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A Meta-Analysis of Randomized Controlled Trials and Prospective Cohort Studies of Eicosapentaenoic and Docosahexaenoic Long-Chain Omega-3 Fatty Acids and Coronary Heart Disease Risk

      Abstract

      Objective

      To conduct meta-analyses of randomized controlled trials (RCTs) to estimate the effect of eicosapentaenoic and docosahexaenoic acid (EPA+DHA) on coronary heart disease (CHD), and to conduct meta-analyses of prospective cohort studies to estimate the association between EPA+DHA intake and CHD risk.

      Methods

      A systematic literature search of Ovid/Medline, PubMed, Embase, and the Cochrane Library from January 1, 1947, to November 2, 2015, was conducted; 18 RCTs and 16 prospective cohort studies examining EPA+DHA from foods or supplements and CHD, including myocardial infarction, sudden cardiac death, coronary death, and angina, were identified. Random-effects meta-analysis models were used to generate summary relative risk estimates (SRREs) and 95% CIs. Heterogeneity was examined in subgroup and sensitivity analyses and by meta-regression. Dose-response was evaluated in stratified dose or intake analyses. Publication bias assessments were performed.

      Results

      Among RCTs, there was a nonstatistically significant reduction in CHD risk with EPA+DHA provision (SRRE=0.94; 95% CI, 0.85-1.05). Subgroup analyses of data from RCTs indicated a statistically significant CHD risk reduction with EPA+DHA provision among higher-risk populations, including participants with elevated triglyceride levels (SRRE=0.84; 95% CI, 0.72-0.98) and elevated low-density lipoprotein cholesterol (SRRE=0.86; 95% CI, 0.76-0.98). Meta-analysis of data from prospective cohort studies resulted in a statistically significant SRRE of 0.82 (95% CI, 0.74-0.92) for higher intakes of EPA+DHA and risk of any CHD event.

      Conclusion

      Results indicate that EPA+DHA may be associated with reducing CHD risk, with a greater benefit observed among higher-risk populations in RCTs.

      Abbreviations and Acronyms:

      CHD (coronary heart disease), DHA (docosahexaenoic acid), EPA (eicosapentaenoic acid), HR (hazard ratio), LDL (low-density lipoprotein), MI (myocardial infarction), n-3 LCPUFA (omega-3 long-chain polyunsaturated fatty acids), RCT (randomized controlled trial), RR (relative risk as represented by rate ratios and hazard ratios), SRRE (summary relative risk estimate)
      Guidance from the American College of Cardiology/American Heart Association Task Force and other major health organizations, agencies, and public health groups recommend dietary patterns that include fish and/or greater intakes of fish or the omega-3 long-chain polyunsaturated fatty acids (n-3 LCPUFA) eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) for heart health.
      • Eckel R.H.
      • Jakicic J.M.
      • Ard J.D.
      • et al.
      2014 AHA/ACC guideline on lifestyle management to reduce cardiovascular risk: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines.
      Fats and fatty acids in human nutrition: report of an expert consultation.
      As the available literature on n-3 LCPUFA intake and coronary heart disease (CHD) risk increases, with some mixed results reported, comprehensive systematic reviews and meta-analyses that evaluate the scientific evidence from both clinical and observational study designs are needed. Therefore, the objective of our study was to perform a comprehensive meta-analysis of randomized controlled trials (RCTs) to estimate the effect of EPA+DHA on CHD, and to conduct a comprehensive meta-analysis of prospective cohort studies to estimate the association between EPA+DHA intake and CHD risk. Additional objectives included examining the effects of dose, as well as the effects of EPA+DHA on specific outcomes (eg, myocardial infarction) and among higher-risk populations (eg, those with elevated triglyceride levels) using subgroup analyses and meta-regression.

      Methods

      We followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines (see Supplemental Figure 1, available online at http://www.mayoclinicproceedings.org) for this systematic review and meta-analysis.
      • Moher D.
      • Liberati A.
      • Tetzlaff J.
      • Altman D.G.
      Prisma Group
      Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement.

      Literature Search and Study Selection

      Comprehensive literature searches using the PubMed, Ovid/Medline, and Embase databases were conducted. The Cochrane Library was also reviewed. Literature searches, which covered studies published from January 1, 1947, through November 2, 2015, were designed to identify RCTs and prospective cohort studies that examined EPA+DHA and CHD outcomes. The full Ovid Medline search strategy is included as Supplemental Material (see Supplemental Figure 2, available online at http://www.mayoclinicproceedings.org). Level I screening included review of all titles and/or abstracts. Supplementary literature searches included examining the reference lists of all relevant studies, published meta-analyses, and the report published by the Agency for Healthcare Research and Quality Technical Review in 2012.
      • Trikalinos T.A.
      • Lee J.
      • Moorthy D.
      • et al.
      Effects of eicosapentanoic acid and docosahexanoic acid on mortality across diverse settings: systematic review and meta-analysis of randomized trials and prospective cohorts.
      In addition, previously published reviews were scrutinized to identify pertinent studies that may not have been captured in our electronic searches.
      • Delgado-Lista J.
      • Perez-Martinez P.
      • Lopez-Miranda J.
      • Perez-Jimenez F.
      Long chain omega-3 fatty acids and cardiovascular disease: a systematic review.
      • Kotwal S.
      • Jun M.
      • Sullivan D.
      • Perkovic V.
      • Neal B.
      Omega 3 fatty acids and cardiovascular outcomes: systematic review and meta-analysis.
      • Kwak S.M.
      • Myung S.K.
      • Lee Y.J.
      • Seo H.G.
      Korean Meta-analysis Study Group
      Efficacy of omega-3 fatty acid supplements (eicosapentaenoic acid and docosahexaenoic acid) in the secondary prevention of cardiovascular disease: a meta-analysis of randomized, double-blind, placebo-controlled trials.
      • Rizos E.C.
      • Ntzani E.E.
      • Bika E.
      • Kostapanos M.S.
      • Elisaf M.S.
      Association between omega-3 fatty acid supplementation and risk of major cardiovascular disease events: a systematic review and meta-analysis.
      • Chen Q.
      • Cheng L.Q.
      • Xiao T.H.
      • et al.
      Effects of omega-3 fatty acid for sudden cardiac death prevention in patients with cardiovascular disease: a contemporary meta-analysis of randomized, controlled trials.
      • Filion K.B.
      • El Khoury F.
      • Bielinski M.
      • Schiller I.
      • Dendukuri N.
      • Brophy J.M.
      Omega-3 fatty acids in high-risk cardiovascular patients: a meta-analysis of randomized controlled trials.
      Full-text publications of all studies not eliminated at level I were retrieved for complete review at level II screening. All search results were screened by 2 individuals, with minor differences resolved by discussion and consultation with a third researcher.
      Included studies were required to report 1 or more of the following CHD outcomes: myocardial infarction (fatal or nonfatal), angina, sudden cardiac death, coronary death, and CHD incidence (for prospective cohort studies). Study populations included nonhospitalized adults (>18 y) with and without CHD but otherwise free of significant non–CHD-related disease pathologies. Studies were required to report hazard ratios (HR) or rate ratios (RR) of outcomes and measures of variance (ie, 95% CIs), or data were required to be available to calculate such measures. Additional information on the inclusion criteria, data extraction methods, and evaluation of study quality are available in Supplemental Figure 3 (available online at http://www.mayoclinicproceedings.org).
      For the RCTs, a composite variable, “any CHD event,” was created and defined as the combination of fatal or nonfatal myocardial infarction (MI), coronary death, sudden cardiac death, and angina. Fatal CHD events included fatal MI, coronary death, and sudden cardiac death. Nonfatal CHD events included nonfatal MI and angina. Coronary death included all fatal events minus sudden cardiac death. Individual events, that is, sudden cardiac death, were also analyzed separately. For the prospective cohort studies, “any CHD event” was defined as the combination of fatal or nonfatal MI, CHD incidence, coronary death, sudden cardiac death, and angina; fatal CHD events included fatal MI, coronary death, and sudden cardiac death; and nonfatal CHD events included angina, CHD incidence, and nonfatal MI.

      Statistical Analyses

      Primary statistical analyses using meta-analysis methodology were based on comparing rates of total CHD events, as well as specific CHD event outcomes between the EPA+DHA group and the control group. If studies did not report RRs, the absolute rate of CHD events was calculated for each group and then compared to produce an RR and 95% CI. Random-effects meta-analysis models were used to generate summary relative risk estimates (SRREs) and 95% CIs. Summary associations were interpreted as statistically significant (ie, P<.05) if the 95% CIs did not include the null value of 1.0 in their range. The study weights were equal to the inverse of the variance of each study's effect estimate according to the methodology developed by DerSimonian and Laird.
      • DerSimonian R.
      • Laird N.
      Meta-analysis in clinical trials.
      If data for specific mutually exclusive CHD events, but not CHD overall, were reported in the same study, results data from that study were combined using a fixed effects model to produce a single risk estimate for total CHD. For the RCTs, meta-analysis models were generated for overall study population analyses as well as for subgroup-specific analyses. Stratified dose meta-analyses based on levels above and below 1 g/d were conducted. In addition, meta-regression analyses based on increasing EPA+DHA dose and CHD risk were performed. Meta-regression was also used to evaluate the impact of study quality on observed summary associations. Given the larger sample size for “any CHD event” compared with specific CHD events, such as fatal MI, a greater number of subgroup-specific and sensitivity analyses were possible for this category. The subgroup analyses were conducted to identify potential sources of between-study variation and to estimate the effect of EPA+DHA for specific subpopulations and study characteristics. To determine the influence that each individual study (RCT or prospective cohort study) had on the overall summary effect in the primary meta-analysis models, one-study removed sensitivity analyses, whereby the meta-analysis is conducted multiple times with a single study removed, were undertaken.
      Statistical heterogeneity was assessed using Cochran's Q, which tests for between-study statistical variation. A Cochran's Q P value of .10 or less in a specific meta-analysis model is an indication of statistically significant heterogeneity of the intervention effects across the RCTs or the associations across the prospective cohort studies. This P value for heterogeneity is not a significance test for the relationship between the exposure (ie, EPA+DHA) and the outcome (eg, CHD). In addition, the I2 statistic, which indicates the percentage of variation attributable to between-study heterogeneity, is shown in the forest plot figures for the primary analyses. The presence of publication bias was assessed visually by examining a funnel plot measuring the standard error as a function of effect size, as well as statistically by using Egger's regression method.
      • Rothstein H.R.
      • Sutton A.J.
      • Borenstein M.
      Publication Bias in Meta-Analysis—Prevention, Assessment and Adjustments.
      All statistical analyses were performed using Comprehensive Meta-Analysis (version 3.2.00089; Biostat).

