Purified EPA versus combined EPA/DHA in coronary heart disease: clinical outcomes, mechanisms, safety, and functional food perspectives

Abstract

Prescription omega-3 fatty acids have been widely investigated as adjunctive therapies for reducing residual cardiovascular risk in patients with coronary heart disease (CHD). Although purified eicosapentaenoic acid (EPA) and combined eicosapentaenoic acid/docosahexaenoic acid (EPA/DHA) formulations both lower triglyceride concentrations, their effects on major cardiovascular outcomes have differed substantially. This review critically compares the clinical efficacy, biological mechanisms, safety considerations, and therapeutic implications of purified EPA and combined EPA/DHA formulations in patients with CHD and related high-risk cardiovascular conditions. Evidence from epidemiological studies, randomized clinical trials, coronary imaging investigations, mechanistic studies, and post-hoc analyses was evaluated. Particular attention was given to formulation, dose, patient population, comparator selection, achieved omega-3 status, lipid responses, major adverse cardiovascular events, plaque characteristics, inflammation, endothelial function, platelet activity, and cardiac electrophysiology. Observational studies generally associate higher dietary or circulating omega-3 status with a lower risk of CHD. Clinical trials consistently demonstrate that prescription EPA and EPA/DHA formulations reduce triglyceride and very-low-density lipoprotein concentrations in statin-treated patients with persistent hypertriglyceridemia. However, cardiovascular outcome trials have produced divergent findings. Purified EPA reduced major adverse cardiovascular events in selected high-risk populations, whereas combined EPA/DHA formulations generally did not demonstrate comparable cardiovascular benefit despite similar triglyceride-lowering effects. Potential explanations include differences in formulation, dose, biological activity, achieved EPA concentrations, patient characteristics, placebo selection, inflammation, oxidative stress, endothelial function, plaque stability, platelet activity, and atrial fibrillation risk. Current evidence indicates that the cardiovascular effects of omega-3 therapy cannot be predicted from triglyceride reduction alone. Purified EPA has demonstrated the most consistent benefit in appropriately selected, statin-treated patients, whereas evidence supporting combined EPA/DHA formulations for cardiovascular event reduction remains less consistent. Direct head-to-head trials and biomarker-guided studies are needed to clarify which formulations, and patient populations provide the greatest benefit with an acceptable safety profile. Novelty of Study: This review integrates formulation-specific cardiovascular outcomes with mechanistic evidence, circulating fatty acid biomarkers, coronary imaging findings, safety considerations, and functional food science. It distinguishes prescription purified EPA, combined EPA/DHA formulations, conventional supplements, and marine food matrices according to their composition, biological exposure, clinical evidence, and intended use, while highlighting opportunities for biomarker-guided patient selection and structured development of marine-derived functional products. Keywords: omega-3 fatty acids; eicosapentaenoic acid; docosahexaenoic acid; coronary heart disease; hypertriglyceridemia; icosapent ethyl; cardiovascular outcomes; plaque stability