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Aspirin and clopidogrel combination less effective and no safer than warfarin therapy in atrial fibrillation

William E. Dager, Pharm.D., FCSHP
December, 2006

Reference: ACTIVE Writing Group on behalf of the ACTIVE Investigators. Clopidogrel plus aspirin versus oral anticoagulation for atrial fibrillation in the Atrial fibrillation Clopidogrel Trial with Irbesartan for prevention of Vascular Events (ACTIVE W): a randomised controlled trial. Lancet. 2006 Jun 10;367(9526):1903-12.

The ACTIVE trial involved analysis of several adjuncts for preventing complications in atrial fibrillation. In the ACTIVE W portion, patients assigned to receive open treatment oral anticoagulation targeting an INR of 2-3 (n=3371) were compared to clopidogrel 75mg orally daily plus low dose (75-100mg) aspirin (n=3335). Both groups had similar CHADS2 stroke risk scores. Warfarin was well controlled with 64% of INR values between 2-3. Interm analysis for the incidence of primary outcomes for occurrence of stroke, non-CNS systemic embolus, myocardial infarction or vascular related death suggested a significant benefit with the use of warfarin compared to the combined anti-platelet therapies (relative risk reduction of 8.3%/yr vs 6.5%/year favoring oral anticoagulation p = 0.0008). Because of the clear benefit observed with warfarin, the trial was stopped prematurely. The benefit was especially notable in those patients who had already been receiving oral anticoagulation therapy prior to enrolling into the trial (77% had been on oral anticoagulation prior to randomization). The primary area of benefit with oral anticoagulation therapy was a reduction ischemic stroke with a relative risk reduction of 2.4%/yr vs 1.4%/yr p = 0.0001, or an absolute risk reduction of 1%/yr. Significance was achieved despite the relatively low incidence rate. Most of the benefit was seen with a lower incidence of small, non-disabling strokes and non-CNS systemic embolism. The incidence of major hemorrhage was similar between the groups (relative risk 2.4% for clopidogrel/ASA vs 2.2% for warfarin).

For patients who were not receiving oral anticoagulation therapy prior to enrolling in the trial, a benefit of improved outcomes was noted at approximately one year while incurring a higher rate of major bleeding. Those subsequently randomized to receive oral anticoagulation were twice as likely to stop therapy during the trial. In contrast, patients previously receiving an oral anticoagulant at trial entry did not show any benefit in reduced major bleeding until approximately one year out, but a notable benefit in primary outcome was observed from the onset. Overall, the observations of the ACTIVE W trial suggest a benefit with continued well-controlled oral anticoagulation therapy if the individual was already receiving it. It still leaves in question the management of individuals who are not receiving oral anticoagulants or antiplatelet therapy, or have previously stopped such therapy.

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