation in AF. First, should
a patient with AF start anticoagulant treatment for
thromboprophylaxis and, secondly, which anticoagulant should be used. Here, we provide a framework to help clinicians answer these questions
(Fig. 1).
Should a patient with AF start anticoagulant treatment?
The risk of stroke in AF is not homogenous, but
depends on a variety of risk factors. The CHADS2
[congestive heart failure, hypertension, age
ª 2015 The Association for the Publication of the Journal of Internal Medicine
Journal of Internal Medicine, 2015, 278; 1–18
5
A. M. Shields & G. Y. H. Lip
>75 years, diabetes, stroke (doubled)] risk score
was developed and successfully validated to assist
in risk stratification for patients with AF [36].
However, a number of important risk factors were
omitted, including the increasing stroke incidence
with age, vascular disease and female gender (in
conjunction with other risk factors), which have
subsequently been incorporated into the CHA2DS2VASc [congestive heart failure, hypertension, age
>75 years (doubled), diabetes, stroke (doubled),
vascular disease, age 65–74, sex category (female)]
score [18, 37].
The CHA2DS2VASc score has been confirmed as a
more effective method of stratifying stroke risk in
patients with AF, compared to CHADS2, and is able
to identify truly low-risk patients who would not
benefit from anticoagulation [38]. Patients with a
CHA2DS2VASc score of 0 (male) or 1 (female) are
‘low risk’ should not be prescribed an anticoagulant for stroke prevention as the risks outweigh the
benefits. Patients with a CHA2DS2VASc score of ≥1
(male) or ≥2 (female) should be considered for
anticoagulation after assessment of their bleeding
risk. The CHA2DS2VASc score has been adopted by
the European Society of Cardiology [39] and NICE
[15] as the gold standard for stratifying stroke risk
in patients with AF. Although trials comparing
NOACs and warfarin have stratified stroke risk
using the older CHADS2 score, the two scores
share many important risk factors; no differences
in the effect size for efficacy and safety have been
observed in the RE-LY [40] and ARISTOTLE [41]
trials in relation to CHA2DS2VASc score strata.
Modelling studies have also demonstrated the net
clinical benefit of different NOACs compared to
warfarin across a range of CHA2DS2VASc scores
[42].
Overestimation of bleeding risk is a major barrier to
anticoagulant therapy, and several scoring systems have been developed to stratify this risk
including ATRIA [43], HEMORR2HAGES [44] and
HAS-BLED [20]. Of these scoring systems, HASBLED [uncontrolled hypertension (1 point), abnormal renal or liver function (1 point each), stroke (1
point), bleeding history or predisposition (1 point),
labile INR (1 point), elderly (age >65 years) or frail
(1 point), concomitant drugs/alcohol excess (1
point each)] offers the best prediction of bleeding
risk and has been validated in both real-world and
clinical trial cohorts [45, 46]. A HAS-BLED score of
≥3 is suggestive of a high risk of bleeding; however,
this should not in itself contraindicate the initia6
ª 2015 The Association for the Publication of the Journal of Internal Medicine
Journal of Internal Medicine, 2015, 278; 1–18
Review: Stroke prevention in atrial fibrillation
tion of anticoagulation but rather alert the clinician
to potential modifiable risk factors (e.g. hypertension, polypharmacy, alcohol excess, concomitant
use of aspirin or nonsteroidal anti-inflammatory
drugs) or guide the decision to initiate a NOAC
instead of warfarin (e.g. labile INR) [47]. For example, in patients with a CHA2DS2VASc score of 1
(e.g. male patients with one identified stroke risk
factor), the net clinical benefit of dabigatran and
apixaban compared to VKA therapy only becomes
positive in patients with a HAS-BLED score >3 [42].
Although either a VKA or NOAC may be successfully used as thromboprophylaxis in these
patients, the decision of which anticoagulant
should be used may be guided by patient choice
and whether the patient is likely to achieve rapid
and satisfactory control of VKA-based anticoagulation (TTR >70%) (see below).
Which anticoagulant class to choose: VKAs or NOACs?
Once the decision to initiate anticoagulation has
been made, assessment of whether the patient is a
suitable candidate for warfarin therapy is required.
The net clinical benefit of warfarin increases the
longer the patient remains within the therapeutic
range achieving net benefit over antiplatelet therapy when the TTR is above 65–70%, with an
optimal TTR defined as >70% in a recent European
consensus document [48, 49].
Difficulty in achieving adequate control of anticoagulation with warfarin has been cited as a common barrier to its use [50]. In a systemic review,
Wan et al. [51] found that poor control of anticoagulation correlated with increased bleeding and
thromboembolic risk. Indeed, it has been shown
that when TTR falls below 50%, stroke outcomes
are worse than if the patient remained untreated
[51, 52], and bleeding risk is higher [53].
