EURO PEAN

SO CIETY O F
Clinical practice CARDIOLOGY ®

European Journal of Preventive

Cardiology

European Primary Care Cardiovascular 2016, Vol. 23(5) 460–473

! The European Society of
Cardiology 2015
Society (EPCCS) consensus guidance on Reprints and permissions:
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stroke prevention in atrial fibrillation DOI: 10.1177/2047487315571890
ejpc.sagepub.com
(SPAF) in primary care

FD Richard Hobbs1, Clare J Taylor2, Geert Jan Geersing3,

Frans H Rutten3 and Judith R Brouwer4, on behalf of the
European Primary Care Cardiovascular Society (EPCCS)
SPAF working group

Abstract
Background: Atrial fibrillation affects 1–2% of the general population and 10% of those over 75, and is responsible for
around a quarter of all strokes. These strokes are largely preventable by the use of anticoagulation therapy, although
many eligible patients are not treated. Recent large clinical trials have added to the evidence base on stroke prevention
and international clinical guidelines have been updated.
Design: Consensus practical recommendations from primary care physicians with an interest in vascular disease and
vascular specialists.
Methods: A focussed all-day meeting, with presentation of summary evidence under each section of this guidance and
review of European guidelines on stroke prevention in atrial fibrillation, was used to generate a draft document, which
then underwent three cycles of revision and debate before all panel members agreed with the consensus statements.
Results: Six areas were identified that included how to identify patients with atrial fibrillation, how to determine their
stroke risk and whether to recommend modification of this risk, and what management options are available, with
practical recommendations on maximising benefit and minimising risk if anticoagulation is recommended and the reasons
why antiplatelet therapy is no longer recommended. The summary evidence is presented for each area and simple
summary recommendations are highlighted, with areas of remaining uncertainty listed.
Conclusions: Atrial fibrillation-related stroke is a major public health priority for most health systems. This practical
guidance can assist generalist community physicians to translate the large evidence base for this cause of preventable
stroke and implement this at a local level.

Keywords
Atrial fibrillation, stroke prevention, stroke risk, bleeding risk, anticoagulation
Received 24 October 2014; accepted 19 January 2015

1
Nuffield Department of Primary Care Health Sciences, University of
Background Oxford, UK
2
Department of Primary Care Clinical Sciences, University of
Despite the large evidence base for preventing stroke Birmingham, UK
in atrial fibrillation (AF), and the recent guideline 3
Julius Center for Health Sciences and Primary Care, University of
updates with recent clinical outcome data and clinical Utrecht, the Netherlands
4
experience (see web version for full details and refer- Medcon International, Heemstede, the Netherlands
ences), the European Primary Cardiovascular Care
Corresponding author:
Society (EPCCS) felt that wider implementation of FD Richard Hobbs, University of Oxford, Radcliffe Observatory Quarter,
the available guidelines (European Society of Woodstock Road, Oxford OX2 6GG, UK.
Cardiology (ESC) and others) in primary care settings Email: [email protected]
Hobbs et al. 461

Introduction
Box 1. Strength of recommendations
Atrial fibrillation (AF) is the most common cardiac
The following colour coding will be used throughout arrhythmia, with about 1–2% of the general popula-
the document, to indicate the strength of the individ- tion estimated to be affected.1,2 It is a particularly
ual recommendations. common disorder in the elderly, with over 5% of
people over the age of 65 suffering from AF, and
Interventions that should (or should not) be used: a around 10% of people over the age of 75.3–5 As a
‘strong’ recommendation consequence of the ageing population, the prevalence
‘Offer’ (and similar words such as ‘refer’ or ‘advise’) of AF is predicted to rise.6 Rising prevalence has also
indicates confidence that, for the vast majority of been attributed to better survival of patients following
patients, an intervention will do more good than acute coronary events, and a greater awareness among
harm, and be cost-effective. Similar forms of words healthcare professionals of the importance of diagnos-
(for example, ‘Do not offer. . .’) are used when we are ing AF.
confident that an intervention will not be of benefit
for most patients.
Interventions that could be used
Clinical picture of patients with atrial fibrillation
‘Consider’ indicates confidence that an intervention Patients with AF may have symptoms such as palpita-
will do more good than harm for most patients, and tions, lack of energy, dizziness, chest discomfort and
be cost-effective, but other options may be similarly shortness of breath, which may impair quality of life.7
cost-effective. The choice of intervention, and The degree of these symptoms varies considerably,
whether or not to have the intervention at all, is from patients who are completely asymptomatic to
more likely to depend on the patient’s values and those who are quite disabled by the arrhythmia. The
preferences than for a strong recommendation, and use of rate and rhythm control to improve symptoms is
so the healthcare professional should spend more beyond the scope of this guideline, which will focus
time considering and discussing the options with the exclusively on stroke prevention.
patient. It is important to note that, for many patients with
Terminology used with permission from NICE. AF, the condition is often asymptomatic - or associated
with minor symptoms that are ignored or unrecognised
by patients – therefore, if the arrhythmia is to be iden-
tified in all, some type of AF screening is needed.
would benefit from adding contextual changes or clari- Perhaps the most important consequence of AF is
fications of the evidence to aid the uptake of guidance the risk of embolic stroke. Patients with AF are at an
in primary care. The EPCCS therefore established a almost fivefold higher risk of stroke compared with
Stroke Prevention in Atrial Fibrillation (SPAF) work- age-matched individuals with normal sinus rhythm,
ing group to develop an evidence-guided pragmatic as shown in the Framingham study,8 as well as at a
guide on SPAF in primary care. twice as high risk of all-cause mortality and heart fail-
The EPCCS Consensus Group made its recommen- ure. About 20–25% of all ischaemic strokes are attrib-
dations based on ‘the trade-off between the benefits and utable to embolism as a result of AF.9 Not only do
harms of any intervention, taking into account the patients with AF have more strokes, they also develop
quality of the underpinning evidence’. The wording more recurrent strokes, both fatal and nonfatal.8 In
used in our recommendations (see Box 1) denotes the addition, strokes are likely to be more severe in
certainty with which the recommendation is made (the patients with AF, than in patients who have a
strength of the recommendation). There should be dis- stroke not associated with AF, regardless of age.10
cussion with the patient about the risks and benefits of Following a stroke, patients with AF are more likely
the interventions, and their values and preferences. This to be left with long-term disability and may require
discussion aims to help clinician and patient to reach a long-term care.11,12 This disability is a major source of
fully informed decision. concern for patients and is associated with high costs
To highlight the summary recommendations, the for healthcare systems. Moreover, AF is often asso-
writing committee chose to indicate where the position ciated with other underlying pathology, such as car-
taken is clearly evidence-based (green), and where it is diovascular comorbidity (coronary artery disease,
more inferred and consensus-based (blue). It is also heart failure, hypertension) and/or non-cardiovascular
specified when studies were carried out in primary comorbidity (chronic obstructive pulmonary disease
care settings, and therefore the evidence is most (COPD), renal failure, etc.). This is especially preva-
relevant. lent in the elderly, and highlights the role general
462 European Journal of Preventive Cardiology 23(5)

