Clinically relevant extracranial bleeding affected approximately one in four patients receiving oral anticoagulation (OAC) for atrial fibrillation (AFib) over two years, potentially providing a more comprehensive measure of bleeding burden than major bleeding alone, according to a recent COMBINE-AF analysis published in Circulation.

The analysis comprised 73,737 patients with AFib enrolled in five pivotal COMBINE-AF trials comparing direct OACs with warfarin or aspirin.

Results over a mean follow-up of 705 days found that 10,634 patients experienced clinically relevant extracranial bleeding (cumulative incidence, 26%; 7.6 per 100 person-years). This included 3,188 major bleeds (cumulative incidence, 7%; 2.1 per 100 person-years) and 7,446 clinically relevant nonmajor bleeds (cumulative incidence, 19%; 5.2 per 100 person-years).

Distribution of bleeding sites was heterogeneous across bleeding severities, with skin/hematoma bleeding the most common site for clinically relevant nonmajor bleeding (27%) and gastrointestinal bleeding the most common site for major bleeding (50%) and total clinically relevant bleeding (26%).

Study investigators Deborah M. Siegal, MD, MSc, et al., note that identified risk factors, broadly similar across bleeding severities, could in total account for only 66%-69% of population attributable bleeding risk.

"The residual unexplained bleeding risk observed in our analysis likely reflects factors that are not fully captured by traditional clinical variables (e.g., frailty, vascular fragility, inflammation, occult pathology)," write Siegal and colleagues. "Our findings highlight the need for novel approaches beyond standard clinical predictors to better elucidate contributors to bleeding risk to inform management."