Various patient factors including alcohol abuse,
polypharmacy and hospitalization have been associated with erratic INR control. Furthermore, factors including concurrent diagnoses of dementia,
cancer, nonalcohol substance misuse and bipolar
disease have been associated with suboptimal
anticoagulation [54]. The SAMeTT2R2 score [sex
female, age <60 years, medical history (more than
two comorbidities), treatment (interacting drugs,
e.g. amiodarone for rhythm control), tobacco use
(doubled), race (doubled)] has been developed to
assist clinicians in deciding which patients are
likely to achieve high-quality anticoagulation if
A. M. Shields & G. Y. H. Lip
treated with warfarin [55]. The SAMeTT2R2 score
has been validated in prospective studies. Scores of
>2 were associated with significantly increased risk
of severe bleeding (RR 1.38, 95% CI 1.12–2.68;
P = 0.002) and major haemorrhage as defined by
the Bleeding Academic Research Consortium
(BARC) (RR 1.77, 95% CI 1.29–2.44; P = 0.0005),
and increasing scores correlated with labile INR,
stroke, severe bleeding, major BARC bleeding and
death [19]. This scoring system has subsequently
been validated in a ‘real-world’ cohort of warfarintreated AF patients, and high scores were associated with significantly increased all-cause mortality [hazard ratio (HR) 1.41, 95% CI 1.16–1.67;
P = 0.001], adverse cardiovascular events (HR
1.52, 95% CI 1.28–1.83; P < 0.001) and a trend
towards increased major bleeding events (HR 1.23,
95% CI 0.99–1.53; P = 0.059) [56].
The importance of achieving satisfactory control of
anticoagulation rapidly after starting warfarin has
been illustrated by studies examining the incidence of stroke in the first month after warfarin
initiation; this period was associated with a 71%
increased relative risk of stroke, presumed to be
due to the hypercoagulable state [57]. Suboptimal
control of INR may contribute to increase the
stroke risk and should not be tolerated. As such,
we recommend that a patient’s SAMeTT2R2 score is
calculated. Those patients with a score of ≤2 are
likely to benefit from warfarin (TTR >70%), and
therefore, this treatment could be considered [19,
56]. Patients with a SAMeTT2R2 score >2 are more
likely to spend a greater amount of time outside the
therapeutic range and to be exposed to the consequent risks of thrombosis and haemorrhage. In
these patients, a NOAC should be considered,
rather than subjecting them to a trial of warfarin
or a ‘warfarin stress test’.
Which NOAC to choose?
Direct comparison of the results from large, international, multicentre randomized control trials of
NOACs versus warfarin for thromboprophylaxis in
AF is difficult due to differences in the mean
CHADS2 score, TTR and rates of stroke and
systemic embolism and haemorrhage in the warfarin arms of the trials [58–60]. Predetermined
subgroup and post hoc analyses, as well as metaanalyses, have examined the risk and benefits of
NOACs in different patient subgroups. These
analyses can be helpful in guiding NOAC choices
in challenging clinical situations; however, formal
Review: Stroke prevention in atrial fibrillation
trials are necessary to validate these existing data
sets. (Fig. 2).
Patients with renal impairment
Renal impairment is associated with an increased
incidence of stroke (secondary to co-existent risk
factors) and is an independent risk factor for
haemorrhage (HR 1.27, 95% CI 1.09–1.49) [61]
due to dysregulation of coagulation and uraemiamediated platelet dysfunction. It is also common
amongst patient with AF; an estimated one-third of
individuals experience some degree of renal
impairment [62]. Balancing thrombotic and haemorrhagic risk in these patients is complex, but of
great importance. Both the incidence of AF and
renal impairment increase with age; therefore,
determining appropriate and safe anticoagulation
for this growing population is an important clinical
issue. The CHA2DS2VASc score has proven useful
in stratifying patients with end-stage renal disease
who require dialysis and are at risk of stroke
secondary to AF, but the risk/benefit ratio of
anticoagulation for these patients remains unclear
[63]. VKAs have a poor safety profile in patients
with nondialysis-dependent severe chronic kidney
disease [estimated glomerular filtration rate (eGFR)
<30 mL min 1], with these patients at a higher risk
of major bleeding events and stroke compared to
individuals with moderate renal impairment (eGFR
30–60 mL min 1) or compared to individuals
with moderate renal impairment (eGRF 30–
60 mL min 1) or those without chronic kidney
disease (eGFR > 60 mL min 1) [64]. Furthermore,
renal impairment of any degree results in patients
spending less time in the therapeutic range, potentially increasing their risk of complications of VKA
therapy [64].
Data on the safety and efficacy of NOACs in
patients with AF and renal impairment are limited.