practice should play in managing this multi-morbid

disorder. AF has considerable impact on individuals
Practical recommendations
and health systems. It is also associated with increased Based on current evidence and experience, we recom-
mortality, heart failure and high rates of hospitalisa- mend the following in a primary care setting:
tion because of stroke. Admission and readmission
rates are the most important factors driving healthcare . All patients with AF, regardless of AF type, are at
expenditure.18–20 increased risk of stroke as they age or develop cer-
tain comorbid conditions and therefore all AF
patients should be offered assessment of their
Types of atrial fibrillation stroke risk (see How to decide whether to treat
ESC guidelines distinguish various types of AF, stroke risk in atrial fibrillation?).
mainly based on duration, for example paroxysmal . Patients who are treated for AF and returned to
(usually 48 hours), persistent (7 days) and long- sinus rhythm should be risk assessed as if they
standing or permanent (>1 year).1,2 These classifica- were still in AF and should remain on their stroke
tions are somewhat arbitrary and their use in clinical prevention therapy if it was indicated prior to
practice might be limited. They may, however, be rele- rhythm control. If a decision is taken to stop antic-
vant to determine how to treat the arrhythmia itself, oagulation in these patients, it should be a specialist
rather than the stroke risk associated with AF. decision.
The risk of stroke is considered similar for all types
of AF.13
It is also important to consider the distinction How is atrial fibrillation detected? Should
between valvular and non-valvular types of AF, as we screen for atrial fibrillation?
this affects management. In the ESC guidelines,1,2 the
term valvular AF is used to indicate that AF is related
Rationale for opportunistic case-finding
to rheumatic valvular disease (predominantly mitral AF is one of the most important causes of preven-
stenosis) or prosthetic heart valves. table stroke, is associated with more severe strokes
Atrial flutter, a different type of atrial arrhythmia, is and is therefore a major health risk to modify in
sometimes considered along with AF. Patients with patients and an important disease target for health
atrial flutter are often referred for consideration of systems. AF meets all the Wilson-Jungner criteria to
curative management, but in the meantime stroke risk be a condition worth screening for. Patients with AF
should be considered and managed in the same way may present with symptoms, and AF should be con-
as AF. sidered in anyone complaining of palpitations (flut-
In summary, all types of AF, with the exception of tering or irregular heart beat), dizziness or fainting
clinically significant valvular AF as defined above, spells, chest discomfort, shortness of breath and/or
should be regarded as the same in terms of stroke reduced exercise tolerance. However, not all patients
risk. Defining the type of AF can provide a diagnostic with AF will have symptoms and may, therefore, be
label, which can be useful when considering rate or unaware they have an arrhythmia. The observation
rhythm management, but stroke risk is similar. that even short episodes of silent AF (as measured
Importantly, re-establishing sinus rhythm will not with implanted devices and by Holter electrocardio-
remove the stroke risk.14–17 grams (ECGs)) convey an increased risk of
stroke22,23 offers the rationale for opportunistic
Role of the general practitioner in stroke prevention screening.
Opportunistic screening by pulse palpation in gen-
in atrial fibrillation
eral practice detected a large number of patients
AF often co-exists with other chronic diseases, and with previously undiagnosed AF compared with usual
these comorbidities may have caused or exacerbated care (1.64% per year by screening vs. 1.04% per year
each other. Over extended periods of time, AF may with care as usual), yielding a feasible number of 169
cause substantial cardiac remodelling that can impact needed to screen.24 These data suggest that active
on the management of both conditions. A recent epi- screening for AF in patients of 65 years and older can
demiological study showed that 5% of over 65-year- identify patients eligible for anticoagulation treatment
olds had AF, and at least three other chronic condi- according to CHADS2 criteria.25 New technologies,
tions.21 This implies that the general practitioner can such as modified sphygmomanometers capable of
play a crucial, central role, as he or she is aware of and detecting an irregular pulse, may also improve pick-
can manage different conditions. up rates.
Hobbs et al. 463

Confirming the diagnosis in suspected atrial Additional work recommended in this area/gaps in the
evidence:
fibrillation
In patients with suspected AF, an ECG, preferably 12- . See web version
lead ECG, can confirm the diagnosis. Loss of P-waves
and completely irregular R-R distances are characteris-
tic features of AF on ECG; however, ECG changes How to decide whether to treat stroke
may be subtle, so judgement by a competent ECG- risk in atrial fibrillation?
reader is required to confidently diagnose AF.5 Risk assessment for stroke prevention in atrial
Adequate interpretation of a single-lead ECG may be
considered as convincing as a 12-lead ECG for detec-
fibrillation
tion or exclusion of AF.26 When giving antithrombotic agents to reduce stroke
Conventionally, an ECG should contain a total risk in AF, both thromboembolic risk and bleeding
of 30 seconds of AF to confirm the diagnosis, but this risk need to be considered. ‘Whom not to treat?’ is a
criterion is consensus not evidence-based, and was question at least as important to ask as ‘whom to
developed for considering which patients to offer cardio- treat?’, as each form of antithrombotic therapy has an
version or pacing. Therefore, a standard 12-lead ECG of inherent, and possibly severe, bleeding risk.
10 seconds is perhaps sufficient in practice settings. The CHADS2 score is a valuable tool that has been
used for some time to assess stroke risk in patients with
AF,27,28 but observational data highlighted the need for
Practical recommendations
a more robust stroke risk score. The CHA2DS2-VASc
Based on current evidence and experiences, we recom- score has since been developed, which includes add-
mend the following case finding efforts in a primary itional risk factors and gives a maximum score of 9
care setting: compared with a maximum of 6 in the CHADS2
score (see Table 1 for components of the CHA2DS2-
Interventions that should be used VASc score). Age can contribute 2 points, rather than
1, if the patient is 75 years old. Vascular disease and
. Opportunistic case finding should be carried out for female sex also add an extra point,1,2 the latter only
timely detection of AF in all patients over 65 years of contributing a score, however, if other stroke risk fac-
age, and in anyone who receives routine cardiovas- tors are present (i.e. if the only ‘risk’ factor is being
cular follow-up: female, the CHA2DS2-VASc score is 0). The improved
 Pulse palpation, at least once a year could be risk stratification with CHA2DS2-VASc as opposed to
incorporated into already existing medical visits, CHADS2 score has been validated in several stu-
for instance during an annual cardiac disease dies,29–33 and CHA2DS2-VASc is the recommended
review, and/or at flu vaccinations or pharmacy score for assessment of stroke risk in the ESC guide-
visits. lines.2 Event rates of hospital admission and death
. In the case of a positive pulse palpation: caused by thromboembolism (including peripheral
 12-lead ECG follow-up should be performed artery embolism, ischaemic stroke, and pulmonary
shortly after pulse assessment. 12-lead ECG embolism) for each CHADS2 and CHA2DS2-VASc cat-
follow-up should be done by a practitioner who egory are shown in Table 2.
is competent in ECG interpretation.
Risk assessment for bleeding risks from
Alternative approach
anticoagulation
. Modified sphygmomanometers or other Bleeding is an important, potentially serious, side effect
devices using single-lead ECG registrations of anticoagulation and should be considered for all
to detect an irregular pulse may be used instead patients prior to treatment initiation.
of pulse palpation, but only where they have Bleeding risk can be assessed with the HAS-BLED
been subject to independent validation with a 12- score, as introduced in the 2010 ESC Guidelines (see
lead ECG. Table 3 for components of the HAS-BLED score).1,34
. If not enough expertise is available in the primary The score takes into account nine risk factors for bleed-
care setting to confidently read a 12-lead ECG, it ing that should be considered before starting antith-
should be reviewed by a specialist. 12-lead ECG rombotic treatment. The most important factor
may also provide other useful information on car- determining both stroke and bleeding risk appears to
diac functioning. be age,2,35–38 which justifies its double weight in the
464 European Journal of Preventive Cardiology 23(5)

Table 1. CHADS2 and CHA2DS2-VASc risk score components.

