Key points
Adding aspirin to warfarin does not seem to prevent stroke and vascular events in patients with atrial fibrillation and stable vascular disease
Bleeding risks are much higher in patients prescribed both warfarin and aspirin
We should stop prescribing aspirin plus warfarin to prevent stroke and vascular events in stable patients with atrial fibrillation who are receiving anticoagulation treatment
The clinical problem
Atrial fibrillation is the commonest cardiac arrhythmia, with increasing prevalence and incidence.1 Adjusted dose oral anticoagulation (such as with warfarin) is the most effective treatment for stroke prevention in high risk patients with atrial fibrillation.2
However, common practice is to add aspirin (or other antiplatelet treatment) to warfarin in atrial fibrillation if there is associated chronic stable coronary or peripheral artery disease.2 This is despite relatively little evidence that adding aspirin to warfarin reduces stroke or other vascular events in patients with atrial fibrillation.
I propose here that we should not add aspirin for associated stable vascular disease in a patient with atrial fibrillation receiving anticoagulation, given the lack of evidence for benefit and the potential for harm.
The evidence for change
Randomised clinical trials in patients with atrial fibrillation using combinations of anticoagulation and aspirin either compared fixed dose (or low intensity, international normalised ratio (INR) <1.5) anticoagulation plus aspirin with adjusted dose warfarin2 or compared adjusted dose anticoagulation (INR 2.0-3.0) plus aspirin with adjusted dose anticoagulation.
The first trial type found that fixed dose anticoagulation plus aspirin was no better than adjusted dose warfarin.2 In the second category, one trial was stopped early owing to poor recruitment but showed a substantially higher bleeding rate in the anticoagulation plus aspirin arm than in the anticoagulation alone arm.3 A retrospective analysis of the combined dataset of two large recent randomised clinical trials4 of warfarin versus ximelagatran (an oral direct thrombin inhibitor) in moderate to high risk patients with atrial fibrillation compared aspirin users with non-users. This analysis found no additive effect of taking aspirin (with either of the anticoagulation treatments) in preventing stroke or reducing vascular events (including death or myocardial infarction).4 Specifically, the rate of myocardial infarction with aspirin and warfarin was not significantly different from that with warfarin alone (0.6% and 1.0% a year respectively). However, aspirin use resulted in a substantial higher bleeding risk compared with warfarin alone (major bleeding 3.9% and 2.3% a year respectively; P<0.01).
Various cohort studies (either case series or registry analyses) in which aspirin was added among patients receiving anticoagulation treatment who were having percutaneous coronary intervention and stenting (only a proportion of patients had atrial fibrillation) also suggest an increase in bleeding risk by adding antiplatelet treatment to warfarin.5 6 7 8 In one registry analysis of 10 093 patients with atrial fibrillation, the use of antiplatelet treatment was associated with a threefold increase in intracranial haemorrhage (relative risk 3.0; 95% confidence interval 1.6 to 5.5).9
Barriers to change
The perception that aspirin plus warfarin is needed in patients with atrial fibrillation and vascular disease is based on the fact that antiplatelet treatment works on the platelet-rich thrombus (“white clot”) associated with vascular disease, whereas warfarin is effective for the fibrin-rich thrombus (“red clot”) associated with atrial fibrillation.
This principle applies particularly in patients with atrial fibrillation who present with acute coronary syndrome or are having percutaneous coronary intervention or stenting, for which aspirin plus clopidogrel is recommended for up to 12 months.10 If such patients with atrial fibrillation are at high risk of stroke they may be prescribed warfarin also, although sound evidence for its efficacy is still lacking and bleeding risk on such triple therapy is not inconsequential.5 6 7 8 10 Also, in patients in atrial fibrillation with prosthetic heart valves, some may do better with warfarin plus aspirin.11 In patients with atrial fibrillation who have such “unstable” vascular disease or valvular disease, the real, long term benefit to risk ratio of combination therapy is not known and should be left to the physician’s discretion.
However, for stable coronary artery disease, warfarin can be a useful antithrombotic drug,12 13 and adding aspirin may substantially increase bleeding risk without much benefit. None the less, the lack of benefit of added aspirin may not apply to all antiplatelet agents. For example, one randomised trial (n=1209) compared triflusal (an antiplatelet drug that is a cyclo-oxygenase inhibitor, not available in the United Kingdom) to acenocoumarol (an anticoagulant) or combination therapy, in intermediate risk and high risk patient groups. In both groups the primary outcome was lower with triflusal plus acenocoumarol than with anticoagulation alone. No difference was found for bleeding complications between the anticoagulant and the combined therapy arms.14
How should we change our practice?
Clinicians should be aware that in patients with atrial fibrillation and stable vascular disease, adding aspirin to warfarin does not seem to prevent stroke and vascular events and increases bleeding risk. If a patient taking aspirin for atrial fibrillation is diagnosed with vascular disease and requires warfarin, the aspirin should be stopped once warfarin is started and therapeutic range (INR 2.0-3.0) achieved. Aspirin plus clopidogrel (without warfarin) is not an alternative in patients with atrial fibrillation at high risk of stroke.15 The message to stop prescribing aspirin alongside warfarin in such patients needs much greater emphasis in prescribing guidelines.
Sources and selection criteria
I performed a comprehensive literature search by using electronic bibliographic databases (Medline, Embase, DARE (Database of Abstracts of Reviews of Effects), Cochrane database), scanning reference lists from included articles, and hand searching abstracts from national and international cardiovascular meetings. For the search, I used the terms “atrial fibrillation” plus “anticoagulation” plus “aspirin”. I reviewed bibliographies of all selected articles and review articles for other relevant articles. Finally, I hand searched the supplements of major journals to identify relevant abstracts that had not been published as peer reviewed articles.
Contributors: GHYL is the sole contributor.
Competing interests: None declared.
Provenance and peer review: Commissioned; externally peer reviewed.
Change Page aims to alert clinicians to the immediate need for a change in practice to make it consistent with current evidence. The change must be implementable and must offer therapeutic or diagnostic advantage for a reasonably common clinical problem. Compelling and robust evidence must underpin the proposal for change.
References
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