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Phase 2b RCT: Abelacimab Significantly Reduces Bleeding Events Compared with Rivaroxaban in Patients with Atrial Fibrillation

27 Jan, 2025 | 11:00h | UTC

Background: Atrial fibrillation (AF) elevates stroke risk roughly fivefold, necessitating anticoagulation therapy to reduce embolic events. Direct oral anticoagulants (DOACs) have replaced vitamin K antagonists as the preferred agents, given their comparable efficacy and lower risk of intracranial hemorrhage. However, significant bleeding—especially gastrointestinal bleeding—still occurs with DOACs, prompting ongoing efforts to develop safer anticoagulants. Abelacimab, a fully human monoclonal antibody targeting factor XI (and its active form, XIa), is hypothesized to “uncouple” thrombosis from hemostasis, potentially lowering bleeding risk. Early data in knee arthroplasty prevention suggested reduced venous thromboembolism (VTE) without increased bleeding. This trial (AZALEA–TIMI 71) aimed to compare the bleeding rates of monthly subcutaneous abelacimab with once-daily rivaroxaban in patients with AF and moderate-to-high stroke risk.

Objective: To evaluate whether subcutaneous abelacimab at two doses (150 mg or 90 mg monthly) leads to fewer major or clinically relevant nonmajor bleeding events than rivaroxaban (20 mg or 15 mg daily) in patients with AF.

Methods: In this phase 2b, parallel-group, partially blind, randomized trial, 1287 adults with AF (CHA2_2DS2_2-VASc ≥3–4 and moderate/high stroke risk) were assigned 1:1:1 to abelacimab 150 mg, abelacimab 90 mg, or open-label rivaroxaban. Treatment continued for a median of 2.1 years. The primary endpoint was major or clinically relevant nonmajor bleeding, adjudicated by a blinded events committee. Levels of free factor XI were measured to gauge abelacimab’s pharmacodynamics. The trial was halted early based on a recommendation from the independent data monitoring committee due to unexpectedly large reductions in bleeding with abelacimab.

Results: Median age was 74 years, and 44% of participants were female. In the final analysis of the complete dataset, major or clinically relevant nonmajor bleeding occurred at rates of 3.2 and 2.6 events per 100 person-years for abelacimab 150 mg and 90 mg, respectively, versus 8.4 per 100 person-years for rivaroxaban. Corresponding hazard ratios were 0.38 (95% CI, 0.24–0.60) for the 150-mg dose and 0.31 (95% CI, 0.19–0.51) for the 90-mg dose (P<0.001 for both comparisons). The incidence of major gastrointestinal bleeding was notably lower with abelacimab (0.5% in both arms) compared with rivaroxaban (4.2%). Although not powered for stroke prevention, ischemic stroke rates were numerically higher with abelacimab, underscoring the need for larger efficacy trials.

Conclusions: Monthly abelacimab led to substantial and sustained reduction of free factor XI and demonstrated significantly lower bleeding rates than rivaroxaban in patients with AF. While these findings suggest a potentially safer profile for abelacimab, definitive conclusions about stroke prevention require phase 3 studies.

Implications for Practice: Should abelacimab maintain efficacy in preventing thromboembolism in forthcoming trials, it may offer an alternative to existing DOACs, particularly for patients at elevated bleeding risk (e.g., gastrointestinal). However, clinicians must consider real-world factors such as possible high drug cost, insurance coverage, and the logistics of monthly subcutaneous injections. Abelacimab is investigational and not yet approved; its role will depend on phase 3 efficacy and cost-effectiveness outcomes.

Study Strengths and Limitations: Strengths include randomized design, relatively long follow-up (median 2.1 years), and direct comparison to an established DOAC. The major limitation is that the trial was not sufficiently powered to evaluate stroke or systemic embolism. Moreover, the open-label design between abelacimab and rivaroxaban could introduce bias, partly mitigated by blinded dose assignments for abelacimab and blinded endpoint adjudication. The predominantly White population may limit generalizability.

Future Research: Ongoing phase 3 studies (e.g., LILAC–TIMI 76) will clarify abelacimab’s efficacy and safety in larger cohorts, particularly regarding stroke prevention. Comparative cost analyses, real-world adherence, and exploration of subcutaneous administration logistics will be crucial in determining abelacimab’s long-term clinical value. Additional investigations into factor XIa inhibitors (e.g., small molecules, antisense oligonucleotides) may further expand this therapeutic class.

Reference:

  1. Ruff CT, Patel SM, Giugliano RP, Morrow DA, Hug B, Kuder JF, et al. “Abelacimab versus Rivaroxaban in Patients with Atrial Fibrillation.” New England Journal of Medicine. 2025;392:361–371. DOI: https://doi.org/10.1056/NEJMoa2406674
  2. Angiolillo DJ, Capodanno D. “Uncoupling Thrombosis and Hemostasis by Inhibiting Factor XI.” New England Journal of Medicine. 2025;392:400–403. DOI: https://doi.org/10.1056/NEJMe2414209
  3. Mandrola JM. “Factor XI Inhibitors May Not Be Dead.” This Week in Cardiology Podcast. January 24, 2025. https://www.medscape.com/viewarticle/1002184#vp_3

 


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