CHADS2 score CHA2DS2-VASc score

Condition Points Points

Congestive heart failure (or left ventricular systolic dysfunction) C 1 C 1

Hypertension: blood pressure consistently above 140/90 mmHg H 1 H 1
(or treated hypertension on medication)
Age  75 years A 1 A2 2
Diabetes mellitus D 1 D 1
Stroke or TIA or thromboembolism in history S2 2 S2 2
Vascular disease (e.g. peripheral artery disease, myocardial infarction, V 1
aortic plaque)
Age 65–74 years A 1
Sex category (i.e. female gender) Sc 1
This table shows the components of the CHADS2 (Gage et al., JAMA 2001)28 and CHA2DS2-VASc scores (Lip et al., Chest 2010)30 tools to assess
stroke risk in patients with AF. These risk assessment tools help to determine who should and who should not receive anticoagulation. CHA2DS2-VASc
improves risk stratification in patients with CHADS2¼0 or 1, and allows for identification of patients at truly low risk.

Table 2. Event rates per CHADS2 and CHA2DS2-VASc category.

Score/risk category 1-year follow-up 5-years follow-up 10-year follow-up

Annual event rate Annual event rate Annual event rate

CHADS2 score:
0 1.67 (1.47–1.89) 1.28 (1.19–1.38) 1.24 (1.16–1.33)
1 4.75 (4.45–5.07) 3.70 (3.55–3.86) 3.56 (3.42–3.70)
2 7.34 (6.88–7.82) 5.58 (5.35–5.83) 5.40 (5.18–5.63)
3 15.47 (14.62–16.36) 10.29 (9.87–10.73) 9.89 (9.50–10.31)
4 21.55 (20.03–23.18) 14.00 (13.22–14.82) 13.70 (12.95–14.48)
5 19.71 (16.93–22.93) 12.98 (11.52–14.63) 12.57 (11.18–14.14)
6 22.36 (14.58–34.30) 16.75 (11.91–23.56) 17.17 (12.33–23.92)
Low risk (0) 1.67 (1.47–1.89) 1.28 (1.19–1.38) 1.24 (1.16–1.33)
Intermediate risk (1) 4.75 (4.45–5.07) 3.70 (3.55–3.86) 3.56 (3.42–3.70)
High risk (2–6) 12.27 (11.84–12.71) 8.30 (8.08–8.51) 7.97 (7.77–8.17)
CHA2DS2-VASc risk score:
0 0.78 (0.58–1.04) 0.69 (0.59–0.81) 0.66 (0.57–0.76)
1 2.01 (1.70–2.36) 1.51 (1.37–1.67) 1.45 (1.32–1.58)
2 3.71 (3.36–4.09) 3.01 (2.83–3.20) 2.92 (2.76–3.09)
3 5.92 (5.53–6.34) 4.41 (4.21–4.61) 4.28 (4.10–4.47)
4 9.27 (8.71–9.86) 6.69 (6.41–6.99) 6.46 (6.20–6.74)
5 15.26 (14.35–16.24) 10.42 (9.95–10.91) 9.97 (9.53–10.43)
6 19.74 (18.21–21.41) 12.85 (12.07–13.69) 12.52 (11.78–13.31)
7 21.50 (18.75–24.64) 13.92 (12.49–15.51) 13.96 (12.57–15.51)
8 22.38 (16.29–30.76) 14.07 (10.80–18.33) 14.10 (10.90–18.23)
9 23.64 (10.62–52.61) 16.08 (8.04–32.15) 15.89 (7.95–31.78)
Low risk (0) 0.78 (0.58–1.04) 0.69 (0.59–0.81) 0.66 (0.57–0.76)
Intermediate risk (1) 2.01 (1.70–2.36) 1.51 (1.37–1.67) 1.45 (1.32–1.58)
High risk (2–9) 8.82 (8.55–9.09) 6.01 (5.88–6.14) 5.72 (5.60–5.84)
Event rates (95% CI) of hospital admission and death caused by thromboembolism (including peripheral artery embolism, ischaemic stroke and
pulmonary embolism) per 100 person years, for each CHADS2 and CHA2DS2-VASc category. Risk profiles are largely similar with different lengths
of follow-up. Adapted from Olesen et al., BMJ 201129.
Hobbs et al. 465

Table 3. HAS-BLED risk score components (Camm et al., Eur Heart J 20101 and Pisters et al., Chest 201034) used to assess bleeding
risk.

Clinical characteristic Points

Hypertension Uncontrolled, >160 mmHg systolic H 1

Abnormal renal and liver function Dialysis, transplant, Cr 200 mmol/L, A 1 or 2
(1 point each) Cirrhosis, bilirubin >2 normal, AST/ALT/AP >3 normal
Stroke history S 1
Bleeding or predisposition to bleeding B 1
Labile INR Unstable/high INRs, time in therapeutic range < 60% L 1
Elderly Age > 65 E 1
Drugs or alcohol Antiplatelet agents, NSAIDs D 1 or 2
(1 point each)  8 drinks/week

Table 4. Incidence of major bleeds per whereas others may accept stroke risk rather than the
HAS-BLED category as seen in non-selected inconvenience of taking anticoagulants.39
AF patients receiving anticoagulation. In general, it should be noted that with an
Incidence area under the curve below 70,38,40,41 these risk
HAS-BLED (%/year) of major scores remain less than perfect predictors of individual
score bleeding events risk.

