Factor XIa Inhibitor Shows No Benefit After Acute Coronary Syndrome

An investigational factor XIa inhibitor did not reduce the risk of recurrent cardiovascular (CV) events in patients with a recent acute coronary syndrome (ACS) event on top of antiplatelet therapy, although there was no increase in the risk for major bleeding with treatment, according to the LIBREXIA ACS trial.

The phase III results showed that for the primary efficacy outcome — a composite of CV death, myocardial infarction, or ischemic stroke evaluated in a time-to-event analysis — one of these events occurred in 384 patients (5.4%) in the milvexian group and 365 patients (5.1%) in the placebo group (HR 1.05, 95% CI 0.91-1.21, P=0.50) after a median follow up of 12.2 months.

LIBREXIA ACS was presented at the European Society of Cardiology (ESC) Congress in Munich, Germany. The results were published simultaneously in the New England Journal of Medicine.

Milvexian’s developer suspended LIBREXIA ACS in November 2025, and issued an update disclosing that, based on an interim analysis, the trial was “unlikely to meet the primary efficacy endpoint.” The data and safety monitoring board (DSMB) recommended halting the trial for futility, according to the update.

But study author P. Gabriel Steg, MD, of Bichat-Claude Bernard Hospital and Paris Diderot University, emphasized that there was some “good news:” Milvexian did not increase the primary safety outcome, Bleeding Academic Research Consortium (BARC) type 3c or 5 bleeding indicating intracranial or intraocular bleeding that compromises vision or fatal bleeding, or any other measures of major bleeding in the trial.

BARC type 3c or 5 bleeding occurred in 23 patients (0.3%) in the milvexian group and in 22 patients (0.3%) in the placebo group (P=0.88).

“Why is this important in terms of safety? Because milvexian is currently being evaluated in two other large trials, one in atrial fibrillation, and one in secondary stroke prevention,” Steg noted, “so that safety is an important feature.”

Those phase III trials, LIBREXIA AF and LIBREXIA STROKE, are ongoing. The DSMB had “recommended these trials continue as planned, with topline data expected in 2026,” per the developer.

ESC discussant Marc S. Sabatine, MD, of Brigham and Women’s Hospital in Boston, pointed out that the high rate of revascularization after ACS in this study, at 92% of patients, and the high use of prolonged dual antiplatelet therapy (DAPT) may have made it more difficult to see a benefit with treatment.

“Nonetheless, the results were clear,” Sabatine said. “There was no benefit for milvexian in this study.” Even though it was stopped early, the 95% CIs “are sufficiently narrow that it’s unlikely that we’re missing a clinically meaningful benefit with this drug, at this dose, for these outcomes in this particular population, and for the duration of treatment.”

The low bleeding risk was positive, but also calls into question how efficacious the drug actually is, Sabatine said. Still, another novel factor XIa inhibitor, asundexian, was ineffective in atrial fibrillation compared to apixaban (Eliquis), but effective against placebo for secondary stroke prevention.

“The optimal degree of factor XI or XIa inhibition that is needed in different patient populations, I think that remains undefined, and therefore, there’s much more to be learned from ongoing trials, testing other doses, and other drugs,” he concluded.

Factor XI is essential for thrombosis, but not hemostasis, raising hope that inhibitors of this factor may produce a safe series of anticoagulants, Steg noted. LIBREXIA ACS compared 25 mg of milvexian twice daily, added to standard antiplatelet therapy within 7 days of an ACS event, to placebo.

The choice of antiplatelet therapy was left to the investigators, either DAPT for more than 90 days, DAPT for less than 90 days, or single platelet therapy, and randomization was stratified by antiplatelet therapy.

The planned interim analysis was based on 556 adjudicated efficacy endpoints, at which time the trial was terminated for futility, the researchers noted. A total of 14,194 patients were enrolled from almost 900 international sites, with 7,094 assigned to milvexian and 7,100 to placebo.

Patients had to have ACS with two or more risk factors, and more than half had three risk factors, Steg noted, making them a group at increased risk. Despite background therapy and percutaneous coronary intervention with prolonged DAPT, plus the majority of patients receiving more potent P2Y12 inhibitors, “the incidence of MACE [major adverse CV events] was high, and there remains an unmet need,” he concluded.