Dabigatran is principally excreted via the renal
route (~80%), and patients with an eGFR
<30 mL min 1 were excluded from the RE-LY trial
[22, 24]. Although dose adjustment in renal
impairment is possible, accumulation of dabigatran in the event of further renal insult is a
significant risk and may lead to haemorrhagic
complications. Subgroup analysis of the RE-LY
trial has shown that the benefits of dabigatran
[both 110 and 150 mg twice daily (b.d.)] in terms of
stroke reduction and haemorrhage were consistent
across all levels of renal function; however, in
patients with an eGFR >80 mL min 1, dabigatran
ª 2015 The Association for the Publication of the Journal of Internal Medicine
Journal of Internal Medicine, 2015, 278; 1–18
7
A. M. Shields & G. Y. H. Lip
Review: Stroke prevention in atrial fibrillation
Individual patient groups and characteristics
Asian
patients
Elderly
patients
Renal
impairment
Previous GI
haemorrhage
High bleeding
risk (HASBLED ≥3)
Recurrent
stroke
despite wellmanaged
VKA
Consider
agents with
reduced risk
of ICH and
major
haemorrhage
in Asian
populations
Consider comorbidities
and agents
with lower
extracranial
haemorrhage
amongst
elderly
(age>75)
Consider
agents with
lower
haemorrhagic
complications
in moderatesevere renal
impairment
Consider
agents with
no increased
risk of GI
haemorrhage
Consider
agents with
lower
incidence of
extracranial
haemorrhage
Consider
agent with
demonstrable
benefit in
reducing both
ischaemic
AND
haemorrhagic
stroke
Preference
for low pill
burden
Consider
oncedaily
formulations
Patient less
likely to do
well on VKA
(SAMeTT2R2
score >2)
Avoid ‘trial of
warfarin’ and
consider
NOAC upfront
when
deciding on
OAC in newly
diagnosed
patient
NOACs with characteristics beneficial to target group
Apixaban
Dabigatran
Edoxaban
Apixaban
Edoxaban
Apixaban
Apixaban
Dabigatran
110 mg
Apixaban
Dabigatran
110 mg
Edoxaban
Dabigatran
150 mg
Edoxaban
Rivaroxaban
Any NOAC,
but consider
patient
characteristics
when
choosing
agent
Fig. 2 Suggested patient groups in which specific non-VKA oral anticoagulants (NOACs) may be relatively advantageous or
disadvantageous. The NOACs are all individually noninferior to warfarin in terms of efficacy for stroke prevention in
patients with nonvalvular atrial fibrillation (AF). The evidence that may favour the use of a particular NOAC in various
subgroups of patients is summarized. ICH, intracranial haemorrhage; GI, gastrointestinal; OAC, oral anticoagulant; VKA,
vitamin K antagonist.
was associated with significantly reduced rates of
major bleeding compared to warfarin [65]. Fatal
haemorrhagic complications have been reported in
elderly patients with low body weight and impaired
renal function treated with dabigatran [66]. In
patients with renal dysfunction (eGFR of 30–
50 mL min 1) enrolled in the ROCKET-AF trial,
there were no significant differences between the
primary end-point of stroke and systemic embolism, and rates of the principal safety end-point of
major and clinically relevant nonmajor bleeding,
between
warfarinand
rivaroxaban-treated
patients, although fatal bleeding occurred significantly less often in the rivaroxaban-treated group
[67].
Apixaban is principally excreted via the biliary
route. Subgroup analysis of the ARISTOTLE trial
based on renal function demonstrated that apixaban was more effective than warfarin in the
8
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Journal of Internal Medicine, 2015, 278; 1–18
prevention of stroke and systemic embolism in
patients regardless of renal function, and the
greatest relative risk reduction of major haemorrhage was found in patients with an eGFR
<50 mL min 1 [68]. This finding suggests that
apixaban may be a favourable choice in patients
with renal impairment. Approximately 35% of
edoxaban is excreted renally. A formal subgroup
analysis of the ENGAGE AF-TIMI 48 trial based on
renal function has yet to be published.
Elderly patients
The prevalence of AF rises with age. Based on
epidemiological studies, the prevalence of AF is
estimated to be between 10.0% and 17.8% in
patients over the age of 85 [69, 70]. Risk factors
for stroke including hypertension, diabetes and
previous transient ischaemic attack (TIA) are also
significantly more likely in elderly patients with AF
A. M. Shields & G. Y. H. Lip
[70]. The results of the Birmingham Atrial Fibrillation Treatment of the Aged (BAFTA) trial [71]
demonstrated that warfarin significantly reduces
the incidence of stroke, systemic embolism or
intracranial haemorrhage versus aspirin (RR
0.48, 95% CI 0.28–0.80; P = 0.003). In addition,
it was shown in the Anticoagulation and Risk
Factors In Atrial Fibrillation (ATRIA) study that
the net clinical benefit of well-controlled warfarin
therapy increases with age [72].
However, despite the evidence demonstrating the
clear benefits of warfarin, it remains underused in
the elderly. The Complications of Atrial Fibrillation
in the BOlogna area (CAFBO) study [73] recently
demonstrated that the majority of ischaemic events
in patients with AF occurred in elderly individuals
who received antiplatelet or no thromboprophylaxis. Furthermore, Hylek et al. [74] found that only
51% of patients aged 65 and over with AF received
warfarin on discharge from hospital, with rates
decreasing with age; perceived increased bleeding
risk, falls and polypharmacy were cited as reasons
for underuse. Of note, in a small study conducted
in Scotland, UK, it was shown that dependency
necessitating domiciliary INR monitoring and not
age was a risk factor for bleeding episodes in
warfarin-treated patients [75]. Furthermore, it has
been estimated that a patient would have to fall
more than 295 times per year for the risk of
intracranial haemorrhage to outweigh the benefit
of warfarin [76].
The NOACs have predictable pharmacokinetic
properties with fewer drug–drug interactions and
can be given without the need for regular therapeutic drug monitoring, thus offering considerable
advantages over warfarin therapy. Patients over
the age of 75 years were well represented in the
RE-LY (43.1%), ROCKET-AF (31.2%), ARISTOTLE
(40.2%) and ENGAGE AF-TIMI 48 (40.1%) trials.