0 0
1 0.83 Practical recommendations
2 1.88 Based on current evidence and experiences, we recom-
3 5.72 mend the following stroke and bleeding risk assessment
4 5.61 strategy in primary care in patients who have been
5 16.48 diagnosed with AF:
Stroke and bleeding risk interventions that should be
N¼937 patients. Median follow-up was 952 (IQR
used
785–1074) days. C-statistic as a quantitative vari-
able: 0.71 and 0.68 as a dichotomised variable.
Adapted from Roldan et al., Chest 2013.41 . CHA2DS2-VASc score is superior to CHADS2 score
for assessing stroke risk in AF, notably in identifying
those that should not receive anticoagulation.
. Alternatively, as CHADS2 is simpler to use, patients’
CHA2DS2-VASc score. An observational retrospective risk of stroke can be initially assessed using
study has confirmed increased bleeding rates in incre- CHADS2 but if their score is 1 or less, then a
mental HAS-BLED scores.35 Table 4 shows the inci- CHA2DS2-VASC score should be performed to
dence of major bleeding per HAS-BLED category as identify those patients who do not require
seen in non-selected patients receiving anticoagulation. anticoagulation.
HAS-BLED should guide the patient and clinician . Patients with a CHA2DS2-VASc score of 0 should
to reduce modifiable bleeding risks (namely high blood not be offered antiplatelet or anticoagulation
pressure, liver and kidney function, INR control and therapy.
use of interacting medications or alcohol), but not . Patients with a CHA2DS2-VASc score of 2 or above
determine whether to offer anticoagulation or not – should be offered anticoagulation. In patients with a
that decision is based on stroke risk estimation. CHA2DS2-VASc score of 1, consider anticoagulation
Falls are sometimes given as an argument not to and base any decision to treat or not treat on patient
anticoagulate a frail patient, yet evidence suggests preference after balancing the benefits with risks of
that patients with low impact falls need to fall a great treatment.
number of times before it actually increases the bleed- . As a second step, HAS-BLED should be used to
ing risk. Patient preferences should determine treat- assess bleeding risk, with the aim of modifying this
ment; some patients are willing to endure many risk through addressing individual risk factors that
bleeds to avoid one stroke and its consequences, can be altered.
466 European Journal of Preventive Cardiology 23(5)

Table 5. Nature of primary events with warfarin or aspirin in an elderly community population with atrial fibrillation.

Warfarin Aspirin Warfarin vs. aspirin

n¼488 n¼485

risk risk
n per year n per year RR (95% CI) p

Stroke 21 1.6% 44 3.4% 0.46 (0.26–0.79) 0.003

By severity
Fatal 13 1.0% 21 1.6% 0.59 (0.27–1.24) 0.14
Disabling-non fatal 8 0.6% 23 1.8% 0.33 (0.13–0.77) 0.005
Type of stroke
Ischaemic 10 0.8% 32 2.5% 0.30 (0.13–0.63) 0.0004
Haemorrhagic 6 0.5% 5 0.4% 1.15 (0.29–4.77) 0.83
Unknown 5 0.4% 7 0.5% 0.69 (0.17–2.51) 0.53
Other intracranial haemorrhage 2 0.2% 1 0.1% 1.92 (0.10–113.3) 0.65
Systemic embolism 1 0.1% 3 0.2% 0.32 (0.01–3.99) 0.36
Total number of events 24 1.8% 48 3.8% 0.48 (0.28–0.80) 0.0027
The BAFTA (Birmingham Atrial Fibrillation Treatment of the Aged) Study was a randomised controlled trial comparing warfarin (target INR 2.0–3.0)
with aspirin (75 mg/day) for stroke prevention in atrial fibrillation in a community population over 75 years of age. Primary events are shown for both
treatments, along with the relative risk (RR) for warfarin versus aspirin. Adapted from: Mant et al., Lancet 200746.

. HAS-BLED should not be used to decide whether

to offer anticoagulation in someone with What are the management options to
a CHA2DS2-VASc score of 2 or above, but con- treat stroke risk in atrial fibrillation?
sider its use to balance the benefits of anticoagu- What is the evidence for anticoagulation in patients
lation in patients with a CHA2DS2-VASc score
with atrial fibrillation in primary care?
of 1.
. On a regular basis, and at least once a year, the risk Different antithrombotic strategies to prevent stroke in
status of patients with AF should be re-evaluated AF have been investigated over time. Early studies sug-
depending on change in risk factors (change of age gested that antiplatelet agents were effective in reducing
category, new hypertension, etc). stroke risk with one meta-analysis showing that acetyl
salicylic acid (ASA) reduced the stroke rate by 22%,42
These scoring tools are available on the EPCCS website and addition of clopidogrel led to a risk reduction of
at: www.epccs.eu. 28%.43 Vitamin K antagonists show risk reductions of
Alternative risk assessment approaches that may be 66%.44,45
used: The BAFTA study specifically studied an elderly
(75 years old) primary care population, and compared
. A more pragmatic strong risk application might warfarin with ASA in a randomised controlled trial,
simply be to consider age, as women over 65 with showing that warfarin was much more effective than
AF and an additional risk factor qualify for antic- ASA at reducing stroke (see Table 5). Strokes occurring
oagulation according to CHA2DS2-VASc stroke risk in the elderly are more likely to be embolic strokes.46
stratification, and so do men over 75. The BAFTA data are supported by the individual
. People under 65 with no additional risk factor to patient data (IPD) meta-analysis of the totality of avail-
their AF, in contrast, do not need anticoagulation. able warfarin and aspirin data in preventing AF stroke
. Risk assessment should also be done in patients by age, which showed that aspirin became less effective
younger than 65 years of age who have multiple and more likely to cause bleeding with increasing age,
risk factors. with no benefits observed beyond age 75.47

Additional work recommended in this area/gaps in the

Comorbidity in atrial fibrillation
evidence:
Patients with AF often have other chronic conditions,
. See web version. which may be a cause or consequence of the arrhythmia
Hobbs et al. 467

or simply co-exist. Multi-morbidity increases with age, the decision to treat with anticoagulation or not
and is common in people over 65 years old. Patients should be based on patient preferences of their pri-
between 65 and 84 were found to have on average 2.6 mary desire to reduce their stroke risk or to avoid
(SD 2.09) morbidities, and 64.9% (95% CI 64.7–65.1) bleeding risk. As their stroke risk is moderate rather
of people in this age group have multi-morbidity. In than high, it is also very important to attempt to
patients of 85 years and older the mean number of modify any bleeding risk factors.
morbidities is 3.62 (SD 2.30), and 81.5% (95% CI . Only in those intolerant of, or declining, anticoagu-
81.1–81.9) of individuals have multi-morbidity. lation may a combination of antiplatelets be con-
Socioeconomic deprivation is associated with earlier sidered (although the bleeding risk of this strategy
onset of multi-morbidity.21 will approach that of anticoagulation).

Stroke risk management in atrial fibrillation patients

with rate or rhythm control strategies What are the therapeutic options to treat
In symptomatic AF patients, it is important to optimise
stroke risk in atrial fibrillation?
and control heart rate and it may also be appropriate to Although vitamin K antagonists (VKAs), and to a
try to re-establish and maintain sinus-rhythm. Now lesser extent other antithrombotic agents, importantly
that all guidelines advocate consideration of the use reduce the risk of stroke in patients with AF, they have
of antithrombotic therapy in all patients based on risk several drawbacks, and a lot of effort has been dedi-
calculation, it is important to consider that control of cated to developing new anticoagulant agents. VKAs
rate and rhythm should only be attempted alongside require intensive monitoring of international normal-
controlling for the stroke risk. Importantly, antithrom- ised ratio (INR) to ensure the drug is effective yet
botic therapy should be continued, even if rhythm con- safe by maintaining figures within a therapeutic range
trol is obtained.14–17 (INR target 2.5, range 2–3 for NVAF). Moreover, it is
important to achieve INR control above 65% time in
therapeutic range (TTR), as shown in Figure 1. Four
Practical recommendations new oral anticoagulants (NOACs) are now available,
Based on current evidence and experiences, we recom- namely dabigatran etexilate, a direct thrombin inhibi-
mend the following stroke risk reduction management tor,48,49 and the direct factor Xa inhibitors apixaban,50
in primary care patients who have been diagnosed rivaroxaban,51 and edoxaban.51,52 These newer agents
with AF: offer additional options to current treatments for
Management strategies that should be used SPAF, as outlined below.

