Non-valvular atrial fibrillation and stroke prevention
Graeme J Hankey, on behalf of the National
Blood Pressure Advisory Committee of the National Heart Foundation*
MJA 2001; 174: 234-239
Warfarin versus control -
Aspirin versus control -
Warfarin versus aspirin -
Warfarin combined with aspirin -
Warfarin versus other antiplatelet agents -
Who to treat and with what? -
Who is at high risk of stroke and thromboembolism without treatment? -
Who is at high risk of haemorrhage with anticoagulant treatment? -
Recommendations for antithrombotic therapy for AF -
More articles on Cardiology and cardiac surgery
- Atrial fibrillation (AF) affects 5% of people older than 65 years.
- Among patients with AF, the risk of stroke averages about 5% per year.
- The risk of stroke increases cumulatively with increasing age,
previous transient ischaemic attack or stroke, hypertension,
diabetes, impaired left ventricular function and a large left
- Management aims to identify and treat the underlying cause, control
the ventricular rate, restore and maintain sinus rhythm, and
minimise the risk of stroke.
- Warfarin reduces the risk of stroke by about two-thirds, and aspirin
by about one-fifth.
- The risk of anticoagulant-associated haemorrhage increases with
serious concomitant disease, and with poorly controlled
hypertension and poorly controlled anticoagulation.
- All patients with chronic AF should be considered for oral
anticoagulant therapy, and the decision based on the balance between
the risks of thromboembolism and bleeding.
- The recommended INR (international normalised ratio) is 2.0-3.0.
- Treating 1000 "average" AF patients (ie, those with a 5% per year risk
of stroke) with warfarin prevents about 30 strokes and causes at least
two episodes of major haemorrhage each year. Treating 1000 AF
patients with aspirin prevents about 15 strokes each year.
Atrial fibrillation (AF) is a common arrhythmia. Its prevalence
increases with age, from about 2% in the general population, to 5% in
people older than 65 years, and 10% in people older than 75
years1,2 (E4; level-of-evidence
codes are described in Box 13). It may occur as a single
episode, a series of recurrent episodes ("paroxysmal" AF), or
continuously ("permanent" or "chronic" AF).
Atrial fibrillation is an important arrhythmia because it may
signify underlying heart disease, it may cause symptoms of decreased
cardiac output (eg, malaise, effort intolerance) or palpitations,
and it is associated with an increased risk of systemic
thromboembolism and stroke. This risk of stroke averages about 5% per
year among all individuals in AF, which is about 5-6 times greater than
for people of the same age who are in sinus rhythm
The management of AF has four principal objectives:
- To confirm and
document the arrhythmia;
- To identify and treat the underlying cause;
- To relieve symptoms of decreased cardiac output by controlling the
ventricular rate and restoring and maintaining sinus rhythm; and
- To reduce the risk of systemic thromboembolism, particularly
All patients, except perhaps the very elderly and infirm, should
undergo investigation for underlying causes of AF, including
thyroid function tests and echocardiography (E4).4
In haemodynamically stable patients, β-blockade,
verapamil or diltiazem can be used to control the heart rate (E4).
Recent-onset AF reverts spontaneously within 24 hours in at least
half of patients (irrespective of whether or not they are taking
Patients who have been in AF for more than 48 hours should be considered
for anticoagulation therapy and strategies to restore and maintain
sinus rhythm. Warfarin should be administered for three weeks before
cardioversion is attempted.6 If cardioversion can not be
postponed for three weeks, the patient should undergo
anticoagulation therapy with intravenous heparin and
warfarin,7 and be considered for
transoesophageal echocardiography (TOE) (E32).
Cardioversion can probably be undertaken safely (with limited risk
of stroke) if TOE excludes left atrial and appendage thrombus (and the
patient is treated with heparin and warfarin) (E2).8,9 However, if
transoesophageal echocardiography identifies left atrial and
appendage thrombus, then cardioversion is contraindicated until
the patient has been anticoagulated for at least three weeks (E4).
The relative merits of cardioversion by electrical shock and medical
therapy have been discussed recently.4,10 Direct current
cardioversion has never been subjected to a randomised trial, but
appears to be the most effective method of restoring sinus rhythm. Its
main disadvantage is the need for general anaesthesia. Digoxin and
verapamil are ineffective for converting AF to sinus rhythm.