Meta-analysis of the trials involving rivaroxaban,
apixaban and dabigatran showed that NOACs were
more effective than conventional warfarin therapy
in the prevention of stroke and systemic embolism;
individual drugs were all found to be noninferior to
warfarin in the elderly. Furthermore, the NOACs
were not associated with any increase in major or
clinically relevant bleeding events in patients over
75 years of age [77], although a nonsignificant
trend towards higher rates of extracranial haemorrhage in these patients has been reported with
dabigatran compared to warfarin [78]. Preliminary
evaluation of data from the ENGAGE AF-TIMI 48
Review: Stroke prevention in atrial fibrillation
trial has shown no significant interaction of age
and major bleeding with edoxaban compared to
warfarin [79].
However, the elderly population is extremely heterogeneous with respect to co-existent comorbidities and in each NOAC trial there were extensive
exclusion criteria making the results difficult to
generalize to the wider elderly population. Further
real-world studies comparing anticoagulant therapies are necessary in this increasingly important
and prevalent population. Currently, where physicians are unable to offer warfarin as a treatment for
older patients with AF, the NOACs potentially
provide an efficacious and arguably safer alternative. When deciding which drug to use, patients’
comorbidities and personal preferences for the
dosing regimen (e.g. once-daily, twice-daily dosing)
should be considered. Also, the fact that dabigatran capsules cannot be crushed and delivered via
feeding tubes should be taken into consideration.
Patients at high risk of haemorrhage
The HAS-BLED score can be used to predict
patients at high risk of haemorrhage, with a score
of 3 or greater signifying significant risk [20]. In the
first instance, attempts should be made to modify
risk factors for bleeding before initiating treatment
with any anticoagulant. However, where these risk
factors cannot be modified, it is prudent to choose
an agent with the lowest associated risk of haemorrhage. Compared to warfarin, each of the NOACs
dramatically reduces the incidence of intracranial
haemorrhage [32].
There are subtle differences between the agents
with respect to other types of major haemorrhage.
Low-dose dabigatran (RR 0.80, 95% CI 0.69–0.93;
P = 0.003), apixaban (RR 0.69, 95% CI 0.60–0.80;
P < 0.001) and edoxaban at high (RR 0.80, 95% CI
0.70–0.91; P < 0.001) and low dose (RR 0.47, 95%
CI 0.41–0.55; P < 0.001) have demonstrated significantly reduced rates of major haemorrhage
compared to warfarin. High-dose dabigatran and
rivaroxaban were equivalent to warfarin in terms of
the incidence of major haemorrhage, although TTR
in the ROCKET-AF trial was lower, potentially
raising the rate of haemorrhage in the warfarin
arm. A recent meta-analysis has suggested that the
NOACs are associated with increased incidence of
gastrointestinal haemorrhage [32]. It is interesting
that high-dose dabigatran (RR 1.50, 95% CI 1.19–
1.89; P < 0.001), high-dose edoxaban (RR 1.23,
ª 2015 The Association for the Publication of the Journal of Internal Medicine
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9
A. M. Shields & G. Y. H. Lip
95% CI 1.02–1.50; P = 0.03) and rivaroxaban
(3.2% vs. 2.2%, P < 0.001) were all associated with
a significantly increased risk of gastrointestinal
haemorrhage compared to warfarin in their respective trials, but low-dose edoxaban was associated
with significantly less gastrointestinal bleeding (RR
0.67, 95% CI 0.53–0.83; P < 0.001). In a further
imputed placebo and multiple treatment analysis,
low-dose edoxaban was associated with significantly reduced rates of major bleeding than any of
the other NOACs, offset by reduced efficacy for
stroke prevention but nevertheless with overall
benefit in terms of mortality [80].
In summary, in patients at high risk of gastrointestinal haemorrhage, it is reasonable to avoid
high-dose dabigatran, high-dose edoxaban and
rivaroxaban; low-dose edoxaban may be preferred,
despite the reduced efficacy for stroke prevention.
In patients with high HAS-BLED scores who have
suffered major haemorrhage, low-dose dabigatran,
apixaban and edoxaban are all appropriate choices
of anticoagulant, but the risk of haemorrhage
should be balanced carefully against the risk of
stroke and patients’ personal preferences (see
below).
Patients with existing coronary or peripheral vascular disease
The co-existence of coronary or peripheral artery
disease and AF has been investigated in a number
of clinical trials and real-world studies. The Atrial
Fibrillation Clopidogrel Trial With Irbesartan for
Prevention of Vascular Events (ACTIVE) W and
ACTIVE A studies demonstrated prevalence rates,
respectively, of 17% and 14% for previous myocardial infarction and 4% and 5% for peripheral
vascular disease in AF patients [81, 82]. Similar
prevalence rates have been found in the Danish
population [83] and the EuroHeart survey of hospitalized AF patients [84]. Thus, there is considerable scope for the overlap of antiplatelet and
anticoagulant treatments in patients with coronary
or peripheral vascular disease and concurrent AF.
Single and dual antiplatelet therapies provide firstline treatments for patients with coronary or
peripheral artery disease [85, 86] and remain the
first-line choice for patients with non-cardioembolic ischaemic stroke or TIA [87].
Management of thrombotic and haemorrhagic risk
becomes extremely complicated in the context of
elective or emergency coronary angioplasty in
patients with AF [88]. Interestingly, De Caterina
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Review: Stroke prevention in atrial fibrillation
et al. [89] suggested that 95.3% of patients receiving dual antiplatelet therapy and an oral anticoagulant and 63.8% treated with single antiplatelet
therapy and an oral anticoagulant did not have an
accepted indication, implying that many patients
are put at an unnecessarily high bleeding risk. A
comprehensive joint European consensus statement on the management of anticoagulation in
patients with acute coronary syndrome or undergoing percutaneous coronary or valve interventions
has recently been issued [90].
