Use of Supplemental Long Chain Omega-3 Fatty Acids and Risk for Cardiac Death: An Updated Meta-Analysis and Review of Research Gaps

By Orsolya M. Palacios, RD, PhD and Kevin C. Maki, PhD

Randomized, controlled trials (RCTs) assessing the use of supplemental long chain omega-3 polyunsaturated fatty acids (LC-OM3), mainly eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), on risk for various types of cardiovascular disease events have yielded mixed results.  Some studies have suggested a beneficial effect, while others shown a neutral effect.  The outcome for which both the observational evidence on LC-OM3 intake or status and RCTs of supplementation appears to show the most consistent association is cardiac death.  Therefore, this meta-analysis and review of research gaps was conducted with two aims: 1) to update and further explore the available RCT data regarding LC-OM3 supplementation and risk for cardiac death; and 2) to briefly review the evidence regarding the effects of LC-OM3 intake on cardiac event risk, and to propose testable hypotheses for the mixed results obtained in RCTs regarding supplemental LC-OM3 use and cardiac event risk.

A literature search was conducted using PubMed and Ovid/Medline to identify RCTs examining supplemental LC-OM3 use (as dietary supplements or pharmaceutical LC-OM3 concentrates) and the outcome of cardiac death.  An intervention period of at least one year was required to be included in the primary analysis.  Studies that provided LC-OM3 in a food vehicle and studies in which the subjects had implanted cardiac defibrillators were excluded from the primary analysis but included in the secondary analysis.  Meta-analysis was employed to compare cumulative frequencies of cardiac death events between the LC-OM3 and control groups, including sensitivity and subset analyses.  Fourteen RCTs were identified for the primary analysis (71,899 subjects).  In the LC-OM3 arms, 1613 cardiac deaths were recorded (4.48% of subjects), compared to 1746 cardiac deaths in the control groups (4.87% of subjects). The pooled relative risk estimate showed an 8.0% (95% confidence interval 1.6%, 13.9%, p = 0.015) lower risk in the LC-OM3 arms vs. controls. Subset analyses showed numerically larger effects (12.9% to 29.1% lower risks, all p < 0.05) in RCTs with EPA+DHA dosages >1 g/d and with higher risk groups (secondary prevention, baseline mean or median triglycerides (TG) ≥150 mg/dL or low-density lipoprotein cholesterol (LDL-C) ≥130 mg/dL, statin use <40% of subjects). Heterogeneity was low (I2 ≤ 15.5%, p > 0.05) for the primary and subset analyses.


The present meta-analysis of RCTs showed a modest, but statistically significant, benefit of LC-OM3 supplementation on risk for cardiac death (8.0% in the primary analysis). Subgroup analyses show numerically larger benefits (12.9% to 29.1%, all p < 0.05) in studies that used >1 g/d of EPA+DHA, and in higher risk groups, including those with greater mean or median levels of TGs (≥150 mg/dL) or LDL-C (≥130 mg/dL), secondary prevention study samples, and studies with lower baseline use of statins (which is also a proxy for use of other cardioprotective agents).  These results suggest that additional research is warranted to further evaluate the potential risk reduction with LC-OM3 supplementation at higher dosages, and in higher risk samples.  Future RCTs should include evaluation of biomarkers of omega-3 status at baseline and during treatment, and should be designed to test specific hypotheses about the mechanisms through which benefits might be produced.  Taken together, the results of this analysis support the recent Science Advisory from the American Heart Association that concluded LC-OM3 “treatment is reasonable” for: 1) secondary prevention of coronary heart disease (CHD) and sudden cardiac death among patients with prevalent CHD, and 2) secondary prevention of adverse outcomes in patients with heart failure.  Because of the low risk for adverse effects with LC-OM3 supplementation, even a modest benefit is clinically meaningful.

A podcast by the lead author discussing this study is posted at Consultant 360:


Photo by Caroline Attwood

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