Non-Major Bleeding With Apixaban vs. Warfarin in AF

Study Questions:

What is the incidence, location, and management of non-major bleeding for patients with atrial fibrillation (AF) receiving either warfarin or apixaban in the ARISTOTLE (Apixaban for Reduction in Stroke and other Thromboembolic Events in Atrial Fibrillation) trial?


The authors explored non-major bleeding events among the 18,140 patients in the ARISTOTLE trial. Non-major bleeding included clinically relevant non-major (CRNM) bleeding and minor bleeding that was not preceded by a major bleeding event. Patients experiencing a non-major bleeding event were followed for any related clinical outcomes (major bleeding and mortality) during the remaining trial period.


Non-major bleeding was three times more common than major bleeding (12.1% vs. 3.8%) among all anticoagulated patients. Non-major bleeding was less frequent among apixaban-treated patients than warfarin-treated patients (6.4 vs. 9.4 per 100 patient-years, adjusted hazard ratio [aHR], 0.69; 95% confidence interval [CI], 0.63-0.75). The most frequent sites of non-major bleeding included hematuria (16.4%), epistaxis (14.8%), gastrointestinal (13.3%), hematoma (11.5%), and bruising/ecchymosis (10.1%). Medical or surgical intervention was similar across patients treated with warfarin versus apixaban (24.7% vs. 24.5%). A change in anticoagulation therapy occurred in 58.6% versus 50.0% (p < 0.0001) warfarin versus apixaban patients. Permanent study drug discontinuations were similar (5.1% vs. 3.6%, p = 0.10) in the two treatment groups. CRNM bleeding was independently associated with an increased hazard of overall death (aHR, 1.70; 95% CI, 1.32-2.18) and subsequent major bleeding (aHR, 2.18; 95% CI, 1.56-3.04).


The authors concluded that non-major bleeding was common, but substantially less frequent with apixaban as compared to warfarin. They also concluded that CRNM bleeding was an independent predictor or all-cause death and subsequent major bleeding.


While use of anticoagulants is critical for preventing thrombotic complications such as stroke, they also place patients at risk for bleeding. This post hoc analysis of the ARISTOTLE trial described the high burden of minor bleeding among patients on warfarin and apixaban. Given that the presence of a CRNM bleeding event predicted future major bleeding and mortality, it was reassuring to see that apixaban use was associated with approximately 30% less minor bleeding compared with warfarin. It should also be noted that approximately 30-35% of all patients on oral anticoagulants were also receiving aspirin therapy. Efforts to reduce the overall bleeding risk may include reducing the number of antithrombotic agents and/or use of gastroprotective agents.

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