      Results

      Descriptive Study Characteristics

      A flow diagram of the literature search and study selection is shown in Figure 1; 18 RCTs (21 publications)
      • Brouwer I.A.
      • Zock P.L.
      • Camm A.J.
      • et al.
      Effect of fish oil on ventricular tachyarrhythmia and death in patients with implantable cardioverter defibrillators: the Study on Omega-3 Fatty Acids and Ventricular Arrhythmia (SOFA) randomized trial.
      • Burr M.L.
      • Fehily A.M.
      • Gilbert J.F.
      • et al.
      Effects of changes in fat, fish, and fibre intakes on death and myocardial reinfarction: diet and reinfarction trial (DART).
      • Burr M.L.
      • Ashfield-Watt P.A.
      • Dunstan F.D.
      • et al.
      Lack of benefit of dietary advice to men with angina: results of a controlled trial.
      • Einvik G.
      • Klemsdal T.O.
      • Sandvik L.
      • Hjerkinn E.M.
      A randomized clinical trial on n-3 polyunsaturated fatty acids supplementation and all-cause mortality in elderly men at high cardiovascular risk.
      • Galan P.
      • Kesse-Guyot E.
      • Czernichow S.
      • et al.
      SU.FOL.OM3 Collaborative Group
      Effects of B vitamins and omega 3 fatty acids on cardiovascular diseases: a randomised placebo controlled trial.
      • Ishikawa Y.
      • Yokoyama M.
      • Saito Y.
      • et al.
      JELIS Investigators
      Preventive effects of eicosapentaenoic acid on coronary artery disease in patients with peripheral artery disease.
      • Johansen O.
      • Brekke M.
      • Seljeflot I.
      • Abdelnoor M.
      • Arnesen H.
      N-3 fatty acids do not prevent restenosis after coronary angioplasty: results from the CART study. Coronary Angioplasty Restenosis Trial.
      • Kromhout D.
      • Giltay E.J.
      • Geleijnse J.M.
      Alpha Omega Trial Group
      n-3 fatty acids and cardiovascular events after myocardial infarction.
      • Kromhout D.
      • Geleijnse J.M.
      • de Goede J.
      • et al.
      n-3 fatty acids, ventricular arrhythmia-related events, and fatal myocardial infarction in postmyocardial infarction patients with diabetes.
      • Leaf A.
      • Albert C.M.
      • Josephson M.
      • et al.
      Fatty Acid Antiarrhythmia Trial Investigators
      Prevention of fatal arrhythmias in high-risk subjects by fish oil n-3 fatty acid intake.
      • Macchia A.
      • Levantesi G.
      • Franzosi M.G.
      • et al.
      GISSI-Prevenzione Investigators
      Left ventricular systolic dysfunction, total mortality, and sudden death in patients with myocardial infarction treated with n-3 polyunsaturated fatty acids.
      • Macchia A.
      • Grancelli H.
      • Varini S.
      • et al.
      GESICA Investigators
      Omega-3 fatty acids for the prevention of recurrent symptomatic atrial fibrillation: results of the FORWARD (Randomized Trial to Assess Efficacy of PUFA for the Maintenance of Sinus Rhythm in Persistent Atrial Fibrillation) trial.
      • Marchioli R.
      • Schweiger C.
      • Tavazzi L.
      • Valagussa F.
      Efficacy of n-3 polyunsaturated fatty acids after myocardial infarction: results of GISSI-Prevenzione trial. Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto Miocardico.
      • Raitt M.H.
      • Connor W.E.
      • Morris C.
      • et al.
      Fish oil supplementation and risk of ventricular tachycardia and ventricular fibrillation in patients with implantable defibrillators: a randomized controlled trial.
      • Rauch B.
      • Schiele R.
      • Schneider S.
      • et al.
      OMEGA Study Group
      OMEGA, a randomized, placebo-controlled trial to test the effect of highly purified omega-3 fatty acids on top of modern guideline-adjusted therapy after myocardial infarction.
      • Roncaglioni M.C.
      • Tombesi M.
      • Silletta M.G.
      n-3 fatty acids in patients with cardiac risk factors.
      • Singh R.B.
      • Niaz M.A.
      • Sharma J.P.
      • Kumar R.
      • Rastogi V.
      • Moshiri M.
      Randomized, double-blind, placebo-controlled trial of fish oil and mustard oil in patients with suspected acute myocardial infarction: the Indian experiment of infarct survival–4.
      • von Schacky C.
      • Angerer P.
      • Kothny W.
      • Theisen K.
      • Mudra H.
      The effect of dietary omega-3 fatty acids on coronary atherosclerosis: a randomized, double-blind, placebo-controlled trial.
      • Yokoyama M.
      • Origasa H.
      • Matsuzaki M.
      • et al.
      Japan EPA lipid intervention study (JELIS) Investigators
      Effects of eicosapentaenoic acid on major coronary events in hypercholesterolaemic patients (JELIS): a randomised open-label, blinded endpoint analysis.
      • Bosch J.
      • Gerstein H.C.
      • Dagenais G.R.
      • et al.
      ORIGIN Trial Investigators
      n-3 fatty acids and cardiovascular outcomes in patients with dysglycemia.
      • Nilsen D.W.
      • Albrektsen G.
      • Landmark K.
      • Moen S.
      • Aarsland T.
      • Woie L.
      Effects of a high-dose concentrate of n-3 fatty acids or corn oil introduced early after an acute myocardial infarction on serum triacylglycerol and HDL cholesterol.
      and 16 prospective cohort studies (18 publications)
      • Albert C.M.
      • Hennekens C.H.
      • O'Donnell C.J.
      • et al.
      Fish consumption and risk of sudden cardiac death.
      • Amiano P.
      • Machon M.
      • Dorronsoro M.
      • et al.
      Intake of total omega-3 fatty acids, eicosapentaenoic acid and docosahexaenoic acid and risk of coronary heart disease in the Spanish EPIC cohort study.
      • Bergkvist C.
      • Berglund M.
      • Glynn A.
      • Wolk A.
      • Akesson A.
      Dietary exposure to polychlorinated biphenyls and risk of myocardial infarction—a population-based prospective cohort study.
      • Ascherio A.
      • Rimm E.B.
      • Stampfer M.J.
      • Giovannucci E.L.
      • Willett W.C.
      Dietary intake of marine n-3 fatty acids, fish intake, and the risk of coronary disease among men.
      • Chiuve S.E.
      • Rimm E.B.
      • Sandhu R.K.
      • et al.
      Dietary fat quality and risk of sudden cardiac death in women.
      • de Goede J.
      • Geleijnse J.M.
      • Boer J.M.
      • Kromhout D.
      • Verschuren W.M.
      Marine (n-3) fatty acids, fish consumption, and the 10-year risk of fatal and nonfatal coronary heart disease in a large population of Dutch adults with low fish intake.
      • Hu F.B.
      • Cho E.
      • Rexrode K.M.
      • Albert C.M.
      • Manson J.E.
      Fish and long-chain omega-3 fatty acid intake and risk of coronary heart disease and total mortality in diabetic women.
      • Iso H.
      • Kobayashi M.
      • Ishihara J.
      • et al.
      JPHC Study Group
      Intake of fish and n3 fatty acids and risk of coronary heart disease among Japanese: the Japan Public Health Center-Based (JPHC) Study Cohort I.
      • Koh A.S.
      • Pan A.
      • Wang R.
      • et al.
      The association between dietary omega-3 fatty acids and cardiovascular death: the Singapore Chinese Health Study.
      • Jarvinen R.
      • Knekt P.
      • Rissanen H.
      • Reunanen A.
      Intake of fish and long-chain n-3 fatty acids and the risk of coronary heart mortality in men and women.
      • Joensen A.M.
      • Schmidt E.B.
      • Dethlefsen C.
      • et al.
      Dietary intake of total marine n-3 polyunsaturated fatty acids, eicosapentaenoic acid, docosahexaenoic acid and docosapentaenoic acid and the risk of acute coronary syndrome—a cohort study.
      • Manger M.S.
      • Strand E.
      • Ebbing M.
      • et al.
      Dietary intake of n-3 long-chain polyunsaturated fatty acids and coronary events in Norwegian patients with coronary artery disease.
      • Mozaffarian D.
      • Ascherio A.
      • Hu F.B.
      • et al.
      Interplay between different polyunsaturated fatty acids and risk of coronary heart disease in men.
      • Pietinen P.
      • Ascherio A.
      • Korhonen P.
      • et al.
      Intake of fatty acids and risk of coronary heart disease in a cohort of Finnish men. The Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study.
      • Streppel M.T.
      • Ocke M.C.
      • Boshuizen H.C.
      • Kok F.J.
      • Kromhout D.
      Long-term fish consumption and n-3 fatty acid intake in relation to (sudden) coronary heart disease death: the Zutphen study.
      • Yuan J.M.
      • Ross R.K.
      • Gao Y.T.
      • Yu M.C.
      Fish and shellfish consumption in relation to death from myocardial infarction among men in Shanghai, China.
      • Takata Y.
      • Zhang X.
      • Li H.
      • et al.
      Fish intake and risks of total and cause-specific mortality in 2 population-based cohort studies of 134,296 men and women.
      • Miyagawa N.
      • Miura K.
      • Okuda N.
      • et al.
      NIPPON DATA80 Research Group
      Long-chain n-3 polyunsaturated fatty acids intake and cardiovascular disease mortality risk in Japanese: a 24-year follow-up of NIPPON DATA80.
      were included in the meta-analysis. Studies excluded after full-text review are listed in Supplemental Table 1 (available online at http://www.mayoclinicproceedings.org). The main study characteristics of the RCTs and prospective cohort studies are summarized in Table 1 and Table 2, respectively. Approximately 93,000 subjects were included in the meta-analysis of RCT data and 732,000 subjects were included in the meta-analysis of prospective cohort studies.
      Figure thumbnail gr1
      Figure 1Flow diagram of literature search and study selection. DHA = docosahexaenoic acid; EPA = eicosapentaenoic acid.
      Table 1Characteristics of Randomized Controlled Trials
      CART = Coronary Angioplasty Restenosis Trial; CHD = coronary heart disease; DART = Diet and Reinfarction Trial; DHA = docosahexaenoic acid; DOIT = Diet and Omega-3 Intervention Trial; 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; GISSI = Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto Miocardio; IEIS-4 = Indian Experiment of Infarct Survival; JELIS = Japan EPA Lipid Intervention Study; LVSD = left ventricular systolic dysfunction; NR = not reported; ORIGIN = Outcome Reduction with an Initial Glargine Intervention; PAD = peripheral arterial disease; PUFA = polyunsaturated fatty acid; SICMO = Study on Prevention of Coronary Atherosclerosis by Intervention with Marine Omega-3 fatty acids; SOFA = Study on Omega-3 Fatty Acids and Ventricular Arrhythmia; SU.FOL.OM4 = Supplémentation en Folates et Omega-3.
      Reference, yearCountryStudy nameDuration (y)n
      Represents the number of subjects initially enrolled in the study.
      Intervention regimenControl
      Intervention typeDose (g/d)
      Dose of entire fish oil supplement or food.
      EPA+DHA (g/d)
      Primary prevention
       Roncaglioni et al,
      • Roncaglioni M.C.
      • Tombesi M.
      • Silletta M.G.
      n-3 fatty acids in patients with cardiac risk factors.
      2013
      Study includes a population with no history of myocardial infarctions, but 12% with angina at baseline.
      ItalyRisk and Prevention Study512,513Ethyl esters10.85Olive oil
       Yokoyama et al,
      • Yokoyama M.
      • Origasa H.
      • Matsuzaki M.
      • et al.
      Japan EPA lipid intervention study (JELIS) Investigators
      Effects of eicosapentaenoic acid on major coronary events in hypercholesterolaemic patients (JELIS): a randomised open-label, blinded endpoint analysis.
      2007
      JapanJELIS (subgroup with no CHD)514,981Ethyl esters1.841.80Control (no supplement)
      Control arm did not receive a placebo.
      Mixed prevention
      Mixed prevention trials include studies where some but not all participants have CHD at baseline.
       Bosch et al,
      • Bosch J.
      • Gerstein H.C.
      • Dagenais G.R.
      • et al.
      ORIGIN Trial Investigators
      n-3 fatty acids and cardiovascular outcomes in patients with dysglycemia.
      2012
      40 countries
      Forty countries from Asia, Australia, Europe, North American, Africa (South Africa), and South America.
      ORIGIN712,611Ethyl esters10.84Olive oil
       Brouwer et al,
      • Brouwer I.A.
      • Zock P.L.
      • Camm A.J.
      • et al.
      Effect of fish oil on ventricular tachyarrhythmia and death in patients with implantable cardioverter defibrillators: the Study on Omega-3 Fatty Acids and Ventricular Arrhythmia (SOFA) randomized trial.
      2006
      8 countries
      Countries include Poland, Germany, the Netherlands, the United Kingdom, Czech Republic, Belgium, Austria, and Switzerland.
      SOFA1546Fish oil20.80Sunflower oil
       Einvik et al,
      • Einvik G.
      • Klemsdal T.O.
      • Sandvik L.
      • Hjerkinn E.M.
      A randomized clinical trial on n-3 polyunsaturated fatty acids supplementation and all-cause mortality in elderly men at high cardiovascular risk.
      2010
      NorwayDOIT3563Fish oil42.02Corn oil
       Galan et al,
      • Galan P.
      • Kesse-Guyot E.
      • Czernichow S.
      • et al.
      SU.FOL.OM3 Collaborative Group
      Effects of B vitamins and omega 3 fatty acids on cardiovascular diseases: a randomised placebo controlled trial.
      2010
      FranceSU.FOL.OM452501Fish oil10.60Gelatin
       Ishikawa et al,
      • Ishikawa Y.
      • Yokoyama M.
      • Saito Y.
      • et al.
      JELIS Investigators
      Preventive effects of eicosapentaenoic acid on coronary artery disease in patients with peripheral artery disease.
      2010
      Subgroup publication of JELIS trial, consulted for additional trial information only, subgroup data not used in meta-analysis.
      JapanJELIS (PAD subgroup)5223Ethyl esters1.841.80Control (no supplement)
      Control arm did not receive a placebo.
       Leaf et al,
      • Leaf A.
      • Albert C.M.
      • Josephson M.
      • et al.
      Fatty Acid Antiarrhythmia Trial Investigators
      Prevention of fatal arrhythmias in high-risk subjects by fish oil n-3 fatty acid intake.
      2005
      United States1402Ethyl esters42.60Olive oil
       Macchia et al,
      • Macchia A.
      • Grancelli H.
      • Varini S.
      • et al.
      GESICA Investigators
      Omega-3 fatty acids for the prevention of recurrent symptomatic atrial fibrillation: results of the FORWARD (Randomized Trial to Assess Efficacy of PUFA for the Maintenance of Sinus Rhythm in Persistent Atrial Fibrillation) trial.
      2013
      ArgentinaFORWARD3586Ethyl esters10.88Olive oil
       Raitt et al,
      • Raitt M.H.
      • Connor W.E.
      • Morris C.
      • et al.
      Fish oil supplementation and risk of ventricular tachycardia and ventricular fibrillation in patients with implantable defibrillators: a randomized controlled trial.
      2005
      United States2200Fish oil1.81.30Olive oil
       Yokoyama et al,
      • Yokoyama M.
      • Origasa H.
      • Matsuzaki M.
      • et al.
      Japan EPA lipid intervention study (JELIS) Investigators
      Effects of eicosapentaenoic acid on major coronary events in hypercholesterolaemic patients (JELIS): a randomised open-label, blinded endpoint analysis.
      2007
      JapanJELIS518,645Ethyl esters1.841.80Control (no supplement)
      Control arm did not receive a placebo.
      Secondary prevention
       Burr et al,
      • Burr M.L.
      • Fehily A.M.
      • Gilbert J.F.
      • et al.
      Effects of changes in fat, fish, and fibre intakes on death and myocardial reinfarction: diet and reinfarction trial (DART).
      1989
      UKDART22,033Fatty fish and/or fish oil41 (fish)/3 (oil)0.75Balanced diet advice
       Burr et al,
      • Burr M.L.
      • Ashfield-Watt P.A.
      • Dunstan F.D.
      • et al.
      Lack of benefit of dietary advice to men with angina: results of a controlled trial.
      2003
      UK23,114Fatty fish and/or fish oil41 (fish)/3 (oil)0.75Balanced diet advice
       Johansen et al,
      • Johansen O.
      • Brekke M.
      • Seljeflot I.
      • Abdelnoor M.
      • Arnesen H.
      N-3 fatty acids do not prevent restenosis after coronary angioplasty: results from the CART study. Coronary Angioplasty Restenosis Trial.
      1999
      NorwayCART0.5500Ethyl esters65.04Corn oil
       Kromhout et al,
      • Kromhout D.
      • Giltay E.J.
      • Geleijnse J.M.
      Alpha Omega Trial Group
      n-3 fatty acids and cardiovascular events after myocardial infarction.
      2010
      The NetherlandsAlpha Omega Trial34,837EPA+DHA enriched margarine23.80.38Oleic acid margarine
       Kromhout et al,
      • Kromhout D.
      • Geleijnse J.M.
      • de Goede J.
      • et al.
      n-3 fatty acids, ventricular arrhythmia-related events, and fatal myocardial infarction in postmyocardial infarction patients with diabetes.
      2011
      Subgroup publication of Alpha Omega trial, consulted for additional trial information only, subgroup data not used in meta-analysis.
      The NetherlandsAlpha Omega Trial (type 2 diabetes subgroup)3511EPA+DHA enriched margarine23.80.38Oleic acid margarine
       Macchia et al,
      • Macchia A.
      • Levantesi G.
      • Franzosi M.G.
      • et al.
      GISSI-Prevenzione Investigators
      Left ventricular systolic dysfunction, total mortality, and sudden death in patients with myocardial infarction treated with n-3 polyunsaturated fatty acids.
      2005
      Subgroup publication of GISSI trial, consulted for additional trial information only, subgroup data not used in meta-analysis.
      ItalyGISSI (LVSD subgroup)44,324Ethyl esters10.88Control (no supplement)
      Control arm did not receive a placebo.
       Marchioli et al,
      • Marchioli R.
      • Schweiger C.
      • Tavazzi L.
      • Valagussa F.
      Efficacy of n-3 polyunsaturated fatty acids after myocardial infarction: results of GISSI-Prevenzione trial. Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto Miocardico.
      2001
      ItalyGISSI3.511,323Ethyl esters10.88Control (no supplement)
      Control arm did not receive a placebo.
       Nilsen et al,
      • Nilsen D.W.
      • Albrektsen G.
      • Landmark K.
      • Moen S.
      • Aarsland T.
      • Woie L.
      Effects of a high-dose concentrate of n-3 fatty acids or corn oil introduced early after an acute myocardial infarction on serum triacylglycerol and HDL cholesterol.
      2001
      Norway2300Ethyl ester43.46Corn oil
       Rauch et al,
      • Rauch B.
      • Schiele R.
      • Schneider S.
      • et al.
      OMEGA Study Group
      OMEGA, a randomized, placebo-controlled trial to test the effect of highly purified omega-3 fatty acids on top of modern guideline-adjusted therapy after myocardial infarction.
      2010
      GermanyOMEGA trial13,851Ethyl esters10.84Olive oil
       Singh et al,
