Formulation-Specific Cardiovascular Outcomes with High-Dose Eicosapentaenoic Acid: A Systematic Review and...

Area of Science:

• Cardiology
• Pharmacology
• Nutritional Science

Background:

• Residual cardiovascular risk persists in patients with established atherosclerotic cardiovascular disease (CVD) despite statin therapy.
• Omega-3 fatty acids, specifically high-dose eicosapentaenoic acid (EPA), are explored as adjunctive treatments.
• Conflicting trial results necessitate a formulation-focused meta-analysis.

Purpose of the Study:

• To evaluate if high-dose EPA-dominant omega-3 supplementation reduces cardiovascular events.
• To quantify the impact of mixed EPA/docosahexaenoic acid (DHA) regimens on efficacy.
• To analyze formulation differences in omega-3 cardiovascular outcomes trials.

Main Methods:

• A PRISMA 2020-guided meta-analysis of randomized controlled trials (RCTs) was performed.
• Searched MEDLINE, Embase, CENTRAL, and trial registries up to May 2025.
• Included trials with high-dose EPA-dominant omega-3 (≥1.8 g/day; ≥50% EPA) in adults with established CVD or high-risk settings; six trials (n=42,738) were eligible.

Main Results:

• EPA-based therapy significantly reduced hospitalizations for unstable angina (RR 0.75).
• Exclusion of mixed EPA/DHA formulations (STRENGTH trial) revealed significant effects on recurrent myocardial infarction and revascularization.
• No significant effects were observed for ischemic stroke, cardiovascular death, or hs-CRP; plaque progression data were not pooled due to heterogeneity.

Conclusions:

• High-dose EPA-dominant therapy is associated with reduced unstable angina hospitalizations.
• Formulation significantly impacts clinical benefit; 4 g/day icosapent ethyl is the only formulation independently linked to reduced cardiovascular events in blinded, placebo-controlled trials.
• Further formulation-specific trials are required to clarify the roles of purified EPA, mixed EPA/DHA, and patient selection in cardiovascular risk reduction.