In all four trials comparing NOACs to warfarin in
patients with AF, concurrent aspirin use was
associated with higher incidence of major haemorrhage regardless of the treatment arm. However,
the incidence of major haemorrhage when a NOAC
was co-administered with aspirin was consistently
lower than that seen with warfarin (dabigatran
150 mg and 110 mg vs. warfarin: 4.08% year 1
and 3.65% year 1 vs. 4.32% year 1; rivaroxaban
vs. warfarin: 2.73% year 1 vs. 3.49% year 1; apixaban vs. warfarin: 2.7% year 1 vs. 3.7%; edoxaban
60 mg and 30 mg vs. warfarin: 3.62% year 1 and
2.00% year 1 vs. 4.71% year 1 [21–24, 78]). These
data suggest that the NOACs offer promising safety
advantages compared to warfarin when used in
conjunction with antiplatelet therapy, but this
must be confirmed in future studies.
The possible association between dabigatran use
and increased risk of myocardial infarction has
been extensively investigated. Dabigatran (both
110 and 150 mg b.d.) was associated with higher
rates of myocardial infarction compared to warfarin in the original RE-LY study (dabigatran
110 mg: RR 1.35; P = 0.07; dabigatran 150 mg:
RR 1.38; P = 0.048) [21], and a meta-analysis
showed an odds ratio of 1.33 (95% CI 1.03–1.71;
P = 0.03) for acute coronary syndrome or myocardial infarction in studies comparing dabigatran to
other anticoagulant treatments for a variety of
indications [91]. However, this effect was not
observed in an Asian subgroup of the RE-LY study
[92], and post hoc analysis of this study including
the incidence of silent myocardial events found no
significant differences between warfarin- and
dabigatran-treated patients [93]. There is some
evidence that this effect may not be restricted to
dabigatran and may reflect the fact that wellcontrolled warfarin can be protective against
cardiac ischaemic events. Numerically, but nonsignificantly, more acute coronary events were
recorded, compared to the warfarin-treated groups,
A. M. Shields & G. Y. H. Lip
in the North American cohort of the ROCKET-AF
trial treated with rivaroxaban [22], the low-dose
edoxaban arm of the ENGAGE AF-TIMI 48 trial [23],
the edoxaban arm of the edoxaban for the treatment
of acute, symptomatic venous thromboembolism
(HOKUSAI-VTE) study [94] and the aspirin plus
clopidogrel arm of ACTIVE-W [82].
Direct evidence of the benefit of NOACs in patients
with AF and concurrent vascular disease is lacking. The Anti-Xa Therapy to Lower cardiovascular
events in Addition to Standard therapy in subjects
with ACS 2 Thrombolysis In Myocardial Infarction
51 (ATLAS ACS 2 TIMI 51) study has shown that
rivaroxaban is superior to placebo in reducing
cardiovascular and all-cause mortality in patients
with recent acute coronary syndrome treated with
single or dual antiplatelet therapy [95]. However,
the dose of rivaroxaban used (2.5 mg b.d.) was less
than that recommended for AF [20 mg once daily
(o.d.)] and patients with AF were excluded; therefore, it is impossible to draw any firm conclusions
from this study.
Currently, there is little evidence to support the use
of NOACs as an alternative to warfarin in patients
with concurrent coronary or peripheral vascular
disease on antiplatelet therapy, particularly in the
early period after an episode of acute coronary
syndrome or after coronary angioplasty. Further
studies are needed to explore whether NOACs may
be beneficial to patients in these circumstances.
The 2014 joint European consensus document
[90], endorsed by the Heart Rhythm Society and
the Asia-Pacific Heart Rhythm Society (APHRS),
recommends a period of triple therapy (oral anticoagulant, aspirin and clopidogrel), followed by
oral anticoagulant and single antiplatelet (preferably clopidogrel) therapy and finally, when the
patient is stable, an oral anticoagulant alone. The
oral anticoagulant can be either a VKA with TTR
>70% or a NOAC. The latter should be given in the
lower tested dose used for AF stroke prevention
(e.g. dabigatran 110 mg b.d., rivaroxaban 15 mg
o.d. and apixaban 2.5 mg b.d.).
Asian patients
Despite a lower prevalence of AF amongst Asian
patients, compared to Caucasians, they have a
comparatively greater stroke prevalence due to a
higher prevalence of stroke risk factors within the
Asian population. However, they also have a much
greater incidence of intracerebral haemorrhage,
Review: Stroke prevention in atrial fibrillation
compared to western populations [96]. The higher
rates of haemorrhage remain poorly understood,
but have led to significant undertreatment of
nonvalvular AF with anticoagulant drugs in the
Asian population [97]. Data from the primary
randomized control trials and from secondary
meta-analyses, regarding the efficacy and bleeding
risks of anticoagulants in Asian subgroups of the
RE-LY, ROCKET-AF, J-ROCKET-AF, ARISTOTLE
and ENGAGE AF-TIMI 48 trials, have recently been
reviewed [98, 99].
