Objective: We describe the incidence, location and management of non-major bleeding, and assess the association between non-major bleeding and clinical outcomes in patients with atrial fibrillation (AF) receiving anticoagulation therapy enrolled in Apixaban for Reduction in Stroke and other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE).
Methods: We included patients who received ≥1 dose of study drug (n=18 140). Non-major bleeding was defined as the first bleeding event considered to be clinically relevant non-major (CRNM) or minor bleeding, and not preceded by a major bleeding event.
Results: Non-major bleeding was three times more common than major bleeding (12.1% vs 3.8%). Like major bleeding, non-major bleeding was less frequent with apixaban (6.4 per 100 patient-years) than warfarin (9.4 per 100 patient-years) (adjusted HR 0.69, 95% CI 0.63 to 0.75). The most frequent sites of non-major bleeding were haematuria (16.4%), epistaxis (14.8%), gastrointestinal (13.3%), haematoma (11.5%) and bruising/ecchymosis (10.1%). Medical or surgical intervention was similar among patients with non-major bleeding on warfarin versus apixaban (24.7% vs 24.5%). A change in antithrombotic therapy (58.6% vs 50.0%) and permanent study drug discontinuation (5.1% (61) vs 3.6% (30), p=0.10) was numerically higher with warfarin than apixaban. CRNM bleeding was independently associated with an increased risk of overall death (adjusted HR 1.70, 95% CI 1.32 to 2.18) and subsequent major bleeding (adjusted HR 2.18, 95% CI 1.56 to 3.04).
Conclusions: In ARISTOTLE, non-major bleeding was common and substantially less frequent with apixaban than with warfarin. CRNM bleeding was independently associated with a higher risk of death and subsequent major bleeding. Our results highlight the importance of any severity of bleeding in patients with AF treated with anticoagulation therapy and suggest that non-major bleeding, including minor bleeding, might not be minor.
Trial registration number: NCT00412984; post-results.
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