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 two 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.