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Safety of Factor XI Inhibition With Abelacimab in Atrial Fibrillation by Kidney Function: A Prespecified Analysis of
Siddharth M Patel1, Robert P Giugliano1, David A Morrow1
1TIMI Study Group, Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts.
Insights
Abelacimab, a novel factor XI inhibitor, significantly reduced bleeding events in atrial fibrillation patients with chronic kidney disease compared to rivaroxaban. This suggests abelacimab offers a safer anticoagulation option for patients with impaired kidney function.
Area of Science:
- Cardiology
- Nephrology
- Pharmacology
Background:
- Chronic kidney disease (CKD) is prevalent in atrial fibrillation (AF) patients.
- CKD increases bleeding risk with anticoagulation therapy.
- Factor XI inhibitors represent a novel therapeutic approach for anticoagulation.
Purpose of the Study:
- To evaluate the safety of abelacimab compared to rivaroxaban in AF patients across varying degrees of kidney function.
- To assess bleeding risk associated with abelacimab and rivaroxaban in patients stratified by creatinine clearance (CrCl).
Main Methods:
- Secondary analysis of the AZALEA-TIMI 71 randomized clinical trial.
- Included 1284 patients with AF, randomized to abelacimab or rivaroxaban.
- Patients were stratified by CrCl (≤50 mL/min vs. >50 mL/min); those with CrCl <15 mL/min or on dialysis were excluded.
Main Results:
- Abelacimab reduced major or clinically relevant nonmajor (CRNM) bleeding compared to rivaroxaban, irrespective of kidney function.
- Patients on rivaroxaban with CrCl ≤50 mL/min had higher bleeding rates than those with CrCl >50 mL/min, despite dose reduction.
- Abelacimab demonstrated consistent risk reduction in bleeding across all CrCl strata.
Conclusions:
- Abelacimab shows a favorable safety profile regarding bleeding risk in AF patients, regardless of kidney function.
- The findings suggest abelacimab may be a safer anticoagulation choice for patients with CKD.
- Further research is needed to confirm abelacimab's efficacy for stroke prevention in AF.
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:
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.
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