Abelacimab versus Rivaroxaban in Patients with Atrial Fibrillation

Author(s): Christian T. Ruff, M.D., M.P.H., Siddharth M. Patel, M.D., M.P.H., Robert P. Giugliano, M.D., David A. Morrow, M.D., M.P.H., Bruce Hug, M.D., Ph.D., Julia F. Kuder, M.A., Erica L. Goodrich, M.S., Shih-Ann Chen, M.D., Shaun G. Goodman, M.D., Boyoung Joung, M.D., Robert G. Kiss, M.D., Jindrich Spinar, M.D., Ph.D., Wojciech Wojakowski, M.D., Ph.D., Jeffrey I. Weitz, M.D., Sabina A. Murphy, M.P.H., Stephen D. Wiviott, M.D., Sanobar Parkar, M.D., Daniel Bloomfield, M.D., and Marc S. Sabatine, M.D., M.P.H., for the AZALEA–TIMI 71 Investigators*

Source: DOI: 10.1056/NEJMoa2406674

Dr. Anjan Patel's Thoughts

This new subcutaneous anticoagulant, abelacimab, binds to the inactive form of FXI and blocks its activation by FXII. This drug seems significantly safer than DOAC’s in terms of bleeding risk. So much so that the study was stopped early due to a greater-than-expected reduction in bleeding events in the study arm. I hope this drug is also going to be studied for the treatment of VTE.

BACKGROUND

Abelacimab is a fully human monoclonal antibody that binds to the inactive form of factor XI and blocks its activation. The safety of abelacimab as compared with a direct oral anticoagulant in patients with atrial fibrillation is unknown.

METHODS

Patients with atrial fibrillation and a moderate-to-high risk of stroke were randomly assigned, in a 1:1:1 ratio, to receive subcutaneous injection of abelacimab (150 mg or 90 mg once monthly) administered in a blinded fashion or oral rivaroxaban (20 mg once daily) administered in an open-label fashion. The primary end point was major or clinically relevant nonmajor bleeding.

RESULTS

A total of 1287 patients underwent randomization; the median age was 74 years, and 44% were women. At 3 months, the median reduction in free factor XI levels with abelacimab at a dose of 150 mg was 99% (interquartile range, 98 to 99) and with abelacimab at a dose of 90 mg was 97% (interquartile range, 51 to 99). The trial was stopped early on the recommendation of the independent data monitoring committee because of a greater-than-anticipated reduction in bleeding events with abelacimab. The incidence rate of major or clinically relevant nonmajor bleeding was 3.2 events per 100 person-years with 150-mg abelacimab and 2.6 events per 100 person-years with 90-mg abelacimab, as compared with 8.4 events per 100 person-years with rivaroxaban (hazard ratio for 150-mg abelacimab vs. rivaroxaban, 0.38 [95% confidence interval {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). The incidence and severity of adverse events appeared to be similar in the three groups.

CONCLUSIONS

Among patients with atrial fibrillation who were at moderate-to-high risk for stroke, treatment with abelacimab resulted in markedly lower levels of free factor XI and fewer bleeding events than treatment with rivaroxaban. (Funded by Anthos Therapeutics; AZALEA–TIMI 71 ClinicalTrials.gov number, NCT04755283.)

Author Affiliations

From the TIMI Study Group, Division of Cardiovascular Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston (C.T.R., S.M.P., R.P.G., D.A.M., J.F.K., E.L.G., S.A.M., S.D.W., M.S.S.); Anthos Therapeutics, Cambridge, MA (B.H., S.P., D.B.); the Heart Rhythm Center, Taipei Veterans General Hospital and Cardiovascular Center, Taipei, Taiwan (S.-A.C.); Taichung Veterans Hospital, Taichung, Taiwan (S.-A.C.); National Yang Ming Chiao Tung University, Hsinchu, Taiwan (S.-A.C.); National Chung Hsing University, Taichung, Taiwan (S.-A.C.); St. Michael’s Hospital, Unity Health Toronto, Peter Munk Cardiac Centre, University Health Network, University of Toronto, Toronto (S.G.G.); Canadian VIGOUR Centre, University of Alberta, Edmonton, Canada (S.G.G.); the Division of Cardiology, Severance Hospital, Yonsei University College of Medicine, Seoul, South Korea (B.J.); the Department of Cardiology, Central Hospital of Northern Pest–Military Hospital, Budapest, Hungary (R.G.K.); the Heart and Vascular Center, Semmelweis University, Budapest, Hungary (R.G.K.); the Internal Cardiology Department, St. Ann University Hospital and Masaryk University, Brno, Czech Republic (J.S.); the Department of Cardiology and Structural Heart Diseases, Medical University of Silesia, Katowice, Poland (W.W.); the Departments of Medicine and of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON, Canada (J.W.); and the Thrombosis and Atherosclerosis Research Institute, Hamilton, ON, Canada (J.W.).

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