      • Singh R.B.
      • Niaz M.A.
      • Sharma J.P.
      • Kumar R.
      • Rastogi V.
      • Moshiri M.
      Randomized, double-blind, placebo-controlled trial of fish oil and mustard oil in patients with suspected acute myocardial infarction: the Indian experiment of infarct survival–4.
      1997
      IndiaIEIS-41240
      Represents the number of subjects in final analysis (number of subjects enrolled was not reported).
      Fish oil61.80Aluminum hydroxide
       Von Schacky et al,
      • von Schacky C.
      • Angerer P.
      • Kothny W.
      • Theisen K.
      • Mudra H.
      The effect of dietary omega-3 fatty acids on coronary atherosclerosis: a randomized, double-blind, placebo-controlled trial.
      1999
      GermanySICMO2223Fish oil30.94Oil mixture without marine n-3 fatty acids
       Yokoyama et al,
      • Yokoyama M.
      • Origasa H.
      • Matsuzaki M.
      • et al.
      Japan EPA lipid intervention study (JELIS) Investigators
      Effects of eicosapentaenoic acid on major coronary events in hypercholesterolaemic patients (JELIS): a randomised open-label, blinded endpoint analysis.
      2007
      JapanJELIS (CHD subgroup)53,664Ethyl esters1.841.80Control (no supplement)
      Control arm did not receive a placebo.
      a CART = Coronary Angioplasty Restenosis Trial; CHD = coronary heart disease; DART = Diet and Reinfarction Trial; DHA = docosahexaenoic acid; DOIT = Diet and Omega-3 Intervention Trial; 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; GISSI = Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto Miocardio; IEIS-4 = Indian Experiment of Infarct Survival; JELIS = Japan EPA Lipid Intervention Study; LVSD = left ventricular systolic dysfunction; NR = not reported; ORIGIN = Outcome Reduction with an Initial Glargine Intervention; PAD = peripheral arterial disease; PUFA = polyunsaturated fatty acid; SICMO = Study on Prevention of Coronary Atherosclerosis by Intervention with Marine Omega-3 fatty acids; SOFA = Study on Omega-3 Fatty Acids and Ventricular Arrhythmia; SU.FOL.OM4 = Supplémentation en Folates et Omega-3.
      b Represents the number of subjects initially enrolled in the study.
      c Dose of entire fish oil supplement or food.
      d Study includes a population with no history of myocardial infarctions, but 12% with angina at baseline.
      e Control arm did not receive a placebo.
      f Mixed prevention trials include studies where some but not all participants have CHD at baseline.
      g Forty countries from Asia, Australia, Europe, North American, Africa (South Africa), and South America.
      h Countries include Poland, Germany, the Netherlands, the United Kingdom, Czech Republic, Belgium, Austria, and Switzerland.
      i Subgroup publication of JELIS trial, consulted for additional trial information only, subgroup data not used in meta-analysis.
      j Subgroup publication of Alpha Omega trial, consulted for additional trial information only, subgroup data not used in meta-analysis.
      k Subgroup publication of GISSI trial, consulted for additional trial information only, subgroup data not used in meta-analysis.
      l Represents the number of subjects in final analysis (number of subjects enrolled was not reported).
      Table 2Characteristics of the Prospective Cohort Studies
      ACS = acute coronary syndrome; ATBC = Finnish Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study; CHD = coronary heart disease; DDCHCS = Danish Diet, Cancer and Health Cohort Study; DHA = docosahexaenoic acid; EPA = eicosapentaenoic acid; EPIC = European Prospective Investigation into Cancer and Nutrition; F = female; FMC = Finnish Mobile Clinic; JPHC = Japan Public Health Center–Based Study Cohort I; HPFS = Health Professionals Follow-up Study; M = male; MI = myocardial infarction; MORGEN = The Monitoring Project on Risk Factors for Chronic Diseases; NIPPON DATA80 = National Integrated Project for Prospective Observation of Non-communicable Disease And its Trends in the Aged, 1980; NHS I = Nurses' Health Study I; PHS = Physicians Health Study; RR = relative risk; SCD = sudden cardiac death; SCHS = Singapore Chinese Healthy Study; SMC = Swedish Mammography Cohort; SMHS = Shanghai Men's Health Study; SWHS = Shanghai Women's Health Study; WENBIT = Western Norway B Vitamin Intervention Trial.
      Reference, yearCountryCohortFollow-up (y)Baseline CHD (%)nHighest vs lowest EPA+DHA intake categories
      All studies assessed dietary intake via food frequency questionnaires, with the exception of Streppel et al,48 who used a cross-check dietary history method.
      RR (95% CI)
      RRs and 95% CIs included in at least 1 of the meta-analyses or combined using a fixed effects model to produce a single risk estimate for “any CHD event” or other composite outcome are shown.
      Albert et al,
      • Albert C.M.
      • Hennekens C.H.
      • O'Donnell C.J.
      • et al.
      Fish consumption and risk of sudden cardiac death.
      1998
      United StatesPHS11020,551 (M)≥0.25 vs <0.09 g/dSCD: 0.43 (0.20-0.93)
      Amiano et al,
      • Amiano P.
      • Machon M.
      • Dorronsoro M.
      • et al.
      Intake of total omega-3 fatty acids, eicosapentaenoic acid and docosahexaenoic acid and risk of coronary heart disease in the Spanish EPIC cohort study.
      2014
      SpainSpanish EPIC13015,444 (M)>0.34 vs <0.08 g/d EPACoronary events: 1.18 (0.90-1.56)
      ≥0.62 vs ≤0.19 g/d DHACoronary events: 1.08 (0.83-1.42)
      25,647 (F)>0.22 vs <0.05 g/d EPACoronary events: 0.71 (0.40-1.25)
      ≥0.41 vs ≤0.12 g/d DHACoronary events: 0.79 (0.44-1.39)
      Ascherio et al,
      • Ascherio A.
      • Rimm E.B.
      • Stampfer M.J.
      • Giovannucci E.L.
      • Willett W.C.
      Dietary intake of marine n-3 fatty acids, fish intake, and the risk of coronary disease among men.
      1995
      United StatesHPFS
      When a series of publications from the same cohort were available, data from only the most recent publication were used in the meta-analysis except in cases in which earlier publications provided estimates for unique outcomes not presented in the most recent publication. In these cases, outcome data from the earlier publication(s) were also included in the meta-analysis. This approach resulted in only 17 prospective cohort studies in the any CHD event model as Mozaffarian et al46 was used in place of Ascherio et al37 because Ascherio et al37 reported only total MI vs Mozaffarian et al,46 which reported more recent data including collective coronary events for the HPFS cohort. Ascherio et al,37 however, was used in the statistical model for total MI because these authors provided this outcome for the HPFS cohort, but Mozaffarian et al46 did not.
      6044,895 (M)0.58 vs 0.07 median g/dTotal MI: 1.09 (0.88-1.35)
      Bergkvist et al,
      • Bergkvist C.
      • Berglund M.
      • Glynn A.
      • Wolk A.
      • Akesson A.
      Dietary exposure to polychlorinated biphenyls and risk of myocardial infarction—a population-based prospective cohort study.
      2015
      SwedenSMC12033,446 (F)5.18 vs 1.48 median g/dTotal MI: 0.74 (0.52-1.06)
      Chiuve et al,
      • Chiuve S.E.
      • Rimm E.B.
      • Sandhu R.K.
      • et al.
      Dietary fat quality and risk of sudden cardiac death in women.
      2012
      United StatesNHS I
      When a series of publications from the same cohort were available, data from only the most recent publication were used in the meta-analysis except in cases in which earlier publications provided estimates for unique outcomes not presented in the most recent publication. In these cases, outcome data from the earlier publication(s) were also included in the meta-analysis. This approach resulted in only 17 prospective cohort studies in the any CHD event model as Mozaffarian et al46 was used in place of Ascherio et al37 because Ascherio et al37 reported only total MI vs Mozaffarian et al,46 which reported more recent data including collective coronary events for the HPFS cohort. Ascherio et al,37 however, was used in the statistical model for total MI because these authors provided this outcome for the HPFS cohort, but Mozaffarian et al46 did not.
      30291,981 (F)0.51 vs 0.05% of total fatSCD: 0.50 (0.35-0.70)
      de Goede et al,
      • de Goede J.
      • Geleijnse J.M.
      • Boer J.M.
      • Kromhout D.
      • Verschuren W.M.
      Marine (n-3) fatty acids, fish consumption, and the 10-year risk of fatal and nonfatal coronary heart disease in a large population of Dutch adults with low fish intake.
      2010
      The NetherlandsMORGEN11.3021342 (M+F)>0.19 vs <0.06 g/dCoronary death: 0.51 (0.27-0.94)
      Fatal MI: 0.38 (0.19-0.77)
      Nonfatal MI: 1.07 (0.74-1.54)
      Hu et al,
      • Hu F.B.
      • Cho E.
      • Rexrode K.M.
      • Albert C.M.
      • Manson J.E.
      Fish and long-chain omega-3 fatty acid intake and risk of coronary heart disease and total mortality in diabetic women.
      2003
      United StatesNHS I
      When a series of publications from the same cohort were available, data from only the most recent publication were used in the meta-analysis except in cases in which earlier publications provided estimates for unique outcomes not presented in the most recent publication. In these cases, outcome data from the earlier publication(s) were also included in the meta-analysis. This approach resulted in only 17 prospective cohort studies in the any CHD event model as Mozaffarian et al46 was used in place of Ascherio et al37 because Ascherio et al37 reported only total MI vs Mozaffarian et al,46 which reported more recent data including collective coronary events for the HPFS cohort. Ascherio et al,37 however, was used in the statistical model for total MI because these authors provided this outcome for the HPFS cohort, but Mozaffarian et al46 did not.
      16084,688 (F)0.24 vs 0.03 median % of total kcalCoronary events: 0.69 (0.57-0.84)
      Coronary death: 0.62 (0.44-0.88)
      Nonfatal MI: 0.73 (0.57-0.93)
      Iso et al,
      • Iso H.
      • Kobayashi M.
      • Ishihara J.
      • et al.
      JPHC Study Group
      Intake of fish and n3 fatty acids and risk of coronary heart disease among Japanese: the Japan Public Health Center-Based (JPHC) Study Cohort I.
      2006
      JapanJPHC11041,578 (M+F)2.1 vs 0.3 median g/dTotal MI: 0.43 (0.24-0.78)
      SCD: 1.24 (0.39-3.98)
      Fatal events: 1.54 (0.60-3.99)
      Nonfatal MI: 0.33 (0.17-0.63)
      Jarvinen et al,
      • Jarvinen R.
      • Knekt P.
      • Rissanen H.
      • Reunanen A.
      Intake of fish and long-chain n-3 fatty acids and the risk of coronary heart mortality in men and women.
      2006
      FinlandFMC21.502,775 (M)0.99 vs 0.13 mean g/dCoronary death: 0.96 (0.68-1.38)
      2,445 (F)0.59 vs 0.09 mean g/dCoronary death: 0.73 (0.44-1.19)
      Joensen et al,
      • Joensen A.M.
      • Schmidt E.B.
      • Dethlefsen C.
      • et al.
      Dietary intake of total marine n-3 polyunsaturated fatty acids, eicosapentaenoic acid, docosahexaenoic acid and docosapentaenoic acid and the risk of acute coronary syndrome—a cohort study.
      2010
      DenmarkDDCHCS7.6024,786 (M)>1.08 vs. ≤0.39 g/dAny CHD event (angina+MI): 0.81 (0.64-1.04)
      29,017 (F)>1.03 vs. ≤0.38 g/dAny CHD event (angina+MI): 0.97 (0.62-1.52)
      Koh et al,
      • Koh A.S.
      • Pan A.
      • Wang R.
      • et al.
      The association between dietary omega-3 fatty acids and cardiovascular death: the Singapore Chinese Health Study.
      2015
      SingaporeSCHS194.160,299 (M+F)0.46 vs 0.19 mean g/dCoronary death: 0.86 (0.77-0.96)
      Manger et al,
      • Manger M.S.
      • Strand E.
      • Ebbing M.
      • et al.
      Dietary intake of n-3 long-chain polyunsaturated fatty acids and coronary events in Norwegian patients with coronary artery disease.
      2010
      NorwayWENBIT4.81002,412 (M+F)2.64 vs 0.58 mean g/dCoronary death: 1.33 (0.67-2.62)
      Total MI: 1.05 (0.72-1.52)
      Coronary events: 0.95 (0.69-1.31)
      Miyagawa et al,
      • Miyagawa N.
      • Miura K.
      • Okuda N.
      • et al.
      NIPPON DATA80 Research Group
      Long-chain n-3 polyunsaturated fatty acids intake and cardiovascular disease mortality risk in Japanese: a 24-year follow-up of NIPPON DATA80.
      2014
      JapanNIPPON DATA802409,190 (M+F)1.72 vs 0.42 mean g/dCoronary death: 0.82 (0.53-1.29)
      Mozaffarian et al,
      • Mozaffarian D.
      • Ascherio A.
      • Hu F.B.
      • et al.
      Interplay between different polyunsaturated fatty acids and risk of coronary heart disease in men.
      2005
      United StatesHPFS
      When a series of publications from the same cohort were available, data from only the most recent publication were used in the meta-analysis except in cases in which earlier publications provided estimates for unique outcomes not presented in the most recent publication. In these cases, outcome data from the earlier publication(s) were also included in the meta-analysis. This approach resulted in only 17 prospective cohort studies in the any CHD event model as Mozaffarian et al46 was used in place of Ascherio et al37 because Ascherio et al37 reported only total MI vs Mozaffarian et al,46 which reported more recent data including collective coronary events for the HPFS cohort. Ascherio et al,37 however, was used in the statistical model for total MI because these authors provided this outcome for the HPFS cohort, but Mozaffarian et al46 did not.
      14045,722 (M)≥0.25 vs <0.25 g/dSCD: 0.52 (0.34-0.79)
      Nonfatal MI: 1.16 (0.99-1.36)
      Coronary events: 1.05 (0.92-1.19)
      Pietinen et al,
      • Pietinen P.
      • Ascherio A.
      • Korhonen P.
      • et al.
      Intake of fatty acids and risk of coronary heart disease in a cohort of Finnish men. The Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study.
      1997
      FinlandATBC6.1021,930 (M)0.8 vs 0.2 median g/dCoronary events: 1.15 (0.97-1.35)
      Coronary death: 1.24 (0.97-1.58)
      Streppel et al,
      • Streppel M.T.
      • Ocke M.C.
      • Boshuizen H.C.
      • Kok F.J.
      • Kromhout D.
      Long-term fish consumption and n-3 fatty acid intake in relation to (sudden) coronary heart disease death: the Zutphen study.
      2008
      The NetherlandsZutphen Study4001,373 (M)>0.25 vs 0 g/dFatal events (SCD+coronary death): 0.65 (0.40-1.06)
      SCD: 0.68 (0.23-2.02)
      Takata et al,
      • Takata Y.
      • Zhang X.
      • Li H.
      • et al.
      Fish intake and risks of total and cause-specific mortality in 2 population-based cohort studies of 134,296 men and women.
      2013
      ChinaSMHS+SWHS136.2134,296 (M+F)0.22 vs 0.01 median g/dCoronary death: 0.79 (0.57-1.09)
      Yuan et al,
      • Yuan J.M.
      • Ross R.K.
      • Gao Y.T.
      • Yu M.C.
      Fish and shellfish consumption in relation to death from myocardial infarction among men in Shanghai, China.
      2001
      ChinaShanghai Cohort Study12018,244 (M)≥0.15 vs <0.04 g/dFatal MI: 0.43 (0.23-0.81)
      CHD death (other than MI): 0.71 (0.32-1.57)
      a ACS = acute coronary syndrome; ATBC = Finnish Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study; CHD = coronary heart disease; DDCHCS = Danish Diet, Cancer and Health Cohort Study; DHA = docosahexaenoic acid; EPA = eicosapentaenoic acid; EPIC = European Prospective Investigation into Cancer and Nutrition; F = female; FMC = Finnish Mobile Clinic; JPHC = Japan Public Health Center–Based Study Cohort I; HPFS = Health Professionals Follow-up Study; M = male; MI = myocardial infarction; MORGEN = The Monitoring Project on Risk Factors for Chronic Diseases; NIPPON DATA80 = National Integrated Project for Prospective Observation of Non-communicable Disease And its Trends in the Aged, 1980; NHS I = Nurses' Health Study I; PHS = Physicians Health Study; RR = relative risk; SCD = sudden cardiac death; SCHS = Singapore Chinese Healthy Study; SMC = Swedish Mammography Cohort; SMHS = Shanghai Men's Health Study; SWHS = Shanghai Women's Health Study; WENBIT = Western Norway B Vitamin Intervention Trial.
      b All studies assessed dietary intake via food frequency questionnaires, with the exception of Streppel et al,
      • Streppel M.T.
      • Ocke M.C.
      • Boshuizen H.C.
      • Kok F.J.
      • Kromhout D.
      Long-term fish consumption and n-3 fatty acid intake in relation to (sudden) coronary heart disease death: the Zutphen study.
      who used a cross-check dietary history method.
      c RRs and 95% CIs included in at least 1 of the meta-analyses or combined using a fixed effects model to produce a single risk estimate for “any CHD event” or other composite outcome are shown.
      d When a series of publications from the same cohort were available, data from only the most recent publication were used in the meta-analysis except in cases in which earlier publications provided estimates for unique outcomes not presented in the most recent publication. In these cases, outcome data from the earlier publication(s) were also included in the meta-analysis. This approach resulted in only 17 prospective cohort studies in the any CHD event model as Mozaffarian et al
      • Mozaffarian D.
      • Ascherio A.
      • Hu F.B.
      • et al.
      Interplay between different polyunsaturated fatty acids and risk of coronary heart disease in men.
      was used in place of Ascherio et al
      • Ascherio A.
      • Rimm E.B.
      • Stampfer M.J.
      • Giovannucci E.L.
      • Willett W.C.
      Dietary intake of marine n-3 fatty acids, fish intake, and the risk of coronary disease among men.
      because Ascherio et al
      • Ascherio A.
      • Rimm E.B.
      • Stampfer M.J.
      • Giovannucci E.L.
      • Willett W.C.
      Dietary intake of marine n-3 fatty acids, fish intake, and the risk of coronary disease among men.
      reported only total MI vs Mozaffarian et al,
      • Mozaffarian D.
      • Ascherio A.
      • Hu F.B.
      • et al.
      Interplay between different polyunsaturated fatty acids and risk of coronary heart disease in men.
      which reported more recent data including collective coronary events for the HPFS cohort. Ascherio et al,
      • Ascherio A.
      • Rimm E.B.
      • Stampfer M.J.
      • Giovannucci E.L.
      • Willett W.C.
      Dietary intake of marine n-3 fatty acids, fish intake, and the risk of coronary disease among men.
      however, was used in the statistical model for total MI because these authors provided this outcome for the HPFS cohort, but Mozaffarian et al
      • Mozaffarian D.
      • Ascherio A.
      • Hu F.B.
      • et al.
      Interplay between different polyunsaturated fatty acids and risk of coronary heart disease in men.
      did not.

