AZALEA–TIMI 71 trial: less bleeding with abelacimab compared to rivaroxaban in atrial fibrillation, but stroke prevention is uncertain

The saga of Factor XI (FXI) inhibitors for anticoagulation in atrial fibrillation (AF) has recently gained new momentum with the publication of the AZALEA–TIMI 71 trial in the New England Journal of Medicine.1 This multinational, phase 2b, parallel-group, partially blind, randomized, active-controlled trial compared monthly doses of 150 mg or 90 mg abelacimab with rivaroxaban in patients with AF at moderate-to-high risk of stroke.1 On 14 September 2023, the trial was stopped early following the recommendation of the Independent Data Monitoring Committee due to a greater-than-anticipated reduction in bleeding with abelacimab.1 This positive result apparently contrasts to the OCEANIC–AF trial,2 which was stopped early due to the lower efficacy of asundexian compared to apixaban. However, several key factors should be considered when interpreting the results of the two trials.1,2 Abelacimab, a fully human monoclonal antibody with once-monthly administration, introduces a new approach to anticoagulation by targeting the catalytic domain of FXI and locking it in its inactive state.3 Abelacimab exerts a dual mechanism of action, additionally inhibiting activated FXI.3 Pharmacodynamic studies demonstrated that abelacimab achieves near-complete suppression of FXI activity within 1 h, maintaining near-maximal inhibition for up to 30 days.3 In a phase 2 study in 412 patients undergoing knee arthroplasty, a single intravenous dose of abelacimab 150 mg reduced the incidence of venous thromboembolism by 80% compared to enoxaparin, with no increase in bleeding risk.3 The trial enrolled 1287 patients at 95 centres across 7 countries.1 Eligible participants were adults aged 55 or older with AF or flutter, a CHA2DS2-VASc score of ≥3, and an indication for long-term anticoagulation. Patients were randomized (1:1:1) to receive subcutaneous injection of abelacimab 90 mg or 150 mg monthly or rivaroxaban 20 mg daily. Abelacimab doses were administered under double-blind conditions, while the abelacimab vs. rivaroxaban comparison was open-label.1 At 3 months, the median reduction in free FXI levels was 99% (interquartile range (IQR): 98–99) for abelacimab 150 mg and 97% (IQR: 51–99) for abelacimab 90 mg. The incidence rate of the primary endpoint, major or clinically relevant non-major bleeding as per International Society on Thrombosis and Haemostasis criteria, was 3.22 events per 100 person-years with abelacimab 150 mg and 2.64 events per 100 person-years with abelacimab 90 mg, compared to 8.38 events per 100 person-years with rivaroxaban [hazard ratio (HR) for 150-mg abelacimab vs. rivaroxaban: 0.38 (95% CI: 0.24–0.60); HR for 90-mg abelacimab vs. rivaroxaban: 0.31 (95% CI: 0.19–0.51); P < 0.001 for both comparisons]. Major gastrointestinal bleeding was nearly abolished with abelacimab (only 2 events in each abelacimab group vs. 18 events in the rivaroxaban group), a critical finding as the gastrointestinal tract is the most common site of bleeding with direct oral anticoagulants (DOACs), where DOACs do not offer a better risk profile than warfarin. Among secondary endpoints, the incidence rate of ischaemic stroke was 1.21 events per 100 person-years with abelacimab 150 mg and 1.24 with abelacimab 90 mg, compared with 0.59 per 100 person-years with rivaroxaban [HR for 150-mg abelacimab vs. rivaroxaban: 2.06 (95% CI: 0.70–6.02); HR for 90-mg abelacimab vs. rivaroxaban: 2.10 (95% CI: 0.72–6.14)].1 The AZALEA–TIMI 71 findings position abelacimab as a promising anticoagulant strategy targeting FXI.1 Despite recent advances, patients with AF remain at high risk for adverse events in practice.4–6 Preventing bleeding while preserving antithrombotic protection is a research priority in cardiology.7–10 In AZALEA–TIMI 71, once-monthly abelacimab dramatically lowered major and non-major clinically relevant bleeding compared to rivaroxaban, but the trial was modestly sized and not powered to draw definitive conclusions about its antithrombotic efficacy.1 While the incidence of thromboembolic events was low overall, ischaemic stroke was numerically higher with abelacimab than rivaroxaban, a finding that warrants careful consideration in light of recent lessons from the OCEANIC–AF trial.2 Another important consideration is abelacimab's once-monthly administration. While this approach is well-established in other therapeutic areas (e.g. lipid-lowering drugs),11,12 it may pose additional challenges for antithrombotic drugs, where rapid reversal can be necessary in urgent situations (e.g. active bleeding and emergent surgeries). A subanalysis of the AZALEA–TIMI 71 was reassuring for the safety of abelacimab in patients undergoing invasive procedures during the study period, but this aspect requires more investigation.13 Further evidence on the antithrombotic efficacy of FXI inhibitors is needed before considering a shift away from the current standard of DOACs.3,14 Additional observations for abelacimab will emerge from the open-label extension of AZALEA–TIMI 71.15 Notably, 84% of eligible patients, including 75% who had been receiving rivaroxaban, voluntarily accepted to receive abelacimab in the extension study. Moreover, the ongoing LILAC–TIMI 76 trial (NCT05712200) is assessing the efficacy of abelacimab vs. placebo in patients with AF who are unsuitable for currently available anticoagulation therapies. Overall, FXI inhibition appears to be at a pivotal juncture, poised either to fulfill its promise as a significant advance in the treatment of AF or to remain an unrealized therapeutic hope. The results of ongoing trials will be crucial in determining whether this novel strategy can effectively overcome the limitations of current anticoagulant therapy. Conflict of interest: F.G., A.C., M.G., and P.C. declare no conflicts of interest related to the content of this article. The data underlying this article were taken from the quoted references.