Skip Navigation

This Article
Right arrow Abstract Freely available
Right arrow FREE Full Text (PDF) Freely available
Right arrow E-letters: Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when E-letters are posted
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrow Disclaimer
Right arrow Request Permissions
Google Scholar
Right arrow Articles by Marchioli, R.
Right arrow Search for Related Content
PubMed
Right arrow Articles by Marchioli, R.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?


Treatment with n-3 polyunsaturated fatty acids after myocardial infarction: results of GISSI-prevenzione trial

R. Marchioli{dagger},*

Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto miocardico, Associazione Nazionale Medici Cardiologi Ospedalieri (ANMCO), Istituto di Ricerche Farmacologiche Mario Negri - Consorzio Mario Negri Sud, Santa Maria Imbaro, Italy

{dagger} Correspondence: Roberto Marchioli, MD, GISSI-Prevenzione Co-ordinating Centre, Consorzio Mario Negri Sud, Via Nazionale, 66030 Santa Maria Imbaro, Italy.

on behalf of the GISSI-Prevenzione investigators

Abstract

GISSI-Prevenzione was conceived as a population, pragmatic trial on patients with recent myocardial infarction conducted in the framework of the Italian public health system. In GISSI-Prevenzione, patients were invited to follow Mediterranean dietary habits, and were treated with up-to-date preventive pharmacological interventions. Long-term n-3 PUFA 1 g daily, but not vitamin E 300 mg daily, was beneficial for death and for combined death, non-fatal myocardial infarction, and stroke. All the benefit, however, was attributable to the decrease in risk for overall, cardiovascular, cardiac, coronary, and sudden death.

At variance from the orientation of a scientific scenario largely dominated by the ‘cholesterol-heart hypothesis’, GISSI-Prevenzione results indicate n-3 PUFA (virtually devoid of any cholesterol-lowering effect) as a relevant pharmacological treatment for secondary prevention after myocardial infarction.

As to the relevance and comparability of GISSI-Prevenzione results, up to 5·7 lives could be saved per 1000 patients with previous myocardial infarction treated with n-3 PUFA (1 g daily) per year. Such a result is comparable to that observed in the LIPID trial, where 5·2 lives could be saved per 1000 hypercholaesterolemic, CHD patients treated with pravastatin for 1 year.

The choice in favour of a relatively low-dose regimen (1 g capsule daily) more acceptable for long-term treatment in a population of patients following Mediterranean dietary habits, the pattern of effects seen in GISSI-Prevenzione (namely, reduction of overall mortality with no decrease in the rate of non-fatal myocardial infarction), all suggest that it can confidently be said that n-3 PUFA treatment should be considered a recommended new component of secondary prevention. The importance of this combined/additive effect is further suggested by the preliminary analyses (to be submitted in the final form for publication) of the interplay between diet and n-3 PUFA: there is an interesting direct correlation between size of the effect and ‘correctness’ of background diets. It can be anticipated that a conceptual barrier must be overcome: a ‘dietary drug’ should be added to ‘dietary advice’, which remains fundamental to allow this statement to become true in clinical practice.

Key Words: n-3 PUFA • clinical trial • CHD • secondary prevention

Footnotes

* The names of GISSI-Prevenzione investigators are reported in Reference 63.

