Highlight
• Abelacimab significantly reduces major and clinically relevant nonmajor (CRNM) bleeding compared to rivaroxaban across a broad spectrum of kidney function in atrial fibrillation (AF) patients.
• Patients with impaired kidney function (creatinine clearance ≤50 mL/min) on rivaroxaban had higher bleeding rates despite dose adjustment, while abelacimab’s safety was consistent regardless of renal function.
• Absolute bleeding risk reduction with abelacimab was most pronounced in patients with moderate renal impairment.
• These findings suggest abelacimab offers a potentially safer anticoagulation option for AF patients with chronic kidney disease (CKD), pending further studies on stroke prevention efficacy.
Study Background and Disease Burden
Atrial fibrillation (AF) is a common cardiac arrhythmia associated with increased risk of stroke and systemic embolism, necessitating long-term anticoagulation. However, the presence of chronic kidney disease (CKD) in patients with AF complicates anticoagulation therapy. CKD is prevalent among AF populations and is strongly linked to elevated bleeding risks during anticoagulant treatment. Dose adjustments of direct oral anticoagulants (DOACs), such as rivaroxaban, are commonly employed based on kidney function to mitigate bleeding risks, but this strategy does not fully normalize the bleeding risk in patients with impaired renal function.
Factor XI (FXI) inhibition has emerged as a promising anticoagulation strategy due to its role in thrombosis with minimal impact on hemostasis, suggesting a potential to reduce bleeding complications. Abelacimab is a novel monoclonal antibody that inhibits FXI and is administered monthly. In the pivotal AZALEA-TIMI 71 randomized clinical trial, abelacimab demonstrated reduced bleeding compared with rivaroxaban in patients with AF. However, the safety profile of abelacimab across varying kidney functions, especially in those with CKD, required further elucidation.
Study Design
The AZALEA-TIMI 71 trial was a randomized, open-label clinical study designed to evaluate the safety of abelacimab versus rivaroxaban in patients with nonvalvular AF. A total of 1284 patients were randomized to receive either abelacimab at one of two doses (90 mg or 150 mg monthly) or rivaroxaban (adjusted daily dose based on kidney function). Patients were stratified by creatinine clearance (CrCl) at baseline, calculated using the Cockcroft-Gault formula. Individuals with severe renal impairment (CrCl <15 mL/min) or requiring dialysis were excluded.
Interventions included:
• Rivaroxaban 20 mg daily for patients with CrCl >50 mL/min
• Rivaroxaban 15 mg daily for patients with CrCl ≤50 mL/min (dose reduction)
• Abelacimab at fixed monthly dosing of either 90 mg or 150 mg regardless of kidney function
The primary safety endpoint was the composite of major bleeding or clinically relevant nonmajor (CRNM) bleeding events. Secondary analyses included evaluation of major bleeding alone and a broader composite of major, CRNM, and minor bleeding.
Key Findings
The median age of participants was 74 years with 44.5% female representation. Median CrCl was 71 mL/min, with 20.6% (n=264) having CrCl ≤50 mL/min. Results showed a significant impact of kidney function on bleeding risk in rivaroxaban-treated patients despite dose adjustment:
- Rivaroxaban patients with CrCl ≤50 mL/min had nearly doubled incidence of major or CRNM bleeding compared to those with CrCl >50 mL/min (13.6 vs 7.0 events per 100 person-years).
- Abelacimab demonstrated a consistent reduction in bleeding risk compared to rivaroxaban across kidney function strata, with hazard ratios (HR) of 0.26 (95% CI, 0.12–0.54) for CrCl ≤50 mL/min and 0.40 (95% CI, 0.26–0.62) for CrCl >50 mL/min (P for interaction = 0.33 indicating no significant difference in effect by kidney function).
- The absolute risk reduction for major or CRNM bleeding was greater in patients with impaired kidney function: 10.1 fewer events per 100 person-years for CrCl ≤50 mL/min versus 4.2 fewer per 100 person-years for CrCl >50 mL/min (P for interaction = .09).
- The reduction in bleeding risk with abelacimab was consistent when analyzed for major bleeding alone and a broader composite inclusive of minor bleeding.
- Both abelacimab dose groups (90 mg and 150 mg) showed similar safety advantages over rivaroxaban regardless of renal function.
Collectively, these results indicate that abelacimab may mitigate the increased bleeding risk posed by impaired renal function that persists with rivaroxaban even after dose reduction.
Expert Commentary
The management of anticoagulation in patients with AF and CKD remains a critical challenge, primarily due to the higher propensity of bleeding complications. Current anticoagulants including DOACs require renal dose adjustments, yet this approach does not entirely avert bleeding risk. The novel anticoagulant approach targeting FXI, as exemplified by abelacimab, offers a mechanistically distinct pathway that appears to preserve hemostasis while reducing thromboembolic risk.
The AZALEA-TIMI 71 prespecified analysis importantly highlights that abelacimab maintains a favorable safety profile across a spectrum of renal function, including moderate impairment, where traditional anticoagulants are more hazardous. These results align with emerging evidence suggesting that FXI inhibition may decouple effective thromboprophylaxis from bleeding risk, addressing a longstanding unmet need.
However, limitations include the exclusion of patients with severe renal impairment (CrCl <15 mL/min) and those on dialysis, which represents a high-risk subset in clinical practice. Moreover, the current study principally evaluates bleeding outcomes; thus, the efficacy of abelacimab in stroke prevention relative to standard anticoagulation in patients with varying kidney function remains to be fully established through larger phase 3 trials.
Conclusion
The AZALEA-TIMI 71 secondary analysis provides compelling evidence that abelacimab reduces bleeding risk compared to rivaroxaban in AF patients irrespective of kidney function. This safety advantage is especially pronounced among patients with moderate chronic kidney disease, a population that traditionally faces heightened bleeding risks under conventional anticoagulation regimens.
While these findings position abelacimab as a promising anticoagulant with a potentially improved safety profile for use in CKD patients with AF, further research is necessary to confirm its efficacy in stroke prevention and expand understanding in patients with advanced renal impairment. The future of anticoagulation might well hinge upon tailored strategies such as factor XI inhibition that effectively balance thrombosis prevention and bleeding risk in vulnerable populations.
References
Patel SM, Giugliano RP, Morrow DA, Goodrich EL, Murphy SA, Hug B, Parkar S, Chen SA, Goodman SG, Joung B, Kiss RG, Wojakowski W, Weitz JI, Bloomfield D, Sabatine MS, Ruff CT. Safety of Factor XI Inhibition With Abelacimab in Atrial Fibrillation by Kidney Function: A Prespecified Analysis of the AZALEA-TIMI 71 Randomized Clinical Trial. JAMA Cardiol. 2025 Sep 1:e253393. doi: 10.1001/jamacardio.2025.3393. Epub ahead of print. PMID: 40888686; PMCID: PMC12403020.
Steffel J, Collins R, Antz M, Cornu P, Desteghe L, Haeusler KG, Kirchhof P, Lip GYH, Weinberg I, Crijns H. 2021 European Heart Rhythm Association Practical Guide on the Use of Non-Vitamin K Antagonist Oral Anticoagulants in Patients with Atrial Fibrillation. Europace. 2021;23(10):1612-1676.
Weitz JI, Fredenburgh JC, Eikelboom JW. A Novel Target for Antithrombotic Therapy: Factor XI. Blood. 2017;129(17):2710-2717.
