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

doi:10.1016/j.eclinm.2021.100997

. 2021 Jul 8:38:100997.

doi: 10.1016/j.eclinm.2021.100997. eCollection 2021 Aug.

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

Safi U Khan¹, Ahmad N Lone¹, Muhammad Shahzeb Khan², Salim S Virani³, Roger S Blumenthal^{4

5}, Khurram Nasir^{6

7}, Michael Miller⁸, Erin D Michos^{4

5}, Christie M Ballantyne³, William E Boden⁹, Deepak L Bhatt¹⁰

Affiliations

¹ Department of Medicine, West Virginia University, Morgantown, WV, United States.
² Department of Medicine, University of Mississippi Medical Center, Jackson, MS, United States.
³ Michael E. DeBakey Veterans Affair Medical Center & Department of Medicine, Baylor College of Medicine, Houston, TX, United States.
⁴ Ciccarone Center for the Prevention of Cardiovascular Disease, Johns Hopkins School of Medicine, Baltimore, MD, United States.
⁵ Division of Cardiology, Johns Hopkins School of Medicine, Baltimore, MD, United States.
⁶ Outcomes Research, Houston Methodist, Houston, TX, United States.
⁷ Division of Cardiovascular Prevention and Wellness, Department of Cardiology, Houston Methodist DeBakey Heart & Vascular Center, Houston, TX, United States.
⁸ Department of Medicine, Division of Cardiology, University of Maryland Medical Center, Baltimore, MD, United States.
⁹ VA New England Healthcare System, Boston University School of Medicine, Boston, MA, United States.
¹⁰ Brigham and Women's Hospital Heart and Vascular Center, Harvard Medical School, 75 Francis Street, Boston, MA 02115, United States.

PMID: 34505026
PMCID: PMC8413259
DOI: 10.1016/j.eclinm.2021.100997

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

Safi U Khan et al. EClinicalMedicine. 2021.

. 2021 Jul 8:38:100997.

doi: 10.1016/j.eclinm.2021.100997. eCollection 2021 Aug.

Authors

Affiliations

¹ Department of Medicine, West Virginia University, Morgantown, WV, United States.
² Department of Medicine, University of Mississippi Medical Center, Jackson, MS, United States.
³ Michael E. DeBakey Veterans Affair Medical Center & Department of Medicine, Baylor College of Medicine, Houston, TX, United States.
⁴ Ciccarone Center for the Prevention of Cardiovascular Disease, Johns Hopkins School of Medicine, Baltimore, MD, United States.
⁵ Division of Cardiology, Johns Hopkins School of Medicine, Baltimore, MD, United States.
⁶ Outcomes Research, Houston Methodist, Houston, TX, United States.
⁷ Division of Cardiovascular Prevention and Wellness, Department of Cardiology, Houston Methodist DeBakey Heart & Vascular Center, Houston, TX, United States.
⁸ Department of Medicine, Division of Cardiology, University of Maryland Medical Center, Baltimore, MD, United States.
⁹ VA New England Healthcare System, Boston University School of Medicine, Boston, MA, United States.
¹⁰ Brigham and Women's Hospital Heart and Vascular Center, Harvard Medical School, 75 Francis Street, Boston, MA 02115, United States.

PMID: 34505026
PMCID: PMC8413259
DOI: 10.1016/j.eclinm.2021.100997

Abstract

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.

Keywords: Docosahexaenoic acid; Eicosapentaenoic acid; Meta-analysis; Omega-3 fatty acid.

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Conflict of interest statement

