A combination of clopidogrel and aspirin reduces major vascular events by 11 percent, including a 28 percent reduction in stroke and a 23 percent reduction in myocardial infarction, according to research presented at the American College of Cardiology's 58th annual scientific session.

The results of ACTIVE-A assessed the safety and efficacy of adding clopidogrel to aspirin in high-risk atrial fibrillation (AF) patients who are unsuited to use vitamin K antagonists (VKA) such as warfarin as a treatment therapy for AF.

Oral anticoagulants, such as warfarin and aspirin, are the only proven effective therapies in treatment for AF, and warfarin has proved to be the more effective of the two. However, many patients who are unsuited to use VKA such as warfarin, and they receive aspirin. Warfarin reduces stroke by 38 percent; however, it increases major hemorrhage by 70 percent and intracranial hemorrhage by greater than 100 percent. It is also difficult to tolerate, requiring monitoring and restrictions of lifestyle. Aspirin alone is modestly effective, reducing stroke by 22 percent.

Guidelines recommend warfarin for high-risk patients but many patients do not take it because of bleeding risk or because of their physician does not recommend it.

"The purpose of the ACTIVE-A trial was to determine if the addition of clopidogrel to aspirin would reduce major vascular events and stroke in patients with AF, at an acceptable risk of increased hemorrhage," said Stuart Connolly, M.D. of McMaster University and one of the principle investigators of ACTIVE-A. "If you treated one thousand patients over the course of three years by adding clopidogrel to aspirin, you would prevent 28 strokes, 17 of which would be fatal or disabling, and you would prevent six heart attacks. This would occur at a cost of 20 major hemorrhages."

In 2006, the ACTIVE-W study reported that adding clopidogrel to aspirin was less effective than warfarin, but this result is difficult to interpret because most patients in that study were on warfarin at the time of enrollment, potentially biasing results in favor of warfarin. In ACTIVE-A the effect of adding clopidogrel to aspirin is directly evaluated in a double-blind placebo- controlled clinical trial of 7,554 patients with documented AF and at least one risk factor for stroke.

In ACTIVE-A, all patients were treated with aspirin (75-100 mg/day, recommended) and randomized to receive either clopidogrel (75 mg/day) or matching placebo. The primary outcome was the composite of stroke, myocardial infarction, non-CNS systemic embolus or vascular death; major bleeding was a secondary safety outcome. Clopidogrel increased risk of major hemorrhage by 58 percent from 1.27 percent to 2 percent/year.

"Addition of clopidogrel to aspirin in many patients with AF, unsuitable for warfarin will provide an overall benefit at an acceptable risk," said Salim Yusuf, M.D. of McMaster University and one of the principle investigators "When compared to aspirin alone, warfarin is more effective than clopidogrel plus aspirin against stroke in AF. However clopidogrel provides only about three-quarters of the benefit of warfarin over aspirin, but with only about three- quarters of the increased risk of major and intracranial hemorrhage."