OBJECTIVES: This study sought to characterize major bleeding on the basis of the 
components of the major bleeding definition, to explore major bleeding by 
location, to define 30-day mortality after a major bleeding event, and to 
identify factors associated with major bleeding.
BACKGROUND: Apixaban was shown to reduce the risk of major hemorrhage among 
patients with atrial fibrillation in the ARISTOTLE (Apixaban for Reduction in 
Stroke and Other Thromboembolic Events in Atrial Fibrillation) trial.
METHODS: All patients who received at least 1 dose of a study drug were 
included. Major bleeding was defined according to the criteria of the 
International Society on Thrombosis and Haemostasis. Factors associated with 
major hemorrhage were identified using a multivariable Cox model.
RESULTS: The on-treatment safety population included 18,140 patients. The rate 
of major hemorrhage among patients in the apixaban group was 2.13% per year 
compared with 3.09% per year in the warfarin group (hazard ratio [HR] 0.69, 95% 
confidence interval [CI]: 0.60 to 0.80; p < 0.001). Compared with warfarin, 
major extracranial hemorrhage associated with apixaban led to reduced 
hospitalization, medical or surgical intervention, transfusion, or change in 
antithrombotic therapy. Major hemorrhage followed by mortality within 30 days 
occurred half as often in apixaban-treated patients than in those receiving 
warfarin (HR 0.50, 95% CI: 0.33 to 0.74; p < 0.001). Older age, prior 
hemorrhage, prior stroke or transient ischemic attack, diabetes, lower 
creatinine clearance, decreased hematocrit, aspirin therapy, and nonsteroidal 
anti-inflammatory drugs were independently associated with an increased risk.
CONCLUSIONS: Apixaban, compared with warfarin, was associated with fewer 
intracranial hemorrhages, less adverse consequences following extracranial 
hemorrhage, and a 50% reduction in fatal consequences at 30 days in cases of 
major hemorrhage.