Effect of omega-3 fatty acids on cardiovascular outcomes: A systematic review and meta-analysis

Safi U. Khan, Ahmad N. Lone, Muhammad Shahzeb Khan, Salim S. Virani, Roger S. Blumenthal, Khurram Nasir, Michael Miller, Erin D. Michos, Christie M. Ballantyne, William E. Boden, Deepak L. Bhatt

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124 Citations (Scopus)


Background: The effects of omega-3 fatty acids (FAs), such as eicosapentaenoic (EPA) and docosahexaenoic (DHA) acids, on cardiovascular outcomes are uncertain. We aimed to determine the effectiveness of omega-3 FAs on fatal and non-fatal cardiovascular outcomes and examine the potential variability in EPA vs. EPA+DHA treatment effects. Methods: We searched EMBASE, PubMed, ClinicalTrials.gov, and Cochrane library databases through June 7, 2021. We performed a meta-analysis of 38 randomized controlled trials of omega-3 FAs, stratified by EPA monotherapy and EPA+DHA therapy. We estimated random-effects rate ratios (RRs) with (95% confidence intervals) and rated the certainty of evidence using GRADE. The key outcomes of interest were cardiovascular mortality, non-fatal cardiovascular outcomes, bleeding, and atrial fibrillation (AF). The protocol was registered in PROSPERO (CRD42021227580). Findings: In 149,051 participants, omega-3 FA was associated with reducing cardiovascular mortality (RR, 0.93 [0.88-0.98]; p = 0.01), non-fatal myocardial infarction (MI) (RR, 0.87 [0.81–0.93]; p = 0.0001), coronary heart disease events (CHD) (RR, 0.91 [0.87–0.96]; p = 0.0002), major adverse cardiovascular events (MACE) (RR, 0.95 [0.92–0.98]; p = 0.002), and revascularization (RR, 0.91 [0.87–0.95]; p = 0.0001). The meta-analysis showed higher RR reductions with EPA monotherapy (0.82 [0.68–0.99]) than with EPA + DHA (0.94 [0.89–0.99]) for cardiovascular mortality, non-fatal MI (EPA: 0.72 [0.62–0.84]; EPA+DHA: 0.92 [0.85–1.00]), CHD events (EPA: 0.73 [0.62–0.85]; EPA+DHA: 0.94 [0.89–0.99]), as well for MACE and revascularization. Omega-3 FA increased incident AF (RR, 1.26 [1.08–1.48]). EPA monotherapy vs. control was associated with a higher risk of total bleeding (RR: 1.49 [1.20–1.84]) and AF (RR, 1.35 [1.10–1.66]). Interpretation: Omega-3 FAs reduced cardiovascular mortality and improved cardiovascular outcomes. The cardiovascular risk reduction was more prominent with EPA monotherapy than with EPA+DHA. Funding: None.

Original languageEnglish
Article number100997
Publication statusPublished - Aug 2021
Externally publishedYes


  • Docosahexaenoic acid
  • Eicosapentaenoic acid
  • Meta-analysis
  • Omega-3 fatty acid


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