Warfarin

Warfarin is an oral anticoagulant which has been demonstrated to be effective in the prevention of cardioembolic stroke. Recent randomized clinical trials have evaluated the relative merits of warfarin or aspirin in patients with asymptomatic nonvalvular atrial fibrillation. Warfarin is beneficial among patients with prosthetic valves and after acute myocardial infarction to reduce the risk of thromboembolic stroke. Those with mechanical valves are usually treated with long-term oral anticoagulants, while those with bioprosthetic valves may be treated with antiplatelet agents. The combination of low-dose aspirin with warfarin was found to be more effective than warfarin alone in reducing mortality and major systemic embolism among patients with prosthetic valves plus atrial fibrillation or a history of thromboembolism. In the Warfarin Reinfarction Study, warfarin was superior to placebo in reducing the likelihood of recurrent MI, mortality, and the incidence of cerebrovascular events among patients under age 75 with acute myocardial infarction. Findings on echocardiogram such as anterior wall akinesis and left ventricular thrombus may help determine who is at increased risk of stroke and select such patients for a 3-6 month course of oral anticoagulants. Combination therapy of warfarin and aspirin is also being evaluated after acute myocardial infarction.

For patients who have already become symptomatic with transient ischemic attacks or ischemic stroke and have a cardiac source of embolism, the European Atrial Fibrillation Trial convincingly demonstrated that anticoagulation therapy reduced the risk of recurrent stroke in patients with atrial fibrillation and TIA or minor stroke from 12% to 4% compared to placebo. The risk reduction of 67% was similar to that found in the other atrial fibrillation trials among persons with no prior neurological events. Oral anticoagulants were more effective than aspirin, and aspirin was better than placebo, but the latter effect was not significant. This clinical trial, in conjunction with the other warfarin studies, provides support that warfarin is the therapy of choice in patients with a cardiac source and a TIA or minor stroke, providing there is no contraindication to its use.

At present, there is considerable debate concerning the use of warfarin after noncardioembolic stroke or TIA and no recent clinical trial evidence to support its use. Most of the early trials were done during the pre-computed tomography, pre-echocardiography era and found no benefit for warfarin. However, many of the studies had an unacceptably small sample size, no clearly defined mechanism of stroke, a higher rate of recurrent stroke than is common at the present time, and far higher rates of anticoagulant complications than those which occur currently. Recently, the SPIRIT (Stroke Prevention in Reversible Ischemia Trial) had to be halted because of the hemorrhagic side effects of an INR of 3-4.5 for patients with nondisabling, noncardioembolic infarction. The debate should be settled by the ongoing Warfarin Aspirin Recurrent Stroke Study which was designed to compare the efficacy of warfarin to aspirin for the prevention of recurrent Stroke or death after noncardioembolic stroke. This randomized, double-blind clinical trial has begun recruiting nearly 2000 patients with non-cardioembolic, non-operable atherosclerotic stroke over age 18 among 50 centers. Patients are followed for 2 years to detect the primary endpoints of recurrent stroke or death and other cardiovascular secondary events. All patients are treated as if they are taking warfarin with monthly prothrombin times. Sham prothrombin times are generated for the aspirin group based on a computer model of actual variations in prothrombin time among patients treated with warfarin. Some important questions regarding the role of warfarin for prevention of recurrent stroke will be answered at the conclusion of this trial in 2006.

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