A meta-analysis of 12 randomized trials of stroke prevention in patients with atrial fibrillation (8932 patients, 63% male, mean age 72 years, 19.6% ≥ 80 years) examined outcomes of ischemic stroke, serious bleeding (systemic or intracranial hemorrhages requiring hospitalization, transfusion, or surgery) and cardiovascular events (ischemic stroke, myocardial infarction, systemic emboli, and vascular death).1 Patients were randomized to oral anticoagulants (3430 patients), antiplatelet therapy (3531 patients), or no therapy (1971 patients).
Warfarin target international normalized ratios (INRs) ranged from 1.5 to 4.2. Previous stoke or transient ischemic attack varied across studies but averaged 22% (patient baseline characteristics were evenly distributed among all arms of all 12 studies, suggesting appropriate randomizations). Fifteen percent of patients had diabetes, 50% had hypertension, and 20% had congestive heart failure. They were followed for a mean of 2 years.
Overall, patients experienced 623 ischemic strokes, 289 serious bleeds, and 1210 cardiovascular events. After adjusting for treatment and covariates, age was independently associated with higher risk for each outcome. For every decade increase in age, the hazard ratio (HR) for ischemic stroke was 1.45 (95% confidence interval [CI], 1.26-1.66); serious hemorrhage, 1.61 (95% CI, 1.47-1.77); and cardiovascular events, 1.43 (95% CI, 1.33-1.53).
Benefits of warfarin outweigh increased risk of hemorrhage
Treatment with vitamin K antagonists, compared with placebo, reduced ischemic strokes (HR = 0.36; 95% CI, 0.29-0.45) and cardiovascular events (HR = 0.59; 95% CI, 0.52-0.66) but increased the risk of serious hemorrhage (HR = 1.56; 95% CI, 1.03-2.37) in patients from 50 to 90 years of age. The benefits of decreased ischemic strokes and cardiovascular events consistently surpassed the increased risk of hemorrhage, however.
Across all age groups, the absolute risk reductions (ARRs) for ischemic stroke and cardiovascular events were 2% to 3% and 3% to 8%, respectively, whereas the absolute risk increase for serious hemorrhage was 0.5% to 1%. For those ages 70 to 75, for example, warfarin decreased the rate of ischemic stroke by 3% per year (number needed to treat [NNT] = 34; rates estimated from graphs) and the rate of cardiovascular events by 7% (NNT = 14) but increased the risk of serious hemorrhage by approximately 0.5% per year (number need to harm = 200).
Warfarin prevents major strokes more effectively than aspirin
A randomized open-label trial with blind assessment of endpoints, included in the meta-analysis, followed 973 patients older than 75 years (mean 81.5 years) with atrial fibrillation for 2 to 7 years.2 Researchers evaluated warfarin compared with aspirin for the outcomes of major stroke, arterial embolism, and intracranial hemorrhage. Major strokes comprised fatal or disabling strokes. Researchers excluded patients with minor strokes, rheumatic heart disease, a major nontraumatic hemorrhage within the previous 5 years, intracranial hemorrhage, peptic ulcer disease, esophageal varices, or a terminal illness.
Compared with aspirin, warfarin significantly reduced all primary events (ARR = 1.8% vs 3.8%; relative risk reduction [RRR] = 0.48; 95% CI, 0.28-0.80; NNT = 50). Warfarin decreased major strokes more than aspirin (21 vs 44 strokes; ARR = 1.8%; relative risk [RR] = 0.46; 95% CI, 0.26-0.79; NNT = 56) but didn’t alter the risk of hemorrhagic strokes (6 vs 5 absolute events, respectively; RRR = 1.15, 95% CI, 0.29-4.77) or other intracranial hemorrhages (2 vs 1 event, respectively; RR = 1.92; 95% CI, 0.10-113.3). Wide confidence intervals and the small number of hemorrhagic events suggest that the study wasn’t powered to detect a significant difference in hemorrhagic events.
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