Abelacimab Versus Rivaroxaban in Patients With Atrial Fibrillation on Antiplatelet Therapy: A Prespecified Analysis of the AZALEA-TIMI 71 Trial

BACKGROUND: Combining antiplatelet therapy (APT) with conventional anticoagulants increases the risk of bleeding. In the AZALEA-TIMI 71 trial (Safety and Tolerability of Abelacimab [MAA868] vs Rivaroxaban in Patients With Atrial Fibrillation), the novel factor XI inhibitor abelacimab significantly reduced the risk of bleeding compared with rivaroxaban in patients with atrial fibrillation. Whether the safety of combination antithrombotic therapy differs in the context of factor XI inhibition has not been well characterized. METHODS: This prespecified analysis of AZALEA-TIMI 71, which randomized patients between March and December of 2021 to 1 of 2 subcutaneous monthly abelacimab doses (90 or 150 mg) or oral rivaroxaban (20 mg daily, dose reduced to 15 mg in patients with creatinine clearance ≤50 mL/min), stratified patients by planned use of concomitant APT. The primary composite end point of major or clinically relevant nonmajor bleeding and other safety and efficacy outcomes were examined by concomitant APT and randomized treatment. RESULTS: Of 1287 patients (44% female; median age 74 years [interquartile range, 69–78]), 318 (24.7%) were on APT at baseline with planned continuation (15.5% aspirin only, 7.5% P2Y 12 inhibitor only, and 1.6% dual APT). In the rivaroxaban arm, the rate of major or clinically relevant nonmajor bleeding was 10.6 per 100 patient-years with concomitant APT versus 7.7 per 100 patient-years without. In the abelacimab arms, the rates were 2.5 and 3.5 per 100 patient-years for the 90-mg and 150-mg doses, respectively, with concomitant APT and 2.7 and 3.1 per 100 patient-years without. Each abelacimab dose significantly reduced major or clinically relevant nonmajor bleeding compared with rivaroxaban, both in those with concomitant APT (adjusted hazard ratio, 0.26 [95% CI, 0.10–0.70] and 0.30 [95% CI, 0.12–0.74] for 90 mg and 150 mg of abelacimab, respectively, versus rivaroxaban) and in those without concomitant APT (adjusted hazard ratio, 0.34 [95% CI, 0.19–0.60] and 0.40 [95% CI, 0.23–0.68] for 90 mg and 150 mg of abelacimab, respectively; P interactions =0.56 and 0.60, respectively). Patients with concomitant APT tended to derive greater absolute risk reductions with abelacimab (8.1 and 7.1 for 90 mg and 150 mg of abelacimab, respectively, versus rivaroxaban) than those without concomitant APT (5.0 and 4.6, respectively). CONCLUSIONS: Inhibition of factor XI with abelacimab consistently reduced bleeding compared with rivaroxaban regardless of concomitant APT use, with greater absolute reductions in bleeding in those requiring concomitant APT. These data suggest that factor XI inhibition may be a safe anticoagulant option in patients with atrial fibrillation requiring concomitant APT. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT04755283.