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Meta-Analysis
. 2018 Mar 1;3(3):225-234.
doi: 10.1001/jamacardio.2017.5205.

Associations of Omega-3 Fatty Acid Supplement Use With Cardiovascular Disease Risks: Meta-analysis of 10 Trials Involving 77 917 Individuals

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Free PMC article
Meta-Analysis

Associations of Omega-3 Fatty Acid Supplement Use With Cardiovascular Disease Risks: Meta-analysis of 10 Trials Involving 77 917 Individuals

Theingi Aung et al. JAMA Cardiol. .
Free PMC article

Abstract

Importance: Current guidelines advocate the use of marine-derived omega-3 fatty acids supplements for the prevention of coronary heart disease and major vascular events in people with prior coronary heart disease, but large trials of omega-3 fatty acids have produced conflicting results.

Objective: To conduct a meta-analysis of all large trials assessing the associations of omega-3 fatty acid supplements with the risk of fatal and nonfatal coronary heart disease and major vascular events in the full study population and prespecified subgroups.

Data sources and study selection: This meta-analysis included randomized trials that involved at least 500 participants and a treatment duration of at least 1 year and that assessed associations of omega-3 fatty acids with the risk of vascular events.

Data extraction and synthesis: Aggregated study-level data were obtained from 10 large randomized clinical trials. Rate ratios for each trial were synthesized using observed minus expected statistics and variances. Summary rate ratios were estimated by a fixed-effects meta-analysis using 95% confidence intervals for major diseases and 99% confidence intervals for all subgroups.

Main outcomes and measures: The main outcomes included fatal coronary heart disease, nonfatal myocardial infarction, stroke, major vascular events, and all-cause mortality, as well as major vascular events in study population subgroups.

Results: Of the 77 917 high-risk individuals participating in the 10 trials, 47 803 (61.4%) were men, and the mean age at entry was 64.0 years; the trials lasted a mean of 4.4 years. The associations of treatment with outcomes were assessed on 6273 coronary heart disease events (2695 coronary heart disease deaths and 2276 nonfatal myocardial infarctions) and 12 001 major vascular events. Randomization to omega-3 fatty acid supplementation (eicosapentaenoic acid dose range, 226-1800 mg/d) had no significant associations with coronary heart disease death (rate ratio [RR], 0.93; 99% CI, 0.83-1.03; P = .05), nonfatal myocardial infarction (RR, 0.97; 99% CI, 0.87-1.08; P = .43) or any coronary heart disease events (RR, 0.96; 95% CI, 0.90-1.01; P = .12). Neither did randomization to omega-3 fatty acid supplementation have any significant associations with major vascular events (RR, 0.97; 95% CI, 0.93-1.01; P = .10), overall or in any subgroups, including subgroups composed of persons with prior coronary heart disease, diabetes, lipid levels greater than a given cutoff level, or statin use.

Conclusions and relevance: This meta-analysis demonstrated that omega-3 fatty acids had no significant association with fatal or nonfatal coronary heart disease or any major vascular events. It provides no support for current recommendations for the use of such supplements in people with a history of coronary heart disease.

Conflict of interest statement

Conflict of Interest Disclosures: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Armitage is a principal investigator, and Dr Collins is Chair of the Trial Steering Committee for the ASCEND trial of omega-3 FA supplements for prevention of vascular disease in diabetes. Dr Collins reports grants from Mylan (formerly Solvay and Abbott) outside the submitted work. Dr Geleijnse reports grants from Unilever during the conduct of the study. Dr Gerstein reports grants and personal fees from Sanofi, grants and personal fees from Eli Lilly, grants and personal fees from Astra Zeneca, grants and personal fees from Boehringer Ingelheim, personal fees from Abbot, grants and personal fees from Novo Nordisk, grants and personal fees from Merck, personal fees from Amgen, and personal fees from Jannsen, all outside the submitted work. Dr Rauch reports grants from Trommsdorff GmbH & Co. KG during the conduct of the study. Dr Tavazzi reports grants from Servier and grants from CVIE Therapeutics outside the submitted work. No other disclosures are reported.

Figures

Figure 1.
Figure 1.. Associations of Omega-3 Fatty Acids With Major Vascular Events
The number of events by allocated treatment are presented for individual trials and subgroups of trials; participants can contribute only once to subtotals and totals of major vascular events. Rate ratios for individual trials or subgroups of trials are indicated by squares and 99% CIs by horizontal lines. Overall totals and their 95% confidence intervals are represented by diamonds. The size of the squares and the diamonds are proportional to the statistical information conveyed.
Figure 2.
Figure 2.. Associations of Omega-3 Fatty Acids With Subtypes of Coronary Heart Disease and Major Vascular Events, by Trial
Symbols and conventions as in Figure 1. Study names are AREDS-2, Age-Related Eye Disease Study 2; DOIT, Diet and Omega-3 Intervention Trial; GISSI-HF, Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto Miocardico-Heart Failure; GISSI-P, Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto Miocardico-Prevenzione; JELIS, Japan Eicosapentaenoic Acid (EPA) Lipid Intervention Study; OMEGA, Effect of Omega 3-Fatty Acids on the Reduction of Sudden Cardiac Death After Myocardial Infarction; ORIGIN, Outcome Reduction With Initial Glargine Intervention; SU.FOL.OM3, Supplémentation en Folates et Omega-3; R&P, Risk and Prevention Study. Rate ratios for individual trials or subgroups of trials are indicated by squares and the 99% CIs by the horizontal lines. Overall totals and their 95% confidence intervals are represented by diamonds. Arrowheads indicate error bars that extend beyond the area shown. Heterogeneity between all trials (χ29 in all cases) for nonfatal myocardial infarction, coronary heart disease death, any coronary heart disease, and major vascular events were 10.18 (P = .34), 12.3 (P = .20), 12.92 (P = .17), and 7.68 (P = .57), respectively.
Figure 3.
Figure 3.. Associations of Omega-3 Fatty Acids With Major Vascular Events, in Prespecified Subgroups
Symbols and conventions as in Figure 1. Total cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, and triglycerides were measured in mg/dL (to convert cholesterol to mmol/L, multiply by 0.0259; triglycerides, multiply by 0.0113). Heterogeneity between all trials (χ21 in all cases) was 0.04 (P = .84) for sex, 5.59 (P = .02) for age, 0.0 (P = .96) for prior coronary heart disease, 7.03 (P = .01) for prior stroke, 0.0 (P > .99) for prior diabetes, 0.87 (P = .35) for total cholesterol, 1.56 (P = .21) for high-density lipoprotein cholesterol, 1.8 (P = .18) for low-density lipoprotein cholesterol, 0.02 (P = .89) for triglycerides, and 2.55 (P = .11) for prior statin use.
Figure 4.
Figure 4.. Associations of Omega-3 Fatty Acids With Fatal and Nonfatal Vascular Events, by Trial Design
Symbols and conventions as in Figure 1. Heterogeneity between trial designs (χ21 in all cases) was 1.05 (P = .31) for nonfatal myocardial infarction, 3.26 (P = .07) for coronary heart disease death, and 4.81 (P = .03) for any coronary heart disease.

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