. Patients with a CHA2DS2-VASc score of 2 or above

should be offered anticoagulation.
Efficacy of NOACs versus warfarin in non-valvular AF
In recent years, new classes of anticoagulants have been
Management strategies that should not be used developed and tested. Data of large trials on their effi-
cacy and safety have been evaluated extensively, includ-
. Patients assessed as low risk on the CHA2DS2-VASc ing ‘real life’ follow-up data. In several, large
score (0) should not be offered antiplatelet or antic- randomised controlled trials (RCTs) of AF patients
oagulation therapy, but may be offered standard without severe valve disease or mechanical valves,
advice regarding improving vascular risk factors NOACs have been shown to be effective at reducing
(smoking cessation, BP and cholesterol control). stroke risk.48–52 These RCTs were designed as non-
. Patients with a CHA2DS2-VASc score of 1, should inferiority studies; thus powered to show that NOACs
not be offered single antiplatelet therapy. are at least as good as warfarin in the prevention of
. Patients at high stroke risk, with a CHA2DS2-VASc stroke in AF. Fuller study details are available in the
score of 2 or more, should not be offered single or web version of this paper.
dual antiplatelet therapy. A systematic review53 that evaluated the results of
the NOAC versus warfarin trials (RE-LY, ROCKET-
Management strategies that may be used AF and ARISTOTLE) concluded that overall mortal-
ity was decreased in patients with AF taking NOACs
. In patients with a CHA2DS2-VASc score of 1, con- (risk difference estimated to be 8 [95% CI 3–11] fewer
sider anticoagulation and base any decision to treat deaths per 1000 patients, RR 0.88, 95% CI 0.82–0.96).
or not to treat on patient preference after balancing In the meta-analysis that also included ENGAGE AF-
the benefits with risks of treatment. In this situation, TIMI, all-cause mortality was also significantly reduced
468 European Journal of Preventive Cardiology 23(5)

100
% time in

% of patients without a stroke

95 therapeutic
range
(INR 2.0-3.0)
90
No warfarin

<30
85
31-40

41-50
80
51-60

61-70
75
>70

0 20 40 60 80 100
Time (months after diagnosis)

Figure 1. Percent of patients free from stroke over time, stratified by time spent in therapeutic range (INR 2.0–3.0). Adapted from
Gallagher et al., Thromb and Haem 2011.60

NOACs and mechanical valves (without AF)

with NOACs (2022 events in 29292 patients [6.9%])
versus warfarin (2245 events in 29221 patients [7.7%], The recent RE-ALIGN study reported that dabigatran
RR 0.90, 95% CI 0.85–0.95, p¼0.0003).54 should not be used in patients with mechanical heart
valves, as more thromboembolic and bleeding events
were observed in patients on dabigatran than in
Safety of NOACs versus warfarin
the warfarin-treated patients (to a higher target
Anticoagulation comes with an inherent bleeding risk, INR than in NVAF). The same contraindication is
thus bleeding events were closely monitored and docu- currently extended to all NOACs in this ‘high flow’
mented in the NOAC trials. When combining all data setting.
of the first three large trials, namely RELY, ROCKET-
AF and ARISTOTLE, on direct thrombin inhibitors
and Factor Xa inhibitors, fatal bleeds were found to
Potential barriers to NOAC use
be significantly reduced in comparison with anticoagu- Reversibility of the anticoagulant effect. Although there
lation with warfarin (RR 0.60, 95% CI 0.46–0.77, esti- are no specific antidotes yet for NOACs, nonspecific
mated risk difference is 1 fewer death per 1000 reversal strategies, such as administration of prothrom-
patients). Reduction in major bleeds did not reach stat- bin complex or recombinant factor VII, may be
istical significance (RR 0.80, 95% CI 0.63–1.01),45,53 applied.
but a substantial reduction in intracranial haemorrhage A large advantage of NOACs in comparison with
was observed (204 events in 29287 [0.70%] patients on VKAs is that NOACs have a much shorter half-life.
NOAC versus 425 events in 29211 [1.45%] patients on Thus, the duration of the effect is much shorter, thereby
warfarin, RR 0.48, 95% CI 0.39–0.59, p<0.0001).52,54 decreasing the need for an antidote. Clinical impact of
The data of individual trials are summarised in Table 9 major bleeds, as seen by, for instance, mortality, or the
in the web version of this paper. need for hospitalisation or intensive care unit stay,
The meta-analysis of all NOAC RCTs also showed indeed appears to be less with the new oral anticoagu-
that NOACs were associated with a higher rate of GI lants than with VKAs, despite the fact that an antidote
bleeds (751 events in 29287 [2.6%] patients on NOACs exists for the latter.55
vs. 591 events in 29211 [2.0%] warfarin-treated Specific antidotes are currently under development,
patients, RR 1.25, 95% CI 1.01–1.55, p¼0.0430).52 such as an antibody against dabigatran 56 and recom-
Meta-analyses of the NOAC trials did not find binant factor Xa.57
a difference in the rate of MI with NOACs versus
warfarin on combined data of all trials evaluated Renal impairment. Severe chronic kidney disease, defined
(RR 0.95, 95% CI 0.81–1.11,53 and RR 0.97, 95% as an eGFR<30 ml/min or <15 ml/min depending on
CI 0.78–1.20 52). type of NOAC, is a contraindication to NOAC use.
Hobbs et al. 469