Dr. Deepak L. Bhatt reports grants from Amarin, grants from AstraZeneca, grants from Bristol-Myers Squibb, grants from Eisai, grants from Ethicon, grants from Medtronic, grants from Sanofi Aventis, grants from The Medicines Company, unfunded research collaborations with FlowCo, grants and other from PLx Pharma, unfunded research collaborations with Takeda, personal fees from Duke Clinical Research Institute, personal fees from Mayo Clinic, personal fees from Population Health Research Institute, personal fees, non-financial support and other from American College of Cardiology, personal fees from Belvoir Publications, personal fees from Slack Publications, personal fees from WebMD, personal fees from Elsevier. Dr Bhatt is on the edvisoty board of Medscape Cardiology and Regado Biosciences, and on the borad of directoprs of Boston VA Research Institute, reports personal fees and non-financial support from Society of Cardiovascular Patient Care, non-financial support from American Heart Association, personal fees from HMP Global, grants from Roche, personal fees from Harvard Clinical Research Institute (now Baim Institute for Clinical Research), other from Clinical Cardiology, personal fees from Journal of the American College of Cardiology, other from VA, grants from Pfizer, grants from Forest Laboratories/AstraZeneca, grants from Ischemix, other from St. Jude Medical (now Abbott), other from Biotronik, grants and other from Cardax, other from Boston Scientific, grants from Amgen, grants from Lilly, grants from Chiesi, grants from Ironwood, personal fees from Cleveland Clinic, personal fees from Mount Sinai School of Medicine, other from Merck, grants from Abbott, grants from Regeneron, other from Svelte, grants and other from PhaseBio, grants from Idorsia, grants from Synaptic, personal fees from TobeSoft, grants, personal fees and other from Boehringer Ingelheim, personal fees from Bayer, grants and other from Novo Nordisk, grants from Fractyl, personal fees from Medtelligence/ReachMD, personal fees from CSL Behring, grants and other from Cereno Scientific, grants from Afimmune, grants from Ferring Pharmaceuticals, other from CSI, grants from Lexicon, personal fees from MJH Life Sciences, personal fees from Level Ex, grants from Contego Medical, grants and other from CellProthera, personal fees from K2P, personal fees from Canadian Medical and Surgical Knowledge Translation Research Group, grants and other from MyoKardia/BMS, grants from Owkin, grants from HLS Therapeutics, grants and other from Janssen, grants from 89Bio, grants and other from Novo Nordisk, grants from Garmin, grants and collaborations from Novartis, outside the submitted work. Dr. Salim S. Virani reports grants from Department of Veterans Affairs, World Heart Federation, Tahir and Jooma Family, other from American College of Cardiology, outside the submitted work. Dr. Michael Miller reports personal fees from Amarin, outside the submitted work. Dr. Christie Ballantyne reports personal fees from Amarin, during the conduct of the study; grants and personal fees from Abbott Diagnostic, personal fees from AstraZeneca, grants and personal fees from Amgen, grants and personal fees from Esperion, personal fees from Matinas BioPharma, personal fees from Pfizer, grants and personal fees from Novartis, grants and personal fees from Regeneron, grants and personal fees from Roche Diagnostic, personal fees from Sanofi-Synthelabo, grants from National Institutes of Health, grants from American Heart Association, grants from American Diabetes Association, personal fees from Althera, personal fees from Novo Nordisk, grants from Akcea, personal fees from Denka Seiken, personal fees from Gilead, personal fees from Genentech, personal fees from Corvidia, personal fees from Arrowhead, personal fees from New Amsterdam, grants from Ionis, outside the submitted work. All the other authors have nothing to disclose.

Figures

**Fig. 1**
Flow chart showing study selection process.

**Fig. 2**
Effect of omega-3 fatty acid on cardiovascular mortality. AREDS2: Age-Related Eye Disease Study 2; ASCEND: A Study of Cardiovascular Events in Diabetes; CI: confidence interval; DHA: Docosahexaenoic acid; DO IT: The Diet and Omega-3 Intervention Trial; EPA: Eicosapentaenoic acid; FA: fatty acid; FAAT: Fatty Acid Antiarrhythmia Trial; GISSI-P: Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto miocardico-Prevenzione; GISSI-HF: Italiano per lo Studio della Sopravvivenza nell'Infarto miocardico-Heart Failure; HARP: Heart Attach Research Program; JELIS: Japan EPA Lipid Intervention Study; OFAMI: Omacor Following Acute Myocardial Infarction; ORIGIN: Outcome Reduction with an Initial Glargine Intervention; OMEMI: Omega-3 fatty acids in Elderly with Myocardial Infarction; REDUCE-IT: Reduction of Cardiovascular Events with Icosapent Ethyl-Intervention Trial; SOFA: Study on Omega-3 Fatty Acids and Ventricular Arrhythmia Trial; SU.FOL.OM3: Supplémentation en Folates et Omega-3; STRENGTH: Long-Term Outcomes Study to Assess Statin Residual Risk with Epanova in High Cardiovascular Risk Patients with Hypertriglyceridemia; TG: triglycerides; VITAL: Vitamin D and Omega-3 Trial.

**Fig. 3**
Effect of omega-3 fatty acid on non-fatal myocardial infarction. AREDS2: Age-Related Eye Disease Study 2; ASCEND: A Study of Cardiovascular Events in Diabetes; CI: confidence interval; DHA: Docosahexaenoic acid; EPA: Eicosapentaenoic acid; FA: fatty acid; FORWARD: Randomized Trial to Assess Efficacy of PUFA for the Maintenance of Sinus Rhythm in Persistent Atrial Fibrillation Fish Oil Research with omega-3 for Atrial Fibrillation Recurrence Delaying; GISSI-P: Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto miocardico-Prevenzione; GISSI-HF: Italiano per lo Studio della Sopravvivenza nell'Infarto miocardico-Heart Failure; HARP: Heart Attach Research Program; JELIS: Japan EPA Lipid Intervention Study; ORIGIN: Outcome Reduction with an Initial Glargine Intervention; OMEMI: Omega-3 fatty acids in Elderly with Myocardial Infarction; REDUCE-IT: Reduction of Cardiovascular Events with Icosapent Ethyl-Intervention Trial; SOFA: Study on Omega-3 Fatty Acids and Ventricular Arrhythmia Trial; SU.FOL.OM3: Supplémentation en Folates et Omega-3; STRENGTH: Long-Term Outcomes Study to Assess Statin Residual Risk with Epanova in High Cardiovascular Risk Patients with Hypertriglyceridemia; VITAL: Vitamin D and Omega-3 Trial.

