IMPORTANCE: Older age is a strong risk factor for bleeding with currently available anticoagulants. Factor XI (FXI) inhibition may offer a safer anticoagulant strategy in this population.
OBJECTIVE: To evaluate the safety of the novel FXI inhibitor abelacimab vs rivaroxaban by age in patients with atrial fibrillation (AF).
DESIGN, SETTING, AND PARTICIPANTS: The randomized clinical trial AZALEA-TIMI 71 randomized patients with AF to receive 1 of 2 subcutaneous abelacimab doses (90 mg or 150 mg monthly) or oral rivaroxaban (20 mg daily, dose reduction to 15 mg). This prespecified analysis of the phase 2b AZALEA-TIMI 71 trial evaluated bleeding risk by age, analyzed continuously and categorically (<75 vs =75 years). The trial was conducted from March 2021 to September 2023; data analysis was performed from February to May 2025.
INTERVENTIONS: Monthly subcutaneous abelacimab (90 or 150 mg) or daily oral rivaroxaban (20/15 mg).
MAIN OUTCOMES AND MEASURES: The primary end point was the composite of major or clinically relevant nonmajor (CRNM) bleeding.
RESULTS: Among 1287 patients randomized, 715 (55.6%) were male and 572 (44.4%) were female; there were 625 patients (49%) 75 years or older. Compared with younger patients, those 75 years or older had lower body mass index (28 vs 32), were less likely to be taking antiplatelet therapy at baseline (17% vs 32%), and were more likely to have creatinine clearance 50 mL/min or less (33% vs 8%). Both abelacimab doses were associated with significantly less major or CRNM bleeding compared with rivaroxaban in those 75 years or older (hazard ratio [HR], 0.32; 95% CI, 0.17-0.60; and HR, 0.40; 95% CI, 0.22-0.73; for abelacimab, 90 and 150 mg, vs rivaroxaban, respectively) and in those younger than 75 years (HR, 0.28; 95% CI, 0.12-0.61; and HR, 0.35; 95% CI, 0.17-0.70; P for interaction, .85 and .84, respectively). Patients 75 years or older tended to derive greater absolute risk reductions with abelacimab (7.1 and 6.2 per 100 patient-years for abelacimab, 90 and 150 mg, vs rivaroxaban, respectively) than those younger than 75 years (4.7 and 4.2 per 100 patient-years, respectively). When modeled continuously, bleeding risk tended to increase with age in the rivaroxaban group but remained stable in the abelacimab group (P for interaction, .33).
CONCLUSIONS AND RELEVANCE: This study found that abelacimab consistently reduced bleeding compared with rivaroxaban regardless of age, with the potential for a greater absolute reduction in bleeding with older age. FXI inhibition with abelacimab may become a particularly attractive option in older patients with AF and higher bleeding risk. The results of ongoing phase 3 trials are necessary to establish the efficacy and benefit-to-risk ratio of abelacimab.
TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04755283.
| Discipline Area | Score |
|---|---|
| Internal Medicine |  |
| Hemostasis and Thrombosis |  |
| Cardiology |  |
This prespecified analysis is clinically relevant showing that abelacimab reduces major or CRNM bleeding versus rivaroxaban consistently across age groups, with potentially greater absolute benefit in patients =75 years. However, as a phase 2b trial primarily focused on safety, it is not powered to assess stroke prevention or overall net clinical benefit. The results are encouraging for FXI inhibition in older AF patients but require confirmation in phase 3 outcome trials.
RCTs should initially report effectiveness in preventing major CV events or, at minimum, the combination of these events with major bleeding. XI inhibitors have failed to prevent CV events compared with X inhibitors.
I would have liked the comparison to be with apixiban, which is usually considered a safer DOAC in the elderly.
I think these results are striking and good news for older adults with atrial infarction. However, abelacimab is currently subcutaneous and adherence also should be investigated. Of course, we need to wait for the efficacy to prevent embolic events. Oral XI/Xia factors are also expected.
