MUNICH — Adding the investigational factor XIa inhibitor milvexian to standard antiplatelet therapy did not reduce cardiovascular (CV) events after acute coronary syndrome (ACS), despite evidence that the drug was exerting its expected pharmacodynamic effect, according to the phase 3 LIBREXIA ACS trial.

The trial was stopped early for futility in November 2025 after a prespecified interim analysis indicated it was unlikely to meet its primary efficacy endpoint.

Final results, presented at the European Society of Cardiology (ESC) Congress 2026, showed CV death, myocardial infarction (MI), or ischemic stroke occurred in 5.4% of patients receiving milvexian compared with 5.1% receiving placebo, with no significant difference between the groups.

There was also no difference in the principal safety endpoint of intracranial, vision-threatening intraocular, or fatal bleeding, which occurred at an equally low rate in both groups. 

“Milvexian did not statistically significantly reduce MACE [major adverse cardiovascular events] after ACS on top of standard-of-care antiplatelet therapy at the dose studied of 25 mg twice daily,” said P. Gabriel Steg, MD, of Hôpital Bichat in Paris, who presented the findings prior to the presentation. However, he described the absence of an observed increase in intracranial or fatal bleeding as reassuring.

The results were simultaneously published in The New England Journal of Medicine.

Factor XIa: Testing a New Approach

Despite modern antiplatelet therapy, statins, and stents, patients remain at risk for recurrent ischemic events following ACS. Adding conventional anticoagulation can reduce thrombotic events but at the cost of increased bleeding.

Factor XIa inhibition has attracted interest as a way to reduce thrombosis without increasing bleeding. Factor XI may be important for thrombosis but less important for normal hemostasis, potentially offering a way to preserve antithrombotic efficacy while reducing bleeding risk, Steg said.

In LIBREXIA ACS, 14,194 patients were randomized across 44 countries to milvexian 25 mg twice daily (7094 patients) or placebo (7100 patients) within 7 days of an ACS. Patients had undergone cardiac catheterization with percutaneous coronary intervention (PCI) or were being managed conservatively and were required to have at least two additional risk factors for recurrent ischemic events. 

All patients received standard antiplatelet therapy as determined by the investigator. The mean age was 63.2 years and 78.1% were men. Around 57% presented with ST-segment elevation myocardial infarction (STEMI), 43% had diabetes, and approximately 92% underwent PCI for the index event.

Importantly, background antiplatelet treatment was intensive, with 95.2% receiving dual antiplatelet therapy (DAPT) at baseline, including 59.8% receiving potent platelet P2Y12 receptor inhibitors. At 1 year, 86.1% remained on DAPT. 

Why Was There No Benefit?

After a median follow-up of 12.2 months, the primary efficacy outcome — cardiovascular death, MI, or ischemic stroke — 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 = .50). 

The lack of efficacy did not appear to result simply from inadequate biological activity. At 4 weeks, trough activated partial thromboplastin time (aPTT) increased 1.59-fold with milvexian compared with 1.03-fold with placebo, consistent with the expected anticoagulant effect of factor XIa inhibition.

Steg said it’s difficult to say why milvexian did not translate into improved clinical outcomes before seeing results of other trials but offered three considerations. 

“First, the dose may have been insufficient, although we have biological evidence of anticoagulation, and a similar daily dose of asundexian [another investigational oral factor XIa inhibitor] was effective in OCEANIC-STROKE. Second, inhibiting thrombin generation with low-dose anticoagulation may be mostly useful in the first few months post-ACS and may lose value over the longer term,” he said.

“Third, previous trials that demonstrated the value of dual-pathway inhibition, combining low-dose anticoagulation and antiplatelet agents, were conducted in the era of monotherapy or dual antiplatelet therapy with aspirin and clopidogrel. In the present trial, the majority of patients were on potent antiplatelet agents, and that may have diminished the value of adding anticoagulation.”

Major Bleeding Not Increased

There was no detectable increase in major bleeding across several definitions, including BARC 3b, 3c, or 5 bleeding; ISTH (International Society on Thrombosis and Haemostasis) major bleeding; or noncoronary artery bypass graft (CABG)-related thrombolysis in myocardial infarction (TIMI) major bleeding. There was, however, a numerical increase in clinically relevant nonmajor BARC type 2 bleeding of 5.2% with milvexian compared with 4.5% with placebo (HR, 1.14; 95% CI, 0.98-1.33).

Steg described the bleeding findings as the “good news” from the trial. “Milvexian did not increase BARC 3c or 5 bleeding, the primary safety outcome, nor did it increase other measures of bleeding,” he said. The investigators noted that this was despite most patients receiving DAPT, many with potent P2Y12 inhibitors.

The trialists acknowledged that around 20% of participants discontinued assigned treatment and noted that the study included too few patients receiving antiplatelet monotherapy to determine whether milvexian might have efficacy with less intensive background antiplatelet treatment.

The findings do not directly answer whether factor XIa inhibition works in other settings. LIBREXIA AF is testing a substantially higher dose of milvexian, 100 mg twice daily, against apixaban in patients with atrial fibrillation, while LIBREXIA Stroke is assessing the 25-mg twice-daily regimen for secondary stroke prevention.

Referring to the two ongoing phase 3 trials, Steg said the safety findings of LIBREXIA ACS are important.

Discussant Marc S. Sabatine, MD, MPH, chair of the TIMI Study Group and professor of medicine at Harvard Medical School in Boston, Massachusetts, said the findings provided clear evidence that milvexian 25 mg twice daily offered no benefit when added to dual antiplatelet therapy in a modern, revascularized ACS population. 

Although the trial was stopped early, he said the confidence intervals were sufficiently narrow that it was unlikely a clinically meaningful benefit had been missed. He noted that 92% of patients underwent revascularization and that use of prolonged and potent dual antiplatelet therapy was high — factors that may have made an additional benefit from prolonged antithrombotic therapy harder to demonstrate.

However, Sabatine cautioned against interpreting the negative result as closing the door on factor XI/XIa inhibition. The absence of excess major bleeding raised the question of whether milvexian was “incredibly safe” or whether the 25-mg twice-daily dose simply provided insufficient inhibition for this setting. “The optimal degree of factor XI or XIa inhibition that is needed in different patient populations remains undefined,” he concluded, adding that ongoing trials of other doses and agents should provide further answers.

The trial was funded by Janssen and Bristol Myers Squibb. Steg has reported receiving consulting or speaking fees from Abcentra, Amarin, Amgen, AstraZeneca, Bayer, Bristol Myers Squibb, Boehringer Ingelheim, Idorsia, Janssen, Lilly, Merck, Novartis, Novo Nordisk, Pfizer, and Sanofi. He is chief medical officer at Bioquantis. Sabatine has declared research contracts with Amgen, AstraZeneca, Beijing Inno Medicine, Boehringer Ingelheim, Daiichi-Sankyo, lonis, Marea, Merck, Novartis, and Pfizer, and consulting, royalties, being an owner, or being a stockholder of a healthcare company for Amgen, General Medicines, Merck, Skeletalis, and Tigermed.