Renal function and factor XI inhibition in atrial fibrillation: a pre-specified analysis of AZALEA-TIMI 71

Patients with atrial fibrillation (AF) and renal impairment represent a particularly challenging patient population for anticoagulation given their increased bleeding risk. Abelacimab is a novel factor XI inhibitor that significantly reduced major/clinically relevant non-major (CRNM) bleeding relative to rivaroxaban in patients with AF in AZALEA-TIMI 71. Abelacimab is a monoclonal antibody which has no renal elimination, whereas approximately one-third of rivaroxaban is directly renally excreted.

We assessed the safety of abelacimab vs. rivaroxaban with respect to major/CRNM bleeding in patients with and without chronic kidney disease (CKD) enrolled in AZALEA-TIMI 71.

AZALEA-TIMI 71 enrolled patients with AF and randomized them in a 1:1:1 manner to one of two abelacimab doses (150 or 90 mg subcutaneously monthly) or to oral rivaroxaban. The abelacimab dosing arms were pooled for this analysis. Randomization was stratified by CrCl ≤50 mL/min, with rivaroxaban 15 mg administered to those with CrCl ≤50 mL/min and rivaroxaban 20 mg administered to those with CrCl >50 mL/min, without any dose adjustment for abelacimab.

Among 1,277 patients, 263 (21%) and 1,014 (79%) had a CrCl ≤50 and >50 mL/min at randomization respectively. Despite dose-reduction of rivaroxaban in those with CrCl ≤50 mL/min, the rate of major/CRNM bleeding was ~2-fold higher compared to those with CrCl >50 mL/min receiving full-dose rivaroxaban (13.6 vs. 7.0 per 100 patient-years [PY]) (Figure A). Abelacimab consistently reduced major/CRNM bleeding irrespective of CrCl and dose-reduction of rivaroxaban (HR 0.26 [0.12-0.54] and 0.40 [0.26-0.62] for CrCl ≤50 and >50 mL/min respectively; p-interaction = 0.33), with tendency toward greater absolute benefit in those with CrCl ≤50 mL/min (ARR 10.1 vs. 4.2 per 100 PY). These findings were consistent when examining only major bleeding (Figure B).

Patients with renal impairment are at higher risk of bleeding despite dose reduction of rivaroxaban. Abelacimab significantly reduces bleeding relative to rivaroxaban irrespective of renal function or rivaroxaban dose-reduction, with potential for greater absolute safety benefit in those with impaired renal function.Figure AFigure B