References

  1. Simopoulos AP. Omega-3 fatty acids in health and disease and growth and development. Am J Clin Nutr. 1991;54:438–463[Abstract/Free Full Text]
  2. Simopoulos AP. {omega}3 fatty acids in the prevention-management of cardiovascular disease. Can J Physiol Pharmacol. 1997;75:234–239[CrossRef][Web of Science][Medline]
  3. Bang HO, Dyerberg J, Hjørne N. The composition of food consumed by Greenland Eskimos. Acta Med Scand. 1976;200:69–73[Web of Science][Medline]
  4. Ascherio A, Rimm EB, Stampfer MJ, Giovannucci EL, Willett WC. 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[Abstract/Free Full Text]
  5. Albert CM, Hennekens CH, O'Donnell CJ, et al. Fish consumption and risk of sudden cardiac death. J Am Med Assoc. 1998;279:23–28[Abstract/Free Full Text]
  6. Kromhout D, Bosschieter EB, de Lezenne CC. The inverse relationship between fish consumption and 20-year mortality from coronary heart disease. N Engl J Med. 1985;312:1205–1209[Abstract]
  7. Daviglus ML, Stamler J, Orencia AJ, et al. Fish consumption and the 30-year risk of fatal myocardial infarction. N Engl J Med. 1997;336:1046–1053[Abstract/Free Full Text]
  8. Dolecek TA. Epidemiological evidence of relationships between dietary polyunsaturated fatty acids and mortality in the Multiple Risk Factor Intervention Trial. Proc Soc Exp Biol Med. 1992. p. 177–182
  9. Rodriguez BL, Sharp DS, Abbott RD, et al. Fish intake may limit the increase in risk of coronary heart disease morbidity and mortality among heavy smokers: The Honolulu Heart Program. Circulation. 1996;94:952–956[Abstract/Free Full Text]
  10. De Lorgeril M, Salen P, Martin J-L, Moniaud I, Delaye J, Mamelle N. Mediterranean diet, traditional risk factors, and the rate of cardiovascular complications after myocardial infarction: final report of the Lyon Diet Heart Study. Circulation. 1999;99:779–785[Abstract/Free Full Text]
  11. Singh RB, Rastogi SS, Verma R, et al. Randomised controlled trial of cardioprotective diet in patients with recent acute myocardial infarction: results of one year follow up. Br Med J. 1992;304:1015–1019
  12. Albert CM, Hennekens CH, O'Donnell CJ, et al. Fish consumption and risk of sudden cardiac death. J Am Med Assoc. 1998;279:23–28
  13. Ascherio A, Rimm EB, Stampfer MJ, Giovannucci EL, Willett WC. 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
  14. Kromhout D, Bosschieter EB, de Lezenne CC. The inverse relationship between fish consumption and 20-year mortality from coronary heart disease. N Engl J Med. 1985;312:1205–1209
  15. Daviglus ML, Stamler J, Orencia AJ, et al. Fish consumption and the 30-year risk of fatal myocardial infarction. N Engl J Med. 1997;336:1046–1053
  16. Dolecek TA. Epidemiological evidence of relationships between dietary polyunsaturated fatty acids and mortality in the Multiple Risk Factor Intervention Trial. Proc Soc Exp Biol Med. 1992. p. 177–182
  17. Rodriguez BL, Sharp DS, Abbott RD, et al. Fish intake may limit the increase in risk of coronary heart disease morbidity and mortality among heavy smokers: The Honolulu Heart Program. Circulation. 1996;94:952–956
  18. De Lorgeril M, Salen P, Martin J-L, Moniaud I, Delaye J, Mamelle N. Mediterranean diet, traditional risk factors, and the rate of cardiovascular complications after myocardial infarction: final report of the Lyon Diet Heart Study. Circulation. 1999;99:779–785
  19. Singh RB, Rastogi SS, Verma R, et al. Randomised controlled trial of cardioprotective diet in patients with recent acute myocardial infarction: results of one year follow up. Br Med J. 1992;304:1015–1019
  20. Singh RB, Niaz MA, Sharma JP, et al. 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. Cardiovasc Drug Ther. 1997;11:485–491[CrossRef][Web of Science][Medline]
  21. von Shacky 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. Ann Intern Med. 1999;130:554–562[Abstract/Free Full Text]