In summary, the data have shown that the NOACs
are equally efficacious compared to warfarin for the
prevention of stroke and systemic embolism in the
Asian cohorts of these studies. Patients treated
with high-dose dabigatran, apixaban or high-dose
edoxaban were all shown to have significantly
reduced incidence rates of stroke and systemic
embolism compared to warfarin (150 mg dabigatran: RR 0.45, 95% CI 0.28–0.72; apixaban: RR
0.64, 95% CI 0.46–0.92; 60 mg edoxaban: HR
0.53, 95% CI 0.31–0.90). Furthermore, dabigatran
(150 and 110 mg b.d.), apixaban and edoxaban (60
and 30 mg o.d.) have all shown lower incidence
rates of intracranial haemorrhage (RR 0.20–0.41)
and major bleeding events (RR 0.52–0.57) than
dose-adjusted warfarin in the Asian cohorts [98,
100]. In the Japanese Rivaroxaban Once Daily Oral
Direct Factor Xa Inhibition Compared with Vitamin
K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (J-ROCKET-AF)
trial, rivaroxaban (15 mg o.d.) was found to be as
effective as warfarin for stroke prevention, with no
difference in the incidence of major haemorrhage
[101]. Analysis of the major NOAC trials showed
that haemorrhagic and thrombotic complications
are more common in Asian patients receiving VKA
therapy than in their Caucasian counterparts. In
the RE-LY trial, a composite negative clinical
outcome (including stroke, systemic embolism,
pulmonary embolism, myocardial infarction, major
bleeding and death) occurred in 9.65% of Asians
compared with 7.61% of non-Asians [102]. Albertsen et al. [103] estimated that the relative risk of
stroke in Asian patients receiving VKA therapy
within the NOAC trials was 1.70 (95% CI 1.42–
2.03) compared to Caucasians. Of interest, within
the RE-LY, ARISTOTLE and ROCKET-AF trials, the
average TTR was lower and the percentage of time
spent with an INR below 2 was higher amongst the
Asian cohorts, compared to non-Asian groups;
thus, their protection against stroke was reduced
[99].
ª 2015 The Association for the Publication of the Journal of Internal Medicine
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11
A. M. Shields & G. Y. H. Lip
The promising results of the NOAC trials have been
reflected in both Japanese [104] and APHRS [105]
guidelines for antithrombotic treatment in patients
with AF, with NOACs (dabigatran and apixaban in
the Japanese and APHRS guidelines, respectively)
recommended as first-line anticoagulants for AF
patients with a CHADS2 or CHA2DS2VASc score of
1. Warfarin is only recommended if the CHADS2 or
CHA2DS2VASc score exceeds 1 and, even then,
dabigatran (Japan) or dabigatran, rivaroxaban and
apixaban (APHRS) are also recommended treatment options. When deciding between warfarin
and a NOAC in Asian patients, it should be noted
that the SAMeTT2R2 score automatically assigns
Asian patients a score of 2 due to the difficulty in
controlling anticoagulation within this population.
Although the SAMeTT2R2 score has yet to be
independently validated in an Asian cohort, warfarin would only be advisable in the absence of other
risk factors that may jeopardize satisfactory control of anticoagulation.
Patients with a high risk of stroke or a previous TIA/stroke
Currently, there is little evidence to suggest the
NOACs are superior to warfarin in the prevention of
secondary stroke in patients with AF. A recent
meta-analysis of the RE-LY, ROCKET-AF and
ARISTOTLE trials demonstrated that dabigatran,
rivaroxaban and apixaban were all noninferior to
warfarin in this respect [106]. Apixaban was associated with the lowest risk of stroke or systemic
embolism in patients who had already suffered a
previous stroke or TIA (RR 0.77, 95% CI 0.57–
1.03), although this finding was not statistically
significant [24]. The ENGAGE AF-TIMI 48 trial
enrolled 1991 (28.3%), 1976 (28.1%) and 2006
(28.5%) patients who had suffered previous stroke
or systemic embolism to receive warfarin, highdose and low-dose edoxaban, respectively [23]. The
results of subgroup analysis from this study have
yet to be published.
In the four major clinical trials of NOACs compared to warfarin, patients were stratified by
stroke risk using the CHADS2 score. Both highdose dabigatran (150 mg b.d.) (RR 0.73, 95% CI
0.58–0.91; P = 0.005) and apixaban (HR 0.79,
95% CI 0.66–0.95; P = 0.01 for superiority) demonstrated superiority to warfarin in the prevention
of stroke and systemic embolism, with high-dose
dabigatran also associated with a significantly
lower incidence of ischaemic stroke compared to
warfarin [21]. Subgroup analysis of the RE-LY trial
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Review: Stroke prevention in atrial fibrillation
by CHADS2 score demonstrated that patients with
the highest stroke risk (CHADS2 ≥3) achieved the
greatest absolute reduction in risk of stroke with
dabigatran 150 mg b.d. compared to warfarin
(absolute risk reduction 0.85% year 1, 95% CI
0.16–1.85). Smaller reductions in absolute risk of
stroke were seen in patients with a CHADS2 score
<3 [107]. However, high-dose dabigatran was
associated with a significantly increased rate of
gastrointestinal bleeding (RR 1.50, 95% CI 1.19–
1.89; P < 0.001), and this risk should be carefully
considered when using dabigatran in patients at
high risk of stroke. In the ARISTOTLE trial,
patients taking apixaban with a CHADS2 score
>3 experienced significantly fewer strokes and
systemic emboli than patients taking warfarin. At
lower CHADS2 scores, apixaban was noninferior to
warfarin. It is noteworthy that the reduced incidence of major haemorrhage associated with
apixaban treatment was maintained in the cohort
of patients with CHADS2 scores >3, suggesting a
potential for use in patients at high risk of both
stroke and haemorrhage [24]. Modified intentionto-treat analysis of the ENGAGE AF-TIMI 48 trial
showed that high-dose edoxaban (60 mg o.d.) was
also superior to warfarin in the prevention of
stroke and systemic embolism (RR 0.79, 95% CI
0.63–0.99; P = 0.02 for superiority), but this did
not reach statistical significance in the intentionto-treat analysis of the overall population
(P = 0.08). Like dabigatran, high-dose edoxaban
was associated with a significantly increased incidence of gastrointestinal haemorrhage (RR 1.23,
95% CI 1.02–1.50; P = 0.03) [23].