      Meta-Analyses Results

      Results from meta-analyses of RCTs and prospective cohort studies are reported in Tables 3 and 4, with the primary meta-analytic findings summarized in Figure 2. Results from additional subgroup and meta-regression analyses are also presented in Supplemental Table 2 (available online at http://www.mayoclinicproceedings.org).
      Table 3Randomized Controlled Trials—Summary of Meta-Analysis Results: EPA+DHA and CHD End Points
      CHD = coronary heart disease; DHA = docosahexaenoic acid; EPA = eicosapentaenoic acid; LDL = low-density lipoprotein; RCT = randomized controlled trial; SRRE = summary relative risk estimate.
      ,
      “Any CHD event” includes fatal and nonfatal MI, coronary death, sudden cardiac death, and angina. “Coronary death” includes fatal MI, death from other acute or subacute forms of CHD, or death from chronic CHD.
      ModelStudies (n)SRRELower 95% CIUpper 95% CICochran's Q Heterogeneity
      Statistical heterogeneity was assessed using Cochran's Q, which tests for between-study statistical variation. In a conventional meta-analysis, a Cochran's Q P value of .10 or less is an indication of statistically significant heterogeneity. It is noteworthy that this P value is only an indication that statistical variability may be present in a specific meta-analysis model, and this P value is not a significance test for the relationship between the exposure (ie, EPA+DHA) and the outcome (eg, CHD).
      test
      Any CHD event—All RCTs
      • Brouwer I.A.
      • Zock P.L.
      • Camm A.J.
      • et al.
      Effect of fish oil on ventricular tachyarrhythmia and death in patients with implantable cardioverter defibrillators: the Study on Omega-3 Fatty Acids and Ventricular Arrhythmia (SOFA) randomized trial.
      • Burr M.L.
      • Fehily A.M.
      • Gilbert J.F.
      • et al.
      Effects of changes in fat, fish, and fibre intakes on death and myocardial reinfarction: diet and reinfarction trial (DART).
      • Burr M.L.
      • Ashfield-Watt P.A.
      • Dunstan F.D.
      • et al.
      Lack of benefit of dietary advice to men with angina: results of a controlled trial.
      • Einvik G.
      • Klemsdal T.O.
      • Sandvik L.
      • Hjerkinn E.M.
      A randomized clinical trial on n-3 polyunsaturated fatty acids supplementation and all-cause mortality in elderly men at high cardiovascular risk.
      • Galan P.
      • Kesse-Guyot E.
      • Czernichow S.
      • et al.
      SU.FOL.OM3 Collaborative Group
      Effects of B vitamins and omega 3 fatty acids on cardiovascular diseases: a randomised placebo controlled trial.
      • Johansen O.
      • Brekke M.
      • Seljeflot I.
      • Abdelnoor M.
      • Arnesen H.
      N-3 fatty acids do not prevent restenosis after coronary angioplasty: results from the CART study. Coronary Angioplasty Restenosis Trial.
      • Kromhout D.
      • Giltay E.J.
      • Geleijnse J.M.
      Alpha Omega Trial Group
      n-3 fatty acids and cardiovascular events after myocardial infarction.
      • Leaf A.
      • Albert C.M.
      • Josephson M.
      • et al.
      Fatty Acid Antiarrhythmia Trial Investigators
      Prevention of fatal arrhythmias in high-risk subjects by fish oil n-3 fatty acid intake.
      • Macchia A.
      • Grancelli H.
      • Varini S.
      • et al.
      GESICA Investigators
      Omega-3 fatty acids for the prevention of recurrent symptomatic atrial fibrillation: results of the FORWARD (Randomized Trial to Assess Efficacy of PUFA for the Maintenance of Sinus Rhythm in Persistent Atrial Fibrillation) trial.
      • Marchioli R.
      • Schweiger C.
      • Tavazzi L.
      • Valagussa F.
      Efficacy of n-3 polyunsaturated fatty acids after myocardial infarction: results of GISSI-Prevenzione trial. Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto Miocardico.
      • Raitt M.H.
      • Connor W.E.
      • Morris C.
      • et al.
      Fish oil supplementation and risk of ventricular tachycardia and ventricular fibrillation in patients with implantable defibrillators: a randomized controlled trial.
      • Rauch B.
      • Schiele R.
      • Schneider S.
      • et al.
      OMEGA Study Group
      OMEGA, a randomized, placebo-controlled trial to test the effect of highly purified omega-3 fatty acids on top of modern guideline-adjusted therapy after myocardial infarction.
      • Roncaglioni M.C.
      • Tombesi M.
      • Silletta M.G.
      n-3 fatty acids in patients with cardiac risk factors.
      • Singh R.B.
      • Niaz M.A.
      • Sharma J.P.
      • Kumar R.
      • Rastogi V.
      • Moshiri M.
      Randomized, double-blind, placebo-controlled trial of fish oil and mustard oil in patients with suspected acute myocardial infarction: the Indian experiment of infarct survival–4.
      • von Schacky C.
      • Angerer P.
      • Kothny W.
      • Theisen K.
      • Mudra H.
      The effect of dietary omega-3 fatty acids on coronary atherosclerosis: a randomized, double-blind, placebo-controlled trial.
      • Yokoyama M.
      • Origasa H.
      • Matsuzaki M.
      • et al.
      Japan EPA lipid intervention study (JELIS) Investigators
      Effects of eicosapentaenoic acid on major coronary events in hypercholesterolaemic patients (JELIS): a randomised open-label, blinded endpoint analysis.
      • Bosch J.
      • Gerstein H.C.
      • Dagenais G.R.
      • et al.
      ORIGIN Trial Investigators
      n-3 fatty acids and cardiovascular outcomes in patients with dysglycemia.
      • Nilsen D.W.
      • Albrektsen G.
      • Landmark K.
      • Moen S.
      • Aarsland T.
      • Woie L.
      Effects of a high-dose concentrate of n-3 fatty acids or corn oil introduced early after an acute myocardial infarction on serum triacylglycerol and HDL cholesterol.
      180.940.851.05P=.07
      Any CHD event—Primary prevention
      • Roncaglioni M.C.
      • Tombesi M.
      • Silletta M.G.
      n-3 fatty acids in patients with cardiac risk factors.
      • Yokoyama M.
      • Origasa H.
      • Matsuzaki M.
      • et al.
      Japan EPA lipid intervention study (JELIS) Investigators
      Effects of eicosapentaenoic acid on major coronary events in hypercholesterolaemic patients (JELIS): a randomised open-label, blinded endpoint analysis.
      20.920.801.05P=.41
      Any CHD event—Secondary prevention
      • Burr M.L.
      • Fehily A.M.
      • Gilbert J.F.
      • et al.
      Effects of changes in fat, fish, and fibre intakes on death and myocardial reinfarction: diet and reinfarction trial (DART).
      • Burr M.L.
      • Ashfield-Watt P.A.
      • Dunstan F.D.
      • et al.
      Lack of benefit of dietary advice to men with angina: results of a controlled trial.
      • Johansen O.
      • Brekke M.
      • Seljeflot I.
      • Abdelnoor M.
      • Arnesen H.
      N-3 fatty acids do not prevent restenosis after coronary angioplasty: results from the CART study. Coronary Angioplasty Restenosis Trial.
      • Kromhout D.
      • Giltay E.J.
      • Geleijnse J.M.
      Alpha Omega Trial Group
      n-3 fatty acids and cardiovascular events after myocardial infarction.
      • Marchioli R.
      • Schweiger C.
      • Tavazzi L.
      • Valagussa F.
      Efficacy of n-3 polyunsaturated fatty acids after myocardial infarction: results of GISSI-Prevenzione trial. Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto Miocardico.
      • Rauch B.
      • Schiele R.
      • Schneider S.
      • et al.
      OMEGA Study Group
      OMEGA, a randomized, placebo-controlled trial to test the effect of highly purified omega-3 fatty acids on top of modern guideline-adjusted therapy after myocardial infarction.
      • Singh R.B.
      • Niaz M.A.
      • Sharma J.P.
      • Kumar R.
      • Rastogi V.
      • Moshiri M.
      Randomized, double-blind, placebo-controlled trial of fish oil and mustard oil in patients with suspected acute myocardial infarction: the Indian experiment of infarct survival–4.
      • von Schacky C.
      • Angerer P.
      • Kothny W.
      • Theisen K.
      • Mudra H.
      The effect of dietary omega-3 fatty acids on coronary atherosclerosis: a randomized, double-blind, placebo-controlled trial.
      • Yokoyama M.
      • Origasa H.
      • Matsuzaki M.
      • et al.
      Japan EPA lipid intervention study (JELIS) Investigators
      Effects of eicosapentaenoic acid on major coronary events in hypercholesterolaemic patients (JELIS): a randomised open-label, blinded endpoint analysis.
      • Nilsen D.W.
      • Albrektsen G.
      • Landmark K.
      • Moen S.
      • Aarsland T.
      • Woie L.
      Effects of a high-dose concentrate of n-3 fatty acids or corn oil introduced early after an acute myocardial infarction on serum triacylglycerol and HDL cholesterol.
      100.920.761.11P=.03
      Any CHD event—0 <1 g
      • Brouwer I.A.
      • Zock P.L.
      • Camm A.J.
      • et al.
      Effect of fish oil on ventricular tachyarrhythmia and death in patients with implantable cardioverter defibrillators: the Study on Omega-3 Fatty Acids and Ventricular Arrhythmia (SOFA) randomized trial.
      • Burr M.L.
      • Fehily A.M.
      • Gilbert J.F.
      • et al.
      Effects of changes in fat, fish, and fibre intakes on death and myocardial reinfarction: diet and reinfarction trial (DART).
      • Burr M.L.
      • Ashfield-Watt P.A.
      • Dunstan F.D.
      • et al.
      Lack of benefit of dietary advice to men with angina: results of a controlled trial.
      • Galan P.
      • Kesse-Guyot E.
      • Czernichow S.
      • et al.
      SU.FOL.OM3 Collaborative Group
      Effects of B vitamins and omega 3 fatty acids on cardiovascular diseases: a randomised placebo controlled trial.
      • Kromhout D.
      • Giltay E.J.
      • Geleijnse J.M.
      Alpha Omega Trial Group
      n-3 fatty acids and cardiovascular events after myocardial infarction.
      • Macchia A.
      • Grancelli H.
      • Varini S.
      • et al.
      GESICA Investigators
      Omega-3 fatty acids for the prevention of recurrent symptomatic atrial fibrillation: results of the FORWARD (Randomized Trial to Assess Efficacy of PUFA for the Maintenance of Sinus Rhythm in Persistent Atrial Fibrillation) trial.
      • Marchioli R.
      • Schweiger C.
      • Tavazzi L.
      • Valagussa F.
      Efficacy of n-3 polyunsaturated fatty acids after myocardial infarction: results of GISSI-Prevenzione trial. Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto Miocardico.
      • Rauch B.
      • Schiele R.
      • Schneider S.
      • et al.
      OMEGA Study Group
      OMEGA, a randomized, placebo-controlled trial to test the effect of highly purified omega-3 fatty acids on top of modern guideline-adjusted therapy after myocardial infarction.
      • Roncaglioni M.C.
      • Tombesi M.
      • Silletta M.G.
      n-3 fatty acids in patients with cardiac risk factors.
      • von Schacky C.
      • Angerer P.
      • Kothny W.
      • Theisen K.
      • Mudra H.
      The effect of dietary omega-3 fatty acids on coronary atherosclerosis: a randomized, double-blind, placebo-controlled trial.
      • Bosch J.
      • Gerstein H.C.
      • Dagenais G.R.
      • et al.
      ORIGIN Trial Investigators
      n-3 fatty acids and cardiovascular outcomes in patients with dysglycemia.
      110.990.911.07P=.34
      Any CHD event—1+ g
      • Einvik G.
      • Klemsdal T.O.
      • Sandvik L.
      • Hjerkinn E.M.
      A randomized clinical trial on n-3 polyunsaturated fatty acids supplementation and all-cause mortality in elderly men at high cardiovascular risk.
      • Johansen O.
      • Brekke M.
      • Seljeflot I.
      • Abdelnoor M.
      • Arnesen H.
      N-3 fatty acids do not prevent restenosis after coronary angioplasty: results from the CART study. Coronary Angioplasty Restenosis Trial.
      • Leaf A.
      • Albert C.M.
      • Josephson M.
      • et al.
      Fatty Acid Antiarrhythmia Trial Investigators
      Prevention of fatal arrhythmias in high-risk subjects by fish oil n-3 fatty acid intake.
      • Raitt M.H.
      • Connor W.E.
      • Morris C.
      • et al.
      Fish oil supplementation and risk of ventricular tachycardia and ventricular fibrillation in patients with implantable defibrillators: a randomized controlled trial.
      • Singh R.B.
      • Niaz M.A.
      • Sharma J.P.
      • Kumar R.
      • Rastogi V.
      • Moshiri M.
      Randomized, double-blind, placebo-controlled trial of fish oil and mustard oil in patients with suspected acute myocardial infarction: the Indian experiment of infarct survival–4.
      • Yokoyama M.
      • Origasa H.
      • Matsuzaki M.
      • et al.
      Japan EPA lipid intervention study (JELIS) Investigators
      Effects of eicosapentaenoic acid on major coronary events in hypercholesterolaemic patients (JELIS): a randomised open-label, blinded endpoint analysis.
      • Nilsen D.W.
      • Albrektsen G.
      • Landmark K.
      • Moen S.
      • Aarsland T.
      • Woie L.
      Effects of a high-dose concentrate of n-3 fatty acids or corn oil introduced early after an acute myocardial infarction on serum triacylglycerol and HDL cholesterol.
      70.830.611.14P=.23
      Any CHD event—Triglycerides <150
      • Galan P.
      • Kesse-Guyot E.
      • Czernichow S.
      • et al.
      SU.FOL.OM3 Collaborative Group
      Effects of B vitamins and omega 3 fatty acids on cardiovascular diseases: a randomised placebo controlled trial.
      • Kromhout D.
      • Giltay E.J.
      • Geleijnse J.M.
      Alpha Omega Trial Group
      n-3 fatty acids and cardiovascular events after myocardial infarction.
      • Bosch J.
      • Gerstein H.C.
      • Dagenais G.R.
      • et al.
      ORIGIN Trial Investigators
      n-3 fatty acids and cardiovascular outcomes in patients with dysglycemia.
      • Nilsen D.W.
      • Albrektsen G.
      • Landmark K.
      • Moen S.
      • Aarsland T.
      • Woie L.
      Effects of a high-dose concentrate of n-3 fatty acids or corn oil introduced early after an acute myocardial infarction on serum triacylglycerol and HDL cholesterol.
      41.040.961.13P=.74
      Any CHD event—Triglycerides 150+
      Indicates statistical significance per SRRE and corresponding CI. Summary associations were interpreted as statistically significant if the 95% CIs did not include the null value of 1.0 in their range.
