This article was originally published on May 21, 2025 on Brigham On A Mission
Gastrointestinal bleeding and other bleeding events are major complications of the direct-acting oral anticoagulants (DOACs) used for stroke prevention in patients with atrial fibrillation. Factor XI inhibitors are potentially safer than DOACs because emerging research suggests factor XI is essential for thrombosis but not essential for hemostasis in most cases.
One investigational drug in this class is abelacimab, a fully human monoclonal antibody that binds to factor XI and locks it in the inactive state. Abelacimab, which is administered subcutaneously, also inhibits activated factor XI.
A multinational, randomized, phase 2b trial reported in The New England Journal of Medicine showed that in patients with atrial fibrillation at moderate to high risk of stroke, abelacimab was associated with sustained marked reduction in factor XI levels and significantly fewer bleeding events compared with rivaroxaban.
The authors are Christian Ruff, MD, MPH, director of General Cardiology within the Division of Cardiovascular Medicine at Brigham and Women’s Hospital and senior investigator at the Thrombolysis in Myocardial Infarction (TIMI) Study Group, Marc S. Sabatine, MD, MPH, Lewis Dexter, MD, endowed chair in Cardiovascular Medicine and chair of the TIMI Study Group, and colleagues.
“It should be enormously satisfying to the cardiovascular field, patients, and providers that Factor XI inhibitors live up to their promise of superior safety,” says Dr. Ruff, principal investigator of AZALEA-TIMI 71.
Between March and December 2021, the 1,287 patients enrolled in AZALEA-TIMI 71 were randomly assigned to abelacimab 150 mg once monthly, abelacimab 90 mg once monthly, or rivaroxaban 20 mg once daily. The participants were at least 55 years old (median age 74), had a history of atrial fibrillation or atrial flutter, and had a CHA2DS2-VASc score ≥4 (or 3 with either planned concomitant use of antiplatelet medications or estimated creatinine clearance ≤50 mL per minute).
Abelacimab use led to sustained reductions in free factor XI levels of 97% or more. The independent data monitoring committee recommended early termination of the trial on September 14, 2023, because the benefit-to-risk ratio favored both abelacimab dosages relative to rivaroxaban, and hazard ratios for the primary endpoint were substantially lower than expected. Patients then had their final visits.
At trial completion, the median follow-up was 2.1 years, longer than in previous trials comparing the bleeding profiles of factor XI inhibitors and DOACs. The incidence of the primary outcome, the composite of major or clinically relevant nonmajor bleeding, was:
The two secondary outcomes analyzed were:
Rates of an exploratory outcome, major gastrointestinal bleeding, were 4.2% in the rivaroxaban group and 0.5% in the 150-mg and 90-mg abelacimab groups (89% lower than with rivaroxaban).
The investigators caution that the trial was not designed to allow definitive conclusions about efficacy. The incidence of stroke or systemic embolism was only about 1% per year), but ischemic strokes were numerically more frequent in both abelacimab groups than in the rivaroxaban group. The composite event of stroke or death from any cause was similar in all three treatment groups.
“The AZALEA-TIMI 71 Study validated that Factor XI inhibitors have an incredibly safe bleeding profile in patients with atrial fibrillation, which is a tremendous potential advance for our patients,” Dr. Ruff says. “Now we can shift our attention as we await the results of the phase 3 trials.” The ongoing phase 3 LILAC–TIMI 76 trial is estimated to be complete in late 2026.