© The European Society of Cardiology 2005. All rights reserved. For Permissions, please e-mail: journals.permissions@oupjournals.org
Current status of stroke prevention in patients with atrial fibrillation
Philip M.W. Bath1,2,*,
Lian Zhao1,2 and
Stan Heptinstall2
1Institute of Neuroscience, University of Nottingham, D Floor, South Block, Queen's Medical Centre, Nottingham NG7 2UH, UK
2Institute for Clinical Research, University of Nottingham, Nottingham, UK
* Corresponding author. Tel: +44 115 970 9348; fax: +44 115 875 4506. E-mail address: philip.bath{at}nottingham.ac.uk
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Abstract
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Atrial fibrillation (AF) is a common dysrhythmia and increases
the risk of stroke. Data from primary and secondary trials have
shown that anticoagulation with vitamin K antagonists such as
warfarin, for example, is the treatment of choice for preventing
stroke and systemic cardioembolism. The recommended international
normalized ratio is 2.0–3.0, which maintains the balance
between risk of ischaemic stroke and bleeding. Anticoagulation
with warfarin is more effective than aspirin monotherapy, but
ongoing studies are assessing the role of dual antiplatelet
therapy (combined aspirin and clopidogrel). Recently, fixed
dose ximelagatran, an oral direct thrombin inhibitor, was shown
to be as effective as warfarin and well-tolerated. Anticoagulation
for patients with acute ischaemic stroke and AF has not resulted
in significant improvements in functional outcome, whilst reductions
in recurrent stroke were counterbalanced by an increase in intracerebral
haemorrhage. Aspirin therefore remains the first line treatment
for these patients. Lowering blood pressure and lipids provide
additional benefits in reducing the rate of stroke in patients
with AF. Other approaches are being assessed, including the
local delivery of nitric oxide, and excision of the left atrial
appendage, the source of most atrial embolic clots.
Key Words: Aspirin • Atrial fibrillation • Blood pressure • Cholesterol • Prevention • Vitamin K antagonists
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Introduction
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Atrial fibrillation (AF) is a common dysrhythmia becoming more
prevalent with increasing age.
1 As AF leads to the formation
of thrombus in the left atrium, especially its appendage, individuals
with AF have a significant six-fold increase in their risk of
ischaemic stroke and systemic cardioembolism when compared with
those subjects with normal sinus rhythm.
1,2 AF increases the
incidence of stroke independently of other important vascular
risk factors such as hypertension, hyperlipidaemia, and diabetes
mellitus. During the last decade, antithrombotic therapy has
been widely advocated in patients with AF in an attempt to reduce
the incidence of cardioembolic events. Many randomized controlled
trials have assessed the effects of anticoagulation, either
compared with a control or other antithrombotic agents. This
review describes current evidence-based approaches for the primary
and secondary prevention of stroke and systemic embolism, and
its acute treatment, in patients with AF.
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Primary prevention
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Five randomized clinical trials (AFASAK-I,
3 BAATAF,
4 CAFA,
5 SPAF-I,
6 and SPINAF
7), involving 3871 subjects, have assessed
the effect of oral anticoagulation [international normalized
ratio (INR), 1.4–4.2] on the risk of first stroke in patients
with AF (
Table 1). Excepting CAFA, each trial demonstrated individually
a significant reduction in the risk of stroke with oral anticoagulant
when compared with control. The CAFA study was stopped early
(having randomized 378 patients) on the basis of the positive
results of AFASAK and SPAF. A pooled analysis of individual
patient data from these five primary prevention trials found
that the annual rate of stroke was 4.3% in the control group
and 1.4% with vitamin K antagonists (VKAs, e.g. warfarin), a
relative risk reduction (RRR) of 68% [95% confidence interval
(CI), 50–79].
8 Although these results reflect the overall
balance between efficacy and hazard, it is important to consider
the risk of serious bleeding separately. Symptomatic intracranial
haemorrhage occurred in 0.3–0.5% of patients randomized
to warfarin and 0.0–0.2% in control subjects (
Table 2),
and the risk of intracranial haemorrhage was related to increasing
patient age and blood pressure.
