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Clinical Trial
. 2024 Feb 13;83(6):669-678.
doi: 10.1016/j.jacc.2023.12.004.

Bleeding Outcomes in Patients Treated With Asundexian in Phase II Trials

John W Eikelboom  1 , Hardi Mundl  2 , John H Alexander  3 , Valeria Caso  4 , Stuart J Connolly  5 , Rosa Coppolecchia  6 , Martin Gebel  2 , Robert G Hart  7 , Gerlind Holberg  8 , Lars Keller  2 , Manesh R Patel  3 , Jonathan P Piccini  3 , Sunil V Rao  9 , Ashkan Shoamanesh  5 , Miriam Tamm  2 , Thomas Viethen  2 , Ashraf Yassen  2 , Marc P Bonaca  10
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Free article
Clinical Trial

Bleeding Outcomes in Patients Treated With Asundexian in Phase II Trials

John W Eikelboom et al. J Am Coll Cardiol. .
Free article

Abstract

Background: Phase II trials of asundexian were underpowered to detect important differences in bleeding.

Objectives: The goal of this study was to obtain best estimates of effects of asundexian vs active control/placebo on major and clinically relevant nonmajor (CRNM) and all bleeding, describe most common sites of bleeding, and explore association between asundexian exposure and bleeding.

Methods: We performed a pooled analysis of 3 phase II trials of asundexian in patients with atrial fibrillation (AF), recent acute myocardial infarction (AMI), or stroke. Bleeding was defined according to the International Society on Thrombosis and Hemostasis (ISTH) criteria.

Results: In patients with AF (n = 755), both asundexian 20 mg and 50 mg once daily vs apixaban had fewer major/CRNM events (3 of 249; incidence rate [IR] per 100 patient-years 5.47 vs 1 of 254 [IR: not calculable] vs 6 of 250 [IR: 11.10]) and all bleeding (12 of 249 [IR: 22.26] vs 10 of 254 [IR: 18.21] vs 26 of 250 [IR: 50.56]). In patients with recent AMI or stroke (n = 3,409), asundexian 10 mg, 20 mg, and 50 mg once daily compared with placebo had similar rates of major/CRNM events (44 of 840 [IR: 7.55] vs 42 of 843 [IR: 7.04] vs 56 of 845 [IR: 9.63] vs 41 of 851 [IR: 6.99]) and all bleeding (107 of 840 [IR: 19.57] vs 123 of 843 [IR: 22.45] vs 130 of 845 [IR: 24.19] vs 129 of 851 [IR: 23.84]). Most common sites of major/CRNM bleeding with asundexian were gastrointestinal, respiratory, urogenital, and skin. There was no significant association between asundexian exposure and major/CRNM bleeding.

Conclusions: Analyses of phase II trials involving >500 bleeds highlight the potential for improved safety of asundexian compared with apixaban and similar safety compared with placebo. Further evidence on the efficacy of asundexian awaits the results of ongoing phase III trials.

Keywords: apixaban; asundexian; atrial fibrillation; bleeding; myocardial infarction; placebo; stroke.

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Conflict of interest statement

Funding Support and Author Disclosures Academic steering committees and the trial sponsor (Bayer AG) were jointly responsible for the design and oversight of the individual PACIFIC trials. The sponsor coordinated the trial conduct and performed the statistical analyses. The PACIFIC trials were funded by Bayer AG. Dr. Eikelboom has received honoraria, fees, or research grants from Anthos, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, DSI, Idorsia, Janssen, Merck, Pfizer, and Servier. Dr. Mundl is an employee of Bayer AG. Dr. Alexander has received research grants through Duke University from Artivion/CryoLife, Bayer, Bristol Myers Squibb, CSL Behring, Ferring, U.S. Food and Drug Administration, Humacyte, U.S. National Institutes of Health, and XaTek; and has received advisory board/consulting fees from AbbVie, Akros, Artivion/CryoLife, AtriCure, Bayer, Bristol Myers Squibb, Ferring, GlaxoSmithKline, Janssen, Novostia, Pfizer, Portola, Quantum Genomics, Theravance, and Veralox. Dr. Caso has received advisory board and speaker fees from Bristol Myers Squibb/Pfizer, Boehringher Ingelheim, EVER Pharma, Daichi-Sankyo, and Bayer. Dr Connolly has received major research grants, consulting fees, and speaker fees from Sanofi, Janssen, Pfizer, Bristol Myers Squibb, Boehringer Ingelheim, Boston Scientific, Abbott, Bayer Pharmaceuticals Inc, Portola Pharmaceutical, Medtronic, Daiichi-Sankyo, and Servier. Drs Coppolecchia and Gebel are employees of Bayer AG. Dr Hart has received a stipend from Bayer AG for international coordination of the phase 2 PACIFIC-Stroke trial. Drs Holberg and Keller are employees of Bayer AG. Dr Piccini has received research funding from Bayer, AHA, and Boston Scientific; and has received consulting fees from Boston Scientific. Dr Shoamanesh has received grants and research support from CIHR, NIH, HSFC, British Heart Foundation, Medical Research Future Fund, AstraZeneca, Bayer AG, Daiichi-Sankyo, Octapharma, Servier, and Marta and Owen Boris Foundation; and has received consulting fees from AstraZeneca, Bayer AG, Bioxodes, Daiichi-Sankyo, Servier, and Takeda Pharmaceuticals. Miriam Tamm, Thomas Viethen, and Dr Yassen are employees of Bayer AG. Dr Bonaca has received support from the AHA SFRN under award numbers 18SFRN3390085 (BWH-DH SFRN Center) and 18SFRN33960262 (BWH-DH Clinical Project); has modest stock holdings in Medtronic and Pfizer; and has received consulting fees from Audentes. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.

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