Safety of Factor XI Inhibition With Abelacimab in Atrial Fibrillation by Kidney Function: A Prespecified Analysis of the AZALEA-TIMI 71 Randomized Clinical Trial

Abstract

Importance: Chronic kidney disease is common in patients with atrial fibrillation (AF) and is associated with higher rates of bleeding with anticoagulation. In the AZALEA-TIMI 71 randomized clinical trial, abelacimab, a novel factor XI inhibitor, reduced rates of major or clinically relevant nonmajor (CRNM) bleeding compared with rivaroxaban in patients with AF. Objective: To examine the safety of abelacimab vs rivaroxaban across a range of kidney function. Design, setting, and participants: The AZALEA-TIMI 71 study randomized patients with AF to 1 of 2 abelacimab doses (150 mg or 90 mg monthly) or to rivaroxaban, with stratification by creatinine clearance (CrCl). Patients with CrCl less than 15 mL/min or receiving dialysis were excluded. This secondary analysis of AZALEA-TIMI 71 examines outcomes by randomized treatment and CrCl at randomization. Intervention: Patients randomized to rivaroxaban with a CrCl greater than 50 mL/min received rivaroxaban, 20 mg, daily, and those with a CrCl of 50 mL/min or less received rivaroxaban, 15 mg, daily. Patients randomized to abelacimab received the assigned dose irrespective of CrCl. Main outcomes and measure: The primary outcome was major bleeding or CRNM bleeding. Results: Among 1284 patients, median (IQR) age was 74 (69-78) years and 572 patients (44.5%) were female. Median (IQR) CrCl was 71 (54-90) mL/min, with 264 patients (20.6%) having a CrCl of 50 mL/min or less. In the rivaroxaban group, patients with CrCl of 50 mL/min or less experienced higher rates of major or CRNM bleeding compared with those with CrCl greater than 50 mL/min despite dose reduction (incidence rates, 13.6 vs 7.0 per 100 person-years). Abelacimab reduced major or CRNM bleeding vs rivaroxaban irrespective of CrCl (CrCl <= 50 mL/min: hazard ratio [HR], 0.26; 95% CI, 0.12-0.54; >50 mL/min: HR, 0.40; 95% CI, 0.26-0.62; P value for interaction = .33), with absolute risk reductions of 10.1 vs 4.2 per 100 person-years in those with CrCl of 50 mL/min or less vs greater than 50 mL/min, respectively (P value for interaction = .09). This risk reduction was consistent for major bleeding alone and for a broader composite inclusive of major, CRNM, and minor bleeding. Results were similar when comparing the individual abelacimab doses to rivaroxaban. Conclusions and relevance:<bold> </bold>In this secondary analysis of the AZALEA-TIMI 71 randomized clinical trial, abelacimab consistently reduced the risk of bleeding relative to rivaroxaban irrespective of kidney function. These findings suggest that abelacimab may offer a particularly favorable safety profile among those with chronic kidney disease; however, larger studies are necessary to characterize the efficacy of abelacimab for stroke prevention in AF.