8,9
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Table 2 Effect of anticoagulation on major bleeding and symptomatic intracranial haemorrhage (SICH) in patients with AF
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The complexities of administering VKAs (including variable doses,
monitoring of INR, contraindications) and the significant risk
of bleeding, especially in the very elderly, mean that alternative
antithrombotic strategies have been sought, particularly with
antiplatelet agents. Two randomized trials evaluated the use
of aspirin for stroke prevention in patients with AF (
Table 1). There was no significant difference in the annual rate of
stroke with aspirin (75 mg daily, 4.5%) when compared with
control (4.8%) in the AFASAK-I study (RRR, 18%; 95% CI, –58
to 60);
3 in contrast, the SPAF-I study found the annual rate
of stroke was 4.2% with aspirin (325 mg daily) and 7.4%
with control (RRR, 44%; 95% CI, 7–66).
6 When data from
both studies were combined, aspirin reduced stroke by one-third
(RRR, 36%; 95% CI, 4–57).
8
Direct comparisons of warfarin with aspirin (or indobufen, another antiplatelet agent) have been assessed in six large trials (AFASAK-I,3 AFASAK-II,10 PATAF,11 SIFA,12 SPAF-II,13 SPAF-III14), although the results varied considerably. Comparable effects were seen in PATAF, SIFA, and SPAF-II, although warfarin was superior in AFASAK-I (RRR, 48%) and SPAF-III (RRR, 45%), with the converse being found in AFASAK-II (RRR, –23%).10 Meta-analysis of five of these trials (AFASAK-I, AFASAK-II, PATAF, SIFA, SPAF-II) revealed a greater risk reduction in stroke with warfarin than aspirin/indobufen (RRR, 32%; 95% CI, 1.0–54).15 Hence, both direct and indirect comparisons of oral anticoagulation and antiplatelet therapy suggest that the former is more effective than the latter.
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Secondary prevention
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Warfarin-based therapy showed a 3.1% annual rate of stroke,
which was less than that found in control subjects (RRR, 66%;
95% CI, 43–80) in the EAFT study (
Table 1),
16 and these
results are comparable with those seen in the five primary prevention
trials described earlier. Not only was warfarin more effective
than aspirin (RRR, 40%; 95% CI, 13–59), but also aspirin
failed to reduce stroke (RRR, 14%; 95% CI, –36 to 15).
Similar results were present when the EAFT data were combined
with those from a subset of the VA-SPINAF trial in a Cochrane
Collaboration meta-analysis (
Table 1).
17,18 Recent antiplatelet
studies have excluded patients with AF following the publication
of EAFT. For example, ESPS-II initially allowed inclusion of
patients with presumed cardioembolic stroke, but subsequently
excluded these once the results of EAFT were known.
19
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Combining data from primary and secondary prevention trials
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When data from primary and secondary prevention trials were
amalgamated in a meta-analysis of six trials (AFASAK-I, SPAF-I,
BAATAF, CAFA, SPINAF, and EAFT;
Table 1), a significant and
clinically important reduction in the rate of stroke was reported
with warfarin (3.7 vs. 9.2%; RRR, 62%; 95% CI, 48–72).
20 Overall, the data from these trials strongly support the use
of anticoagulation therapy in the prevention of primary and
secondary stroke.
The risk reduction with aspirin was lower (9.8 vs. 12%, RRR, 22%; 95% CI, 2–38; Table 1) in a meta-analysis of six trials (AFASAK-I, SPAF-I, EAFT, ESPS-II, UK-TIA, and LASAF).20 The ESPS-II and UK-TIA studies involved patients with previous ischaemic stroke for secondary prevention, whereas LASAF randomized patients with AF for primary prevention. The meta-analysis also revealed that the absolute risk reduction for stroke was less for primary prevention (1.5% per year) than for secondary prevention (2.5%),20 reflecting the greater risk of stroke in subjects who have already had a cerebrovascular event.
