N-3 polyunsaturated fatty acids in coronary heart disease: a meta-analysis of randomized controlled trials



      Observational studies have shown an inconsistent association between n-3 polyunsaturated fatty acids and the risk of coronary heart disease. We investigated the effects of dietary and nondietary (supplemental) intake of n-3 polyunsaturated fatty acids on coronary heart disease.

      Subjects and methods

      We searched the literature to identify randomized controlled trials that compared dietary or nondietary intake of n-3 polyunsaturated fatty acids with a control diet or placebo in patients with coronary heart disease. Studies had to have at least 6 months of follow-up data, and to have reported clinical endpoint data. We identified 11 trials, published between 1966 and 1999, which included 7951 patients in the intervention and 7855 patients in the control groups.


      The risk ratio of nonfatal myocardial infarction in patients who were on n-3 polyunsaturated fatty acid-enriched diets compared with control diets or placebo was 0.8 (95% confidence interval [CI]: 0.5 to 1.2, P = 0.16; Breslow-Day test for heterogeneity, P = 0.01), and the risk ratio of fatal myocardial infarction was 0.7 (95% CI: 0.6 to 0.8, P <0.001; heterogeneity P >0.20). In 5 trials, sudden death was associated with a risk ratio of 0.7 (95% CI: 0.6 to 0.9, P <0.01; heterogeneity P >0.20), whereas the risk ratio of overall mortality was 0.8 (95% CI: 0.7 to 0.9, P <0.001; heterogeneity P >0.20). There was no difference in summary estimates between dietary and nondietary interventions of n-3 polyunsaturated fatty acids for all endpoints.


      This meta-analysis suggests that dietary and nondietary intake of n-3 polyunsaturated fatty acids reduces overall mortality, mortality due to myocardial infarction, and sudden death in patients with coronary heart disease.