There are limited trial data for VKA and NOACs in Management strategies that should be used
frail elderly patients.
. All AF patients at high risk of stroke should be
Costs. Although NOACs may still be more expensive offered anticoagulation.
than VKA, INR monitoring is also expensive. . In patients with mechanical valves or severe valve
Logistics and available resources may vary between disease (defined by a specialist), this anticoagulation
countries or by region and will determine specific should be high-intensity VKA.
cost-effect balances. Cost-effectiveness of AF-related . For patients with AF but without mechanical valves
stroke prevention strategies is being explored, and or clinically significant valve disease, both warfarin,
efforts are dedicated to determine the impact of to adjusted INR target of 2.5, and NOACs are anti-
NOACs on health economics. Available evidence sug- coagulant options.
gests that NOACs are cost-effective alternatives to war- . NOACs may represent a more convenient, at least
farin with regard to efficacy and safety, although the as safe, and at least equally as effective option in
final balance will depend on individual healthcare set- the prevention of stroke in AF compared
tings.58 Comparisons between NOACs are emerging, with VKAs. Treatment adherence is an important
but are based on indirect comparisons. issue with NOAC use. Thus, on the basis of
these issues, as well as cost and access, NOACs
Treatment adherence. Because of the shorter half-life of and VKAs both represent good treatment options
NOACs compared with VKAs, compliance is very for SPAF.
important. It is therefore vital for physicians to empha- . Patients should be fully counselled, including
sise the need for daily treatment adherence. written information, on the risks and benefits of
An advantage of NOACs may lie in their fixed dose, anticoagulation or on changing to or initiating a
compared with VKA doses that need to be adjusted NOAC.
based on INR measurements. However, this lack of . Patient preferences should guide decision-making
need for monitoring drug levels reinforces the import- over whether to initiate anticoagulation, and on
ance of stressing drug adherence with patients. It what to prescribe, including estimation of a patient’s
should not be underestimated that although the new compliance.
agents are more convenient, they are still powerful anti- . The patient groups in whom use of a NOAC
coagulants. A dosage box with all medications to dis- is preferable to warfarin are patients who
pense may facilitate compliance (although not for are unable or unwilling to take warfarin, and
dabigatran which requires original packaging). patients who are difficult to maintain at a
Rivaroxaban needs to be taken with food as taking it stable INR (less than 65% time in therapeutic
on an empty stomach may reduce therapeutic drug range).
levels by up to 40%. . If prescribing NOACs, the importance of
treatment adherence must be emphasised.
Real-life data. Observational studies comparing the Compliance may be facilitated with the use of a
actual impact of NOAC use in daily clinical care are dosage box, except for dabigatran which should
now emerging; some show similar and comparable only be dispensed in its original packaging
results on the efficacy and safety of NOAC use. From (although dabigatran is available in blister pack-
a primary care perspective, such observational studies ages so, if desired, individual doses can be cut out
will help show efficacy and safety of NOAC use in frail with their original blister preserved and put in
elderly patients not included in the large trials. dosage box).
In summary, NOACs are at least as safe as VKA.
Barriers for implementation still exist but these may Management strategies that may be used
improve with the growing body of trial data on safety
and subgroup analyses. Moreover, generalisability may . ASA alone has no role in SPAF.
expand as a result of having more registries. In add- . In patients at all ages who are unable or unwilling to
ition, growing confidence in reversal strategies should take VKAs or NOACs, ASA may be used in com-
facilitate implementation. bination with clopidogrel as antiplatelet therapy to
prevent stroke.
Practical recommendations
Additional work recommended in this area/gaps in the
Based on current evidence and experiences, we recom- evidence
mend the following anticoagulation treatment strategy
in a primary care setting: . See web version.
470 European Journal of Preventive Cardiology 23(5)

OPPORTUNISTIC CASE-FINDING
Pulse Palpitation
In all patients over 65 years old and anyone routinely receiving cardiovascular follow-up

DIAGNOSIS
12-lead ECG : confirm or rule out AF
Referral to cardiologist (if symptomatic AF/complications)

RISK ASSESSMENT
CHA 2DS 2 -VASc score: assess stroke risk
HAS-BLED score: identify modifiable risk factors to minimise bleeding risk

CHA 2 DS 2 -VASc=0 CHA 2DS 2 -VASc=1 CHA 2 DS2-VASc >2

No anti-platelet/
anticoagulation
ANTICOAGULATION THERAPY
Advise on improving VKA NOACs
vascular risk factors

• Counselling on risk and benefits

In patients declining / of anticoagulation
intolerant to OACs: • Emphasise importance of treatment
antiplatelet therapy
adherence
(ASA+clopidogrel)

MONITORING TREATMENT

Figure 2. Flow chart of recommendations. Management of stroke prevention in atrial fibrillation as recommended in this document.
Strength of recommendations is indicated by colour, with recommendations that should be used in green, and interventions that may
be considered in blue. See text for explanation of HAS-BLED and CHA2DS2-VASc scores.
AF: atrial fibrillation; OACs: oral anticoagulants; NOACs: novel oral anticoagulants; ASA: acetyl salicylic acid; VKA: vitamin K
antagonists.

Practical considerations for atrial according to the structure of the healthcare system
fibrillation stroke prevention in primary and expertise of the team. The full web version of this
paper provides a list of practical guidance on: Finding
care the patient with atrial fibrillation; Making the diagnosis
A large evidence base on the effectiveness of warfarin of atrial fibrillation; Risk assessment; Preferable anti-
regimes, the limitations of antiplatelets, and the licen- coagulant; NOAC use with impaired renal function;
sing of several new anticoagulants, has meant that trad- and initiating and monitoring treatment.
itional management strategies of SPAF have been
challenged in recent years. The practicalities of screen-
Practical guidance on the use of NOACs
ing, diagnosis, stroke risk assessment, treatment initi-
ation, monitoring and, where appropriate, cessation of The European Heart Rhythm Association (EHRA) has
therapy will need to be determined at a local level assembled an excellent practical guide on the use of
Hobbs et al. 471

