Patients with atrial fibrillation (AF) face an increased risk of stroke, yet many remain undertreated because of the bleeding risks associated with direct oral anticoagulants (DOACs), the current standard of care. However, results from the phase IIb, randomized AZALEA-TIMI 71 trial, published in the New England Journal of Medicine, suggest that abelacimab — a factor XI inhibitor — may offer a safer alternative.
The study demonstrated that abelacimab significantly reduced major and clinically relevant non-major (CRNM) bleeding events compared with rivaroxaban, a widely used DOAC, signaling a potential shift in anticoagulation therapy for patients with AF.
“We’ve anticoagulated patients for over half a century, but many patients either discontinue them or never start due to bleeding concerns. We need to do better,” said Christian T. Ruff, MD, MPH, principal investigator of the AZALEA-TIMI 71 trial and associate professor of medicine at Harvard Medical School in Massachusetts.
The AZALEA-TIMI 71 trial has the longest follow-up to date evaluating a factor XI inhibitor against a DOAC in patients with AF. The trial enrolled 1,280 patients at 95 centers across seven countries, all of whom had AF and moderate to high stroke risk. Participants were randomized to receive either abelacimab (150 mg or 90 mg subcutaneously, once monthly) or rivaroxaban (20 mg orally, once daily), with a median follow-up of 2.1 years. The primary endpoint was rate of major or CRNM bleeding, and key exploratory endpoints included gastrointestinal (GI) bleeding and stroke or systemic embolism.
The trial was terminated early on the recommendation of an independent data monitoring committee because of a greater-than-expected reduction in bleeding events.
At three months, abelacimab produced sustained and significant reduction in free factor XI levels in both the 150 mg and 90 mg groups (median 99% and 97% reduction, respectively) compared with baseline, which, evidence suggests, may be required to achieve maximum efficacy in preventing thrombosis.
Overall, both doses of abelacimab significantly reduced major or CRNM bleeding events. Measured against rivaroxaban’s incidence rate of 8.4 events per 100 person-years, abelacimab 150 mg showed an incidence of 3.2 events per 100 person-years (hazard ratio [HR] = 0.38, 95% CI 0.24-0.60; p<0.001), while abelacimab 90 mg had an incidence of 2.6 events per 100 person-years (HR=0.31, 95% CI 0.19-0.51; p<0.001). In particular, abelacimab essentially eliminated GI bleeding; two patients in each abelacimab group experienced GI bleeding (HR=0.11 for both the 90 mg and 150 mg group, 95% CI 0.03-0.49 and 95% CI 0.03-0.48, respectively), compared with 18 patients in the rivaroxaban group.
“GI bleeding is the most common type of major bleeding in patients with AF who are on DOACs and one type of bleeding in which DOACs do not have an advantage over warfarin. In addition, the remarkably low risk of bleeding with abelacimab suggests that local exposure of the GI tract to DOACs may contribute to bleeding risk,” Dr. Ruff said.
The trial was not designed or powered to determine the relative efficacy of abelacimab compared with rivaroxaban. While the incidence of stroke or systemic embolism were low, they were numerically greater than rivaroxaban in both 150 mg and 90 mg abelacimab groups (0.83 vs. 1.21 and 1.36 events per 100 person-years, respectively). Ongoing phase III trials are required to determine the efficacy of abelacimab and other factor XI inhibitors to provide stroke protection comparable to DOACs while significantly reducing bleeding risk.
A limitation was the trial’s comparison of abelacimab to only rivaroxaban, restricting generalizability of results to other anticoagulants.
“We finally have a class of agents, particularly abelacimab, that has delivered on the ability to provide incredibly safe anticoagulation. This level of safety potentially allows us to extend anticoagulation to our most vulnerable patients — those at high bleeding risk or with comorbidities — who are often reluctant or unable to take standard anticoagulants. If these agents prove effective, this could truly change how we treat AF going forward,” Dr. Ruff said. “Stay tuned.”
Any conflicts of interest declared by the authors can be found in the original article.
Reference
Ruff C, Patel S, Sabatine M, et al. Abelacimab versus rivaroxaban in patients with atrial fibrillation. N Engl J Med. 2025;392(4):361-371.