      ,
      • Einvik G.
      • Klemsdal T.O.
      • Sandvik L.
      • Hjerkinn E.M.
      A randomized clinical trial on n-3 polyunsaturated fatty acids supplementation and all-cause mortality in elderly men at high cardiovascular risk.
      • Marchioli R.
      • Schweiger C.
      • Tavazzi L.
      • Valagussa F.
      Efficacy of n-3 polyunsaturated fatty acids after myocardial infarction: results of GISSI-Prevenzione trial. Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto Miocardico.
      • Roncaglioni M.C.
      • Tombesi M.
      • Silletta M.G.
      n-3 fatty acids in patients with cardiac risk factors.
      • Singh R.B.
      • Niaz M.A.
      • Sharma J.P.
      • Kumar R.
      • Rastogi V.
      • Moshiri M.
      Randomized, double-blind, placebo-controlled trial of fish oil and mustard oil in patients with suspected acute myocardial infarction: the Indian experiment of infarct survival–4.
      • von Schacky C.
      • Angerer P.
      • Kothny W.
      • Theisen K.
      • Mudra H.
      The effect of dietary omega-3 fatty acids on coronary atherosclerosis: a randomized, double-blind, placebo-controlled trial.
      • Yokoyama M.
      • Origasa H.
      • Matsuzaki M.
      • et al.
      Japan EPA lipid intervention study (JELIS) Investigators
      Effects of eicosapentaenoic acid on major coronary events in hypercholesterolaemic patients (JELIS): a randomised open-label, blinded endpoint analysis.
      60.840.720.98P=.21
      Any CHD event—LDL <130
      • Galan P.
      • Kesse-Guyot E.
      • Czernichow S.
      • et al.
      SU.FOL.OM3 Collaborative Group
      Effects of B vitamins and omega 3 fatty acids on cardiovascular diseases: a randomised placebo controlled trial.
      • Kromhout D.
      • Giltay E.J.
      • Geleijnse J.M.
      Alpha Omega Trial Group
      n-3 fatty acids and cardiovascular events after myocardial infarction.
      • Bosch J.
      • Gerstein H.C.
      • Dagenais G.R.
      • et al.
      ORIGIN Trial Investigators
      n-3 fatty acids and cardiovascular outcomes in patients with dysglycemia.
      31.030.951.12P=.83
      Any CHD event—LDL 130+
      Indicates statistical significance per SRRE and corresponding CI. Summary associations were interpreted as statistically significant if the 95% CIs did not include the null value of 1.0 in their range.
      ,
      • Einvik G.
      • Klemsdal T.O.
      • Sandvik L.
      • Hjerkinn E.M.
      A randomized clinical trial on n-3 polyunsaturated fatty acids supplementation and all-cause mortality in elderly men at high cardiovascular risk.
      • Marchioli R.
      • Schweiger C.
      • Tavazzi L.
      • Valagussa F.
      Efficacy of n-3 polyunsaturated fatty acids after myocardial infarction: results of GISSI-Prevenzione trial. Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto Miocardico.
      • Roncaglioni M.C.
      • Tombesi M.
      • Silletta M.G.
      n-3 fatty acids in patients with cardiac risk factors.
      • von Schacky C.
      • Angerer P.
      • Kothny W.
      • Theisen K.
      • Mudra H.
      The effect of dietary omega-3 fatty acids on coronary atherosclerosis: a randomized, double-blind, placebo-controlled trial.
      • Yokoyama M.
      • Origasa H.
      • Matsuzaki M.
      • et al.
      Japan EPA lipid intervention study (JELIS) Investigators
      Effects of eicosapentaenoic acid on major coronary events in hypercholesterolaemic patients (JELIS): a randomised open-label, blinded endpoint analysis.
      50.860.760.98P=.30
      Any CHD event—<25% of population taking diabetes medication
      • Brouwer I.A.
      • Zock P.L.
      • Camm A.J.
      • et al.
      Effect of fish oil on ventricular tachyarrhythmia and death in patients with implantable cardioverter defibrillators: the Study on Omega-3 Fatty Acids and Ventricular Arrhythmia (SOFA) randomized trial.
      • Burr M.L.
      • Fehily A.M.
      • Gilbert J.F.
      • et al.
      Effects of changes in fat, fish, and fibre intakes on death and myocardial reinfarction: diet and reinfarction trial (DART).
      • Burr M.L.
      • Ashfield-Watt P.A.
      • Dunstan F.D.
      • et al.
      Lack of benefit of dietary advice to men with angina: results of a controlled trial.
      • Einvik G.
      • Klemsdal T.O.
      • Sandvik L.
      • Hjerkinn E.M.
      A randomized clinical trial on n-3 polyunsaturated fatty acids supplementation and all-cause mortality in elderly men at high cardiovascular risk.
      • Johansen O.
      • Brekke M.
      • Seljeflot I.
      • Abdelnoor M.
      • Arnesen H.
      N-3 fatty acids do not prevent restenosis after coronary angioplasty: results from the CART study. Coronary Angioplasty Restenosis Trial.
      • Kromhout D.
      • Giltay E.J.
      • Geleijnse J.M.
      Alpha Omega Trial Group
      n-3 fatty acids and cardiovascular events after myocardial infarction.
      • Macchia A.
      • Grancelli H.
      • Varini S.
      • et al.
      GESICA Investigators
      Omega-3 fatty acids for the prevention of recurrent symptomatic atrial fibrillation: results of the FORWARD (Randomized Trial to Assess Efficacy of PUFA for the Maintenance of Sinus Rhythm in Persistent Atrial Fibrillation) trial.
      • Marchioli R.
      • Schweiger C.
      • Tavazzi L.
      • Valagussa F.
      Efficacy of n-3 polyunsaturated fatty acids after myocardial infarction: results of GISSI-Prevenzione trial. Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto Miocardico.
      • Raitt M.H.
      • Connor W.E.
      • Morris C.
      • et al.
      Fish oil supplementation and risk of ventricular tachycardia and ventricular fibrillation in patients with implantable defibrillators: a randomized controlled trial.
      • Yokoyama M.
      • Origasa H.
      • Matsuzaki M.
      • et al.
      Japan EPA lipid intervention study (JELIS) Investigators
      Effects of eicosapentaenoic acid on major coronary events in hypercholesterolaemic patients (JELIS): a randomised open-label, blinded endpoint analysis.
      • Nilsen D.W.
      • Albrektsen G.
      • Landmark K.
      • Moen S.
      • Aarsland T.
      • Woie L.
      Effects of a high-dose concentrate of n-3 fatty acids or corn oil introduced early after an acute myocardial infarction on serum triacylglycerol and HDL cholesterol.
      110.930.801.09P=.12
      Any Fatal CHD event—0 <1 g
      • Burr M.L.
      • Fehily A.M.
      • Gilbert J.F.
      • et al.
      Effects of changes in fat, fish, and fibre intakes on death and myocardial reinfarction: diet and reinfarction trial (DART).
      • Burr M.L.
      • Ashfield-Watt P.A.
      • Dunstan F.D.
      • et al.
      Lack of benefit of dietary advice to men with angina: results of a controlled trial.
      • Kromhout D.
      • Giltay E.J.
      • Geleijnse J.M.
      Alpha Omega Trial Group
      n-3 fatty acids and cardiovascular events after myocardial infarction.
      • Macchia A.
      • Grancelli H.
      • Varini S.
      • et al.
      GESICA Investigators
      Omega-3 fatty acids for the prevention of recurrent symptomatic atrial fibrillation: results of the FORWARD (Randomized Trial to Assess Efficacy of PUFA for the Maintenance of Sinus Rhythm in Persistent Atrial Fibrillation) trial.
      • Marchioli R.
      • Schweiger C.
      • Tavazzi L.
      • Valagussa F.
      Efficacy of n-3 polyunsaturated fatty acids after myocardial infarction: results of GISSI-Prevenzione trial. Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto Miocardico.
      • Rauch B.
      • Schiele R.
      • Schneider S.
      • et al.
      OMEGA Study Group
      OMEGA, a randomized, placebo-controlled trial to test the effect of highly purified omega-3 fatty acids on top of modern guideline-adjusted therapy after myocardial infarction.
      • Roncaglioni M.C.
      • Tombesi M.
      • Silletta M.G.
      n-3 fatty acids in patients with cardiac risk factors.
      • Bosch J.
      • Gerstein H.C.
      • Dagenais G.R.
      • et al.
      ORIGIN Trial Investigators
      n-3 fatty acids and cardiovascular outcomes in patients with dysglycemia.
      70.970.811.17P=.003
      Any fatal CHD event —1+ g
      • Einvik G.
      • Klemsdal T.O.
      • Sandvik L.
      • Hjerkinn E.M.
      A randomized clinical trial on n-3 polyunsaturated fatty acids supplementation and all-cause mortality in elderly men at high cardiovascular risk.
      • Johansen O.
      • Brekke M.
      • Seljeflot I.
      • Abdelnoor M.
      • Arnesen H.
      N-3 fatty acids do not prevent restenosis after coronary angioplasty: results from the CART study. Coronary Angioplasty Restenosis Trial.
      • Leaf A.
      • Albert C.M.
      • Josephson M.
      • et al.
      Fatty Acid Antiarrhythmia Trial Investigators
      Prevention of fatal arrhythmias in high-risk subjects by fish oil n-3 fatty acid intake.
      • Raitt M.H.
      • Connor W.E.
      • Morris C.
      • et al.
      Fish oil supplementation and risk of ventricular tachycardia and ventricular fibrillation in patients with implantable defibrillators: a randomized controlled trial.
      • Singh R.B.
      • Niaz M.A.
      • Sharma J.P.
      • Kumar R.
      • Rastogi V.
      • Moshiri M.
      Randomized, double-blind, placebo-controlled trial of fish oil and mustard oil in patients with suspected acute myocardial infarction: the Indian experiment of infarct survival–4.
      • von Schacky C.
      • Angerer P.
      • Kothny W.
      • Theisen K.
      • Mudra H.
      The effect of dietary omega-3 fatty acids on coronary atherosclerosis: a randomized, double-blind, placebo-controlled trial.
      • Yokoyama M.
      • Origasa H.
      • Matsuzaki M.
      • et al.
      Japan EPA lipid intervention study (JELIS) Investigators
      Effects of eicosapentaenoic acid on major coronary events in hypercholesterolaemic patients (JELIS): a randomised open-label, blinded endpoint analysis.
      70.890.581.37P=.68
      Any nonfatal CHD event—0 <1 g
      • Brouwer I.A.
      • Zock P.L.
      • Camm A.J.
      • et al.
      Effect of fish oil on ventricular tachyarrhythmia and death in patients with implantable cardioverter defibrillators: the Study on Omega-3 Fatty Acids and Ventricular Arrhythmia (SOFA) randomized trial.
      • Burr M.L.
      • Fehily A.M.
      • Gilbert J.F.
      • et al.
      Effects of changes in fat, fish, and fibre intakes on death and myocardial reinfarction: diet and reinfarction trial (DART).
      • Galan P.
      • Kesse-Guyot E.
      • Czernichow S.
      • et al.
      SU.FOL.OM3 Collaborative Group
      Effects of B vitamins and omega 3 fatty acids on cardiovascular diseases: a randomised placebo controlled trial.
      • Marchioli R.
      • Schweiger C.
      • Tavazzi L.
      • Valagussa F.
      Efficacy of n-3 polyunsaturated fatty acids after myocardial infarction: results of GISSI-Prevenzione trial. Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto Miocardico.
      • von Schacky C.
      • Angerer P.
      • Kothny W.
      • Theisen K.
      • Mudra H.
      The effect of dietary omega-3 fatty acids on coronary atherosclerosis: a randomized, double-blind, placebo-controlled trial.
      • Bosch J.
      • Gerstein H.C.
      • Dagenais G.R.
      • et al.
      ORIGIN Trial Investigators
      n-3 fatty acids and cardiovascular outcomes in patients with dysglycemia.
      60.970.801.19P=.06
      Any nonfatal CHD event—1+ g
      • Singh R.B.
      • Niaz M.A.
      • Sharma J.P.
      • Kumar R.
      • Rastogi V.
      • Moshiri M.
      Randomized, double-blind, placebo-controlled trial of fish oil and mustard oil in patients with suspected acute myocardial infarction: the Indian experiment of infarct survival–4.
      • Yokoyama M.
      • Origasa H.
      • Matsuzaki M.
      • et al.
      Japan EPA lipid intervention study (JELIS) Investigators
      Effects of eicosapentaenoic acid on major coronary events in hypercholesterolaemic patients (JELIS): a randomised open-label, blinded endpoint analysis.
      • Nilsen D.W.
      • Albrektsen G.
      • Landmark K.
      • Moen S.
      • Aarsland T.
      • Woie L.
      Effects of a high-dose concentrate of n-3 fatty acids or corn oil introduced early after an acute myocardial infarction on serum triacylglycerol and HDL cholesterol.
      30.800.591.10P=.25
      Coronary death—All RCTs
      Indicates statistical significance per SRRE and corresponding CI. Summary associations were interpreted as statistically significant if the 95% CIs did not include the null value of 1.0 in their range.
      ,
      • Burr M.L.
      • Fehily A.M.
      • Gilbert J.F.
      • et al.
      Effects of changes in fat, fish, and fibre intakes on death and myocardial reinfarction: diet and reinfarction trial (DART).
      • Johansen O.
      • Brekke M.
      • Seljeflot I.
      • Abdelnoor M.
      • Arnesen H.
      N-3 fatty acids do not prevent restenosis after coronary angioplasty: results from the CART study. Coronary Angioplasty Restenosis Trial.
      • Marchioli R.
      • Schweiger C.
      • Tavazzi L.
      • Valagussa F.
      Efficacy of n-3 polyunsaturated fatty acids after myocardial infarction: results of GISSI-Prevenzione trial. Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto Miocardico.
      • Roncaglioni M.C.
      • Tombesi M.
      • Silletta M.G.
      n-3 fatty acids in patients with cardiac risk factors.
      • Yokoyama M.
      • Origasa H.
      • Matsuzaki M.
      • et al.
      Japan EPA lipid intervention study (JELIS) Investigators
      Effects of eicosapentaenoic acid on major coronary events in hypercholesterolaemic patients (JELIS): a randomised open-label, blinded endpoint analysis.
      50.810.651.00P=.17
      Coronary death—Primary prevention
      • Roncaglioni M.C.
      • Tombesi M.
      • Silletta M.G.
      n-3 fatty acids in patients with cardiac risk factors.
      • Yokoyama M.
      • Origasa H.
      • Matsuzaki M.
      • et al.
      Japan EPA lipid intervention study (JELIS) Investigators
      Effects of eicosapentaenoic acid on major coronary events in hypercholesterolaemic patients (JELIS): a randomised open-label, blinded endpoint analysis.
      21.090.811.46P=.98
      Coronary death—Secondary prevention