  22. Burr ML, Fehily AM, Gilbert JF, et al. Effects of changes in fat, fish, and fibre intakes on death and myocardial reinfarction: diet and reinfarction trial (DART). Lancet. 1989;ii:757–761
  23. Harris WS. n-3 fatty acids and serum lipoproteins: human studies. Am J Clin Nutr. 1997;65(Suppl 5):1645S–1654S[Abstract/Free Full Text]
  24. Harris WS. n-3 fatty acids and serum lipoproteins: animal studies. Am J Clin Nutr. 1997;65(Suppl 5):1611S–1616S[Abstract/Free Full Text]
  25. McLennan PL, Bridle TM, Abeywardena MY, Charnok JS. Dietary lipid modulation of ventricular fibrillation threshold in the marmoset monkey. Am Heart J. 1992;123:1555–1561[CrossRef][Web of Science][Medline]
  26. McLennan PL. Relative effects of dietary saturated, monounsaturated, and polyunsaturated fatty acids on cardiac arrhythmias in rats. Am J Clin Nutr. 1993;57:207–212[Abstract/Free Full Text]
  27. Kang JX, Leaf A. Antiarrhythmic effects of polyunsaturated fatty acids: recent studies. Circulation. 1996;94:1774–1780[Free Full Text]
  28. Billman GE, Kang JX, Leaf A. Prevention of ischemia-induced ventricular arrhythmias by dietary pure n-3 polyunsaturated fatty acids in dogs. Circulation. 1999;99:2452–2457[Abstract/Free Full Text]
  29. Sellmayer A, Witzgall H, Lorenz RL, Weber PC. Effects of dietary fish oil on ventricular premature complexes. Am J Cardiol. 1995;76:974–977[CrossRef][Web of Science][Medline]
  30. Christensen JH, Gustenhoff P, Eilersen E, et al. n-3 fatty acids and ventricular extra systoles in patients with ventricular tachyarrhythmias. Nutr Res. 1995;15:1–8
  31. Christensen JH, Korup E, Aaroe J, et al. Fish consumption, {omega}3 fatty acids in cell membranes, and heart rate variability in survivors of myocardial infarction with left ventricular dysfunction. Am J Cardiol. 1997;79:1670–1673[CrossRef][Web of Science][Medline]
  32. Siscovick DS, Raghunathan TE, King I, et al. Dietary intake and cell membrane levels of long-chain {omega}3 polyunsaturated fatty acids and the risk of primary cardiac arrest. J Am Med Assoc. 1995;274:1363–1367[Abstract/Free Full Text]
  33. Kang JX, Leaf A. Effects of long-chain polyunsaturated fatty acids on the contraction of neonatal rat cardiac myocytes. Proc Natl Acad Sci USA. 1994. p. 9886–9890
  34. Kang JX, Leaf A. Prevention and termination of the ß-adrenergic agonist-induced arrhythmias by free polyunsaturated fatty acids in neonatal rat cardiac myocytes. Biochem Biophys Res Commun. 1995;208:629–636[CrossRef][Web of Science][Medline]
  35. Kang JX, Xiao Y-F, Leaf A. Free, long-chain, polyunsaturated fatty acids reduce membrane electrical excitability in neonatal rat cardiac myocytes. Proc Natl Acad Sci USA. 1995. p. 3997–4001
  36. Kang JX, Xiao Y-F, Leaf A. Free, long-chain, polyunsaturated fatty acids reduce membrane electrical excitability in neonatal rat cardiac myocytes. Proc Natl Acad Sci USA. 1995. p. 3997–4001
  37. Xiao Y-F, Kang JX, Morgan JP, Leaf A. Blocking effects of polyunsaturated fatty acids on Na+ channels of neonatal rat ventricular myocytes. Proc Natl Acad Sci USA. 1995. p. 1100–1104
  38. Xiao Y-F, Gomez AM, Morgan JP, Lederer WJ, Leaf A. Suppression of voltage-gated L-type Ca2+ currents by polyunsaturated fatty acids in adult and neonatal rat cardiac myocytes. Proc Natl Acad Sci USA. 1997. p. 4182–4187
  39. Xiao Y-F, Wright SN, Wang JK, Morgan JP, Leaf A. n-3 fatty acids suppress voltage-gated Na+ currents in HEK293t cells transfected with the (subunit of the human cardiac Na+ channel. Proc Natl Acad Sci USA. 1998. p. 2680–2685
  40. Marchioli R. Di Pasquale A per i Ricercatori GISSI-Prevenzione. Il quadro di riferimento biochimico, farmacologico, epidemiologico del GISSI-Prevenzione. G Ital Cardiol. 1993;23:933–964[Medline]
  41. Gruppo Italiano Studio sulla Sopravvivenza nell'Infarto miocardico (GISSI). Il protocollo dello studio GISSI-Prevenzione: Studio di intervento preventivo sulle componenti aterosclerotica e trombotica del rischio post-infarto. G Ital Cardiol. 1993;23:1053–1061[Medline]