NOACs, to help physicians use NOACs in specific clin- References

ical situations.59 The different clinical scenarios as out- 1. Camm AJ, Kirchhof P, Lip GY, et al. Guidelines for the
lined in the EHRA practical guide, which are useful for management of atrial fibrillation: the Task Force for the
both physician and patients to learn how to use these Management of Atrial Fibrillation of the European
new agents safely and effectively, are summarised in the Society of Cardiology (ESC). Eur Heart J 2010; 31:
web version. 2369–2429.
All recommendations given in this consensus docu- 2. Camm AJ, Lip GY, De Caterina R, et al. 2012 focused
ment are summarised in the flow chart in Figure 2 for update of the ESC Guidelines for the management of
easy reference. atrial fibrillation: an update of the 2010 ESC Guidelines
for the management of atrial fibrillation. Developed with
the special contribution of the European Heart Rhythm
Conclusions Association. Eur Heart J 2012; 33: 2719–2747.
3. Hobbs FD, Fitzmaurice DA, Mant J, et al. A randomised
Atrial fibrillation is a common disorder, especially in controlled trial and cost-effectiveness study of systematic
those aged over 75, and is a major cause of preventable screening (targeted and total population screening) versus
embolic stroke. Anticoagulation therapy, available for routine practice for the detection of atrial fibrillation in
50 years as vitamin K antagonist derivatives like war- people aged 65 and over. The SAFE study. Health
farin, can reduce this risk by up to two-thirds, but its Technol Assess 2005; 9: iii–iv, ix–x, 1–74.
use has been complicated by major food and drug inter- 4. Heeringa J, van der Kuip DA, Hofman A, et al.
actions, significant bleeding risks, a narrow therapeutic Prevalence, incidence and lifetime risk of atrial fibrilla-
range and the need to monitor. As a consequence, in tion: the Rotterdam study. Eur Heart J 2006; 27:
most countries, only around half of those eligible for 949–953.
anticoagulation are on treatment and many of those 5. Fuster V, Ryden LE, Cannom DS, et al. 2011 ACCF/
AHA/HRS focused updates incorporated into the
treated are poorly controlled. The evidence base for
ACC/AHA/ESC 2006 guidelines for the management of
atrial fibrillation stroke risk is considerable and grow-
patients with atrial fibrillation: a report of the American
ing, resulting in recent major changes to clinical guid- College of Cardiology Foundation/American Heart
ance internationally. This guidance has particular Association Task Force on practice guidelines.
implications for primary care with many new recom- Circulation 2011; 123: e269–e367.
mendations on better AF diagnosis, more reliable 6. Friberg J, Buch P, Scharling H, et al. Rising rates of
methods of determining stroke risk to guide treatment hospital admissions for atrial fibrillation. Epidemiology
choice for patients and bleeding risks to manage the 2003; 14: 666–672.
risk factors better, and revised treatment options, 7. Zhang L, Gallagher R and Neubeck L. Health-related
with the exclusion of low-dose aspirin as an option quality of life in atrial fibrillation patients over 65
for most patients, the importance of good therapeutic years: a review. Eur J Prev Cardiol 2014; Jun 12; pii:
control if warfarin is used, and the availability of 2047487314538855. [Epub ahead of print].
8. Wolf PA, Abbott RD and Kannel WB. Atrial fibrillation
a range of new rapid-onset, short-acting, anticoagu-
as an independent risk factor for stroke: the Framingham
lants with few interactions and no monitoring
Study. Stroke 1991; 22: 983–988.
requirements. 9. Albers GW, Amarenco P, Easton JD, et al.
Antithrombotic and thrombolytic therapy for ischemic
Declaration of conflicting interests stroke: the Seventh ACCP Conference on
The author(s) declared the following potential conflicts of Antithrombotic and Thrombolytic Therapy. Chest 2004;
interest with respect to the research, authorship, and/or pub- 126: 483S–512S.
lication of this article: The idea, rationale, and methods in 10. Jorgensen HS, Nakayama H, Reith J, et al. Acute stroke
generating the guidance originated with the EPCCS. All prep- with atrial fibrillation. The Copenhagen Stroke Study.
aration, presentations, document drafting and printing was Stroke 1996; 27: 1765–1769.
done by the EPCCS and its Secretariat. The EPCCS 11. Lin HJ, Wolf PA, Kelly-Hayes M, et al. Stroke severity in
approached the sponsors. The sponsors had no input or atrial fibrillation. The Framingham Study. Stroke 1996;
role in producing or commenting on the guidance. A full 27: 1760–1764.
list of competing interests is available in the web version. 12. Lamassa M, Di Carlo A, Pracucci G, et al.
Characteristics, outcome, and care of stroke associated
with atrial fibrillation in Europe: data from a multicenter
Funding multinational hospital-based registry (The European
The costs of producing this document were met by the Community Stroke Project). Stroke 2001; 32: 392–398.
EPCCS which itself received an unrestricted educational 13. Friberg L, Hammar N and Rosenqvist M. Stroke in par-
grant from Bayer, Boehringer Ingelheim and Pfizer/BMS to oxysmal atrial fibrillation: report from the Stockholm
support these costs. FDR Hobbs is supported by NIHR BRC Cohort of Atrial Fibrillation. Eur Heart J 2010; 31:
and CLAHRC. 967–975.
472 European Journal of Preventive Cardiology 23(5)

14. Carlsson J, Miketic S, Windeler J, et al. Randomized trial 30. Lip GY, Nieuwlaat R, Pisters R, et al. Refining clinical
of rate-control versus rhythm-control in persistent atrial risk stratification for predicting stroke and thromboem-
fibrillation: the Strategies of Treatment of Atrial bolism in atrial fibrillation using a novel risk factor-based
Fibrillation (STAF) study. J Am Coll Cardiol 2003; 41: approach: the euro heart survey on atrial fibrillation.
1690–1696. Chest 2010; 137: 263–72.
15. Gronefeld GC, Lilienthal J, Kuck KH and Hohnloser 31. Potpara TS, Polovina MM, Licina MM, et al. Reliable
SH. Impact of rate versus rhythm control on quality of identification of ‘‘truly low’’ thromboembolic risk in
life in patients with persistent atrial fibrillation. Results patients initially diagnosed with ‘‘lonerdquo; atrial fibril-
from a prospective randomized study. Eur Heart J 2003; lation: the Belgrade atrial fibrillation study. Circ
24: 1430–1436. Arrhythm Electrophysiol 2012; 5: 319–326.
16. Van Gelder IC, Hagens VE, Bosker HA, et al. A com- 32. Van Staa TP, Setakis E, Di Tanna GL, et al. A compari-
parison of rate control and rhythm control in patients son of risk stratification schemes for stroke in 79,884
with recurrent persistent atrial fibrillation. N Engl J atrial fibrillation patients in general practice. J Thromb
Med 2002; 347: 1834–1840. Haemost 2011; 9: 39–48.
17. Wyse DG, Waldo AL, DiMarco JP, et al. A comparison 33. Abu-Assi E, Otero-Ravina F, Allut Vidal G, et al.
of rate control and rhythm control in patients with atrial Comparison of the reliability and validity of four contem-
fibrillation. N Engl J Med 2002; 347: 1825–1833. porary risk stratification schemes to predict thrombo-
18. Wattigney WA, Mensah GA and Croft JB. Increased embolism in non-anticoagulated patients with atrial
atrial fibrillation mortality: United States, 1980–1998. fibrillation. Int J Cardiol 2013; 166: 205–209.
Am J Epidemiol 2002; 155: 819–826. 34. Pisters R, Lane DA, Nieuwlaat R, et al. A novel user-
19. Wattigney WA, Mensah GA and Croft JB. Increasing friendly score (HAS-BLED) to assess 1-year risk of major
trends in hospitalization for atrial fibrillation in the bleeding in patients with atrial fibrillation: the Euro
United States, 1985 through 1999: implications for pri- Heart Survey. Chest 2010; 138: 1093–1100.
mary prevention. Circulation 2003; 108: 711–716. 35. Olesen JB, Lip GY, Hansen PR, et al. Bleeding risk in ‘real
20. Rosamond W, Flegal K, Furie K, et al. Heart disease and world’ patients with atrial fibrillation: comparison of two
stroke statistics–2008 update: a report from the American established bleeding prediction schemes in a nationwide
Heart Association Statistics Committee and Stroke cohort. J Thromb Haemost 2011; 9: 1460–1467.
Statistics Subcommittee. Circulation 2008; 117: e25–e146. 36. Gallego P, Roldan V, Torregrosa JM, et al. Relation of
21. Barnett K, Mercer SW, Norbury M, et al. Epidemiology the HAS-BLED bleeding risk score to major bleeding,
of multimorbidity and implications for health care, cardiovascular events, and mortality in anticoagulated
research, and medical education: a cross-sectional study. patients with atrial fibrillation. Circ Arrhythm
Lancet 2012; 380: 37–43. Electrophysiol 2012; 5: 312–318.
22. Healey JS, Connolly SJ, Gold MR, et al. Subclinical 37. Lip GY, Frison L, Halperin JL and Lane DA.
atrial fibrillation and the risk of stroke. N Engl J Med Comparative validation of a novel risk score for predicting
2012; 366: 120–129. bleeding risk in anticoagulated patients with atrial fibrilla-
23. Binici Z, Intzilakis T, Nielsen OW, et al. Excessive supra- tion: the HAS-BLED (Hypertension, Abnormal Renal/
ventricular ectopic activity and increased risk of atrial Liver Function, Stroke, Bleeding History or
fibrillation and stroke. Circulation 2010; 121: 1904–1911. Predisposition, Labile INR, Elderly, Drugs/Alcohol
24. Fitzmaurice DA, Hobbs FD, Jowett S, et al. Screening Concomitantly) score. J Am Coll Cardiol 2011; 57:
versus routine practice in detection of atrial fibrillation in 173–180.
patients aged 65 or over: cluster randomised controlled 38. Friberg L, Rosenqvist M and Lip GY. Evaluation of risk
trial. BMJ 2007; 335: 383. stratification schemes for ischaemic stroke and bleeding
25. Fitzmaurice DA, McCahon D, Baker J, et al. Is screening in 182 678 patients with atrial fibrillation: the Swedish
for AF worthwhile? Stroke risk in a screened population Atrial Fibrillation cohort study. Eur Heart J 2012; 33:
from the SAFE study. Fam Pract 2014; 31: 298–302. 1500–1510.
26. Tieleman RG, Plantinga Y, Rinkes D, et al. Validation 39. Devereaux PJ, Anderson DR, Gardner MJ, et al.
and clinical use of a novel diagnostic device for screening Differences between perspectives of physicians and
of atrial fibrillation. Europace 2014; 16: 1291–1295. patients on anticoagulation in patients with atrial fibril-
27. van Walraven C, Hart RG, Wells GA, et al. A clinical lation: observational study. BMJ 2001; 323: 1218–1222.
prediction rule to identify patients with atrial fibrillation 40. Lip GY, Banerjee A, Lagrenade I, et al. Assessing the risk
and a low risk for stroke while taking aspirin. Arch Intern of bleeding in patients with atrial fibrillation: the Loire
Med 2003; 163: 936–943. Valley Atrial Fibrillation project. Circ Arrhythm
28. Gage BF, Waterman AD, Shannon W, et al. Validation Electrophysiol 2012; 5: 941–948.
of clinical classification schemes for predicting stroke: 41. Roldan V, Marin F, Fernandez H, et al. Predictive value
results from the National Registry of Atrial Fibrillation. of the HAS-BLED and ATRIA bleeding scores for the
JAMA 2001; 285: 2864–2870. risk of serious bleeding in a ‘‘real-world’’ population with
29. Olesen JB, Lip GY, Hansen ML, et al. Validation of risk atrial fibrillation receiving anticoagulant therapy. Chest
stratification schemes for predicting stroke and thrombo- 2013; 143: 179–184.
embolism in patients with atrial fibrillation: nationwide 42. Hart RG, Pearce LA and Aguilar MI. Meta-analysis:
cohort study. BMJ 2011; 342, d124. antithrombotic therapy to prevent stroke in patients
Hobbs et al. 473