      Indicates statistical significance per SRRE and corresponding CI. Summary associations were interpreted as statistically significant if the 95% CIs did not include the null value of 1.0 in their range.
      ,
      • Burr M.L.
      • Fehily A.M.
      • Gilbert J.F.
      • et al.
      Effects of changes in fat, fish, and fibre intakes on death and myocardial reinfarction: diet and reinfarction trial (DART).
      • Johansen O.
      • Brekke M.
      • Seljeflot I.
      • Abdelnoor M.
      • Arnesen H.
      N-3 fatty acids do not prevent restenosis after coronary angioplasty: results from the CART study. Coronary Angioplasty Restenosis Trial.
      • Marchioli R.
      • Schweiger C.
      • Tavazzi L.
      • Valagussa F.
      Efficacy of n-3 polyunsaturated fatty acids after myocardial infarction: results of GISSI-Prevenzione trial. Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto Miocardico.
      • Yokoyama M.
      • Origasa H.
      • Matsuzaki M.
      • et al.
      Japan EPA lipid intervention study (JELIS) Investigators
      Effects of eicosapentaenoic acid on major coronary events in hypercholesterolaemic patients (JELIS): a randomised open-label, blinded endpoint analysis.
      40.800.640.99P=.20
      a CHD = coronary heart disease; DHA = docosahexaenoic acid; EPA = eicosapentaenoic acid; LDL = low-density lipoprotein; RCT = randomized controlled trial; SRRE = summary relative risk estimate.
      b “Any CHD event” includes fatal and nonfatal MI, coronary death, sudden cardiac death, and angina. “Coronary death” includes fatal MI, death from other acute or subacute forms of CHD, or death from chronic CHD.
      c Statistical heterogeneity was assessed using Cochran's Q, which tests for between-study statistical variation. In a conventional meta-analysis, a Cochran's Q P value of .10 or less is an indication of statistically significant heterogeneity. It is noteworthy that this P value is only an indication that statistical variability may be present in a specific meta-analysis model, and this P value is not a significance test for the relationship between the exposure (ie, EPA+DHA) and the outcome (eg, CHD).
      d Indicates statistical significance per SRRE and corresponding CI. Summary associations were interpreted as statistically significant if the 95% CIs did not include the null value of 1.0 in their range.
      Table 4Prospective Cohort Studies—Summary of Meta-Analysis Results: EPA+DHA and CHD End Points
      CHD = coronary heart disease; DHA = docosahexaenoic acid; EPA = eicosapentaenoic acid; MI = myocardial infarction; SRRE = summary relative risk estimate.
      ,
      “Any CHD event” includes fatal and nonfatal MI, coronary death, sudden cardiac death, and angina. “Coronary death” includes fatal MI, death from other acute or subacute forms of CHD, or death from chronic CHD.
      Model
      Statistical heterogeneity was assessed using Cochran's Q, which tests for between-study statistical variation. In a conventional meta-analysis, a Cochran's Q P value of .10 or less is an indication of statistically significant heterogeneity. It is noteworthy that this P value is only an indication that statistical variability may be present in a specific meta-analysis model, and this P value is not a significance test for the relationship between the exposure (ie, EPA+DHA) and the outcome (eg, CHD).
      Studies (n)SRRELower 95% CIUpper 95% CICochran's Q Heterogeneity
      Statistical heterogeneity was assessed using Cochran's Q, which tests for between-study statistical variation. In a conventional meta-analysis, a Cochran's Q P value of .10 or less is an indication of statistically significant heterogeneity. It is noteworthy that this P value is only an indication that statistical variability may be present in a specific meta-analysis model, and this P value is not a significance test for the relationship between the exposure (ie, EPA+DHA) and the outcome (eg, CHD).
      test
      Any CHD event
      Indicates statistical significance per SRRE and corresponding CI. Summary associations were interpreted as statistically significant if the 95% CIs did not include the null value of 1.0 in their range.
      ,
      • Albert C.M.
      • Hennekens C.H.
      • O'Donnell C.J.
      • et al.
      Fish consumption and risk of sudden cardiac death.
      • Amiano P.
      • Machon M.
      • Dorronsoro M.
      • et al.
      Intake of total omega-3 fatty acids, eicosapentaenoic acid and docosahexaenoic acid and risk of coronary heart disease in the Spanish EPIC cohort study.
      • Bergkvist C.
      • Berglund M.
      • Glynn A.
      • Wolk A.
      • Akesson A.
      Dietary exposure to polychlorinated biphenyls and risk of myocardial infarction—a population-based prospective cohort study.
      • Chiuve S.E.
      • Rimm E.B.
      • Sandhu R.K.
      • et al.
      Dietary fat quality and risk of sudden cardiac death in women.
      • de Goede J.
      • Geleijnse J.M.
      • Boer J.M.
      • Kromhout D.
      • Verschuren W.M.
      Marine (n-3) fatty acids, fish consumption, and the 10-year risk of fatal and nonfatal coronary heart disease in a large population of Dutch adults with low fish intake.
      • Hu F.B.
      • Cho E.
      • Rexrode K.M.
      • Albert C.M.
      • Manson J.E.
      Fish and long-chain omega-3 fatty acid intake and risk of coronary heart disease and total mortality in diabetic women.
      • Iso H.
      • Kobayashi M.
      • Ishihara J.
      • et al.
      JPHC Study Group
      Intake of fish and n3 fatty acids and risk of coronary heart disease among Japanese: the Japan Public Health Center-Based (JPHC) Study Cohort I.
      • Koh A.S.
      • Pan A.
      • Wang R.
      • et al.
      The association between dietary omega-3 fatty acids and cardiovascular death: the Singapore Chinese Health Study.
      • Jarvinen R.
      • Knekt P.
      • Rissanen H.
      • Reunanen A.
      Intake of fish and long-chain n-3 fatty acids and the risk of coronary heart mortality in men and women.
      • Joensen A.M.
      • Schmidt E.B.
      • Dethlefsen C.
      • et al.
      Dietary intake of total marine n-3 polyunsaturated fatty acids, eicosapentaenoic acid, docosahexaenoic acid and docosapentaenoic acid and the risk of acute coronary syndrome—a cohort study.
      • Manger M.S.
      • Strand E.
      • Ebbing M.
      • et al.
      Dietary intake of n-3 long-chain polyunsaturated fatty acids and coronary events in Norwegian patients with coronary artery disease.
      • Mozaffarian D.
      • Ascherio A.
      • Hu F.B.
      • et al.
      Interplay between different polyunsaturated fatty acids and risk of coronary heart disease in men.
      • Pietinen P.
      • Ascherio A.
      • Korhonen P.
      • et al.
      Intake of fatty acids and risk of coronary heart disease in a cohort of Finnish men. The Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study.
      • Streppel M.T.
      • Ocke M.C.
      • Boshuizen H.C.
      • Kok F.J.
      • Kromhout D.
      Long-term fish consumption and n-3 fatty acid intake in relation to (sudden) coronary heart disease death: the Zutphen study.
      • Yuan J.M.
      • Ross R.K.
      • Gao Y.T.
      • Yu M.C.
      Fish and shellfish consumption in relation to death from myocardial infarction among men in Shanghai, China.
      • Takata Y.
      • Zhang X.
      • Li H.
      • et al.
      Fish intake and risks of total and cause-specific mortality in 2 population-based cohort studies of 134,296 men and women.
      • Miyagawa N.
      • Miura K.
      • Okuda N.
      • et al.
      NIPPON DATA80 Research Group
      Long-chain n-3 polyunsaturated fatty acids intake and cardiovascular disease mortality risk in Japanese: a 24-year follow-up of NIPPON DATA80.
      170.820.740.92P<.001
      Fatal events
      Indicates statistical significance per SRRE and corresponding CI. Summary associations were interpreted as statistically significant if the 95% CIs did not include the null value of 1.0 in their range.
      ,
      • Albert C.M.
      • Hennekens C.H.
      • O'Donnell C.J.
      • et al.
      Fish consumption and risk of sudden cardiac death.
      • Chiuve S.E.
      • Rimm E.B.
      • Sandhu R.K.
      • et al.
      Dietary fat quality and risk of sudden cardiac death in women.
      • de Goede J.
      • Geleijnse J.M.
      • Boer J.M.
      • Kromhout D.
      • Verschuren W.M.
      Marine (n-3) fatty acids, fish consumption, and the 10-year risk of fatal and nonfatal coronary heart disease in a large population of Dutch adults with low fish intake.
      • Hu F.B.
      • Cho E.
      • Rexrode K.M.
      • Albert C.M.
      • Manson J.E.
      Fish and long-chain omega-3 fatty acid intake and risk of coronary heart disease and total mortality in diabetic women.
      • Iso H.
      • Kobayashi M.
      • Ishihara J.
      • et al.
      JPHC Study Group
      Intake of fish and n3 fatty acids and risk of coronary heart disease among Japanese: the Japan Public Health Center-Based (JPHC) Study Cohort I.
      • Koh A.S.
      • Pan A.
      • Wang R.
      • et al.
      The association between dietary omega-3 fatty acids and cardiovascular death: the Singapore Chinese Health Study.
      • Jarvinen R.
      • Knekt P.
      • Rissanen H.
      • Reunanen A.
      Intake of fish and long-chain n-3 fatty acids and the risk of coronary heart mortality in men and women.
      • Manger M.S.
      • Strand E.
      • Ebbing M.
      • et al.
      Dietary intake of n-3 long-chain polyunsaturated fatty acids and coronary events in Norwegian patients with coronary artery disease.
      • Mozaffarian D.
      • Ascherio A.
      • Hu F.B.
      • et al.
      Interplay between different polyunsaturated fatty acids and risk of coronary heart disease in men.
      • Pietinen P.
      • Ascherio A.
      • Korhonen P.
      • et al.
      Intake of fatty acids and risk of coronary heart disease in a cohort of Finnish men. The Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study.
      • Streppel M.T.
      • Ocke M.C.
      • Boshuizen H.C.
      • Kok F.J.
      • Kromhout D.
      Long-term fish consumption and n-3 fatty acid intake in relation to (sudden) coronary heart disease death: the Zutphen study.
      • Yuan J.M.
      • Ross R.K.
      • Gao Y.T.
      • Yu M.C.
      Fish and shellfish consumption in relation to death from myocardial infarction among men in Shanghai, China.
      • Takata Y.
      • Zhang X.
      • Li H.
      • et al.
      Fish intake and risks of total and cause-specific mortality in 2 population-based cohort studies of 134,296 men and women.
      • Miyagawa N.
      • Miura K.
      • Okuda N.
      • et al.
      NIPPON DATA80 Research Group
      Long-chain n-3 polyunsaturated fatty acids intake and cardiovascular disease mortality risk in Japanese: a 24-year follow-up of NIPPON DATA80.
      140.770.660.90P<.001
      Nonfatal events
      • de Goede J.
      • Geleijnse J.M.
      • Boer J.M.
      • Kromhout D.
      • Verschuren W.M.
      Marine (n-3) fatty acids, fish consumption, and the 10-year risk of fatal and nonfatal coronary heart disease in a large population of Dutch adults with low fish intake.
      • Hu F.B.
      • Cho E.
      • Rexrode K.M.
      • Albert C.M.
      • Manson J.E.
      Fish and long-chain omega-3 fatty acid intake and risk of coronary heart disease and total mortality in diabetic women.
      • Iso H.
      • Kobayashi M.
      • Ishihara J.
      • et al.
      JPHC Study Group
      Intake of fish and n3 fatty acids and risk of coronary heart disease among Japanese: the Japan Public Health Center-Based (JPHC) Study Cohort I.
      • Mozaffarian D.
      • Ascherio A.
      • Hu F.B.
      • et al.
      Interplay between different polyunsaturated fatty acids and risk of coronary heart disease in men.
      40.810.551.19P<.001
      Coronary death
      Indicates statistical significance per SRRE and corresponding CI. Summary associations were interpreted as statistically significant if the 95% CIs did not include the null value of 1.0 in their range.
      ,
      • Ascherio A.
      • Rimm E.B.
      • Stampfer M.J.
      • Giovannucci E.L.
      • Willett W.C.
      Dietary intake of marine n-3 fatty acids, fish intake, and the risk of coronary disease among men.
      • de Goede J.
      • Geleijnse J.M.
      • Boer J.M.
      • Kromhout D.
      • Verschuren W.M.
      Marine (n-3) fatty acids, fish consumption, and the 10-year risk of fatal and nonfatal coronary heart disease in a large population of Dutch adults with low fish intake.
      • Hu F.B.
      • Cho E.
      • Rexrode K.M.
      • Albert C.M.
      • Manson J.E.
      Fish and long-chain omega-3 fatty acid intake and risk of coronary heart disease and total mortality in diabetic women.
      • Iso H.
      • Kobayashi M.
      • Ishihara J.
      • et al.
      JPHC Study Group
      Intake of fish and n3 fatty acids and risk of coronary heart disease among Japanese: the Japan Public Health Center-Based (JPHC) Study Cohort I.
      • Koh A.S.
      • Pan A.
      • Wang R.
      • et al.
      The association between dietary omega-3 fatty acids and cardiovascular death: the Singapore Chinese Health Study.
      • Jarvinen R.
      • Knekt P.
      • Rissanen H.
      • Reunanen A.
      Intake of fish and long-chain n-3 fatty acids and the risk of coronary heart mortality in men and women.
      • Manger M.S.
      • Strand E.
      • Ebbing M.
      • et al.
      Dietary intake of n-3 long-chain polyunsaturated fatty acids and coronary events in Norwegian patients with coronary artery disease.
      • Pietinen P.
      • Ascherio A.
      • Korhonen P.
      • et al.
      Intake of fatty acids and risk of coronary heart disease in a cohort of Finnish men. The Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study.
      • Streppel M.T.
      • Ocke M.C.
      • Boshuizen H.C.
      • Kok F.J.
      • Kromhout D.
      Long-term fish consumption and n-3 fatty acid intake in relation to (sudden) coronary heart disease death: the Zutphen study.
      • Yuan J.M.
      • Ross R.K.
      • Gao Y.T.
      • Yu M.C.
      Fish and shellfish consumption in relation to death from myocardial infarction among men in Shanghai, China.
      • Takata Y.
      • Zhang X.
      • Li H.
      • et al.
