Oral factor xia inhibitor milvexian after a recent acute coronary syndrome: Rationale and design of the phase 3 (Librexia ACS)
- PMID: 39986336
- DOI: 10.1016/j.ahj.2025.02.011
Oral factor xia inhibitor milvexian after a recent acute coronary syndrome: Rationale and design of the phase 3 (Librexia ACS)
Abstract
Background: Despite current antiplatelet therapy, patients remain at risk of recurrent ischemic events after acute coronary syndromes (ACS), which may reflect persistently elevated thrombin generation. Factor XIa inhibition reduces thrombin generation and may improve clinical outcomes with minimal bleeding risk.
Design: Librexia ACS (ClinicalTrials.gov NCT05754957) is a Phase 3, randomized, double-blind, placebo-controlled, event-driven trial to test the efficacy and safety of milvexian, an oral, selective factor XIa inhibitor, in addition to conventional antiplatelet therapy after a recent ACS. Eligibility criteria include symptoms of spontaneous ischemia, a diagnosis of ACS and cardiac biomarker elevation indicative of myonecrosis within 7 days before randomization, along with at least 2 risk-enhancing factors. Participants are randomly assigned to oral milvexian (25 mg twice daily) or a matched placebo. Randomization is stratified according to the planned duration and type of antiplatelet therapy. The primary efficacy endpoint is the time to first occurrence of the composite of cardiovascular death, myocardial infarction (MI), or ischemic stroke that will enroll approximately 16,000 patients with follow-up until 875 events are accrued. The first major secondary endpoint is time to the first occurrence of cardiovascular death, MI, ischemic stroke, major adverse limb events, and symptomatic venous thromboembolism. The principal safety endpoint is Bleeding Academic Research Consortium 3c or 5 bleeding.
Summary: The Librexia-ACS trial will determine the efficacy and safety of milvexian after ACS and will be the first trial to test whether factor XIa inhibition in addition to standard-of-care antiplatelet therapy reduces major adverse cardiovascular events without an increased risk of significant bleeding.
Copyright © 2025 The Author(s). Published by Elsevier Inc. All rights reserved.
Conflict of interest statement
Conflict of interest C.M.G. reports receiving research grant support from Johnson and Johnson, M.C.B reports receiving modest honoraria from Johnson and Johnson, Bristol-Myers Squibb, Anthos Therapeutics, Merck; R.M. reports institutional research payments from: Abbott, Affluent Medical, Alleviant Medical, Amgen, Boston Scientific, Bristol-Myers Squibb, CardiaWave, Chiesi, Concept Medical, Daiichi Sankyo, Duke, Faraday, Idorsia, Janssen, MedAlliance, Medscape, Mediasphere, Medtelligence, Medtronic, Novartis, OrbusNeich, Pi- Cardia, Protembis, RM Global Bioaccess Fund Management, Sanofi; and personal fees from: Affluent Medical, Boehringer Ingelheim, Chiesi USA, Cordis, IQVIA, Medscape/WebMD Global, NovoNordisk, PeerView Institute for Medical Education, Radcliffe; S.R.M. has received institutional research grants or consulting fees from Abbott, Amgen, Canadian Institutes of Health Research, Heart and Stroke Foundation of Canada, Diapin, Janssen, Merck (data monitoring committee), Novartis, NovoNordisk; R.A-L. serves on advisory boards for Janssen Pharmaceuticals, Abbott, and Philips; and has received speaker fees from Abbott, Philips, Medtronic, Servier, Omniprex, and Menarini; S.G. report modest honoraria from from Johnson and Johnson, Anthos Therapeutics, Merck; R.M, and Amgen.; J.I.W reports receiving honoraria from BMS and Johnson and Johnson and grant support to his institution.; J.H. is a former employee of Bristol Myers Squibb; E.S.B. is an employee of and owns stock in Johnson and Johnson; R.A.H. has received research grants/contracts from NHLBI (ISCHEMIA), Duke/PCORI (ADAPTABLE),Janssen (Factor XIa inhibitor), CSL (HDL), Baim Institute, UColorado, Harvard (BWH), and Merck; has served as a consultant/advisor for NHLBI (COVID/CONNECTS), Atropos Health, Bitterroot Bio, Bristol Myers Squibb, Bridge Bio, Chiesi, CSL Behring, Edwards Lifesciences Corp, Element Science, Foresight, Merck, and WebMD; and serves on the Board of Directors for AHA and Cytokinetics; K.W.M.’s financial disclosure can be reviewed at http://med.stanford.edu/profiles/kenneth-mahaffey; C.S.P.L. is supported by a Clinician Scientist Award from the National Medical Research Council of Singapore; has Received research support from Novo Nordisk and Roche Diagnostics; has Served as consultant or on the Advisory Board/ Steering Committee/ Executive Committee for Alleviant Medical, Allysta Pharma, AnaCardio AB, Applied Therapeutics, AstraZeneca, Bayer, Biopeutics, Boehringer Ingelheim, Boston Scientific, Bristol Myers Squibb, CardioRenal, CPC Clinical Research, Eli Lilly, Hanmi, Impulse Dynamics, Intellia Therapeutics, Ionis Pharmaceutical, Janssen Research & Development LLC, Medscape/WebMD Global LLC, Merck, Novartis, Novo Nordisk, Prosciento Inc, Quidel Corporation, Radcliffe Group Ltd., Recardio Inc, ReCor Medical, Roche Diagnostics, Sanofi, Siemens Healthcare Diagnostics and Us2.ai; and serves as Co-founder and nonexecutive director of Us2.ai.; K.S.P is a member of The Thrombosis Research Institute which has received institutional research grant support from Anthos Therapeutics and Bayer Pharmaceuticals. She has received honoraria from Element Science and Artivion, Inc.; S.C.J. has received research support from Jansen, BMS, and AstraZeneca; G.J.H. reports personal honoraria outside the submitted work from the American Heart Association (Associate Editor, Circulation), Bristol Myers Squibb (Steering Committee, AXIOMATIC-SSP trial of milvexian [factor XIa inhibitor] for secondary stroke prevention) and Janssen (Co-chair, Executive Committee, Librexia Stroke trial of milvexian for secondary stroke prevention); A.P. is an employee of Johnson and Johnson; D.L. is an employee of BMS; P.G.S reports receiving research grants from Amarin, Sanofi; honoraria for clinical trial work from Amarin, AstraZeneca, Bayer, Bristol-Myers Squibb, Idorsia, Janssen R&D LLC, Novartis, Pfizer, Sanofi, Servier; honoraria for consulting or speaking: Amarin, Amgen, BMS/Myokardia, Novo-Nordisk, and is Senior Associate Editor at Circulation.
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