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Original research
Omega-3 supplementation and cardiovascular disease: formulation-based systematic review and meta-analysis with trial sequential analysis
  1. Evangelos C Rizos1,2,
  2. Georgios Markozannes3,
  3. Apostolos Tsapas4,5,
  4. Christos S Mantzoros6,7,
  5. Evangelia E Ntzani3,8,9
  1. 1 Department of Internal Medicine, University Hospital of Ioannina, Ioannina, Greece
  2. 2 School of Medicine, European University of Cyprus, Nicosia, Cyprus
  3. 3 Evidence-Based Medicine Unit, Department of Hygiene and Epidemiology, University of Ioannina School of Medicine, Ioannina, Greece
  4. 4 Clinical Research and Evidence-Based Medicine Unit, Aristotle University of Thessaloniki, Hippokration Hospital, Thessaloniki, Greece
  5. 5 Harris Manchester College, University of Oxford, Oxford, UK
  6. 6 Department of Medicine, Beth Isreal Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA
  7. 7 Section of Endocrinology, Boston VA Healthcare System, Harvard Medical School, Boston, Massachusetts, USA
  8. 8 Center for Evidence Synthesis in Health, Department of Health Services, Policy and Practice, School of Public Health, Brown University, Providence, Rhode Island, USA
  9. 9 Institute of Biosciences, University Research Center of loannina, University of Ioannina, Ioannina, Greece
  1. Correspondence to Dr Evangelia E Ntzani, Department of Hygiene and Epidemiology, University of Ioannina School of Medicine (UISM), Ioannina 45110, Greece; entzani{at}


Background Omega-3 supplements are popular for cardiovascular disease (CVD) prevention. We aimed to assess the association between dose-specific omega-3 supplementation and CVD outcomes.

Design We included double-blind randomised clinical trials with duration ≥1 year assessing omega-3 supplementation and estimated the relative risk (RR) for all-cause mortality, cardiac death, sudden death, myocardial infarction and stroke. Primary analysis was a stratified random-effects meta-analysis by omega-3 dose in 4 a priori defined categories (<1, 1, 2, ≥3 of 1 g capsules/day). Complementary approaches were trial sequential analysis and sensitivity analyses for triglycerides, prevention setting, intention-to-treat analysis, eicosapentaenoic acid, sample size, statin use, study duration.

Results Seventeen studies (n=83 617) were included. Omega-3 supplementation as ≤1 capsule/day was not associated with any outcome under study; futility boundaries were crossed for all-cause mortality and cardiac death. For two capsules/day, we observed a statistically significant reduction of cardiac death (n=3, RR 0.55, 95% CI 0.33 to 0.90, I2=0%); for ≥3 capsules/day we observed a statistically significant reduction of cardiac death (n=3, RR 0.82, 95% CI 0.68 to 0.99, I2=0%), sudden death (n=1, RR 0.70, 95% CI 0.51 to 0.97) and stroke (n=2, RR 0.74, 95% CI 0.57 to 0.95, I2=0%).

Conclusion Omega-3 supplementation at <2 1 g capsules/day showed no association with CVD outcomes; this seems unlikely to change from future research. Compared with the robust scientific evidence available for low doses, the evidence for higher doses (2–4 1 g capsules/day) is weak. The emerging postulated benefit from high-dose supplementation needs replication and further evaluation as to the precise formulation and indication.

  • meta-analysis
  • coronary artery disease
  • stroke
  • cardiac risk factors and prevention

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  • ECR and GM are joint first authors.

  • ECR and GM contributed equally.

  • Contributors EEN had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Concept and design: all authors. Acquisition, analysis or interpretation of data: all authors. Drafting of the manuscript: ECR, GM, EEN. Critical revision of the manuscript for important intellectual content: all authors. Statistical analysis: GM, EEN. Supervision: EEN.

  • Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

  • Competing interests None declared.

  • Patient and public involvement Patients and/or the public were not involved in the design, conduct, reporting or dissemination plans of this research.

  • Patient consent for publication Not required.

  • Ethics approval Ethical approval was not required by our institution because this study retrieved and synthesised anonymous data only from already published studies (not raw data provided by the authors).

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Data availability statement All data relevant to the study are included in the article or uploaded as supplementary information.

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