      Fish intake and risks of total and cause-specific mortality in 2 population-based cohort studies of 134,296 men and women.
      • Miyagawa N.
      • Miura K.
      • Okuda N.
      • et al.
      NIPPON DATA80 Research Group
      Long-chain n-3 polyunsaturated fatty acids intake and cardiovascular disease mortality risk in Japanese: a 24-year follow-up of NIPPON DATA80.
      90.820.690.98P=.01
      Coronary events
      • Amiano P.
      • Machon M.
      • Dorronsoro M.
      • et al.
      Intake of total omega-3 fatty acids, eicosapentaenoic acid and docosahexaenoic acid and risk of coronary heart disease in the Spanish EPIC cohort study.
      • Hu F.B.
      • Cho E.
      • Rexrode K.M.
      • Albert C.M.
      • Manson J.E.
      Fish and long-chain omega-3 fatty acid intake and risk of coronary heart disease and total mortality in diabetic women.
      • Manger M.S.
      • Strand E.
      • Ebbing M.
      • et al.
      Dietary intake of n-3 long-chain polyunsaturated fatty acids and coronary events in Norwegian patients with coronary artery disease.
      • Mozaffarian D.
      • Ascherio A.
      • Hu F.B.
      • et al.
      Interplay between different polyunsaturated fatty acids and risk of coronary heart disease in men.
      • Pietinen P.
      • Ascherio A.
      • Korhonen P.
      • et al.
      Intake of fatty acids and risk of coronary heart disease in a cohort of Finnish men. The Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study.
      50.960.811.14P=.001
      Total MI
      • Bergkvist C.
      • Berglund M.
      • Glynn A.
      • Wolk A.
      • Akesson A.
      Dietary exposure to polychlorinated biphenyls and risk of myocardial infarction—a population-based prospective cohort study.
      • Ascherio A.
      • Rimm E.B.
      • Stampfer M.J.
      • Giovannucci E.L.
      • Willett W.C.
      Dietary intake of marine n-3 fatty acids, fish intake, and the risk of coronary disease among men.
      • de Goede J.
      • Geleijnse J.M.
      • Boer J.M.
      • Kromhout D.
      • Verschuren W.M.
      Marine (n-3) fatty acids, fish consumption, and the 10-year risk of fatal and nonfatal coronary heart disease in a large population of Dutch adults with low fish intake.
      • Iso H.
      • Kobayashi M.
      • Ishihara J.
      • et al.
      JPHC Study Group
      Intake of fish and n3 fatty acids and risk of coronary heart disease among Japanese: the Japan Public Health Center-Based (JPHC) Study Cohort I.
      • Manger M.S.
      • Strand E.
      • Ebbing M.
      • et al.
      Dietary intake of n-3 long-chain polyunsaturated fatty acids and coronary events in Norwegian patients with coronary artery disease.
      50.850.661.10P=.03
      Nonfatal MI
      • de Goede J.
      • Geleijnse J.M.
      • Boer J.M.
      • Kromhout D.
      • Verschuren W.M.
      Marine (n-3) fatty acids, fish consumption, and the 10-year risk of fatal and nonfatal coronary heart disease in a large population of Dutch adults with low fish intake.
      • Hu F.B.
      • Cho E.
      • Rexrode K.M.
      • Albert C.M.
      • Manson J.E.
      Fish and long-chain omega-3 fatty acid intake and risk of coronary heart disease and total mortality in diabetic women.
      • Iso H.
      • Kobayashi M.
      • Ishihara J.
      • et al.
      JPHC Study Group
      Intake of fish and n3 fatty acids and risk of coronary heart disease among Japanese: the Japan Public Health Center-Based (JPHC) Study Cohort I.
      • Mozaffarian D.
      • Ascherio A.
      • Hu F.B.
      • et al.
      Interplay between different polyunsaturated fatty acids and risk of coronary heart disease in men.
      40.810.551.19P<.001
      Sudden cardiac death
      Indicates statistical significance per SRRE and corresponding CI. Summary associations were interpreted as statistically significant if the 95% CIs did not include the null value of 1.0 in their range.
      ,
      • Albert C.M.
      • Hennekens C.H.
      • O'Donnell C.J.
      • et al.
      Fish consumption and risk of sudden cardiac death.
      • Chiuve S.E.
      • Rimm E.B.
      • Sandhu R.K.
      • et al.
      Dietary fat quality and risk of sudden cardiac death in women.
      • Iso H.
      • Kobayashi M.
      • Ishihara J.
      • et al.
      JPHC Study Group
      Intake of fish and n3 fatty acids and risk of coronary heart disease among Japanese: the Japan Public Health Center-Based (JPHC) Study Cohort I.
      • Mozaffarian D.
      • Ascherio A.
      • Hu F.B.
      • et al.
      Interplay between different polyunsaturated fatty acids and risk of coronary heart disease in men.
      • Streppel M.T.
      • Ocke M.C.
      • Boshuizen H.C.
      • Kok F.J.
      • Kromhout D.
      Long-term fish consumption and n-3 fatty acid intake in relation to (sudden) coronary heart disease death: the Zutphen study.
      50.530.410.67P=.62
      a CHD = coronary heart disease; DHA = docosahexaenoic acid; EPA = eicosapentaenoic acid; MI = myocardial infarction; SRRE = summary relative risk estimate.
      b “Any CHD event” includes fatal and nonfatal MI, coronary death, sudden cardiac death, and angina. “Coronary death” includes fatal MI, death from other acute or subacute forms of CHD, or death from chronic CHD.
      c Statistical heterogeneity was assessed using Cochran's Q, which tests for between-study statistical variation. In a conventional meta-analysis, a Cochran's Q P value of .10 or less is an indication of statistically significant heterogeneity. It is noteworthy that this P value is only an indication that statistical variability may be present in a specific meta-analysis model, and this P value is not a significance test for the relationship between the exposure (ie, EPA+DHA) and the outcome (eg, CHD).
      d Indicates statistical significance per SRRE and corresponding CI. Summary associations were interpreted as statistically significant if the 95% CIs did not include the null value of 1.0 in their range.
      Figure thumbnail gr2
      Figure 2Forest plots derived from random-effects meta-analysis models depicting the effect of EPA+DHA on any CHD event in RCTs among all subjects (A), among subjects with baseline triglyceride levels of more than 150 mg/dL (B), and among subjects with baseline low-density lipoprotein cholesterol levels of more than 130 mg/dL (C), and the association between EPA+DHA intake and any CHD event in prospective cohort studies (D). Circles represent the RR within the individual studies; 95% CIs are represented by horizontal lines. Circle size is proportional to the weight of each study. Diamonds represent the SRRE. Summary associations were interpreted as statistically significant if the 95% CIs did not include the null value of 1.0 in their range. Any CHD event includes fatal or nonfatal MI, coronary death, sudden cardiac death, and angina, as well as CHD incidence in prospective cohort studies. If a study did not report a variable for total CHD events, specific events were combined to create a composite CHD variable. When a series of publications from the same prospective cohort study were available, data only from the most recent publication were used in the meta-analysis except in cases in which earlier publications provided estimates for unique outcomes not presented in the most recent publication. In these cases, outcome data from the earlier publication(s) were also included in the meta-analysis. This approach resulted in only 17 prospective cohort studies in the any CHD event model as Mozaffarian et al
      • Mozaffarian D.
      • Ascherio A.
      • Hu F.B.
      • et al.
      Interplay between different polyunsaturated fatty acids and risk of coronary heart disease in men.
      was used in place of Ascherio et al
      • Ascherio A.
      • Rimm E.B.
      • Stampfer M.J.
      • Giovannucci E.L.
      • Willett W.C.
      Dietary intake of marine n-3 fatty acids, fish intake, and the risk of coronary disease among men.
      because Ascherio et al
      • Ascherio A.
      • Rimm E.B.
      • Stampfer M.J.
      • Giovannucci E.L.
      • Willett W.C.
      Dietary intake of marine n-3 fatty acids, fish intake, and the risk of coronary disease among men.
      reported only total MI vs Mozaffarian et al,
      • Mozaffarian D.
      • Ascherio A.
      • Hu F.B.
      • et al.
      Interplay between different polyunsaturated fatty acids and risk of coronary heart disease in men.
      which reported more recent data including collective coronary events for the HPFS cohort. Ascherio et al,
      • Ascherio A.
      • Rimm E.B.
      • Stampfer M.J.
      • Giovannucci E.L.
      • Willett W.C.
      Dietary intake of marine n-3 fatty acids, fish intake, and the risk of coronary disease among men.
      however, was used in the statistical model for total MI because these authors provided this outcome for the HPFS cohort, but Mozaffarian et al did not. CHD = coronary heart disease; DHA = docosahexaenoic acid; EPA = eicosapentaenoic acid; HPFS = Health Professionals Follow-up Study; MI = myocardial infarction; P-H = P value for heterogeneity in statistical model; RCT = randomized controlled trial; RR = relative risk; SRRE = summary relative risk estimate. Statistical heterogeneity was assessed using Cochran's Q, which tests for between-study statistical variation. In a conventional meta-analysis, a Cochran's Q P value of .10 or less is an indication of statistically significant heterogeneity. It is noteworthy that this P value is only an indication that statistical variability may be present in a specific meta-analysis model, and this P value is not a significance test for the relationship between the exposure (ie, EPA+DHA) and the outcome (eg, CHD).
      In the overall meta-analysis of RCT data, EPA+DHA provision was associated with a nonstatistically significant SRRE of 0.94 (95% CI, 0.85-1.05) for any CHD event (Figure 2A). Statistical heterogeneity in this RCT model (P=.07) was explained in part by differences in several study characteristics, including baseline triglyceride and low-density lipoprotein cholesterol. Participants with elevated triglyceride levels (≥150 mg/dL) (SRRE=0.84; 95% CI, 0.72-0.98) (Figure 2A) and elevated low-density lipoprotein cholesterol (SRRE=0.86; 95% CI, 0.76-0.98) (Figure 2C) experienced statistically significant reduced CHD events, respectively. Furthermore, higher dose (above 1 g/d of EPA+DHA) had a stronger impact among those with elevated triglyceride levels (SRRE=0.75; 95% CI, 0.64-0.89) compared with trials of less than 1 g/d of EPA+DHA (SRRE=0.93; 95% CI, 0.82-1.07).
      The SRRE for any CHD event was 0.83 in the subgroup analysis of RCTs administering 1 g/d or more of EPA+DHA, but this finding was not statistically significant (95% CI, 0.61-1.14) (see Supplemental Figure 4, available online at http://www.mayoclinicproceedings.org). Meta-regression did not produce a continuous dose-response effect when including data for less than 1 g/d of EPA+DHA with all other dose groups (see Supplemental Figure 5, available online at http://www.mayoclinicproceedings.org). Participants in RCTs who received EPA+DHA were less likely (SRRE=0.81; 95% CI, 0.65-1.00) to have a coronary death event compared with those who received a placebo; the effect was not modified by dose level but the summary association was stronger among secondary prevention studies (Table 3). No apparent effect modification was found by prevention status (primary, secondary, or mixed), prevalence of diabetes medication use (Table 3), or in subgroup analyses by duration of follow-up, use of an implantable cardioverter defibrillator, or hypertensive status (Supplemental Table 2) among participants in RCTs.
      Visual examination of funnel plots and statistical testing of data from the RCTs revealed no apparent publication bias (see Supplemental Figure 6, available online at http://www.mayoclinicproceedings.org). In the overall analysis of any CHD event, removal of any single RCT did not modify appreciably the summary association (range of SRRE based on 1 study removed at a time, 0.92-0.98) (see Supplemental Figure 7, available online at http://www.mayoclinicproceedings.org) or alter the level of statistical significance. The Cochrane Bias Assessment score for each RCT (see Supplemental Figure 8, available online at http://www.mayoclinicproceedings.org) was modeled as a linear variable. Meta-regression of the log risk ratio of the Cochrane Bias Assessment score on CHD risk did not result in a statistically significant quality response trend (beta coefficient=0.01; P=.64) (see Supplemental Figure 9, available online at http://www.mayoclinicproceedings.org).
      Statistically significant inverse associations were observed among prospective cohort studies for any CHD event (SRRE=0.82; 95% CI, 0.74-0.92) (Figure 2D), fatal CHD events (SRRE=0.77; 95% CI, 0.66-0.90), coronary death (SRRE=0.82; 95% CI, 0.69-0.98), and sudden cardiac death (SRRE=0.53; 95% CI, 0.41-0.67), with nonstatistically significant inverse associations found for nonfatal CHD events, coronary events, and nonfatal MI (Table 4). Between-study statistical variation was observed in all prospective cohort models (indicated by the P values for heterogeneity), except for sudden cardiac death (P=.62; Table 4). However, of note, the direction of association was similar for the large majority of prospective cohort studies (ie, most individual study's RRs were below 1.0; Table 4). The funnel plot revealed slight asymmetry around the effect size but the potential for publication bias was inconsequential (see Supplemental Figure 10, available online at http://www.mayoclinicproceedings.org). The number of Newcastle-Ottawa Score stars for each prospective cohort study (see Supplemental Table 3, available online at http://www.mayoclinicproceedings.org) was modeled as a linear variable. Meta-regression of the log risk ratio of the Newcastle-Ottawa Score stars on CHD risk did not result in a statistically significant quality response trend (beta coefficient=0.04; P=.50) (see Supplemental Figure 11, available online at http://www.mayoclinicproceedings.org). Furthermore, removal of any single prospective cohort study did not modify the summary association for any CHD event (range of SRRE based on 1 study removed at a time, 0.80-0.85; data not shown) or alter the precision of the CIs.

