Effects of icosapent ethyl on coagulation biomarkers and their association with event-free survival in high-risk cardiovascular patients: a post hoc analysis of the REDUCE-IT

Introduction The Reduction of Cardiovascular Events with Icosapent Ethyl-Intervention Trial (REDUCE-IT) showed that icosapent ethyl (IPE) reduces major adverse cardiovascular events (MACE) in high-risk patients with hypertriglyceridemia. While IPE is approved as an adjunct to statins for triglyceride reduction, emerging data indicate additional cardioprotective actions beyond lipid modulation. As elevated baseline pro-coagulant activity is linked to higher cardiovascular (CV) risk, this analysis aimed to evaluate whether IPE, a highly purified ethyl ester of eicosapentaenoic acid (EPA), affects coagulation or fibrinolytic pathways. Methods This post hoc analysis examined a subset of high-risk patients from the REDUCE-IT (n=100 IPE; n=100 placebo) who had experienced myocardial infarction or unstable angina within the 12 months before randomization. Blood samples collected at baseline and after 2 years were analyzed using Luminex 200 technology to quantify circulating levels of tissue factor (TF), TF pathway inhibitor (TFPI), and plasminogen activator inhibitor-1 (PAI-1). Group comparisons were performed using generalized linear models. For the time-to-event analyses, patients were stratified by the median baseline TF level (46.5 pg/mL) across the entire cohort, resulting in four subgroups: placebo-low TF, placebo-high TF, IPE-low TF, and IPE-high TF. Kaplan–Meier curves were generated to assess the first occurrence of the primary composite endpoint as defined in REDUCE-IT. Complementary in vitro experiments were conducted in primary human aortic endothelial cells (HAECs) treated with increasing EPA concentrations prior to stimulation with tumor necrosis factor (TNF)-α. Protein expression of TF, TFPI, and PAI-1 were assessed by western blot. Results TF blood levels were reduced after 2 years in IPE-treated patients compared with placebo (median 49.4 and 55.8 pg/mL, p=0.046). Consistently, EPA (8×10-5 M) decreased TF protein expression in TNF-α–stimulated HAECs (p=0.032), whereas TFPI and PAI-1 levels were unaffected in patients or in vitro (Figure 1). Event-free survival varied across the four TF-stratified groups (log-rank p=0.022), with the placebo-high baseline TF group experiencing the highest incidence of events over time. This contrast was most evident when comparing placebo-high baseline TF patients with IPE treated-high baseline TF patients (red and gold curves, Figure 2). Conclusion IPE reduces circulating TF levels in a subset of high-risk CV patients of the REDUCE-IT; similarly, it reduces TF in HAECs exposed to TNF-α. Patients with higher baseline TF demonstrated more favorable event-free survival under IPE treatment, whereas the placebo-high baseline TF subgroup exhibites the greatest incidence of events. The findings herein offer an additional mechanistic explanation for the MACE reduction reported in REDUCE-IT and support an antithrombotic effect of IPE, especially among patients with high baseline TF.