When comparing warfarin and aspirin in meta-analyses of five trials (AFASAK-I, AFASAK-II, EAFT, PATAF, and SPAF-II; Table 1), warfarin was more efficacious than aspirin at reducing the rate of stroke (5.8 vs. 8.7%, RRR, 36%; 95% CI, 14–52).20 A pooled analysis of six trials (with SPAF-III added) showed a similar outcome (4.1 vs. 8.0%, RRR, 52%; 95% CI, 37–63).21 Overall, these results demonstrate that warfarin is superior to aspirin for primary and secondary prevention of stroke in patients with AF.
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Acute intervention
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In the 1980s, the most frequent indication for emergent anticoagulation
was prevention of recurrent stroke in patients with acute ischaemic
stroke, despite a lack of clinical trial evidence.
22 Over the
following years, six medium, large, or mega trials evaluated
the efficacy of heparin in patients with recent ischaemic stroke.
Three trials compared heparin [unfractionated heparin (UFH),
low-molecular-weight heparin (LMWH), or heparinoid] with control
(FISS,
23 IST,
24 and TOAST
25) and three compared heparin (UFH,
LMWH) with aspirin (IST,
24 HAEST,
26 and TAIST
27). One trial
(TOPAS) examined four different doses of another LMWH without
a control group.
28 Only one of the trials specifically studied
patients with AF (HAEST).
26
Table 3 shows the incidence of recurrent stroke during the treatment period. Although the smallest of the trials, FISS, found a positive benefit of anticoagulation on functional outcome (combined death and dependency),23 the remaining studies were neutral. Similarly, none of the trials found an overall benefit with anticoagulation on early stroke recurrence. The largest trial, IST,24 showed that patients treated with UFH had significantly fewer early recurrent ischaemic strokes [2.9 vs. 3.5%; absolute risk reduction (ARR), 0.6%; P=0.005] but this was offset almost exactly by an increase in the risk of intracerebral haemorrhage (1.1 vs. 0.4%; ARR, –0.7%; P<0.001). IST was of sufficient size to assess efficacy and hazard in subgroups and did not find that patients with AF benefited from low or medium dose UFH.
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Table 3 Effect of anticoagulation on functional outcome (combined death and dependency at 3 or 6 months), recurrent stroke, and SICH in patients with acute ischaemic stroke
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In a
post hoc analysis, TOAST found that dose-adjusted intravenous
danaparoid sodium (ORG 10172, a heparinoid) might improve functional
outcome in patients with presumed large artery ischaemic stroke,
29 although this was not found with weight adjusted tinzaparin
(LMWH) in TAIST,
27 nor in meta-analyses.
30 None of the studies
found efficacy in patients with presumed cardioembolic stroke
(secondary to AF).
30
Three trials compared heparin with aspirin. Aspirin-treated patients did not show a lower rate of recurrent stroke (2.1–7.5%) than those given an anticoagulant (3.2–8.5%) but had lower rates of intracranial bleeding (0.2–1.8% vs. 0.7–2.7%; Table 3). TOPAS examined the effect of different doses of certoparin: a two-fold increase in bleeding was observed in patients receiving the highest dose of certoparin when compared with the lowest dose (4 vs. 2%) in the uncontrolled TOPAS trial. Overall, anticoagulation does not appear to reduce functional dependency or early stroke recurrence in patients with acute ischaemic stroke but does promote significant intracranial and extracranial bleeding.31 As a result, aspirin is the first-line antithrombotic agent for use in patients with acute ischaemic stroke, including those with AF and presumed cardioembolism.
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Bleeding
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Two meta-analyses have assessed, the rates of major and intracranial
haemorrhage with antithrombotic therapy (primary and secondary
preventions;
Table 2).
20,32 The overall rate of major haemorrhage
was significantly higher with warfarin than that with placebo
[2.2 vs. 0.9%, odds ratio (OR), 2.35; 95% CI, 1.30–4.24].
The highest haemorrhage rate occurred in the EAFT secondary
prevention study (6 vs. 1.4%, OR, 3.47; 95% CI, 1.28–9.40).
The overall rate of major haemorrhage was also higher with warfarin
compared with aspirin (1.6 vs. 1.0%, OR, 1.56; 95% CI, 0.77–3.18).