who have nonvalvular atrial fibrillation. Ann Intern Med 51. Patel MR, Mahaffey KW, Garg J, et al. Rivaroxaban
2007; 146: 857–867. versus warfarin in nonvalvular atrial fibrillation. N Engl
43. Connolly SJ, Pogue J, Hart RG, et al. Effect of clopido- J Med 2011; 365: 883–891.
grel added to aspirin in patients with atrial fibrillation. 52. Giugliano RP, Ruff CT, Braunwald E, et al. Edoxaban
N Engl J Med 2009; 360: 2066–2078. versus warfarin in patients with atrial fibrillation. N Engl
44. ACTIVE Writing Group of the ACTIVE Investigators, J Med 2013; 369: 2093–2104.
Connolly S, Pogue J, Hart R, et al. Clopidogrel plus 53. Adam SS, McDuffie JR, Ortel TL and Williams JW, Jr.
aspirin versus oral anticoagulation for atrial fibrillation Comparative effectiveness of warfarin and new oral anti-
in the Atrial fibrillation Clopidogrel Trial with coagulants for the management of atrial fibrillation and
Irbesartan for prevention of Vascular Events (ACTIVE venous thromboembolism: a systematic review. Ann
W): a randomised controlled trial. Lancet 2006; 367: Intern Med 2012; 157: 796–807.
1903–1912. 54. Ruff CT, Giugliano RP, Braunwald E, et al. Comparison
45. Granger CB and Armaganijan LV. Newer oral anti- of the efficacy and safety of new oral anticoagulants with
coagulants should be used as first-line agents to prevent warfarin in patients with atrial fibrillation: a meta-analy-
thromboembolism in patients with atrial fibrillation and sis of randomised trials. Lancet 2014; 383: 955–962.
risk factors for stroke or thromboembolism. Circulation 55. Majeed A, Hwang HG, Connolly SJ, et al. Management
2012; 125: 159–164; discussion 164. and outcomes of major bleeding during treatment with
46. Mant J, Hobbs FD, Fletcher K, et al. Warfarin versus dabigatran or warfarin. Circulation 2013; 128: 2325–2332.
aspirin for stroke prevention in an elderly community 56. Schiele F, van Ryn J, Canada K, et al. A specific antidote
population with atrial fibrillation (the Birmingham for dabigatran: functional and structural characteriza-
Atrial Fibrillation Treatment of the Aged Study, tion. Blood 2013; 121: 3554–3562.
BAFTA): a randomised controlled trial. Lancet 2007; 57. Lu G, DeGuzman FR, Hollenbach SJ, et al. A specific
370: 493–503. antidote for reversal of anticoagulation by direct and
47. van Walraven C, Hart RG, Connolly S, et al. Effect of indirect inhibitors of coagulation factor Xa. Nat Med
age on stroke prevention therapy in patients with atrial 2013; 19: 446–451.
fibrillation: the atrial fibrillation investigators. Stroke 58. Kasmeridis C, Apostolakis S, Ehlers L, et al. Cost effect-
2009; 40: 1410–1416.
iveness of treatments for stroke prevention in atrial fib-
48. Wallentin L, Yusuf S, Ezekowitz MD, et al. Efficacy and
rillation: focus on the novel oral anticoagulants.
safety of dabigatran compared with warfarin at different
Pharmacoeconomics 2013; 31: 971–980.
levels of international normalised ratio control for stroke
59. Heidbuchel H, Verhamme P, Alings M, et al. European
prevention in atrial fibrillation: an analysis of the RE-LY
Heart Rhythm Association Practical Guide on the use of
trial. Lancet 2010; 376: 975–983.
new oral anticoagulants in patients with non-valvular
49. Connolly SJ, Ezekowitz MD, Yusuf S, et al. Dabigatran
atrial fibrillation. Europace 2013; 15: 625–651.
versus warfarin in patients with atrial fibrillation. N Engl
60. Gallagher AM, Setakis E, Plumb JM, et al. Risks of
J Med 2009; 361: 1139–1151.
stroke and mortality associated with suboptimal anticoa-
50. Granger CB, Alexander JH, McMurray JJ, et al.
gulation in atrial fibrillation patients. Thromb Haemost
Apixaban versus warfarin in patients with atrial fibrilla-
tion. N Engl J Med 2011; 365: 981–992. 2011; 106: 968–977.