Formulation-Specific Cardiovascular Outcomes with High-Dose Eicosapentaenoic Acid: A Systematic Review and Meta-analysis
Abstract
Background/objective: Residual cardiovascular risk persists despite intensive statin therapy in patients with established atherosclerotic cardiovascular disease (CVD). Omega-3 fatty acids, particularly high-dose eicosapentaenoic acid (EPA), have been proposed as adjunctive therapy, yet trial results conflict, likely due to formulation differences. We conducted a formulation-focused meta-analysis to determine whether high-dose EPA-dominant supplementation reduces cardiovascular events and to quantify the impact of mixed EPA/docosahexaenoic acid (DHA) regimens on efficacy.
Methods: Following Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) 2020 guidelines, we searched MEDLINE, Embase, CENTRAL, and trial registries through May 2025 for randomized controlled trials, including placebo-controlled and open-label designs, of high-dose EPA-dominant omega-3 (≥ 1.8 g/day; ≥ 50% EPA) in adults with established CVD or other high-risk settings. Six trials (n = 42,738; 31-85% male) were eligible. Random-effects models generated pooled risk ratios (RRs), with I2 assessing heterogeneity; sensitivity analyses excluded mixed EPA/DHA formulations. Imaging surrogate outcomes were summarized narratively when study modalities were not directly comparable.
Results: EPA-based therapy significantly reduced hospitalizations for unstable angina (RR 0.75, 95% CI 0.66-0.87; I2 = 0%). Overall effects on recurrent myocardial infarction and revascularization were not statistically…
How strong is the evidence?
Evidence Hub reads this as a meta-analysis, done in people. Its evidence level is 1 of 5 (Highest · pooled evidence). Pooled evidence from several studies sits at the top of the evidence pyramid. Reported size: 42,738 participants or records.
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