RISK-FACTORS FOR STROKE AND EFFICACY OF ANTITHROMBOTIC THERAPY IN ATRIAL-FIBRILLATION - ANALYSIS OF POOLED DATA FROM 5 RANDOMIZED CONTROLLED TRIALS

Background and Methods: Atrial fibrillation is associated with an incr eased risk of ischemic stroke. Data on individual patients were pooled from five recently completed randomized trials comparing warfarin (al l studies) or aspirin (the Atrial Fibrillation, Aspirin, Anticoagulati on Study and the Stroke Prevention in Atrial Fibrillation Study) with control in patients with atrial fibrillation. The purpose of the analy sis was to (1) identify patient features predictive of a high or low r isk of stroke, (2) assess the efficacy of antithrombotic therapy in ma jor patient subgroups (eg, women), and (3) obtain the most precise est imate of the efficacy and risks of antithrombotic therapy in atrial fi brillation. For the warfarin-control comparison there were 1889 patien t-years receiving warfarin and 1802 in the control group. For the aspi rin-placebo comparison there were 1132 patient-years receiving aspirin and 1133 receiving placebo. The daily dose of aspirin was 75 mg in th e Atrial Fibrillation, Aspirin, Anticoagulation Study and 325 mg in th e Stroke Prevention in Atrial Fibrillation Study. To monitor warfarin dosage, three studies used prothrombin time ratios and two used intern ational normalized ratios. The lowest target intensity was a prothromb in time ratio of 1.2 to 1.5 and the highest target intensity was an in ternational normalized ratio of 2.8 to 4.2. The primary end points wer e ischemic stroke and major hemorrhage, as assessed by each study. Res ults: At the time of randomization the mean age was 69 years and the m ean blood pressure was 142/82 mm Hg. Forty-six percent of the patients had a history of hypertension, 6% had a previous transient ischemic a ttack or stroke, and 14% had diabetes. Risk factors that predicted str oke on multivariate analyses in control patients were increasing age, history of hypertension, previous transient ischemic attack or stroke, and diabetes. Patients younger than 65 years who had none of the othe r predictive factors (15% of all patients) had an annual rate of strok e of 1.0%, 95% confidence interval (CI) 0.3% to 3.0%. The annual rate of stroke was 4.5% for the control group and 1.4% for the warfarin gro up (risk reduction, 68%; 95% CI, 50% to 79%). The efficacy of warfarin was consistent across all studies and subgroups of patients. In women , warfarin decreased the risk of stroke by 84% (95% CI, 55% to 95%) co mpared with 60% (95% CI, 35% to 76%) in men. The efficacy of aspirin w as not as consistent. The risk reduction with 75 mg of aspirin in the Atrial Fibrillation, Aspirin, Anticoagulation Study was 18% (95% CI, 6 0% to 58%), and with 325 mg of aspirin in the Stroke Prevention in Atr ial Fibrillation Study the risk reduction was 44% (95% CI, 7% to 66%). When both studies were combined the risk reduction was 36% (95% CI, 4 % to 57%). The annual rate of major hemorrhage (intracranial bleeding or a bleed requiring hospitalization or 2 units of blood) was 1.0% for the control group, 1.0% for the aspirin group, and 1.3% for the warfa rin group. Conclusion: In these five randomized trials warfarin consis tently decreased the risk of stroke in patients with atrial fibrillati on (a 68% reduction in risk) with virtually no increase in the frequen cy of major bleeding. Patients with atrial fibrillation younger than 6 5 years without a history of hypertension, previous stroke or transien t ischemic attack, or diabetes were at very low risk of stroke even wh en not treated. The efficacy of aspirin was Ibs consistent. Further st udies are needed to clarify the role of aspirin in atrial fibrillation .