Oral Anticoagulants Versus Antiplatelet Therapy for Preventing Stroke in Patients With Nonvalvular Atrial Fibrillation and No History of Stroke or Transient Ischemic Attacks
Graeme J. Hankey MD, FRCP Section Editor:
Nonvalvular atrial fibrillation (AF) is a common cardiac arrhythmia, affecting about 0.7% of the general population.1,2 Its prevalence increases with age; about 5% of people over age 65 years and 10% of people over the age of 80 years experience AF.1
Nonvalvular AF carries an increased risk of stroke mediated by embolism of stasis-precipitated thrombi originating in the left atrial appendage. Both oral anticoagulants and antiplatelet agents have proven effective for stroke prevention in many patients at high risk for vascular events (ie, for secondary prevention), but primary stroke prevention in patients with nonvalvular AF potentially merits separate consideration because of the suspected cardioembolic mechanism of most strokes in AF patients.
We set out to characterize the relative effect of long-term oral anticoagulant treatment compared with antiplatelet therapy on major vascular events in patients with nonvalvular AF and no history of stroke or transient ischemic attack (TIA).
We searched the Cochrane Stroke Group Trials Register (June 2006). We also searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library Issue 2, 2006), MEDLINE (1966 to June 2006) and EMBASE (1980 to June 2006). We contacted the Atrial Fibrillation Collaboration and experts working in the field to identify unpublished and ongoing trials.
All unconfounded, randomized trials in which long-term (>12 weeks) adjusted-dose oral anticoagulant treatment was compared with antiplatelet therapy in patients with chronic nonvalvular AF.
Data Collection and Analysis
Two physician authors independently assessed trials for inclusion, recorded quality parameters, and extracted data. The Peto method was used for combining odds ratios after assessing for heterogeneity.
Eight randomized trials, including 9598 patients, tested adjusted-dose warfarin versus aspirin (in dosages ranging from 75 to 325 mg/d; 6 trials, 2178 patients), aspirin plus clopidogrel (1 trial, 6706 patients), or trifusal (1 trial, 479 patients) in AF patients without prior stroke or TIA. The mean overall follow-up was 1.9 years/participant. Oral anticoagulants were associated with lower risk of all stroke (odds ratio [OR] 0.68, 95% CI 0.54 to 0.85), ischemic stroke (OR 0.53, 95% CI 0.41 to 0.68) and systemic emboli (OR 0.48, 95% CI 0.25 to 0.90). All disabling or fatal strokes (OR 0.71, 95% CI 0.59 to 1.04) and myocardial infarction (OR 0.69, 95% CI 0.47 to 1.01) were substantially, but not statistically significantly, reduced by oral anticoagulants. Vascular death (OR 0.93, 95% CI 0.75 to 1.15) and all-cause mortality (OR 0.99, 95% CI 0.83 to 1.18), were similar with these treatments. Intracranial hemorrhages (OR 1.98, 95% CI 1.20 to 3.28) were increased by oral anticoagulation relative to antiplatelet therapy.
The Figure shows the effect of anticoagulation versus antiplatelet therapy on ischemic stroke (fatal and nonfatal).
Adjusted-dose warfarin and related oral vitamin K antagonists reduce stroke, disabling stroke and other major vascular events for those with nonvalvular AF by about one third when compared with antiplatelet therapy. Based on meta-analysis of other trials, antiplatelet agents reduce stroke by about 20% in AF patients compared with no therapy, offering a less efficacious therapeutic option for those deemed not eligible for anticoagulation therapy. Considering the results from all available relevant randomized trials, oral anticoagulants reduce stroke in AF patients more effectively than antiplatelet agents, reducing ischemic strokes by half and doubling the less frequent hemorrhagic strokes for an overall net reduction. The threshold of absolute benefit that warrants anticoagulation instead of antiplatelet therapy remains controversial and depends on patient’s preferences and availability of optimal anticoagulation monitoring.
Implications for Practice
Adjusted-dose warfarin and related oral anticoagulants reduce stroke and other major ischemic vascular events for those with nonvalvular AF, and the effect is still significant (about 40%) when compared with the effect of aspirin (which reduces stroke by about 20% in AF patients). Adjusted-dose warfarin offers larger, more predictable reductions in stroke for AF patients who can safely receive it.3 Most guidelines recommend adjusted-dose warfarin for AF patients at high risk for stroke and aspirin for those deemed at low risk or for those who cannot safely receive adjusted-dose warfarin. Stroke risk stratification schemes have been developed and validated for AF patients that allow reliable classification of risk.4–6
Implications for Research
Antithrombotic agents that are more efficacious than aspirin and that are safer and easier to use than adjusted-dose warfarin are needed for the growing population of elderly patients with nonvalvular AF. A substantial unmet need remains for those who are unable to receive oral anticoagulants, yet whose stroke risk remains unacceptably high with antiplatelet therapy.
Note: For full review please refer to Issue 3, 2007 of The Cochrane Library.7
R.H. has served as a consultant to Astellas Pharmaceuticals and to Sanofi-Aventis/Bristol-Myers Squibb for design of clinical trials involving patients with atrial fibrillation.
- Received July 30, 2007.
- Accepted August 9, 2007.
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Mant J, Hobbs FD, Fletcher K, et al; on behalf of the BAFTA investigators and the Midland Research Practices Network. Warfarin versus aspirin for stroke prevention in an elderly community population with atrial fibrillation (the Birmingham Atrial Fibrillation Treatment of the Aged study, BAFTA): a randomized controlled trial. Lancet. 2007; 370: 493–503.