Abstract Body: Background: Patients with ischemic stroke or transient ischemic attack (TIA) have a high risk of subsequent ischemic stroke despite antiplatelet therapy. Factor XIa inhibitors are anticoagulants that suppress thrombosis predominantly through the intrinsic pathway while preserving hemostasis through the extrinsic pathway. The phase 2 AXIOMATIC-SSP trial in patients with acute ischemic stroke or high-risk TIA showed that the oral factor XIa inhibitor milvexian numerically reduced symptomatic ischemic stroke across an 8-fold dose range while demonstrating rates similar to placebo for the principal bleeding endpoint at doses of 25 mg once or twice daily. However, the primary composite endpoint (ischemic stroke or MRI evidence of brain infarction) did not reveal a dose-response relationship with milvexian.
Objective: The ongoing phase 3 LIBREXIA-Stroke Trial (ClinicalTrials.gov: NCT05702034; sponsored by Bristol Myers Squibb and Janssen Research & Development, LLC) is addressing whether milvexian is superior to placebo in reducing the risk of subsequent ischemic stroke among patients presenting acutely with ischemic stroke or high-risk TIA.
Design: LIBREXIA-Stroke is an international, double-blind, placebo-controlled trial in patients with acute non-cardioembolic ischemic stroke (NIHSS ≤7) or high-risk TIA (ABCD² score ≥6) who are randomized within 48 hours of symptom onset to milvexian (25 mg twice daily) or matching placebo, with all patients receiving background antiplatelet therapy (Figure 1). Patients undergoing thrombolysis or thrombectomy are eligible if enrolled more than 24 hours after the procedure. The primary efficacy outcome is time to first occurrence of ischemic stroke, and the principal safety outcome is BARC 3c or 5 hemorrhage (intracranial, symptomatic intraocular, or fatal hemorrhage). Patients with an elevated risk of hemorrhage at screening are excluded. For this outcome event-driven trial, it was estimated that approximately 15,000 subjects will be randomized in 47 countries (Figure 2) and followed until 909 primary efficacy outcome events have occurred to achieve 90% power to detect a 20% hazard reduction with milvexian.
Conclusions: The LIBREXIA-Stroke trial will assess the efficacy and safety of milvexian. This new anticoagulant may have a favorable risk-benefit profile in a large international population of patients presenting acutely with ischemic stroke or high-risk TIA.