Asundexian versus Apixaban in Patients with Atrial Fibrillation

Jonathan P Piccini; Manesh R Patel; Jan Steffel; Keith Ferdinand; Isabelle C Van Gelder; Andrea M Russo; Chang-Sheng Ma; Shaun G Goodman; Jonas Oldgren; Christopher Hammett; Renato D Lopes; Masaharu Akao; Raffaele De Caterina; Paulus Kirchhof; Diana A Gorog; Martin Hemels; Michiel Rienstra; W Schuyler Jones; Josephine Harrington; Gregory Y H Lip; Stephen J Ellis; Frank W Rockhold; Christoph Neumann; John H Alexander; Thomas Viethen; James Hung; Rosa Coppolecchia; Hardi Mundl; Valeria Caso; OCEANIC-AF Steering Committee and Investigators

doi:10.1056/NEJMoa2407105

Asundexian versus Apixaban in Patients with Atrial Fibrillation

N Engl J Med. 2024 Sep 1. doi: 10.1056/NEJMoa2407105. Online ahead of print.

Authors

Jonathan P Piccini¹, Manesh R Patel¹, Jan Steffel¹, Keith Ferdinand¹, Isabelle C Van Gelder¹, Andrea M Russo¹, Chang-Sheng Ma¹, Shaun G Goodman¹, Jonas Oldgren¹, Christopher Hammett¹, Renato D Lopes¹, Masaharu Akao¹, Raffaele De Caterina¹, Paulus Kirchhof¹, Diana A Gorog¹, Martin Hemels¹, Michiel Rienstra¹, W Schuyler Jones¹, Josephine Harrington¹, Gregory Y H Lip¹, Stephen J Ellis¹, Frank W Rockhold¹, Christoph Neumann¹, John H Alexander¹, Thomas Viethen¹, James Hung¹, Rosa Coppolecchia¹, Hardi Mundl¹, Valeria Caso¹; OCEANIC-AF Steering Committee and Investigators

Affiliation

¹ From Duke Clinical Research Institute, Duke University School of Medicine (J.P.P., M.R.P., R.D.L., W.S.J., J. Harrington, S.J.E., F.W.R., J.H.A.), and Duke University Medical Center (J.P.P., M.R.P., R.D.L., W.S.J., J. Harrington, F.W.R., J.H.A.) - both in Durham, NC; Hirslanden Clinic Zurich, Zurich, Switzerland (J.S.); the School of Medicine, Tulane University, New Orleans (K.F.); the University Medical Center, University of Groningen, Groningen (I.C.V.G., M.R.), Radboud University Medical Center, Nijmegen (M.H.), Rijnstate Hospital, Arnhem (M.H.), and the Dutch Network for Cardiovascular Research, Utrecht (M.H.) - all in the Netherlands; Cooper Medical School of Rowan University, Camden (A.M.R.), and Bayer U.S., Whippany (R.C.) - both in New Jersey; the Cardiology Center of Beijing, Anzhen Hospital No. 2, Beijing (C.-S.M.); the Canadian VIGOUR Centre, University of Alberta, Edmonton, and St. Michael's Hospital, Unity Health Toronto, and Peter Munk Cardiac Centre, University Health Network, University of Toronto, Toronto - all in Canada (S.G.G.); the Uppsala Clinical Research Center and the Department of Medical Sciences, Uppsala University, Uppsala, Sweden (J.O.); the Department of Cardiology, Royal Brisbane and Women's Hospital, Brisbane, QLD, Australia (C.H.); the Department of Cardiology, National Hospital Organization Kyoto Medical Center, Kyoto, Japan (M.A.); the School of Cardiology, University of Pisa, and the Cardiology Division, Pisa University Hospital, Pisa (R.D.C.), and Santa Maria della Misericordia Hospital, University of Perugia, Perugia (V.C.) - all in Italy; the Department of Cardiology, University Heart and Vascular Center Hamburg, and the German Center for Cardiovascular Research, Hamburg (P.K.), and Bayer, Wuppertal (C.N., T.V., H.M.) - all in Germany; the Institute of Cardiovascular Sciences, University of Birmingham, Birmingham (P.K.), the Faculty of Medicine, National Heart and Lung Institute, Imperial College, London (D.A.G.), the Centre for Health Services and Clinical Research, Faculty of Life and Medical Sciences, University of Hertfordshire, Hatfield (D.A.G.), and the Liverpool Centre for Cardiovascular Science at University of Liverpool and John Moores University and Liverpool Heart and Chest Hospital, Liverpool (G.Y.H.L.) - all in the United Kingdom; the Department of Clinical Medicine, Danish Center for Health Services Research, Aalborg University, Aalborg, Denmark (G.Y.H.L.); and Bayer, São Paulo (J. Hung).

PMID: 39225267
DOI: 10.1056/NEJMoa2407105

Abstract

Background: Stroke prevention with direct-acting oral anticoagulant agents in patients with atrial fibrillation confers a risk of bleeding and limits their use. Asundexian, an activated factor XI (XIa) inhibitor, is an oral anticoagulant that may prevent strokes with less bleeding.

Methods: In a phase 3, international, double-blind trial, we randomly assigned high-risk patients with atrial fibrillation in a 1:1 ratio to receive asundexian at a dose of 50 mg once daily or standard-dose apixaban. The primary efficacy objective was to determine whether asundexian is at least noninferior to apixaban for the prevention of stroke or systemic embolism. The primary safety objective was to determine whether asundexian is superior to apixaban with respect to major bleeding events.

Results: A total of 14,810 randomly assigned patients were included in the intention-to-treat population. The mean (±SD) age of the patients was 73.9±7.7 years, 35.2% were women, 18.6% had chronic kidney disease, 18.2% had a previous stroke or transient ischemic attack, 16.8% had received oral anticoagulants for no more than 6 weeks, and the mean CHA₂DS₂-VASc score (range, 0 to 9, with higher scores indicating a greater risk of stroke) was 4.3±1.3. The trial was stopped prematurely at the recommendation of the independent data monitoring committee. Stroke or systemic embolism occurred in 98 patients (1.3%) assigned to receive asundexian and in 26 (0.4%) assigned to receive apixaban (hazard ratio, 3.79; 95% confidence interval [CI], 2.46 to 5.83). Major bleeding occurred in 17 patients (0.2%) who received asundexian and in 53 (0.7%) who received apixaban (hazard ratio, 0.32; 95% CI, 0.18 to 0.55). The incidence of any adverse event appeared to be similar in the two groups.

Conclusions: Among patients with atrial fibrillation at risk for stroke, treatment with asundexian at a dose of 50 mg once daily was associated with a higher incidence of stroke or systemic embolism than treatment with apixaban in the period before the trial was stopped prematurely. There were fewer major bleeding events with asundexian than with apixaban during this time. (Funded by Bayer; OCEANIC-AF ClinicalTrials.gov number, NCT05643573; EudraCT number, 2022-000758-28.).

Associated data

ClinicalTrials.gov/NCT05643573
EudraCT/2022-000758-28