Incidence and outcomes of major bleeding among first-time oral factor Xa inhibitor users: multinational observational cohort studies.

Background: Despite the favorable risk-benefit profile of factor (F)Xa inhibitors (FXai) vs vitamin K antagonists, major bleeding remains a concern. Objectives: This study sought to describe the incidence and mortality rates of major bleeding in FXai-treated patients using large national registries. Methods: This multinational, retrospective cohort study analyzed electronic health records and administrative claims data across Canada and 4 European countries. Adults initiated on FXai for atrial fibrillation, venous thromboembolism, nonmechanical cardiac valve replacement, and other indications were included. Major bleeding was defined as bleeding at critical sites or leading to hospitalization or fatality. Pooled incidence rates of major bleeding, case fatality rates, and associated all-cause mortality up to ≤3 years after the index bleeding event were calculated across countries. Results: This study included 358,143 new FXai users, of whom 23,418 experienced major bleeding. The pooled incidence rate of major bleeding was 11.0 per 100 person-years (95% CI, 6.1-15.9) at 3 months, 8.2 (95% CI, 4.5-11.8) at 1 year, and 6.7 (95% CI, 3.7-9.7) at 3 years, and the case fatality rate was 9.0%, 8.9%, and 9.0%, respectively. Gastrointestinal bleeds were the most common major bleed observed, but intracranial hemorrhage had the highest case fatality rate. In patients with major bleeding, all-cause mortality incidence was 57.5 per 100 person-years (95% CI, 29.1-85.8) at 3 months and 28.9 (95% CI, 17.6-40.3) at 1 year. Conclusion: Results of this large-scale study indicate that the incidence of major bleeding remains elevated during the first 3 years after initiating FXai treatment and that these bleeding events seemed to be associated with significant mortality.