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  •    Risk of Stroke is Low with Clopidogrel Plus Aspirin in Patients with Atrial Fibrillation
    Darbhamulla V Nagarajan, MRCP.

    Patients with atrial fibrillation are at a greater risk for stroke compared to population in normal sinus rhythm. This increased risk of stroke is probably attributable to the increased platelet activation and hypercoagulable state associated with atrial fibrillation. Both vitamin K antagonists and aspirin have proven benefit in reducing this risk of stroke. Vitamin K antagonists like warfarin are currently recommended for patients with atrial fibrillation who are at highest risk of stroke, and aspirin to the patients with atrial fibrillation at a lower risk of stroke. A combination of dual platelet therapy with aspirin and clopidogrel (Plavix®, Sanofi Aventis) is of proven benefit in patients with acute coronary syndrome. The Atrial Fibrillation Clopidogrel Trial with Irbesartan for prevention of Vascular Events (ACTIVE) study was designed to study the efficacy of this dual platelet therapy as compared to aspirin alone in patients with atrial fibrillation at a high risk of vascular events and for whom therapy with vitamin K antagonist was deemed to be unsuitable.

    This study led by Dr.Stuart J Connolly published in The New England Journal of Medicine (Connoly SJ et al. Effect of clopidogrel added to aspirin in patients with atrial fibrillation. NEJM 2009;360:2066-78), enrolled patients with permanent atial fibrillation or at least two episodes of atrial fibrillation in the preceding six moths, with at least one risk factor for stroke and for whom vitamin K antagonist was deemed to be unsuitable were enrolled in to the study. A total of 7554 eligible patients (mean age of 71 years and 58.2% men) were randomized in a double blind fashion to receive either Clopidogrel 75 mg or a matching placebo once daily. All patients received Aspirin 75 mg once daily. Patients were followed up for a median duration of 3.6 years. The primary study outcome was any major vascular event including stroke, myocardial infarction, non-central nervous system systemic embolism or death from vascular causes. The secondary outcomes included individual components of primary outcome and the composite of the primary outcome and major haemorrhage.

    Fewer patients receiving clopidogrel (832 patients out of the total 3772) as compared  to the patients receiving placebo (924 out of the 3782)  reached primary end point during the follow up period (6.8% vs 7.6% per year ; relative risk, 0.89; 95% CI, 0.81-0.98; P=0.01). Stroke occurred in 296 patients receiving clopidogrel compared to 408 in placebo group (2.4% vs 3.3% per year; relative risk, 0.72; 95% CI, 0.62-0.83; P < 0.001). The rate of ischemic stroke was significantly lower in the clopidogrel group compared to placebo group (1.9% per year vs 2.8% per year, P < 0.001), however there was no significant increase in the rate of hemorrhagic stroke in clopidogrel group (0.23% vs 0.17% per year). Myocardial infarction occurred in fewer patients in clopidogrel group compared to placebo group, however the difference was statistically not significant (0.7% vs 0.9% per year; relative risk, 0.78; 95% CI, 0.59-1.03; P=0.08).Annual rates of non-central nervous system systemic embolism and death from vascular causes were similar in both groups. There was increased incidence of major bleeding in clopidogrel group compared to the placebo group (2.0% vs 1.3% per year; relative risk, 1.57; 95% CI, 1.29-1.92; P < 0.001).

    With the composite of primary outcome and major bleeding there was no significant difference in the overall event rate between the two groups.

    Treatment with clopidogrel plus aspirin , as compared with aspirin alone reduced the rate of major vascular events among patients with atrial fibrillation who were at increased risk for stroke and for whom therapy with a vitamin K antagonist was considered to be unsuitable. This reduction is mainly due to reduction in the risk of stroke. There was a significant increase in risk of major bleeding. This study establishes the superiority of dual anti platelet therapy over aspirin alone in patients with atrial fibrillation who are at an increased risk for stroke and for whom therapy with a vitamin K antagonist is not a feasible option.


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