Clopidogrel plus aspirin cuts vascular events.
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.
To weigh the benefits and risks of adding clopidogrel to aspirin therapy in this population, consider 1,000 patients treated for 3 years, Dr. Connolly said. Adding clopidogrel would prevent 28 strokes, 17 of which would be disabling or fatal, and would avert six myocardial infarctions, three of which would be fatal, at a cost of 20 major bleeds.
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. For these patients there is a major unmet medical need, which has now been addressed by the results of the ACTIVE-A trial."
Dr. Connolly and his colleagues in the ACTIVE-A investigation enrolled 7,554 patients who had atrial fibrillation and at least one risk factor for stroke between June 2003 and May 2006. Study participants were deemed either to be unsuitable for warfarin therapy because of bleeding risk or did not want to begin warfarin therapy. The mean patient age was 71 years.
The primary study outcome was any major vascular event, including stroke, non-CNS systemic embolism, myocardial infarction, or vascular death. The secondary outcomes included the occurrence of any of the primary outcomes, as well as major hemorrhage and total mortality, Dr. Connolly explained.
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 (N. Eng. J. Med. 2009 March 31 [doi: 10.1056/NEJMoa09013101]).
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 did not 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.
Most of the strokes that occurred in this study were either disabling or severe, "and clopidogrel reduces strokes that were both not so severe and the more severe disabling strokes to an almost equal extent," Dr. Connolly noted.
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.
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|Title Annotation:||CARDIOVASCULAR MEDICINE|
|Publication:||Internal Medicine News|
|Date:||May 1, 2009|
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