Similarly, the rate of intracranial haemorrhage was doubled in patients taking warfarin when compared with those taking placebo (0.4 vs. 0.2%), and remained higher than with aspirin (1.2 vs. 0.5%). No intracranial haemorrhage events occurred in the warfarin-treated patients in the EAFT secondary prevention study and aspirin did not result in any greater risk of major bleeding or intracranial haemorrhage than control. Minor haemorrhage was increased two-fold with warfarin when compared with control, whereas it was rarely observed in the aspirin treatment arm.
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International normalized ratio range
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The target INR in the warfarin trials varied between 1.4 and
4.2 (
Table 1). Although two thirds of individuals who had a
recurrent ischaemic event had an INR<2.0, and intracerebral
haemorrhage was associated with a high INR >4.0–4.5,
it is generally recommended that the INR should be maintained
between 2.0 and 3.0 in patients with AF.
33,34 It should, however,
be noted that the INR was measured every 2–6 weeks in
the trials, i.e. more frequently than is typically undertaken
in clinical practice.
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Patients of advanced age
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Almost half of all AF-associated stroke occurs in patients >75
years old.
35–37 Clinical trials have tended to exclude
older patients, as in the five primary prevention trials (AFASAK,
BAATAF, CAFA, SPAF, and SPINAF), where only 20% of subjects
were aged >75 years.
8 As older individuals are at increased
risk of anticoagulant-related bleeding and of suffering from
relative or absolute contraindications to anticoagulation, they
are less likely to be treated with oral anticoagulation.
9 A
recent cohort study, including a significant proportion of elderly
patients (23% of
80 years of age),
38 found a RRR of 41% (95%
CI, 27–52) in ischaemic stroke and peripheral embolism
in patients taking warfarin. Warfarin therapy was associated
with a two-fold increased risk of intracranial haemorrhage when
compared with no warfarin therapy. A target INR of 1.6–2.5
39 or 1.75–2.25, is therefore generally considered to be
reasonably safe and effective in patients >70 years of age
with AF.
40
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Disability
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As with increasing age, patients with disability, and dependency
tend to be excluded from clinical trials. The primary prevention
trials assessing antithrombotic therapy in AF focussed on patients
with little comorbidity, whereas EAFT excluded patients with
significant residual disability following stroke. Similarly,
the acute intervention trials excluded patients with prior dependency
(typically those with a modified Rankin Scale of >2), usually
because the primary outcome comprised the composite of death
and dependency—interventions are unlikely to improve dependency
beyond its pre-morbid level. Hence, the role of anticoagulation
in such patients remains unclear.
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Blood pressure
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The risk of stroke is increased among patients who have hypertension.
41 Approximately 70% of strokes are associated with hypertension,
which is often less than ideally controlled.
42 Lowering blood
pressure is thus a central strategy in reducing the rate of
stroke. Indeed, a meta-analysis of 36 major randomized trials
evaluated the benefits of lowering blood pressure treatment
on reducing stroke risk.
43 Five trials of angiotensin-converting
enzyme (ACE)-inhibitor and four trials of calcium channel blockers
(CCB) compared active treatment with placebo. The reduction
of stroke risk was 28% (95% CI, 19–36) with ACE-inhibitor
and 38% (95% CI, 18–53) with CCBs, such that the reduction
of stroke seen with an ACE-inhibitor appeared to be less than
that for CCB (RRR, –12%; 95% CI, –25 to –1).
CCBs (nine trials), but not ACE-inhibitors (five trials), were
more effective at reducing stroke than diuretics or ß-blockers
(RRR, 7%; 95% CI, 0–14). Additionally, larger reductions
in blood pressure were associated with larger reductions in
stroke risk.
