CLINICAL QUESTION

In patients with atrial fibrillation (AF) and a moderate to high risk of stroke, how do the benefits and harms of abelacimab compare with those of rivaroxaban (Xarelto)?

BOTTOM LINE

The researchers found that the new monoclonal antibody abelacimab has a lower risk of bleeding than rivaroxaban (the direct oral anticoagulant [DOAC] with the highest bleeding risk). The study was stopped prematurely, which is concerning because of an emerging trend of higher rates of stroke in the abelacimab groups. Although abelacimab received fast-track designation from the US Food and Drug Administration in 2022, it still awaits full approval. (Level of Evidence = 1b−)

SYNOPSIS

Abelacimab is a monoclonal antibody anticoagulant that binds and inactivates Factor XI. The researchers identified 1,287 adults 55 years and older with AF and a moderate or higher risk of stroke based on a CHA₂DS₂-VASc (congestive heart failure, hypertension, age 75 years and older [doubled], diabetes, stroke [doubled], vascular disease, age 65 to 74 years, sex [female]) score of 4 or higher (3 or higher if taking an antiplatelet drug or if there was impaired kidney function). The patients were randomized to receive a subcutaneous injection of abelacimab, 90 mg or 150 mg once monthly or oral rivaroxaban, 20 mg once daily (15 mg if kidney function was impaired). At baseline, groups were similar with a mean age of 74 years, 47% had persistent or permanent AF, and a median CHA₂DS₂-VASc score of 5. The primary outcome was major bleeding or clinically relevant nonmajor bleeding events. The study was stopped prematurely due to a significant reduction in bleeding events with abelacimab at 2.1 years. The primary end point occurred significantly less often in the abelacimab groups: 2.6 per 100 person-years for 90 mg, 3.2 per 100 person-years for 150 mg, and 8.4 per 100 person-years for rivaroxaban. The numbers needed to treat to prevent one bleed were 17 for abelacimab, 90 mg and 19 for abelacimab, 150 mg. The hazard ratios were 0.31 (95% CI, 0.19–0.51) for the 90-mg dose and 0.38 (95% CI, 0.24–0.60) for the 150-mg dose. There were nonsignificant trends in the wrong direction for ischemic stroke, with 5 in the rivaroxaban group and 10 in each of the abelacimab groups (hazard ratio = 2.1; 95% CI, 0.7–6.0). The study was open label and used rivaroxaban as the comparator, but it has a higher rate of major bleeding than other DOACs, such as apixaban (Eliquis). Stopping the trial prematurely once the difference in bleeding events was statistically significant, but before the difference in ischemic stroke could potentially become significant, is another important bias.