Adding clopidogrel to aspirin therapy significantly reduces the risk of stroke and other major vascular events in patients who have atrial fibrillation and are not candidates for anticoagulation therapy with a vitamin K antagonist, according to Dr. Stuart Connolly of the Population Health Research Institute in Hamilton, Ont.
The rate of major vascular events was 6.8% at a median 3.6 years of follow-up among 3,772 study participants randomized to receive 75 mg per day of the oral antiplatelet agent in addition to aspirin in the multicenter Atrial Fibrillation Clopidogrel Trial with Irbesartan for Prevention of Vascular Events-A (ACTIVE-A). The rate of major vascular events was 7.6% among the 3,782 patients randomized to placebo and aspirin therapy.
The clopidogrel and aspirin regimen was associated “with an acceptable increase in risk of major hemorrhage,” Dr. Connolly reported in a press conference at the annual meeting of the American College of Cardiology.
The rate of major hemorrhage, defined as requiring a transfusion of at least two units of blood, increased from 1.3% in the placebo and aspirin group to 2.0% in the clopidogrel and aspirin group. However, this risk is less than the risk of major hemorrhage that has been reported with warfarin therapy, he said.
Additionally, there was a nonsignificant trend toward an increased risk in fatal strokes from 0.2% per year to 0.3% per year with clopidogrel plus aspirin therapy.
Dr. Connolly emphasized that oral anticoagulation therapy with vitamin K antagonists such as warfarin is still the most effective way to reduce major vascular events in high risk patients with atrial fibrillation. However, “40%-50% of the patients who are at high risk for stroke because of atrial fibrillation don't receive anticoagulation therapy because they've been judged to be unsuitable for this treatment.”
Dr. Connolly and his colleagues enrolled 7,554 patients who had atrial fibrillation and at least one risk factor for stroke between June 2003 and May 2006. Participants were deemed either to be unsuitable for warfarin therapy because of bleeding risk or did not want to begin warfarin. The mean patient age was 71 years.
The primary study outcome was any major vascular event, including stroke, non-central nervous system systemic embolism, myocardial infarction, or vascular death.
The primary composite outcome was reduced by 11% in the clopidogrel group relative to aspirin only, “a highly statistically significant result,” Dr. Connolly noted. “What is of particular importance, however, is that this effect was driven almost entirely by a substantial reduction in strokes of all severities.” Strokes were reduced from 3.3% per year to 2.4% per year.
There was a trend of fewer myocardial infarctions, 0.9% per year in the aspirin only group and 0.7% per year in the clopidogrel plus aspirin group, which didn't achieve statistical significance, Dr. Connolly said. However the number of heart attacks in the study was relatively small [90 in the clopidogrel group; 115 in the aspirin plus placebo group], reducing the study's power to detect a significant difference. In studies of several other types of patients, clopidogrel has been shown to reduce heart attacks.
Dr. Connolly reported receiving consulting fees, lecture fees, and grant support from Sanofi-Aventis, Bristol-Myers Squibb, and Boehringer Ingelheim, and grant support from Portola Pharmaceuticals.
This study was published online in the New England Journal of Medicine (doi 10.1056/NEJMoa09013101
Aspirin plus clopidogrel was associated 'with an acceptable increase in risk of major hemorrhage.' DR. CONNOLLY