Rivaroxaban should also be considered for the
treatment of patients at high risk of stroke or who
have suffered a previous TIA/stroke. The ROCKETAF trial enrolled a cohort of patients at higher
baseline risk of stroke (mean CHADS2 score of 3.5)
and more patients who had suffered a previous
stroke or TIA (55%) compared to the other NOAC
trials [22]. Consequently, although it is clear that
rivaroxaban is noninferior to warfarin in the prevention of stroke and systemic embolism in this
cohort, further studies may be necessary to fully
address the relative benefit of rivaroxaban compared to warfarin and other NOACs in patients at
low risk of stroke (CHADS2 score of 0–1).
Side effects and patient preference
Adherence to medication is of greater importance
with the NOACs than with warfarin due to their
A. M. Shields & G. Y. H. Lip
relatively shorter half-lives. Missed doses can lead
to suboptimal anticoagulant effect and increased
risk of stroke. As such, choosing a medication and
achieving a regimen that is agreeable to the patient
is essential. Consideration must be given to
whether the patient is capable of and wishes to
take a twice-daily (dabigatran and apixaban) or
once-daily regimen (rivaroxaban and edoxaban).
The common side effects of the NOACs are also
becoming clear (e.g. dyspepsia with dabigatran)
and should allow physicians to select medication
choices to better suit their patients’ preferences.
Of note, some patients may refuse or be unsuitable
for warfarin or NOAC thromboprophylaxis. Combination antiplatelet therapy may have some benefits
in reducing the risk of stroke in some patients with
AF, although this benefit declines with increasing
age and the risk of major bleeding remains [108].
The ACTIVE A trial investigated whether the addition of clopidogrel to aspirin offered any benefit in
reducing the risk of vascular events including
stroke in patients not suitable for VKA therapy
[81]. The results showed that the addition of
clopidogrel to aspirin significantly reduced the
incidence of major vascular events (RR 0.89, 95%
CI 0.81–0.98; P = 0.01) and ischaemic stroke (RR
0.72, 95% CI 0.62–0.83; P < 0.001) but also
increased the incidence of major haemorrhage
(RR 1.57, 95% CI 1.29–1.92; P < 0.001). Accordingly, the risks and benefits of such treatment
should be carefully considered.
Considering the individual: a patient-centred approach to
anticoagulation
The impact of AF on patients is considerable. In
addition to the well-documented affect on organic
disease, levels of psychological morbidity in AF
patients are similar to those seen in patients with
myocardial infarction and this negatively influences quality of life [109]. Indeed, individuals
with AF have a significantly poorer quality of life
compared to patients with coronary heart disease,
the general population and matched healthy
controls [110]. Stroke contributes to this poorer
quality of life and is more severe with greater
neurological deficits in patients with AF [111].
The risk of stroke is readily modified by anticoagulant therapy, yet the uptake of this therapy in
individuals at high risk of stroke secondary to A
with additional risk factors is poor, ranging from
54.9% in UK general practices [112] to 19–51% in
patients enrolled in US health insurance schemes
Review: Stroke prevention in atrial fibrillation
[113]. Thus, the delivery of safe and effective
thromboprophylaxis for patients with AF is inherently challenging. Ingelgard et al. [114] classified
the barriers to warfarin use into four categories:
patient medical characteristics, healthcare system
factors, patient capability and patient preferences.
Education of both patients and physicians will
continue to play an important role in encouraging
further use of anticoagulants for thromboprophylaxis. The Atrial Fibrillation Awareness and Risk
Education (AF AWARE) group investigated the
understanding of and attitudes towards AF of
physicians and patients [115]. From the patients’
perspective, 55% of individuals recognized that AF
was life threatening, but their principal concern
was that of suffering a myocardial infarction or
sudden cardiac event, rather than the risk of future
stroke. Appropriate assessment and communication of the risk of stroke and the consequent risks
and benefits of initiating anticoagulation should
form the cornerstone of shared decision-making
with patients regarding the management of their
AF; communication is most successful when statistical information regarding risk is personalized
to the individual [116]. Therefore, NICE has developed a decision-making aid [117] which, through
pictorial representation, clearly considers the risk
of stroke and haemorrhage associated with anticoagulant use, based on an individual’s CHA2DS2VASc score.
