Atrial fibrillation is a common cardiac arrhythmia that increases the risk of stroke and other vascular events. Oral anticoagulation is more effective at preventing vascular complications than aspirin, but it is associated with a significantly increased risk of major bleeding complications. ACTIVE W (Atrial fibrillation Clopidogrel Trial with Irbesartan for prevention of Vascular Events) was designed to compare oral anticoagulation with aspirin plus clopidogrel (Plavix) in preventing vascular complications from atrial fibrillation.

The study included 6,706 patients who had atrial fibrillation plus at least one risk factor for stroke (e.g., 75 years or older, hypertension, history of transient ischemic attack [TIA], left ventricular ejection fraction less than 45 percent, peripheral arterial disease). Patients were excluded if they had contraindications to study medications, peptic ulcer disease, mitral stenosis, thrombocytopenia, or previous intracerebral hemorrhage. Study participants were randomly assigned to receive clopidogrel (75 mg daily) plus aspirin (75 to 100 mg daily) or oral anticoagulation sufficient to maintain an International Normalized Ratio (INR) between 2.0 and 3.0. The INR was monitored monthly in the anticoagulation group. The primary outcome was occurrence of stroke, systemic embolism, myocardial infarction, or vascular death. Patients were monitored for bleeding events and adverse effects from study medications.

The 3,335 patients assigned to clopidogrel plus aspirin were comparable to the 3,371 assigned to oral anticoagulation. The average age of study participants was 70 years, and about 60 percent reported atrial fibrillation for more than two years. More than one fourth had documented coronary artery disease, and 15 percent reported previous stroke or TIA. Beta blockers and angiotensin-converting enzyme inhibitors were used by more than one half of study participants, digoxin by more than one third, and statins by about 37 percent.

The study was discontinued early (within one year) because anticoagulation therapy was clearly superior. The 164 events in patients treated with anticoagulation were equivalent to a 3.9 percent annual risk, compared with 234 events equivalent to a 5.6 percent annual risk in patients treated with aspirin plus clopidogrel. Although the anticoagulation group had an advantage in all outcomes, the greatest reduction was in stroke. Oral anticoagulation significantly reduced all types of stroke and appeared significantly more likely to prevent minor events. The rates of major hemorrhage were similar in both treatment groups (about 2 percent per year), but minor bleeding was significantly more common during aspirin plus clopidogrel therapy. The lowest discontinuation rates and best outcomes occurred in a subgroup already taking anticoagulation on entry to the study.

The authors conclude that oral anticoagulation is superior to aspirin plus clopidogrel in preventing vascular complications of atrial fibrillation, especially stroke. They calculate a reduction of one stroke plus two major vascular events or major bleeds per 100 patient-years with oral anticoagulation therapy.