      Discussion

      To our knowledge, this is the most comprehensive quantitative assessment of the relationship between EPA+DHA supplementation and intake and CHD risk to date. Our inclusion criteria were specific for CHD, which distinguishes our findings from those of other meta-analyses that included a mixture of vascular as well as less well defined coronary outcomes. Collectively, the SRREs for RCT data were relatively consistent across all types of analyses with many statistically significant inverse effects that were supported by inverse associations between EPA+DHA intake and all coronary outcomes across the prospective cohort studies.
      A well-documented effect of n-3 LCPUFA supplementation is the reduction in serum triglyceride levels in subjects with hypertriglyceridemia.
      • Bernstein A.M.
      • Ding E.L.
      • Willett W.C.
      • Rimm E.B.
      A meta-analysis shows that docosahexaenoic acid from algal oil reduces serum triglycerides and increases HDL-cholesterol and LDL-cholesterol in persons without coronary heart disease.
      Although large-scale RCTs examining the effect of lowering triglyceride levels among those with hypertriglyceridemia are underway (eg, Outcomes Study to Assess STatin Residual Risk Reduction with EpaNova in HiGh CV Risk PatienTs with Hypertriglyceridemia [STRENGTH], see clintrials.gov), results from currently available prospective cohort studies indicate that elevated triglyceride levels are associated with increasing CHD risk.
      • Nordestgaard B.G.
      • Varbo A.
      Triglycerides and cardiovascular disease.
      Our results indicate that EPA+DHA provision reduced CHD risk among subjects with triglyceride levels of 150 mg/dL or more in RCTs but not among those with triglyceride levels within normal limits. Similarly, a CHD risk reduction benefit of n-3 LCPUFA provision was found among RCT subjects with low-density lipoprotein (LDL) cholesterol levels of 130 mg/dL or more but not for those with LDL cholesterol levels of less than 130 mg/dL. Although past meta-analyses have shown that n-3 LCPUFA administration may increase LDL cholesterol levels (particularly in patients with very high triglyceride levels),
      • Bernstein A.M.
      • Ding E.L.
      • Willett W.C.
      • Rimm E.B.
      A meta-analysis shows that docosahexaenoic acid from algal oil reduces serum triglycerides and increases HDL-cholesterol and LDL-cholesterol in persons without coronary heart disease.
      • Wei M.Y.
      • Jacobson T.A.
      Effects of eicosapentaenoic acid versus docosahexaenoic acid on serum lipids: a systematic review and meta-analysis.
      the beneficial effect of n-3 LCPUFA on CHD seen in subjects with higher LDL cholesterol levels in this analysis may reflect the redistribution of LDL cholesterol to larger, less atherogenic LDL particles that has been reported following n-3 LCPUFA supplementation in a number of RCTs.
      • Mori T.A.
      • Burke V.
      • Puddey I.B.
      • et al.
      Purified eicosapentaenoic and docosahexaenoic acids have differential effects on serum lipids and lipoproteins, LDL particle size, glucose, and insulin in mildly hyperlipidemic men.
      • Maki K.C.
      • McKenney J.M.
      • Reeves M.S.
      • Lubin B.C.
      • Dicklin M.R.
      Effects of adding prescription omega-3 acid ethyl esters to simvastatin (20 mg/day) on lipids and lipoprotein particles in men and women with mixed dyslipidemia.
      These findings are particularly relevant for the management of CHD risk in the general US population because 25% of Americans older than 20 years are estimated to have triglyceride levels of 150 mg/dL
      • Carroll M.
      • Kit B.
      • Lacher D.
      Trends in elevated triglyceride in adults: United States, 2001-2012.
      or more and 27% of Americans aged between 40 and 74 years have LDL cholesterol levels of 130 mg/dL or more.
      • Kuklina E.V.
      • Carroll M.D.
      • Shaw K.M.
      • Hirsch R.
      Trends in high LDL cholesterol, cholesterol-lowering medication use, and dietary saturated-fat intake: United States, 1976-2010.
      Blood pressure is another well-documented CHD risk factor impacted favorably by n-3 LCPUFA administration.
      • Miller P.E.
      • Van Elswyk M.
      • Alexander D.D.
      Long-chain omega-3 fatty acids eicosapentaenoic acid and docosahexaenoic acid and blood pressure: a meta-analysis of randomized controlled trials.
      Our findings are relatively consistent with previous meta-analyses from the last 10 years for which 10% to 30% decreased risks of cardiac/coronary death have been observed with provision or greater intakes of n-3 LCPUFA.
      • Delgado-Lista J.
      • Perez-Martinez P.
      • Lopez-Miranda J.
      • Perez-Jimenez F.
      Long chain omega-3 fatty acids and cardiovascular disease: a systematic review.
      • Kotwal S.
      • Jun M.
      • Sullivan D.
      • Perkovic V.
      • Neal B.
      Omega 3 fatty acids and cardiovascular outcomes: systematic review and meta-analysis.
      • Kwak S.M.
      • Myung S.K.
      • Lee Y.J.
      • Seo H.G.
      Korean Meta-analysis Study Group
      Efficacy of omega-3 fatty acid supplements (eicosapentaenoic acid and docosahexaenoic acid) in the secondary prevention of cardiovascular disease: a meta-analysis of randomized, double-blind, placebo-controlled trials.
      • Rizos E.C.
      • Ntzani E.E.
      • Bika E.
      • Kostapanos M.S.
      • Elisaf M.S.
      Association between omega-3 fatty acid supplementation and risk of major cardiovascular disease events: a systematic review and meta-analysis.
      • Chen Q.
      • Cheng L.Q.
      • Xiao T.H.
      • et al.
      Effects of omega-3 fatty acid for sudden cardiac death prevention in patients with cardiovascular disease: a contemporary meta-analysis of randomized, controlled trials.
      • Wen Y.T.
      • Dai J.H.
      • Gao Q.
      Effects of Omega-3 fatty acid on major cardiovascular events and mortality in patients with coronary heart disease: a meta-analysis of randomized controlled trials.
      • Casula M.
      • Soranna D.
      • Catapano A.L.
      • Corrao G.
      Long-term effect of high dose omega-3 fatty acid supplementation for secondary prevention of cardiovascular outcomes: a meta-analysis of randomized, placebo controlled trials [corrected].
      • Wang C.
      • Harris W.S.
      • Chung M.
      • et al.
      n-3 Fatty acids from fish or fish-oil supplements, but not alpha-linolenic acid, benefit cardiovascular disease outcomes in primary- and secondary-prevention studies: a systematic review.
      In a meta-analysis of prospective cohort studies, Chowdhury et al
      • Chowdhury R.
      • Warnakula S.
      • Kunutsor S.
      • et al.
      Association of dietary, circulating, and supplement fatty acids with coronary risk: a systematic review and meta-analysis.
      reported a statistically significant 13% (RR=0.87; 95% CI, 0.78-0.97) CHD risk reduction with greater n-3 LCPUFA intake and a statistically significant 25% (RR=0.75; 95% CI, 0.62-0.89) CHD risk reduction with higher circulating EPA+DHA levels. Casula et al
      • Casula M.
      • Soranna D.
      • Catapano A.L.
      • Corrao G.
      Long-term effect of high dose omega-3 fatty acid supplementation for secondary prevention of cardiovascular outcomes: a meta-analysis of randomized, placebo controlled trials [corrected].
      conducted a meta-analysis of RCTs in which at least 1 g/d of n-3 LCPUFA was administered, and reported statistically significant inverse effects for cardiac death (RR=0.68; 95% CI, 0.56-0.83), sudden death (RR=0.67; 95% CI, 0.52-0.87), and MI (RR=0.75; 95% CI, 0.63-0.88). In our subgroup analysis of RCTs in which at least 1 g/d of EPA+DHA was administered, reduced risks of most coronary outcomes, including any CHD event, MI, nonfatal MI, coronary death, and angina, were observed, although most were not statistically significant, with the exception of nonfatal MI (SRRE=0.71; 95% CI, 0.53-0.97).
      Findings from our meta-analysis models of RCTs were supported by strong and consistent, statistically significant inverse associations in meta-analyses of prospective cohort studies. These results expand upon findings from a previous meta-analysis of prospective cohort studies that examined fish consumption and CHD mortality; Zheng et al
      • Zheng J.
      • Huang T.
      • Yu Y.
      • Hu X.
      • Yang B.
      • Li D.
      Fish consumption and CHD mortality: an updated meta-analysis of seventeen cohort studies.
      reported RRs of 0.79 (95% CI, 0.67-0.92) and 0.83 (95% CI, 0.68-1.01) for 2 to 4 servings of fish/wk and 5+ servings of fish/wk, respectively, and CHD. Stronger inverse associations for n-3 LCPUFA and CHD in observational studies (including prospective cohort studies) compared with RCTs have also been reported in other reviews and meta-analyses.
      • Saravanan P.
      • Davidson N.C.
      • Schmidt E.B.
      • Calder P.C.
      Cardiovascular effects of marine omega-3 fatty acids.
      • Mozaffarian D.
      • Rimm E.B.
      Fish intake, contaminants, and human health: evaluating the risks and the benefits.
      There are many design and methodological differences between RCTs and prospective cohort studies. More than 50% of cardiac deaths occur among individuals without diagnosed heart disease, and large prospective cohort studies are able to evaluate populations that are healthy at baseline and free of the changes in dietary habits and medications that result from disease diagnosis.
      • Mozaffarian D.
      Fish and n-3 fatty acids for the prevention of fatal coronary heart disease and sudden cardiac death.
      Moreover, it is more feasible and economical to evaluate longer follow-up periods using a prospective cohort study design. Prospective cohort studies are typically longer in duration than RCTs, and dietary intake data collected in these studies may be more representative of life-long eating habits. Cardiovascular benefits have been observed at lower EPA+DHA intake levels in studies of longer duration.
      • Mozaffarian D.
      • Ascherio A.
      • Hu F.B.
      • et al.
      Interplay between different polyunsaturated fatty acids and risk of coronary heart disease in men.
      Most RCTs, in comparison, are shorter in duration and evaluate subjects with established CHD or who are at high risk to maximize power and minimize cost.
      • Mozaffarian D.
      Fish and n-3 fatty acids for the prevention of fatal coronary heart disease and sudden cardiac death.
      However, a foremost advantage of RCTs is the ostensibly greater ability to control for confounding through random allocation of exposure. Findings from prospective cohort studies and RCTs are both important, and results from prospective cohort studies may provide guidance for first-line treatments for the prevention of CHD.
      • Mozaffarian D.
      Fish and n-3 fatty acids for the prevention of fatal coronary heart disease and sudden cardiac death.
      Despite methodological differences, our analyses by study type (ie, RCTs and prospective cohort studies) should be viewed as complementary, offering a comprehensive summary of the state-of-the-epidemiologic science on EPA+DHA provision and intake.
      As expected when summarizing and analyzing data from the peer-reviewed literature, some potential limitations and sources of variability should be noted. In the current meta-analysis, the individual RCTs differed in terms of CHD prevalence at baseline, the EPA+DHA dosage provided, follow-up duration, and the methods of patient selection and randomization. The benefit of n-3 LCPUFA intake is thought to accrue over time; however, RCTs of longer duration may suffer from poorer compliance with dietary supplementation. For example, at the end of 5 years in the study by Roncaglioni et al,
      • Roncaglioni M.C.
      • Tombesi M.
      • Silletta M.G.
      n-3 fatty acids in patients with cardiac risk factors.
      almost 1 in 5 participants in the n-3 LCPUFA group had discontinued supplementation. Our method of data extraction was designed to specifically address CHD outcomes. Despite these differences, our sensitivity analyses did not indicate that these factors contributed meaningfully to differing patterns of summary effects. The variable use of terminology specific to CHD outcomes, or a lack of specificity required to discern CHD from broader cardiovascular disease outcomes, may have resulted in the exclusion of some publications. All but 1 study
      • Yokoyama M.
      • Origasa H.
      • Matsuzaki M.
      • et al.
      Japan EPA lipid intervention study (JELIS) Investigators
      Effects of eicosapentaenoic acid on major coronary events in hypercholesterolaemic patients (JELIS): a randomised open-label, blinded endpoint analysis.
      provided EPA+DHA in combination as opposed to either independently; therefore, more RCTs are needed to fully evaluate the relationship between EPA and DHA, alone or in combination, for reducing CHD outcomes. Many of the RCTs lack statistical power to detect an effect because of relatively small sample sizes and/or few observed events due to the increased survival rate associated with current standards of care.
      • Mozaffarian D.
      • Wu J.H.
      Omega-3 fatty acids and cardiovascular disease: effects on risk factors, molecular pathways, and clinical events.
      However, an inherent methodological strength in meta-analyses is that combining data from similar studies enhances the power to detect a statistically significant difference between groups, given that the evidence base of studies reflects the true nature of associations. Finally, most RCTs did not measure baseline intake of EPA+DHA from the diet nor track EPA+DHA intake from sources other than that supplemented during the course of study, thus making it impossible to determine whether background dietary EPA+DHA intake affected the relationship between supplemental EPA+DHA and CHD. Prospective cohort studies in nutritional epidemiology suffer from several methodological limitations, namely, the potential for inaccurate ascertainment and classification of exposure, and uncontrolled and residual confounding. Analyses in the prospective cohort studies included in the present meta-analyses were based on self-reported dietary intakes, although the CHD outcomes were based on clinical reporting and validation. These limitations notwithstanding, summary associations across the prospective cohort study meta-analyses were remarkably consistent, showing a benefit for CHD outcomes.
      Heart disease morbidity and mortality is the foremost public health burden in the United States
      • Murray C.J.
      • Atkinson C.
      • Bhalla K.
      • et al.
      U.S. Burden of Disease Collaborators
      The state of U.S. health, 1990-2010: burden of diseases, injuries, and risk factors.
      and many countries worldwide.
      GBD 2013 Mortality and Causes of Death Collaborators
      Global, regional, and national age-sex specific all-cause and cause-specific mortality for 240 causes of death, 1990-2013: a systematic analysis for the Global Burden of Disease Study 2013.
      Poor diet is a leading cause of CHD burden and one of the leading risk factors related to disability-adjusted life-years.
      • Murray C.J.
      • Atkinson C.
      • Bhalla K.
      • et al.
      U.S. Burden of Disease Collaborators
      The state of U.S. health, 1990-2010: burden of diseases, injuries, and risk factors.
      Because a diet low in seafood omega-3 fatty acids is reported as a contributor to ischemic heart disease disability-adjusted life-years and is considered a dietary risk factor with potentially significant effects on mortality worldwide,
      • Lim S.S.
      • Vos T.
      • Flaxman A.D.
      • et al.
      A comparative risk assessment of burden of disease and injury attributable to 67 risk factors and risk factor clusters in 21 regions, 1990-2010: a systematic analysis for the Global Burden of Disease Study 2010.
      • Danaei G.
      • Ding E.L.
      • Mozaffarian D.
      • et al.
      The preventable causes of death in the United States: comparative risk assessment of dietary, lifestyle, and metabolic risk factors.
      authoritative bodies recommend intake of EPA+DHA for heart and overall health.
      Fats and fatty acids in human nutrition: report of an expert consultation.
      EFSA Panel on Dietetic Products, Nutrition, Allergies
      Scientific Opinion on Dietary Reference Values for fats, including saturated fatty acids, polyunsaturated fatty acids, monounsaturated fatty acids, trans fatty acids, and cholesterol.
      National Health and Medical Research Council
      Nutrient reference values for Australia and New Zealand including recommended dietary intakes.

      Conclusion

      Our comprehensive meta-analysis of data from RCTs and prospective cohort studies supports this recommendation. Although not statistically significant, a 6% reduced risk of any CHD event was observed among RCTs, a finding supported by a statistically significant 18% reduced risk of CHD among the prospective cohort studies. From a clinical perspective, our results indicate that EPA+DHA may be associated with reducing CHD risk to a greater extent in populations with elevated triglyceride levels or LDL cholesterol, which are risk factors that impact a significant portion of the general adult population in the United States. Additional RCTs with more homogeneous exposure and outcome classifications with longer follow-up periods may continue to provide a better understanding of the promising beneficial relationship between EPA+DHA and CHD risk.

      Supplemental Online Material

      Supplemental Online Material

      Supplemental material can be found online at http://www.mayoclinicproceedings.org. Supplemental material attached to journal articles has not been edited, and the authors take responsibility for the accuracy of all data.

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