Flecainide or sotalol are the preferred medical therapies in younger
patients without structural heart disease, and amiodarone in older
patients (E2).11 The chances of successful
cardioversion are greater if the AF is of recent onset and the left
atrial size is normal (E33).12
After successful cardioversion, warfarin therapy should be
continued for at least four weeks to prevent clot formation in the
"stunned" left atrium (E33).13,14 Antiarrhythmic drug
therapy should also be continued to prevent recurrent AF, but this
still occurs in 40%-50% of patients after 12 months' follow-up
despite drug therapy. If the patient has a low risk of recurrence of AF
(eg, "lone" AF) and remains in sinus rhythm for one month after
cardioversion, anticoagulation therapy with warfarin can be ceased
(E4). In patients at higher risk of recurrence (Box 2), it may be more
appropriate to continue warfarin therapy for longer or indefinitely
For patients who are elderly (in whom AF is usually chronic and
antiarrhythmic drug therapy may be risky) or have asymptomatic
chronic AF, it is often reasonable to avoid attempted cardioversion,
accept the AF and aim for adequate ventricular rate control (digoxin
combined with β-blockade,
verapamil or diltiazem) and long term anticoagulation therapy (E4).
The results of clinical trials in patients with asymptomatic AF (of
rate control and antithrombotic therapy versus attempted
cardioversion and maintenance of sinus rhythm to avoid warfarin) are
Strategies for reducing the risk of stroke and systemic
thromboembolism in patients with AF have been studied in several
randomised controlled trials over the past decade.15-25
Five large randomised controlled primary prevention trials have
shown that, in people with chronic non-valvular AF, warfarin reduced
the risk of stroke by about two-thirds (68%; 95% CI, 50%-79%; P
< 0.001), from about 4.5% to 1.4% per year overall, with little
increase in frequency of major bleeding (warfarin, 1.2%; control,
1.0%), or intracranial haemorrhage (warfarin, 0.3% per year;
control, 0.1% per year) (E1).15-19,26 This means that
warfarin will prevent about 30 strokes per 1000 patient-years of
treatment at a cost of at least two serious bleeding episodes per 1000
patients treated for one year. It must be stressed, however, that this
acceptable rate of bleeding was achieved in patients who were
carefully selected, screened and closely followed; 53%-93% of
eligible patients with AF were not included in the trials because of an
increased risk of bleeding. Exclusion criteria included old age
(> 75 years), serious illness (liver, kidney, brain or malignant
disease), alcoholism, fall risk (eg, syncope), forgetfulness,
non-steroidal anti-inflammatory drug therapy, and uncontrolled
One secondary prevention trial (the European Atrial Fibrillation
Trial [EAFT]) showed that, in people with chronic non-valvular AF and
symptoms of previous transient ischaemic attack (TIA) or stroke, who
have a risk of stroke of 12% per year, warfarin therapy (target INR,
2.5-4.0) reduced the risk of stroke by about two-thirds (66%; 95% CI,
53%-80%), to 4% per year (E2).20 The annual incidence of
major bleeding complications was 2.8% in the anticoagulant group and
0.7% in the placebo group. No intracranial bleeds were identified in
patients assigned to warfarin. Thus, warfarin prevents about 80
strokes per 1000 patient-years in patients who have had a TIA or stroke
and who are in AF, at a cost of at least 20 serious bleeding episodes per
1000 patients treated for one year.
The timing of anticoagulation therapy after recent ischaemic stroke
depends on the risk of recurrent thromboembolism (Box 2) and the risk
of haemorrhagic transformation of the brain infarct (which is higher
within the first two weeks and in patients with large brain infarcts
and uncontrolled hypertension [E32]27). Common
empirical practice is to treat patients with fibrillating acute
ischaemic stroke immediately with aspirin (300 mg daily) and then,
depending on the above factors, begin warfarin (5 mg daily) between
days three and 14 after stroke onset, aiming to achieve an INR of
2.0.28 However, randomised
trials comparing aspirin with heparin during the first two weeks of
acute ischaemic stroke among patients in AF show no benefit from early
anticoagulation, because any net gains from reduction in recurrent
ischaemic stroke are offset by the excess hazards of haemorrhagic
Three primary prevention and three secondary prevention trials have
shown that, in people with AF, aspirin reduced the incidence of stroke
by 22% (95% CI, 2%-38%), from 5.2% (placebo) to 3.7% (aspirin) per year
for primary prevention (absolute risk reduction: 1.5% per year), and
from 12.9% (placebo) to 10.4% (aspirin) per year for secondary
prevention (absolute risk reduction, 2.5% per year)
Aspirin was not associated with any significant excess of
intracranial haemorrhage (aspirin, 0.16%; control, 0.13%) or major
extracranial bleeding (aspirin, 0.5%; control, 0.6%)
(E1).31 This means that aspirin
might prevent about 10 to 20 strokes per 1000 patient-years of
treatment, depending on the type of patient treated and their
baseline risk of stroke, with little risk of major bleeding.