  42. Meydani M, Natiello F, Goldin B, et al. Effect of long-term fish oil supplementation on vitamin E status and lipid peroxidation in women. J Nutr. 1991;121:484–491
  43. Marchioli R. Antioxidant vitamins and prevention of cardiovascular disease: laboratory epidemiological, and clinical trial data. Pharmacol Res. 1999;40:227–238[CrossRef][Web of Science][Medline]
  44. Steinberg D, Parthasarathy S, Carew TE, Khoo JC, Witztum JL. Beyond cholesterol: modifications of low-density lipoprotein that increase its atherogenicity. N Engl J Med. 1989;320:915–924[Web of Science][Medline]
  45. Steinberg D. Antioxidants and atherosclerosis: a current assessment. Circulation. 1991;84:1420–1425[Free Full Text]
  46. Steinberg D, workshop participants. Antioxidants in the prevention of human atherosclerosis. Circulation. 1992;85:2337–2344[Free Full Text]
  47. Diaz MN, Frei B, Vita JA, Keaney JF. Antioxidants and atherosclerotic heart disease. N Engl J Med. 1997;337:408–416[Free Full Text]
  48. The Alpha-TocopherolBeta Carotene Cancer Prevention Study Group. The effect of vitamin E and beta carotene on the incidence of lung cancer and other cancers in male smokers. N Engl Med. 1994;330:1029–1035[Abstract/Free Full Text]
  49. Stephens NG, Parsons A, Schofield PM, et al. Randomised controlled trial of vitamin E in patients with coronary disease: Cambridge Heart Antioxidant Study (CHAOS). Lancet. 1996;347:781–786[CrossRef][Web of Science][Medline]
  50. Mitchinson MJ, Stephens NG, Parsons A, Blight E, Schoefield PM, Brown MJ. Mortality in the CHAOS trial. Lancet. 1999;353:381[CrossRef][Web of Science][Medline]
  51. Ness A, Davey Smith G. Mortality in the CHAOS trial. Lancet. 1999;353:1017–1018
  52. Brown M. Do vitamin E and fish oil protect against ischaemic heart disease? Lancet. 1999;354:441–442[CrossRef][Web of Science][Medline]
  53. Rapola JM, Virtamo J, Ripatti S, et al. Randomised trial of alpha-tocopherol and beta-carotene supplements on incidence of major coronary events in men with previous myocardial infarction. Lancet. 1997;349:1715–1720[CrossRef][Web of Science][Medline]
  54. Omenn GS. What accounts for the association of vegetables and fruit with lower incidence of cancers and coronary heart disease? Ann Epidemiol. 1995;5:333–335[CrossRef][Medline]
  55. Rimm EB, Stampfer MJ, Ascherio A, Giovannucci F, Colditz GA, Willett WC. Vitamin E consumption and the risk of coronary heart disease in men. N Engl J Med. 1993;328:1450–1456[Abstract/Free Full Text]
  56. Stampfer MJ, Hennekens CH, Manson JE, Colditz GA, Rosner B, Willett WC. Vitamin E consumption and the risk of coronary disease in women. N Engl J Med. 1993;328:1444–1449[Abstract/Free Full Text]
  57. Kushi LH, Folsom AR, Prineas RJ, et al. Dietary antioxidant vitamins and death from coronary heart disease in postmenopausal women. N Engl J Med. 1996;334:1156–1162[Abstract/Free Full Text]
  58. Princen HMG, van Duyvenvoorde W, Buytenhek R, et al. Supplementation with low doses of vitamin E protects LDL from lipid peroxidation in men and women. Arterioscler Thromb Vasc Biol. 1995;15:325–333[Abstract/Free Full Text]
  59. Suzukawa M, Ishikawa T, Yoshida H, Nakamura K. Effect of in-vivo supplementation with low-dose vitamin E on susceptibility of low-density lipoprotein and high-density lipoprotein to oxidative modification. J Am Coll Nutr. 1995;14:46–52[Abstract]
  60. Weber P, Bendich A, Machlin LJ. Vitamin E and human health: rationale for determining recommended intake levels. Nutrition. 1997;13:450–460[CrossRef][Web of Science][Medline]
  61. Porkkala-Sarataho EK, Nyyssonen MK, Kaikkonen JE, et al. A randomized, single-blind, placebo-controlled trial of the effects of 200 mg {alpha}-tocopherol on the oxidation resistance of atherogenic lipoproteins. Am J Clin Nutr. 1998;68:1034–1041[Abstract]
  62. De Waart FJ, Moser U, Kok FJ. Vitamin E supplementation in elderly lowers the oxidation rate of linoleic acid in LDL. Atherosclerosis. 1997;133:255–263[CrossRef][Web of Science][Medline]
