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Background/Objective <p>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.</p> Methods <p>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 (≥&#xa0;1.8 g/day; ≥&#xa0;50% EPA) in adults with established CVD or other high-risk settings. Six trials (<i>n</i> = 42,738; 31–85% male) were eligible. Random-effects models generated pooled risk ratios (RRs), with <i>I</i><sup>2</sup> assessing heterogeneity; sensitivity analyses excluded mixed EPA/DHA formulations. Imaging surrogate outcomes were summarized narratively when study modalities were not directly comparable.</p> Results <p>EPA-based therapy significantly reduced hospitalizations for unstable angina (RR 0.75, 95% CI 0.66–0.87; <i>I</i><sup>2</sup> = 0%). Overall effects on recurrent myocardial infarction and revascularization were not statistically significant, but both became significant after exclusion of STRENGTH, the only mixed EPA/DHA cardiovascular outcomes trial. No significant effect was observed for ischemic stroke, cardiovascular death, or high-sensitivity C-reactive protein (hs-CRP). CHERRY and EVAPORATE both suggested attenuation of plaque progression, but these imaging studies were not pooled because intravascular ultrasound and coronary computed tomography angiography-derived measures were not directly comparable.</p> Conclusion <p>High-dose EPA-dominant therapy was associated with fewer unstable angina hospitalizations, and formulation appeared to modify clinical benefit. Among blinded, placebo-controlled, cardiovascular outcomes trials, 4 g/day icosapent ethyl is the only formulation independently associated with reduced cardiovascular events. Larger formulation-specific trials are needed to clarify the roles of purified EPA, mixed EPA/DHA regimens, and patient selection.</p> Registration <p>PROSPERO identifier number: CRD420251063069.</p>

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

  • 期刊论文

  • 发表日期：

    2026年5月2日

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  • Muhammad Anas Faheem,
  • Bazil Azeem,
  • Talha Ali,
  • Rabia Asim,
  • Tazheen Saleh Muhammad,
  • Mata-e-Alla Dogar,
  • Muhammad Abdullah Naveed

摘要

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 significant, but both became significant after exclusion of STRENGTH, the only mixed EPA/DHA cardiovascular outcomes trial. No significant effect was observed for ischemic stroke, cardiovascular death, or high-sensitivity C-reactive protein (hs-CRP). CHERRY and EVAPORATE both suggested attenuation of plaque progression, but these imaging studies were not pooled because intravascular ultrasound and coronary computed tomography angiography-derived measures were not directly comparable.

Conclusion

High-dose EPA-dominant therapy was associated with fewer unstable angina hospitalizations, and formulation appeared to modify clinical benefit. Among blinded, placebo-controlled, cardiovascular outcomes trials, 4 g/day icosapent ethyl is the only formulation independently associated with reduced cardiovascular events. Larger formulation-specific trials are needed to clarify the roles of purified EPA, mixed EPA/DHA regimens, and patient selection.

Registration

PROSPERO identifier number: CRD420251063069.