A speculative interpretation of these data is that, in patients with
AF, aspirin prevents strokes due to atherothromboembolism, but not
cardiogenic embolism. This interpretation is based on the magnitude
of the effect (a 20% relative risk reduction), which is very similar to
the effect of aspirin in patients with symptomatic
atherothromboembolism of the brain, heart and limbs.32 Whether
aspirin combined with adjusted-dose warfarin would be safe and more
effective (in preventing both atherothrombotic and cardiogenic
strokes) than warfarin alone in patients with AF remains
The relative benefits and risks of warfarin and aspirin have been
studied in three trials,15,20,21 all of which showed
that warfarin was associated with half the risk of stroke compared
with aspirin (47% relative risk reduction; 95% CI, 28%-61%; P
< 0.01) (E1).26|
For patients with AF who are at high risk of stroke, adding aspirin (325
mg daily) to low-intensity, fixed-dose warfarin, adjusted to an INR
of 1.2-1.5, was not as effective in preventing stroke or systemic
thromboembolism as standard adjusted-dose warfarin therapy,
maintaining an INR of 2.0-3.0 (event rates, 7.9% per year v. 1.9% per
year, respectively; P < 0.0001), and there is no
difference in the rates of major bleeding (E2).22 Three
subsequent trials also suggested that adjusted-dose warfarin (INR,
2.0-3.0) was superior to low-intensity anticoagulant therapy or an
aspirin- anticoagulation regimen (E1).23-25|
An Italian study reported that a new antiplatelet agent, indobufen
(100-200 mg twice daily), was as effective as adjusted-dose warfarin
(INR, 2.0-3.5) in preventing stroke, systemic embolism, myocardial
infarction or vascular death in 916 patients with non-valvular AF and
recent (within 15 days) TIA or non-disabling ischaemic stroke
(E2).34 The 12-month event rates
were 10% in the warfarin group and 12% in the indobufen group (P
= 0.47). However, the number of patients and outcome events were quite
small, follow-up was short, and it is possible that a true difference
was not detected.
Future studies are planned to evaluate the safety and effectiveness
of other, newer antiplatelet agents (such as clopidogrel, oral
glycoprotein IIb/IIIa receptor inhibitors, and oral thrombin
inhibitors) and combination antiplatelet therapies (such as
aspirin-ticlopidine, aspirin-clopidogrel, and
aspirin-dipyridamole) as strategies of thromboprophylaxis in AF.
Not all patients with AF benefit from thromboprophylactic
treatment. The decision to treat depends on the balance between the
risk of thromboemboli without treatment and the risks of
thromboemboli and haemorrhage with treatment in each patient, as
well as the patient's willingness to accept the potential risks,
costs, and inconvenience of treatment in order to possibly benefit.
The current profile of individual risk of thromboembolism and
bleeding complications (see below) remains imprecise and continues
to be refined as new data emerge.7|
The important independent prognostic factors for an increased risk
of stroke among individuals with AF are increasing age, a history of
previous TIA or stroke, hypertension, diabetes mellitus, and
transthoracic echocardiographic evidence of moderate to severe
left ventricular systolic dysfunction (E1).7,26,35-37
Echocardiographic evidence of left atrial enlargement (E2) and left
atrial spontaneous echo densities ("smoke"), possibly indicative
of stasis of blood, are also significant risk factors for
These risk factors are cumulative: for people younger than 65 years
with no risk factors the untreated annual risk of stroke is about 1%,
whereas with one or more risk factors it is about 5%; for people aged
65-75 years with no risk factors the annual risk of stroke is about 4%,
and with one or more risk factors it is about 6% per year; and for people
older than 75 years with no risk factors the risk of stroke is about
3%-4%, whereas with one or more risk factors it is about 8% (see Box 2)
The major risk factors for anticoagulant-associated intracranial
haemorrhage include fragile intracranial blood vessels (previous
symptomatic cerebrovascular disease, computed tomography brain
scan evidence of small vessel disease ["leukoaraioisis"]), high
blood pressure (poorly controlled hypertension), and excessive
anticoagulation (INR, > 3.5) or factors predisposing to it, such
as confusion, dementia, inadequate anticoagulant monitoring,
alcoholic liver disease, and a tendency to falls (E2).40,41
Increasing age is a risk factor for all of these risk factors, and is
thus a potent risk factor for anticoagulant-associated
haemorrhage. Among a subgroup of patients in the Stroke Prevention in
Atrial Fibrillation (SPAF) II trial (mean age, 80 years), the rate of
intracranial haemorrhage was as high as 1.8% per year in those
allocated to warfarin therapy (target INR, 2.0-4.5) and 0.8% among
those who were assigned to aspirin (E2).21 Although the target INR in
this study was higher than currently recommended (INR, 2.0-3.0),
these data suggest that the low rate of intracranial haemorrhage
documented in the five primary prevention AF trials15-19 may not
apply to very elderly individuals (who were not well represented in
many of these trials -- the mean age of the patients studied in the AF
trials was 69 years, and only about a quarter were older than 75 years).
