Promising results show that abelacimab could revolutionize anticoagulation therapy by slashing bleeding risks without compromising stroke protection for patients with atrial fibrillation.
Study: Abelacimab versus Rivaroxaban in Patients with Atrial Fibrillation. Image Credit: Lightspring / Shutterstock
A recent study published in the New England Journal of Medicine evaluated abelacimab, a monoclonal antibody targeting factor XI—the protein involved in blood clot formation and hemostasis—as a safer alternative to standard anticoagulants such as rivaroxaban for patients with atrial fibrillation at moderate-to-high risk of stroke. The researchers investigated the ability of abelacimab to reduce bleeding events while maintaining effective stroke prevention.
Background
Atrial fibrillation is the most common sustained heart rhythm disorder, and it significantly increases the risk of stroke. Current treatments rely on anticoagulants such as direct oral anticoagulants (DOACs) and vitamin K antagonists, which lower stroke risk but are associated with bleeding complications, especially in the gastrointestinal tract.
Although DOACs are safer than traditional therapies in preventing intracranial bleeding, challenges such as undertreatment continue to occur due to concerns about bleeding risks. Factor XI, a key player in clot formation, has emerged as a promising therapeutic target because its inhibition could prevent clots without increasing bleeding risks.
People with hereditary factor XI deficiencies experience fewer clots without notable bleeding, making this pathway an attractive focus for safer anticoagulants. Preliminary studies using factor XI inhibitors such as abelacimab have shown promise. However, data from large-scale, long-term trials comparing them with existing therapies are limited, highlighting the need for further investigation into their safety and efficacy.
About the Study
The trial reported in the present study was a multinational, phase 2b, partially blinded, randomized study enrolling 1,287 patients with atrial fibrillation and moderate-to-high stroke risk. The participants were randomly assigned to one of three groups — one group each received subcutaneous injections of abelacimab at 90 mg or 150 mg once monthly, while the third group was prescribed oral rivaroxaban at 20 mg daily (or 15 mg for those with reduced kidney function).
The study population included adults aged 55 and older with a history of atrial fibrillation and specific stroke risk scores. Notably, 92% of participants had previously received anticoagulants (mostly DOACs), reflecting a population familiar with standard therapies. The screening lasted up to four weeks, and the patients were then followed monthly for safety assessments and laboratory testing. The primary endpoint was the occurrence of major or clinically significant nonmajor bleeding, defined by international guidelines.
The researchers also considered secondary endpoints such as major bleeding, any bleeding, gastrointestinal bleeding, and net clinical outcomes combining bleeding, stroke, embolism, and mortality.
The study monitored patients for a median of 2.1 years (interquartile range, 2.0–2.3). During that time, the independent data monitoring committee recommended early trial termination due to significant reductions in bleeding events with abelacimab compared to rivaroxaban.
Furthermore, safety evaluations in the study included adverse events, injection-site reactions, and antibody development, which were assessed by a blinded adjudication committee. Most participants were White, limiting generalizability to other racial groups.
Results
The results showed that abelacimab significantly reduced bleeding risks compared to rivaroxaban in patients with atrial fibrillation with moderate-to-high risk of stroke. Monthly administration of abelacimab (150 mg and 90 mg) was found to lead to a 62% and 69% reduction, respectively, in major or clinically significant bleeding events compared to rivaroxaban.
The incidence rates for bleeding events were 3.22 and 2.64 per 100 person-years for the 150 mg and 90 mg doses of abelacimab, respectively, versus 8.38 for rivaroxaban. Notably, gastrointestinal bleeding, which is a common complication with DOACs, was significantly lower with abelacimab. Moreover, total bleeding events, including minor bleeds, were also lower with abelacimab.
However, ischemic stroke rates were numerically higher but not statistically significant with abelacimab than with rivaroxaban (hazard ratios included confidence intervals crossing 1.0), though the overall incidence was low. Hemorrhagic strokes were rare, with similar rates across all groups. Furthermore, the mortality rates were comparable between treatments, suggesting no significant safety concerns beyond bleeding risks.
The molecular and biochemical effects of abelacimab showed sustained reductions in free factor XI levels, with the 150 mg dose achieving a 99% median reduction over the study period. Additionally, the safety profiles across groups were generally comparable, with no differences in serious adverse events or discontinuations due to drug reactions. Injection-site reactions were also infrequent and mild, and no patients developed antibodies against abelacimab.
Conclusions
Overall, the findings suggested that abelacimab was a safer anticoagulant alternative for reducing bleeding risks while maintaining acceptable stroke prevention. The trial also demonstrated that abelacimab significantly lowered bleeding risks compared to rivaroxaban.
The findings supported the potential of factor XI inhibitors to improve the safety profile of anticoagulant therapy. However, the researchers stated that the numerically higher ischemic stroke rates (though not statistically significant) with abelacimab warrant further investigation in more extensive phase 3 studies to establish its long-term efficacy and safety. They also emphasized the need for trials in more racially diverse populations, given the study’s demographic limitations.
The paper further highlighted distinctions between abelacimab and other factor XI inhibitors like asundexian, noting abelacimab’s dual mechanism of action and prior proof-of-concept data in thromboprophylaxis.
Journal reference:
- Ruff, C. T., Patel, S. M., Giugliano, R. P., Morrow, D. A., Hug, B., Kuder, J. F., Goodrich, E. L., Chen, S.-A., Goodman, S. G., Joung, B., Kiss, R. G., Spinar, J., Wojciech Wojakowski, Weitz, J. I., Murphy, S. A., Wiviott, S. D., Sanobar Parkar, Bloomfield, D., & Sabatine, M. S. (2025). Abelacimab versus rivaroxaban in patients with atrial fibrillation. New England Journal of Medicine, 392, 4. DOI: 10.1056/NEJMoa2406674 https://www.nejm.org/doi/full/10.1056/NEJMoa2406674