Safety of factor XI inhibitors compared to factor X inhibitors in atrial fibrillation: a systematic review and meta-analysis

Atrial fibrillation (AF) increases the risk of ischemic stroke (IS) and systemic embolism, necessitating thromboprophylaxis with direct oral anticoagulants (DOAC), which increase bleeding. Drugs that inhibit factor XI (FXI) have been developed to provide thromboprophylaxis with lower bleeding risk. We performed a systematic review and meta-analysis of randomised controlled trials comparing FXI inhibitors versus DOAC in patients with AF, reporting primary outcomes of International Society of Thrombosis and Haemostasis (ISTH) major bleeding or clinically relevant non-major bleeding (CRNMB), and exploratory outcomes of ischaemic stroke (IS), intracranial hemorrhage (ICH) and death. Three trials were identified. The PACIFIC-AF (Phase 2) and OCEANIC-AF (Phase 3) trials compared asundexian, an oral, small-molecule FXIa inhibitor, with apixaban. AZALEA-TIMI 71 (Phase 2) compared abelacimab, a subcutaneous monoclonal antibody against FXI/FXIa, with rivaroxaban. FXI inhibitors reduced the composite of major bleeding or CRNMB (pooled-OR 0.39, 95%CI 0.30–0.50, p = 0.0005), major bleeding (OR 0.30, 95%CI 0.22–0.41, p = 0.004) and CRNMB (pooled-OR 0.44, 95% CI 0.36–0.55, p = 0.0004) compared to DOAC. Effects were consistent across sex, clinical risk factors and concomitant antiplatelet therapy. Exploratory analyses showed FXI inhibitor use was associated with greater risk of IS (OR 3.37, 95%CI 2.18–5.19, p = 0.001), similar rate of ICH and lower all-cause mortality (OR 0.82, 95%CI 0.71–0.94, p = 0.02) than DOAC. Compared to DOAC, FXI inhibitors significantly reduced major bleeding or CRNMB. Exploratory analyses indicate similar risk of ICH, but possible increased IS risk with FXI inhibitors compared to DOAC. Results from ongoing trials will help determine the relative usefulness of FXI inhibitors in patients with AF.