Current practice necessitates individualisation of therapy after
an integrated clinical assessment that evaluates thromboembolic
risk due to AF, other potential indications for anticoagulant
therapy, risk of haemorrhage, and non-medical factors relating to
compliance, capacity to have the INR monitored at least monthly, gait
instability, risk of other trauma, and patient values and
preferences.42,43 Decision analysis can
also be useful.44|
The role of transthoracic echocardiography (TTE), in addition to
excluding structural heart disease in all patients who first present
with AF, is to further refine stroke risk in the small group of patients
with a low risk of stroke according to clinical factors. Although TOE
is more sensitive in detecting left atrial thrombus and spontaneous
echo contrast, which are markers for increased risk of
thromboembolism,36-39 it is more invasive and
is usually only required to improve risk stratification among
individuals with a relative contraindication to warfarin or in whom
TTE is inadequate.
The choices of thromboprophylactic agents for atrial fibrillation
include warfarin, which is the most effective but also the most risky
treatment, and aspirin, which is less effective than warfarin but
safer (E1). The combination of aspirin and low dose warfarin is no more
effective than aspirin alone (E1).22,23 The most appropriate
treatment regimen is one in which patients at high risk of stroke and
low risk of haemorrhage are treated with warfarin, and patients at low
risk of stroke or high risk of haemorrhage are treated with aspirin.
Who not to treat
Individuals with AF who are aged less than 60 years and have no evidence
of any concurrent heart disease have a very low risk of a
thromboembolic event (about 0.6% per year).45 The potential benefits of
aspirin in these patients (which may reduce the risk of stroke by 0.12%
per year [20% of 0.6%]) may be offset by an equal potential risk of
aspirin-associated haemorrhagic stroke of 0.12%.46|
Who to treat with aspirin
Aspirin is indicated for individuals in AF who are at fairly low
absolute risk of stroke, such as those without any of the independent
thromboembolic risk factors listed above, or those at risk of an
anticoagulant-related haemorrhage which exceeds the risk of stroke
(more than 1% per year) (E1). For some people, such as the elderly and
those with hypertension, whose risks of stroke and
haemorrhage are both high, the treatment decision can be
difficult, and may be determined ultimately by the patient's
Patients taking aspirin should be monitored over time and their
treatment changed to warfarin if risk factors emerge; this occurs in
10%-15% of patients being treated with aspirin per year.21
Who to treat with warfarin
Warfarin is indicated for individuals with chronic AF who are at high
absolute risk of stroke (> 4% per year), such as those with any of
the independent thromboembolic risk factors listed above, and a
lower risk of haemorrhage (E1) (see Box 2).
Similarly, anticoagulant therapy should also be considered in
patients with paroxysmal AF, again depending on the thromboembolic
risk factors (Box 2) as well as the frequency and duration of the
paroxysms. Although clinical trial evidence suggests the stroke
rate of patients with paroxysmal AF is similar to that of patients with
chronic AF,26 the trials did not
specifically examine the benefits of antithrombotic therapy in
patients with paroxysmal AF. Furthermore, the range of
thromboembolic risk in such patients is likely to be extremely wide,
from very low for patients who have one short paroxysm once a year to
considerably higher for patients who have daily lengthy paroxysms.
What is the optimal target INR?