Lahaye et al. [118] recently investigated the attitudes of a cohort of 172 inpatients to the initiation
of anticoagulation for AF and found considerable
interindividual variance in tolerance of bleeding
risk in the context of anticoagulation for stroke
prevention. In this study, patients were made
aware of their individualized stroke risk, based
on their CHA2DS2VASc score. On average, to
initiate anticoagulation therapy, patients would
tolerate a minimum absolute risk reduction in
stroke per annum of 0.8%, or a 15% relative risk
reduction. Furthermore, patients were willing to
accept the risk of 4.4 major haemorrhages to
prevent one stroke [118]. In general, patients were
extremely stroke averse, regarding a minor stroke
as only marginally worse than a major haemorrhage and a moderate or major stroke as equal to
or worse than death, respectively [118]. This study,
with participants knowing their individualized
risk, confirms previous studies performed both in
inpatient and outpatient settings demonstrating
ª 2015 The Association for the Publication of the Journal of Internal Medicine
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13
A. M. Shields & G. Y. H. Lip
considerable tolerance towards bleeding episodes
in the context of thromboprophylaxis [118–120].
Only 12% of patients were medication averse,
unwilling to consider treatment even if it was likely
to be 100% effective [118]. Ingelgard et al. [114]
found that the most common reason why individuals with AF were unwilling to initiate anticoagulation therapy was a reluctance to undertake
regular INR monitoring.
Physicians, however, have historically been more
cautious in recommending anticoagulation therapy
for patients with AF, reflected by the low rates of
use of VKAs in patients at high risk of stroke [112,
113]. Advancing age, perceived bleeding risk and
the risk of falls were all cited as major determinants of the failure to prescribe anticoagulants to
patients with AF [114, 121]. Yet, Devereaux et al.
[119] found that patients at high risk of stroke from
AF placed much greater value on stroke avoidance
than their physicians. Collectively, these findings
suggest that physicians are not only under-treating
patients at risk of debilitating strokes, but are also
failing to acknowledge the importance patients
place on avoiding these events. As such, physicians
must be supported by clear evidence-based guidelines and/or algorithms to assist them in explaining the risk of stroke and anticoagulant-associated
haemorrhage to patients with AF, and in managing
these risks in partnership with the patient. Unfortunately, only 35% of physicians surveyed by the
AF AWARE group thought that information available to patients with AF was easy to understand
and 52% of patients surveyed in the West Birmingham Atrial Fibrillation Project study understood
why anticoagulation treatment had been initiated
for their AF [122].
Conclusion
Despite overwhelming evidence demonstrating the
net clinical benefit of anticoagulation for stroke
prevention in patients with AF and emerging
evidence that AF patients generally accept the risk
of major haemorrhage to reduce their risk of
disabling and debilitating strokes, the rates of
anticoagulant prescription for patients with AF
remain unacceptably low. The failure to recommend and prescribe anticoagulation is undoubtedly contributing to the stroke epidemic.
Selecting and adhering to anticoagulant therapy
remains challenging for physicians and patients
with AF. Until 2010, VKAs were the only available
14
ª 2015 The Association for the Publication of the Journal of Internal Medicine
Journal of Internal Medicine, 2015, 278; 1–18
Review: Stroke prevention in atrial fibrillation
oral anticoagulants for patients with AF; the NOACs have revolutionized the field by offering predictable, easy-to-use drugs that are as efficacious
as warfarin for stroke prevention, and associated
with lower rates of intracranial haemorrhage and,
in some circumstances, major haemorrhage. Moreover, it is becoming increasingly clear that in
certain groups of patients at high risk of stroke
who have historically been undertreated with warfarin (e.g. the elderly or those with renal impairment), the NOACs are superior to warfarin in terms
of efficacy and/or safety. Further studies are
needed to explore NOAC use in these groups to
allow the development of clear unambiguous
guidelines that may empower physicians to manage stroke risk more comprehensively in these
high-risk patients.
We propose a patient-centred, individualized
approach to the management of thromboembolic
risk in patients with AF. Indeed, with several
NOAC drugs now available, we are perhaps ‘spoilt
for choice’ and can fit the drug to the patient
profile (and vice versa). The cornerstone of this
approach is the effective communication of stroke
risk and the relative risks and benefits of anticoagulation by the physician to the patient with AF.
This depends on calculating patients’ individualized risks of stroke and haemorrhage (using
CHA2DS2VASc and HAS-BLED) and their potential
to achieve tight control of warfarin-based anticoagulation (using the SAMeTT2R2 score). More
importantly, physicians must facilitate patients’
understanding of their individual risks and consider patients’ personal preferences to allow a fully
informed and shared decision to be made about
initiating anticoagulant therapy. Decision-making
aids, such as that developed by NICE, can assist in
this process.
Conflict of interest statement
Dr Adrian Shields has no conflict of interest to
declare. Prof. Gregory Lip is a consultant for Bayer,
Medtronic, Sanofi, BMS/Pfizer, Daiichi-Sankyo
and Boehringer Ingelheim and has been a speaker
for Bayer, BMS/Pfizer, Boehringer Ingelheim, Daiichi-Sankyo and Medtronic.
Acknowledgements
We thank Dr Kaivan Khavandi for medical editorial
assistance. Financial support for this assistance
was provided by Daiichi Sankyo Europe GmbH.
A. M. Shields & G. Y. H. Lip
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Correspondence: Gregory Y. H. Lip, University of Birmingham
Centre for Cardiovascular Sciences, City Hospital, Birmingham
B187QH, UK.
(fax: 0121 554 4083; e-mail: [email protected]).