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Effect of Clopidogrel Added to Aspirin in Patients with Atrial Fibrillation

In patients who were "unsuitable" for warfarin, clopidogrel plus aspirin prevented more ischemic strokes than aspirin alone.

The Atrial Fibrillation Clopidogrel Trial with Irbesartan for Prevention of Vascular Events (ACTIVE) W trial showed that warfarin therapy was superior to clopidogrel plus aspirin for patients with atrial fibrillation who have at least one stroke risk factor (JW Neurol Sep 6 2006). Now, the same research group report results of the international ACTIVE A study, comparing aspirin plus placebo with aspirin plus clopidogrel for stroke prevention in patients with atrial fibrillation and at least one stroke risk factor who were considered "not suitable" for warfarin therapy.

A total of 7554 patients were randomized to receive 75 mg of clopidogrel or placebo daily, in addition to aspirin (75–100 mg daily), for a median of 3.6 years. The primary outcome measure was occurrence of major vascular events (stroke, myocardial infarction, non-CNS systemic embolism, or vascular death). Stroke was defined as sudden onset of a focal neurological deficit lasting more than 24 hours and classified as ischemic (including hemorrhagic transformation), hemorrhagic, or of uncertain type. The manufacturer of clopidogrel sponsored the study.

The clopidogrel group had significantly fewer major vascular events than the placebo group (6.8% vs. 7.6% per year), including fewer ischemic strokes (1.9% vs. 2.8% per year), but also significantly more major hemorrhagic events (2.0% vs. 1.3% per year), including intracerebral hemorrhage. An editorialist calculates that, by adding clopidogrel to aspirin, one serious stroke could be prevented for every 200 patients treated for 1 year, but one additional major bleeding episode or one intracranial hemorrhage would occur in every 143 and 500 patients, respectively.

Comment: The design and statistical analysis of this study seem appropriate, as was leaving to the treating physician and patient decisions about which patients were "unsuitable" candidates for warfarin. However, without a clear definition of unsuitability, the introduction of bias is possible. Furthermore, the sheer size of the study makes the collection and transmission of precise data logistically complex, potentially rendering doubtful the precision of the recorded stroke diagnoses.

Nonetheless, the take-home message of the study and editorial is of interest: In patients who are truly unsuitable for warfarin therapy, clopidogrel plus aspirin is somewhat better than aspirin alone for preventing ischemic stroke, but neither is as effective as warfarin. This is true for patients with all levels of predicted stroke risk, even those without any risk factors (Arch Intern Med 1994; 154:1449).

We seem to need easier, safer, more standardized ways to deliver warfarin therapy, to reduce the number of patients who are unnecessarily considered "unsuitable." Many institutions with reliable anticoagulation services already provide such therapy. One solution might be a coordinated national network of interested antithrombotic-therapy services. Safer antithrombotic agents and better identification of those truly at risk for embolism would also be helpful.

— J. Philip Kistler, MD

Dr. Kistler is Professor of Neurology, Harvard Medical School and Massachusetts General Hospital, Boston.

Published in Journal Watch Neurology August 11, 2009

Citation(s):

Connolly SJ et al. for the ACTIVE Investigators. Effect of clopidogrel added to aspirin in patients with atrial fibrillation. N Engl J Med 2009 May 14; 360:2066.

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Go AS. The ACTIVE pursuit of stroke prevention in patients with atrial fibrillation. N Engl J Med 2009 May 14; 360:2127.

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• Medline abstract (Free)