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        • Daviglus M.L
        • Stamler J
        • Orencia A.J
        • et al.
        Fish consumption and the 30-year risk of fatal myocardial infarction.
        N Engl J Med. 1997; 336: 1046-1053
        • Kromhout D
        • Bosschieter E.B
        • de Lezenne Coulander C
        The inverse relation between fish consumption and 20-year mortality from coronary heart disease.
        N Engl J Med. 1985; 312: 1205-1209
        • Ascherio A
        • Rimm E.B
        • Stampfer M.J
        • et al.
        Dietary intake of marine n-3 fatty acids, fish intake, and the risk of coronary disease among men.
        N Engl J Med. 1995; 332: 977-982
        • Morris M.C
        • Manson J.E
        • Rosner B
        • et al.
        Fish consumption and cardiovascular disease in the Physicians’ Health Study.
        Am J Epidemiol. 1995; 142: 166-175
        • Morris M.C
        • Sacks F
        • Rosner B
        Does fish oil lower blood pressure? A meta-analysis of controlled trials.
        Circulation. 1993; 88: 523-533
      1. The effects of nonpharmacologic interventions on blood pressure of persons with high normal levels. Results of the Trials of Hypertension Prevention, Phase I.
        JAMA. 1992; 267: 1213-1220
        • Wing L.M
        • Nestel P.J
        • Chalmers J.P
        • et al.
        Lack of effect of fish oil supplementation on blood pressure in treated hypertensives.
        J Hypertens. 1990; 8: 339-843
        • Connor W.E
        Importance of n-3 fatty acids in health and disease.
        Am J Clin Nutr. 2000; 71: 171S-175S
        • Tagawa H
        • Shimokawa H
        • Takawa T
        • et al.
        Long-term treatment with eicosapentaenoic acid augments both nitric oxide-mediated and non-nitric oxide-mediated endothelium-dependent forearm vasodilatation in patients with coronary artery disease.
        J Cardiovasc Pharmacol. 1999; 33: 633-640
        • Chen L.Y
        • Lawson D.L
        • Mehta J.L
        Reduction in human neutrophil superoxide anion generation by n-3 polyunsaturated fatty acids.
        Thromb Res. 1994; 76: 317-322
        • Albert C.M
        • Hennekens C.H
        • O’Donnell C.J
        • et al.
        Fish consumption and risk of sudden cardiac death.
        JAMA. 1998; 279: 23-28
        • Sellmayer A
        • Witzgall H
        • Lorenz R.L
        • Weber P.C
        Effects of dietary fish oil on ventricular premature complexes.
        Am J Cardiol. 1995; 76: 974-977
        • Billman G.E
        • Kang J.X
        • Leaf A
        Prevention of ischemia-induced cardiac sudden death by n-3 polyunsaturated fatty acids in dogs.
        Lipids. 1997; 32: 1161-1168
        • Gapinski J.P
        • Van Ruiswyk J.V
        • Heudebert G.R
        • Schectman G.S
        Preventing restenosis with fish oils following coronary angioplasty. A meta-analysis.
        Arch Intern Med. 1993; 153: 1595-1601
        • Leaf A
        • Jorgensen M.B
        • Jacobs A.K
        • et al.
        Do fish oils prevent restenosis after coronary angioplasty?.
        Circulation. 1994; 90: 2248-2257
        • Jadad A.R
        • Moore R.A
        • Jenkinson C
        • et al.
        Assessing the quality of reports of randomized clinical trials.
        Control Clin Trials. 1996; 17: 1-12
        • DerSimonian R
        • Laird N
        Meta-analysis in clinical trials.
        Control Clin Trials. 1986; 7: 177-188
        • Fleiss J.L
        The statistical basis of meta-analysis.
        Stat Methods Med Res. 1993; 2: 121-145
        • Kang J.X
        • Leaf A
        Antiarrhythmic effects of polyunsaturated fatty acids. Recent studies.
        Circulation. 1996; 94: 1774-1780
        • Burr M.L
        • Gilbert J.F
        • Holliday R.M
        • et al.
        Effects of changes in fat, fish, and fibre intakes on death and myocardial reinfarction.
        Lancet. 1989; 2: 757-761
        • de Lorgeril M
        • Salen P
        • Martin J.L
        • et al.
        Mediterranean diet, traditional risk factors and the rate of cardiovascular complications after myocardial infarction.
        Circulation. 1999; 99: 779-785
        • Reis G.J
        • Boucher T.M
        • Sipperly M.E
        • et al.
        Randomised trial of fish oil for prevention of restenosis after coronary angioplasty.
        Lancet. 1989; 2: 177-181
        • Kaul U
        • Sanghvi S
        • Bahl V.K
        • et al.
        Fish oil supplements for prevention of restenosis after coronary angioplasty.
        Int J Cardiol. 1992; 35: 87-93
        • Sacks F.M
        • Stone P.H
        • Gibson C.M
        • et al.
        Controlled trial of fish oil for regression of human coronary atherosclerosis.
        J Am Coll Cardiol. 1995; 25: 1492-1498
        • Singh R.B
        • Niaz M.A
        • Sharma J.P
        • et al.
        Randomized, double-blind, placebo-controlled trial of fish oil and mustard oil in patients with suspected acute myocardial infarction.
        Cardiovasc Drugs Ther. 1997; 11: 485-491
        • Leng G.C
        • Lee A.J
        • Fowkes F.G
        • et al.
        Randomized controlled trial of gamma-linolenic acid and eicosapentaenoic acid in peripheral arterial disease.
        Clin Nutr. 1998; 17: 265-271
        • Johansen O
        • Brekke M
        • Seljeflot I
        • et al.
        N-3 fatty acids do not prevent restenosis after coronary angioplasty.
        J Am Coll Cardiol. 1999; 33: 1619-1626
        • von Schacky C
        • Angerer P
        • Kothny W
        • et al.
        The effect of dietary omega-3 fatty acids on coronary atherosclerosis. A randomized, double-blind, placebo-controlled trial.
        Ann Intern Med. 1999; 130: 554-562
        • GISSI Prevenzione Investigators
        Dietary supplementation with n-3 polyunsaturated fatty acids and vitamin E after myocardial infarction.
        Lancet. 1999; 354: 447-455
        • Moher D
        • Pham B
        • Jones A
        • et al.
        Does quality of reports of randomised trials affect estimates of intervention efficacy reported in meta-analyses?.
        Lancet. 1998; 352: 609-613
        • Schulz K.F
        • Chalmers I
        • Grimes D.A
        • Altman D.G
        Assessing the quality of randomization from reports of controlled trials published in obstetrics and gynecology.
        JAMA. 1995; 272: 125-128
        • Chin J.P
        • Gust A.P
        • Nestel P.J
        • Dart A.M
        Marine oils dose-dependently inhibit vasoconstriction of forearm resistance in humans.
        Hypertension. 1993; 21: 22-28
        • Hughes D.A
        • Pinder A.C
        N-3 polyunsaturated fatty acids inhibit antigen-presenting function of human monocytes.
        Am J Clin Nutr. 2000; 71: 357S-360S
        • Caughey G.E
        • Mantzioris E
        • Gibson R.A
        • et al.
        The effect on human tumor necrosis factor alpha and interleukin 1 beta production of diets enriched in n-3 fatty acids from vegetable oil or fish oil.
        Am J Clin Nutr. 1996; 63: 116-122
        • Johansen O
        • Seljeflot I
        • Hostmark A.T
        • Arnesen H
        The effect of supplementation with omega-3 fatty acids on soluble markers of endothelial function in patients with coronary heart disease.
        Arterioscler Thromb Vasc Biol. 1999; 19: 1681-1686
        • Feskens E.J
        • Bowles C.H
        • Kromhout D
        Inverse association between fish intake and risk of glucose intolerance in normoglycemic elderly men and women.
        Diabetes Care. 1991; 14: 935-941
        • Harris W.S
        Fish oils and plasma lipid and lipoprotein metabolism in humans.
        J Lipid Res. 1989; 30: 785-807
        • Stampfer M.J
        • Krauss R.M
        • Ma J
        • et al.
        A prospective study of triglyceride level, low-density lipoprotein particle diameter, and risk of myocardial infarction.
        JAMA. 1996; 276: 882-888
        • Kannel W.B
        Lipids, diabetes, and coronary heart disease.
        Am Heart J. 1985; 110: 1100-1107
        • McLennan P.L
        • Bridle T.M
        • Abeywardena M.Y
        • Charnock J.S
        Comparative efficacy of n-3 and n-6 polyunsaturated fatty acids in modulating ventricular fibrillation threshold in marmoset monkeys.
        Am J Clin Nutr. 1993; 58: 666-669
        • Leaf A
        • Kang J.X
        Prevention of cardiac sudden death by n-3 fatty acids.
        J Intern Med. 1996; 240: 5-12
        • Kang J.X
        • Leaf A
        Prevention of fatal cardiac arrhythmias by polyunsaturated fatty acids.
        Am J Clin Nutr. 2000; 71: 202S-207S