The intensity of oral anticoagulant therapy that provides the best
balance between the prevention of thromboembolism and the
occurrence of bleeding complications appears to be an INR of between
2.0 and 3.0, but may be lower (INR, 1.8 to 2.0) in patients at
greater risk of bleeding (eg, the elderly), and may be higher
in patients at greater risk of thromboembolism, such as those with
prosthetic heart valves [INR, 3.0-4.0])
It is important to emphasise that, in people in whom anticoagulant
therapy is indicated, the risk of stroke increases substantially
when the INR falls below 2.0. Patients with an INR of 1.7 have twice the
odds of stroke (95% CI, 1.6-2.4 times), and those with an INR of 1.5 have
3.3 times the odds of stroke (95% CI, 2.4-4.6 times) as those with an INR
of 2.047 (E32).
What if warfarin therapy needs to be ceased?
When cessation of warfarin therapy is required because of other
(usually surgical) procedures, it is necessary to stratify the
invasiveness of the procedure (minimal versus major) and the
short-term risk of thromboembolism. Warfarin can be discontinued
for five days before a major procedure and continued at a decreased
dose for a minor procedure. Therapy should be reinstituted as soon as
possible after invasive procedures. Patients at high risk of
thromboembolism (eg, severe mitral stenosis, mechanical mitral
prosthesis, left ventricular dysfunction) should be admitted to
hospital early for intravenous administration of heparin during
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Background and evidence basis of recommendations
The National Heart Foundation (NHF) Consensus Guidelines
for Non-valvular Atrial Fibrillation and Stroke Prevention were written
by Clinical Associate Professor Graeme J Hankey on behalf of the National
Blood Pressure Advisory Committee of the NHF, which comprises Professor
L Wing (chair), Dr A Boyden, Dr A Dart, Dr K Duggan, Clinical Associate
Professor G Hankey, Dr M Nelson, Professor I Puddey, Dr M Stowasser, and
Dr J Vial. The draft guidelines were circulated for comment to the above
members of the committee, who have clinical and research expertise or
interests in hypertension, atrial fibrillation, and stroke prevention.
Comment was also sought from the Medical Director of the Heart Foundation,
Professor Andrew Tonkin. All comments were incorporated into the final
document, which was ratified by the Heart Foundation's Cardiovascular
Health Advisory Committee. All available evidence from controlled experimental
and observational studies was combined with clinical experience to provide
recommendations according to the National Health and Medical Research
Council Quality of Evidence ratings.3
National Heart Foundation of Australia, Melbourne, VIC.
Graeme J Hankey, MD, FRACP, Consultant Neurologist and Head
of Stroke Unit, Royal Perth Hospital, Perth, WA, and Clinical
Associate Professor, Department of Medicine, University of Western
Reprints will not be available from the author.
Clinical Associate Professor G J Hankey, Stroke Unit, Royal Perth
Hospital, Wellington Street, Perth, WA 6001.
* L Wing (chair), A Boyden, A Dart, K Duggan, M Nelson, I Puddey, M
Stowasser, J Vial
|1: Level-of-evidence codes
|Evidence for the statements made in this article
is graded according to the NHMRC system3 for assessing the level of evidence:
|| Level I
|| Evidence obtained from a systematic review
of all relevant randomised controlled trials.
||Evidence obtained from at least one properly
designed randomised controlled trial.
||Evidence obtained from well-designed pseudo-randomised
controlled trials (alternate allocation or some other method).
||Evidence obtained from comparative studies
with concurrent controls and allocation not randomised (cohort studies),
case-control studies, or interrupted time series without a parallel control
||Evidence obtained from comparative studies
with historical control, two or more single-arm studies, or interrupted
time series without a parallel control group.
|| Evidence obtained from case-series, either
post-test, or pretest and post-test.
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|2: Risk stratification and
prophylaxis in atrial fibrillation
| High risk (6%-12% per
year risk of stroke)
- Age >65 years and hypertension or diabetes
- Previous transient ischaemic attack (TIA) or stroke
- Valvular heart disease o Heart failure
- Recent myocardial infarction
- Impaired left ventricular function on echocardiography
- Thyroid disease o Left atrial thrombus or left atrial
spontaneous echo contrast (TOE done on basis of clinical suspicion)
||Warfarin (target INR 2.0-3.0) if possible
and not contraindicated.
risk (2%-5% per year risk of stroke)
- Age 65 years and hypertension or diabetes
- Age >65 years and not in high risk group
||Warfarin (target INR 2.0-3.0) or aspirin
75-300mg daily, depending on individual case and echocardiography findings.
per year risk of stroke)
- Age 65 and no hypertension, diabetes, TIA, stroke,
or other clinical risk factors
|| None, or aspirin 75-300mg daily.
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