Regardless of patients’ kidney function, abelacimab (Anthos Therapeutics) had consistently reduced the risk of bleeding compared with rivaroxaban (Xarelto; Bayer HealthCare; Johnson & Johnson), wrote investigators of the AZALEA-TIMI 71 clinical trial (NCT04755283). The findings, which were published in JAMA Cardiology, suggested that abelacimab might offer a notably favorable safety profile, especially among those with chronic kidney disease (CKD), but larger studies are needed.1,2
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About the Trial
Trial Name: Safety and Tolerability of Abelacimab (MAA868) vs. Rivaroxaban in Patients With Atrial Fibrillation (AZALEA-TIMI 71)
ClinicalTrials.gov ID: NCT04755283
Sponsor: Anthos Therapeutics, Inc.
Completion Date (Estimated): December 29, 2028
CKD is a common disease present in patients with atrial fibrillation (AF) and is often associated with higher rates of bleeding with anticoagulation, explained the authors. Although direct oral anticoagulants (DOACs) are safer than vitamin K antagonists (VKAs) regarding bleeding across a range of kidney function, bleeding risk with DOACs in those with impaired kidney function remains a considerable risk.1
The authors explain that factor XI (FXI) inhibitors are an experimental class of anticoagulants that cause less bleeding than DOACs. Abelacimab, a novel FXI inhibitor, is a monoclonal antibody without renal elimination, whereas about one-third of rivaroxaban is directly renally excreted. In the multicenter, randomized, active-controlled phase 2b AZALEA-TIMI 71 trial, the investigators evaluated the safety and tolerability of 2 blinded doses of abelacimab compared with open-label rivaroxaban in patients with AF who had a range of kidney function.1,2
The trial enrolled 1284 patients aged 55 years and older (median age: 74 years) with AF and a CHA₂DS₂VASc score of 4 or higher, or 3 or higher for those with planned concomitant antiplatelet use or creatinine clearance (CrCl) of 50 mL/min or less, who were randomly assigned to receive either 150 mg or 90 mg of abelacimab administered subcutaneously monthly or to rivaroxaban daily. Patients with a CrCl less than 15 mL/min or receiving dialysis were not eligible for enrollment.1,2
The primary end point for this analysis was International Society on Thrombosis and Haemostasis (ISTH) major or clinically relevant or nonmajor (CRNM) bleeding. Other outcomes for this analysis included ISTH major bleeding alone and a broader bleeding composite of ISTH major, CRNM bleeding, or minor bleeding. Further, exploratory efficacy outcomes—including stroke or systemic embolism and a net clinical outcome composite of ischemic stroke, systemic embolism, major or CRNM bleeding, or death—were also evaluated. Outcomes were prospectively captured during trial follow-up and adjudicated by an independent clinical events committee who were blinded to treatment assignment.1,2
The findings demonstrated that, in the rivaroxaban group, patients with a CrCl of 50 mL/min or less experienced higher rates of major or CRNM bleeding compared with those with a CrCl greater than 50 mL/min despite dose reduction (incidence rates: 13.6 vs 7.0/100 person-years). Additionally, abelacimab reduced major or CRNM bleeding compared with rivaroxaban regardless 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 about 10.1 and 4.2 per 100 person-years in those with CrCl of 50 mL/min or less and greater than 50 mL/min, respectively (P value for interaction = .09).1
This risk reduction was consistent for major bleeding alone and for a broader composite inclusive of major, CRNM, and minor bleeding, wrote the study authors. Notably, results were similar when comparing the individual abelacimab doses to rivaroxaban.1
“[Limitations include] AZALEA-TIMI 71[’s design] to assess the bleeding profile of abelacimab relative to rivaroxaban; larger studies are necessary to examine the efficacy of abelacimab for stroke prevention. Each of the 4 approved DOACs for AF have variable renal elimination and may differ in their bleeding profiles; thus, our results may not be generalizable to other DOACs,” wrote the study authors. “In this secondary analysis of the AZALEA-TIMI 71 randomized clinical trial, abelacimab consistently reduced the risk of bleeding compared with rivaroxaban across a range of kidney function and irrespective of rivaroxaban dose reduction among patients with AF; however, further data are necessary to evaluate the efficacy of abelacimab for stroke prevention in AF.”1