**Fig. 4**
Effect of omega-3 fatty acid on coronary heart disease events. AREDS2: Age-Related Eye Disease Study 2; ASCEND: A Study of Cardiovascular Events in Diabetes; CI: confidence interval; DHA: Docosahexaenoic acid; DO IT: The Diet and Omega-3 Intervention Trial; EPE-A: Ethyl-eicosapentanoic Acid; EPA: Eicosapentaenoic acid; FORWARD: Randomized Trial to Assess Efficacy of PUFA for the Maintenance of Sinus Rhythm in Persistent Atrial Fibrillation Fish Oil Research with omega-3 for Atrial Fibrillation Recurrence Delaying; FA: fatty acid; FOSTAR: Fish oil in osteoarthritis; GISSI-P: Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto miocardico-Prevenzione; GISSI-HF: Italiano per lo Studio della Sopravvivenza nell'Infarto miocardico-Heart Failure; HARP: Heart Attach Research Program; JELIS: Japan EPA Lipid Intervention Study; LDL-C: Low-density lipoprotein-cholesterol; OFAMI: Omacor Following Acute Myocardial Infarction; ORIGIN: Outcome Reduction with an Initial Glargine Intervention; OMEMI: Omega-3 fatty acids in Elderly with Myocardial Infarction; REDUCE-IT: Reduction of Cardiovascular Events with Icosapent Ethyl-Intervention Trial; SHOT: Shunt Occlusion Trial; SCIMO: Study on Prevention of Coronary Atherosclerosis by Intervention with Marine Omega-3 fatty acids; SOFA: Study on Omega-3 Fatty Acids and Ventricular Arrhythmia Trial; SU.FOL.OM3: Supplémentation en Folates et Omega-3; STRENGTH: Long-Term Outcomes Study to Assess Statin Residual Risk with Epanova in High Cardiovascular Risk Patients with Hypertriglyceridemia; TG: triglycerides; VITAL: Vitamin D and Omega-3 Trial; y: years.

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References

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[1] Mason R.P., Libby P., Bhatt DL. Emerging mechanisms of cardiovascular protection for the omega-3 fatty acid eicosapentaenoic acid. Arterioscler Thromb Vasc Biol. 2020;40(5):1135–1147. - PMC - PubMed

[2] Mason R.P., Libby P., Bhatt DL. Emerging mechanisms of cardiovascular protection for the omega-3 fatty acid eicosapentaenoic acid. Arterioscler Thromb Vasc Biol. 2020;40(5):1135–1147. - PMC - PubMed

[3] Yokoyama M., Origasa H., Matsuzaki M. Effects of eicosapentaenoic acid on major coronary events in hypercholesterolaemic patients (JELIS): a randomised open-label, blinded endpoint analysis. Lancet. 2007;369(9567):1090–1098. - PubMed

[4] Yokoyama M., Origasa H., Matsuzaki M. Effects of eicosapentaenoic acid on major coronary events in hypercholesterolaemic patients (JELIS): a randomised open-label, blinded endpoint analysis. Lancet. 2007;369(9567):1090–1098. - PubMed

[5] Bowman L., Mafham M., Wallendszus K. Effects of n-3 fatty acid supplements in diabetes mellitus. N Engl J Med. 2018;379(16):1540–1550. - PubMed

[6] Bowman L., Mafham M., Wallendszus K. Effects of n-3 fatty acid supplements in diabetes mellitus. N Engl J Med. 2018;379(16):1540–1550. - PubMed

[7] Bhatt D.L., Steg P.G., Miller M. Cardiovascular risk reduction with icosapent ethyl for hypertriglyceridemia. N Engl J Med. 2019;380(1):11–22. - PubMed

[8] Bhatt D.L., Steg P.G., Miller M. Cardiovascular risk reduction with icosapent ethyl for hypertriglyceridemia. N Engl J Med. 2019;380(1):11–22. - PubMed

[9] Manson J.E., Cook N.R., Lee I.M. Marine n-3 fatty acids and prevention of cardiovascular disease and cancer. N Engl J Med. 2019;380(1):23–32. - PMC - PubMed

[10] Manson J.E., Cook N.R., Lee I.M. Marine n-3 fatty acids and prevention of cardiovascular disease and cancer. N Engl J Med. 2019;380(1):23–32. - PMC - PubMed

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

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

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