44
When considering trials specifically recruiting patients with prior stroke or transient ischaemic attack (TIA), antihypertensive therapy was associated with significant reduction in the risk of stroke, 24% (95% CI, 8–37). When analysing individual drug class, ß-blockers did not appear to alter stroke rates. In contrast, stroke was reduced by 32% with diuretics, and by 45% (95% CI, 32–56) with the combination of an ACE-inhibitor and diuretic.45 Once again, a dose response was seen between the magnitude of blood pressure lowering and reduction in stroke.45
The effect of lowering blood pressure in patients with AF has only been studied within subgroup analyses of large trials. For example, 4% of patients (527 in total) had AF in the LIFE and SCOPE studies.46,47 Overall, an angiotensin-receptor antagonist reduced the incidence of stroke by 25% (95% CI, 11–37) when compared with a ß-blocker in the LIFE study, and by 24% (95% CI, –410 to 170) against control in the SCOPE study. Of the 324 patients with AF in the LIFE study, stroke was 49% lower in patients randomized to an angiotensin-receptor antagonist when compared with a ß-blocker (P=0.018).46
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Lowering lipids
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In addition to cardioembolism, atherothrombosis and its risk
factors are key causes of ischaemic stroke.
48 Patients with
AF often have other vascular risk factors, including hypercholesterolaemia.
Several randomized trials have demonstrated that lowering cholesterol
with 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors
(statins) reduces the risk of cardiovascular events and stroke.
A recent meta-analysis reviewed 11 major clinical controlled
trials and compared the clinical benefit of reduction on the
composite vascular outcome comprising heart attack, stroke,
or death.
49 Over 5 years of follow up, the stroke risk was reduced
with atorvastatin (RRR, 41%),
50,51 simvastatin (RRR, 25–34%),
52,53 and pravastatin (RRR, 31%).
54–56 The analysis suggested
that the beneficial reduction in the rate of cardiovascular
events was independent of change in cholesterol concentration
and might be related to delaying the growth of vascular plaque.
No studies (or subgroup analyses within larger trials) assessing
the effect of lipid lowering in patients with AF have been reported
to date.
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Future
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A number of trials have found that dual antiplatelet therapy
can be more effective than monotherapy even when accounting
for safety, especially bleeding. For example, the combination
of aspirin and dipyridamole was superior to either drug alone
in preventing recurrence in patients with prior ischaemic stroke
or TIA.
19 Similarly, aspirin and clopidogrel were more effective
than aspirin alone in the CURE and CREDO trials involving patients
with ischaemic heart disease.
57,58 Four trials have compared
aspirin and ticlopidine vs. aspirin and warfarin in patients
undergoing coronary artery stent placement procedures. These
trials showed a trend in favour of the combination of aspirin
and ticlopidine, and two of the trials showed a statistically
significant benefit.
59–62 Bleeding rates were lower with
aspirin plus ticlopidine than with aspirin plus warfarin.
59–61 Similar studies have been performed with the combination of
aspirin and clopidogrel in patients having undergone stent insertion.
63,64 Although the pathophysiological mechanisms are different from
that occurring in AF, these trials of dual antiplatelet therapy
provide strong support for performing similar studies in patients
with AF, as is now planned.
65
Pathophysiological mechanisms underlying AF-induced thromboembolic events have been investigated in animal models. These experimental studies indicated that there is an inverse relationship between the nitric oxide production and the incidence of thromboembolic complications in the left atrial endocardium.66 Thus, local or systemic delivery of nitric oxide donors might prevent thromboembolic events associated with AF. Improvements in anticoagulation may also lead to further prevention of strokes. For example, fixed dose ximelagatran, an oral direct thrombin inhibitor not requiring coagulation monitoring, was as effective as warfarin and well-tolerated in preventing stroke in patients with AF in two trials (SPORTIF III and V).67,68 Another approach involves surgical excision or removal of the left atrial appendage as this is the source of many cardioembolic events in AF.69,70 Such novel approaches may be alternatives to warfarin therapy.
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Acknowledgements
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Thrombosis Quorum is supported by an educational grant from
AstraZeneca. This Supplement has been developed as part of the
Thrombosis Quorum initiative, under the direction of the Thrombosis
Quorum Steering Group [G. Agnelli (Chairman), P. Bath, J. Emmerich,
B. Gersh, M. Ögren, S. Schulman, and J. Weitz].
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Conflict of interest
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P. Bath has consulted for AstraZeneca and given lectures at
sponsored symposia.
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Abstract
Introduction