LIBREXIA ACS: Milvexian Fails to Reduce MACE after Acute Coronary Syndrome

The factor XIa inhibitor milvexian did not reduce major adverse cardiovascular events (MACE) compared with placebo when added to standard antiplatelet therapy after a recent acute coronary syndrome (ACS), according to results from the phase 3 LIBREXIA ACS trial presented in a Hot Line session at the European Society of Cardiology (ESC) Congress 2026 and published simultaneously in the New England Journal of Medicine.¹

The trial was halted early in November 2025 after the Independent Data Monitoring Committee recommended discontinuation based on a preplanned interim analysis showing the primary endpoint was unlikely to be met.¹

“There has been increasing interest in developing factor XIa inhibitors to prevent harmful thrombosis, while preserving normal clotting processes to minimise bleeding,” said Philippe Gabriel Steg, MD, principal investigator of LIBREXIA ACS, Hôpital Bichat, Paris, France. “We conducted the LIBREXIA ACS trial to assess the efficacy and safety of the selective factor XIa inhibitor, milvexian, after ACS when added to standard antiplatelet therapy.”

Milvexian efficacy and trial design in LIBREXIA ACS

LIBREXIA ACS randomized 14,194 participants across 893 sites in 44 countries to oral milvexian 25 mg twice daily or matched placebo, both added to investigator-determined standard antiplatelet therapy.¹ Eligible patients had an ACS event within 7 days, had undergone percutaneous coronary intervention or were managed conservatively, and had at least 2 factors associated with increased risk of recurrent ischemic events.¹ Most participants received background dual antiplatelet therapy, with a majority on potent P2Y12 inhibitors, reflecting contemporary post-ACS management.

After a median follow-up of 10 months, the primary efficacy endpoint of cardiovascular death, myocardial infarction (MI), or ischemic stroke occurred in 5.4% of patients in the milvexian group and 5.1% of patients in the placebo group (HR, 1.05; 95% CI, 0.91-1.21; P = .50).¹ No difference emerged for any individual component of the primary endpoint. Despite background PCI and prolonged dual antiplatelet therapy, the overall incidence of MACE in both arms remained high, underscoring persistent residual ischemic risk in this population.

Milvexian safety profile and bleeding outcomes

The principal safety endpoint of Bleeding Academic Research Consortium (BARC) 3c or 5 bleeding, encompassing intracranial or fatal bleeding, occurred in 0.3% of patients in both the milvexian and placebo groups (HR, 1.04; 95% CI, 0.58-1.87; P = .88).¹ Milvexian did not increase this principal safety endpoint relative to placebo. No difference was observed on any major secondary efficacy endpoint, including all-cause mortality.¹

Patients in the milvexian group had a prolonged activated partial thromboplastin time, consistent with the drug's expected anticoagulant activity at the dose studied.¹ The absence of an observed increase in intracranial or fatal bleeding did not translate into a corresponding efficacy benefit at 25 mg twice daily in this ACS population.

“While no effect on efficacy was shown, the absence of an observed increase in intracranial or fatal bleeding is reassuring given that two further trials are ongoing,” Steg said. “These studies are distinct from LIBREXIA ACS in several aspects, including patient populations, endpoints, type and duration of background therapy and disease pathology.”¹

Two additional milvexian trials remain active outside the ACS setting: LIBREXIA AF in atrial fibrillation and LIBREXIA Stroke for secondary stroke prevention.¹ Milvexian previously demonstrated a favorable thrombosis-hemostasis trade-off in the AXIOMATIC-TKR trial for venous thromboembolism prevention after total knee replacement, though ACS represents a substantially different ischemic and bleeding risk environment.² The trial was funded by Bristol Myers Squibb and Janssen Research & Development, LLC, a Johnson & Johnson company.¹

References

1. Steg PG, et al. Milvexian after Recent Acute Coronary Syndromes: The LIBREXIA ACS Trial. N Engl J Med. Presented at: ESC Congress 2026; August 29, 2026; Munich, Germany.

2. HCPLive. AXIOMATIC-TKR: Milvexian decouples thrombosis, hemostasis in DVT. https://www.hcplive.com/view/axiomatic-tkr-milvexian-decouples-thrombosis-hemostasis-in-dvt. Published July 14, 2026. Accessed August 29, 2026.