The AZALEA-TIMI 71 trial, published in the New England Journal of Medicine, reveals that abelacimab, an investigational Factor XI inhibitor, significantly reduces bleeding events compared to rivaroxaban (Xarelto) in patients with atrial fibrillation (AFib) at moderate-to-high risk for stroke. The study's findings suggest abelacimab could offer a safer alternative to current anticoagulants, addressing a critical unmet need in cardiovascular care.
The multinational, Phase IIb trial enrolled 1,287 patients with AFib across 95 centers in seven countries. Participants were randomized to receive either subcutaneous abelacimab (150 mg or 90 mg monthly) or oral rivaroxaban (20 mg daily). The primary endpoint was major or clinically relevant non-major bleeding, with secondary endpoints including major bleeding and any bleeding event.
Significant Reduction in Bleeding Events
The trial was stopped early by the Data Monitoring Committee due to the overwhelmingly positive results. Abelacimab demonstrated a significant decrease in bleeding events compared to rivaroxaban. Specifically, major or clinically relevant non-major bleeding events occurred at a rate of 3.2 events per 100 person-years in the 150 mg abelacimab group and 2.6 events per 100 person-years in the 90 mg group, compared to 8.4 events per 100 person-years in the rivaroxaban group (hazard ratio for 150-mg abelacimab vs. rivaroxaban, 0.38 [95% CI, 0.24 to 0.60]; hazard ratio for 90-mg abelacimab vs. rivaroxaban, 0.31 [95% CI, 0.19 to 0.51]; P<0.001 for both comparisons).
Impact on Gastrointestinal Bleeding
Notably, the incidence of major gastrointestinal bleeding was markedly lower with abelacimab. There were only two events in each abelacimab group compared to 18 events in the rivaroxaban group. According to the study authors, this is particularly important because the gastrointestinal tract is the most common site of bleeding with DOACs, and DOACs do not have a better risk profile than warfarin for this type of bleeding.
Safety and Tolerability
In terms of safety, the incidence and severity of adverse events were similar across all three cohorts. Injection site reactions were reported in 2.8% of patients in the 150 mg dose cohort and 1.6% in the 90 mg dose cohort.
Ongoing Phase III Trial
The efficacy of abelacimab in preventing ischemic stroke and systemic embolization among high-risk patients with atrial fibrillation who are unable to take currently available anticoagulation medications is currently under investigation in the Phase III LILAC–TIMI 76 trial (NCT05712200).
Expert Commentary
"It should be enormously satisfying to the cardiovascular field, patients and providers that Factor XI inhibitors live up to their promise of superior safety," said Christian Ruff, MD, MPH, director of General Cardiology within the Cardiovascular Division at Brigham and Women’s Hospital, senior investigator in the TIMI Study Group and principal investigator of the AZALEA-TIMI 71 Study. He added, "Atrial fibrillation is a common medical condition, and bleeding with currently available anticoagulants resulting in significant undertreatment is still one of the greatest shortcomings in cardiovascular disease."
Dan Bloomfield, MD, chief medical officer of Anthos Therapeutics, stated, "Building on the overwhelmingly positive data from the AZALEA study, data on the safety of abelacimab in patients undergoing surgical procedures as well as data in patients taking antiplatelet therapy further reinforce the fundamental premise of the promise of Factor XI inhibition – the potential to prevent thrombotic events without affecting normal hemostasis."
