Highlight
– Abelacimab, a novel factor XI inhibitor, significantly reduces major and clinically relevant nonmajor bleeding compared to rivaroxaban in atrial fibrillation (AF) patients.
– This bleeding risk reduction is consistent regardless of concurrent use of antiplatelet therapy (APT).
– Patients on concomitant APT experience greater absolute risk reductions with abelacimab.
– Factor XI inhibition offers a promising, safer anticoagulant option for AF patients requiring antiplatelet therapy.
Study Background and Disease Burden
Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia worldwide and a major risk factor for thromboembolic stroke. Oral anticoagulation with direct oral anticoagulants (DOACs), including rivaroxaban, has become standard to reduce stroke risk in AF. However, many patients with AF also require concurrent antiplatelet therapy (APT) for comorbid cardiovascular conditions such as coronary artery disease. Combining APT with anticoagulants increases bleeding risk substantially, complicating management.
Factor XI inhibition has emerged as a novel anticoagulant strategy that disrupts pathological thrombosis with potentially less impact on hemostasis. Abelacimab is a human monoclonal antibody targeting factor XI, showing promise in reducing bleeding complications. The AZALEA-TIMI 71 trial was conducted to assess the safety and tolerability of abelacimab versus rivaroxaban in AF patients, particularly examining the impact of concomitant APT on bleeding risk.
Study Design
The AZALEA-TIMI 71 trial is a randomized, open-label, phase 2 study conducted from March through December 2021. The study enrolled 1287 patients with nonvalvular AF, randomized to receive monthly subcutaneous injections of abelacimab at doses of 90 mg or 150 mg or oral rivaroxaban daily (20 mg or 15 mg depending on renal function). Stratification was based on planned concomitant use of APT at baseline.
The primary composite endpoint was the incidence of major or clinically relevant nonmajor bleeding. Secondary safety and efficacy outcomes were also evaluated. The analysis was prespecified to assess bleeding rates according to APT status and treatment arm.
Key Findings
Among 1287 participants (44% female; median age 74 years), 318 (24.7%) were receiving concomitant APT at baseline. The APT regimens included aspirin alone (15.5%), P2Y12 inhibitor alone (7.5%), and dual APT (1.6%).
In the rivaroxaban arm, major or clinically relevant nonmajor bleeding rates were higher with concomitant APT (10.6 per 100 patient-years) compared to those without APT (7.7 per 100 patient-years).
In the abelacimab groups, bleeding rates remained low irrespective of APT: with APT, 2.5 and 3.5 per 100 patient-years for the 90 mg and 150 mg doses, respectively; without APT, rates were 2.7 and 3.1 per 100 patient-years. Both doses of abelacimab significantly reduced bleeding compared to rivaroxaban in patients with APT (adjusted hazard ratios: 0.26 [90 mg] and 0.30 [150 mg]) and without APT (0.34 [90 mg] and 0.40 [150 mg]). The P values for interaction indicated no significant difference in treatment effect by APT status (0.56 and 0.60, respectively).
Absolute risk reductions were more pronounced in patients on concomitant APT: 8.1% and 7.1% reductions with 90 mg and 150 mg abelacimab, versus 5.0% and 4.6% in those without APT.
No unexpected safety signals were observed, and abelacimab was well tolerated. These results suggest abelacimab offers a potent anticoagulant effect with better bleeding safety compared to rivaroxaban, especially in patients requiring combination therapy.
Expert Commentary
Emerging anticoagulants targeting factor XI represent a paradigm shift in balancing thrombosis prevention and bleeding risk. The AZALEA-TIMI 71 prespecified analysis confirms the potential of abelacimab to safely manage AF patients at high bleeding risk due to concomitant APT. Importantly, the comparable efficacy across APT strata implies that factor XI inhibition may mitigate the additive hemorrhagic risks inherent to combined antithrombotic strategies.
While the study provides compelling evidence, the phase 2 design and relatively short follow-up necessitate larger, longer-term phase 3 trials to confirm thromboembolic outcomes, bleeding safety, and mortality impacts. In clinical practice, abelacimab might fill an unmet need for AF patients with coronary disease requiring dual or single APT, who are often challenging to anticoagulate safely.
Mechanistically, factor XI plays a critical role in sustaining pathologic thrombin generation without severely compromising hemostasis. Inhibiting this pathway aligns with the goal of more precisely modulating coagulation cascades to reduce bleeding complications.
Conclusion
The AZALEA-TIMI 71 trial prespecified analysis demonstrates that abelacimab, a factor XI inhibitor, significantly reduces the risk of bleeding compared with rivaroxaban in AF patients, regardless of concomitant antiplatelet use. Greater absolute bleeding risk reductions in patients on APT suggest abelacimab may provide a safer anticoagulant option for this high-risk population. These findings support further investigation of factor XI inhibitors in clinical practice to optimize antithrombotic management balancing efficacy and safety.
References
Al Said S, 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. Abelacimab Versus Rivaroxaban in Patients With Atrial Fibrillation on Antiplatelet Therapy: A Prespecified Analysis of the AZALEA-TIMI 71 Trial. Circulation. 2025 Aug 5;152(5):290-296. doi: 10.1161/CIRCULATIONAHA.125.074037. Epub 2025 Jun 23. PMID: 40546068.