  63. GISSI-Prevenzione Investigators. Dietary supplementation with n-3 polyunsaturated fatty acids and vitamin E after myocardial infarction: results of the GISSI-Prevenzione trial. Lancet. 1999;354:447–455[CrossRef][Web of Science][Medline]
  64. Graziani MS, Ceriotti F, Carobene A, et al. Accuracy of cholesterol measurements in Italian clinical laboratories: joint project SIBioC GISSI-Prevenzione Italian Society of Biochemistry Group. on behalf of SIBioC GSSI-Prevenzione GroupEur J Clin Chem Clin Biochem. 1997;35:311–315[Web of Science][Medline]
  65. Stampfer MJ, Buring JE, Willett W, Rosner B, Eberlein K, Hennekens CH. The 2 x 2 factorial design: its applications to a randomized trial of aspirin and carotene in U.S. Physicians. Stat Med. 1985;4:111–116[Web of Science][Medline]
  66. Byar DP, Piantadosi S. Factorial designs for randomized clinical trials. Cancer Treat Rep. 1985;69:1055–1062[Web of Science][Medline]
  67. Marubini E, Valsecchi MG. Analysing Survival Data from Clinical Trials and Observational Studies. Chichester, UK: John Wiley; 1995.
  68. De Vita C, Franzosi MG, Geraci E, et al. GISSI-2 mortality plus extensive left ventricular damage as ‘end-points’. Lancet. 1990;335:289[CrossRef][Web of Science][Medline]
  69. Dyerberg J, Bang HO, Stofferson E. Eicosapentaenoic acid and prevention of thrombosis and atherosclerosis. Lancet. 1978;ii:117–119
  70. Pietinen P, Ascerio A, Korhonen P, et al. Intake of fatty acids and risk of coronary heart disease in a cohort of Finish men: The Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study. Am J Epidemiol. 1997;145:876–887[Abstract/Free Full Text]
  71. Guallar E, Aro A, Jimenez FJ, et al. Omega-3 fatty acids in adipose tissue and risk of myocardial infarction: the EURAMIC study. Arterioscler Thromb Vasc Biol. 1999;19:1111–1118[Abstract/Free Full Text]
  72. Seidelin KN, Myrup B, Fischer-Hansen B. n-3 fatty acids in adipose tissue and coronary heart disease are inversely related. Am J Clin Nutr. 1992;55:1117–1119[Abstract/Free Full Text]
  73. The Long-Term Intervension with Pravastatin in Ischaemic Disease (LIPID) Study Group. Prevention of cardiovascular events and death with pravastatin in patients with coronary heart disease and a broad range of initial cholesterol levels. N Engl J Med. 1988;339:1349–1354
  74. Scandinavian Simvastatin Survival Study Group. Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). Lancet. 1994;344:1383–1389[CrossRef][Web of Science][Medline]
  75. Antiplatelet Trialists' Collaboration. Secondary prevention of vascular events by prolonged antiplatelet therapy. Br med J. 1988;296:320–331
  76. Sacks FM, Pfeffer MA, Moye LA, et al, for the Cholesterol and Recurrent Events Trial Investigators. The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels. N Engl J Med. 1996;335:1001–1009[Abstract/Free Full Text]
  77. Fauchier L, Babuty D, Cosnay P, Fauchier JP. Prognostic value of heart rate variability for sudden death and major arrhythmic events in patients with idiopathic dilated cardiomyopathy. J Am Coll Cardiol. 1999;33:1203–1207[Abstract/Free Full Text]
  78. Marchioli R, Valagussa F. The results of the GISSI-Prevenzione trial in the general framework of secondary prevention. behalf of GISSI-Prevenzione InvestigatorsEur Heart J. 2000;21:949–952[Free Full Text]
  79. De Caterina R, Cybulsky MI, Clinton SK, Gimbrone MA, Libby P. The omega-3 fatty acid decosahexanoate reduces cytokine-induced expression of proatherogenic and proinflammatory proteins in human endothelial cells. Arterioscler Thromb. 1994;14:1829–1836[Abstract/Free Full Text]
  80. Sacks FM, Stone PH, Gibson CM, Silverman DI, Rosner B, Pasternak RC. Controlled trial of fish oil for regression of human coronary atherosclerosis. HARP research group. J Am Coll Cardiol. 1995;25:1492–1498[Abstract]
  81. Eritsland J, Arnesen H, Gronseth K, Fjeld NB, Abdelnoor M. Effect of dietary supplementation with n-3 fatty acids on coronary artery bypass graft patency. Am J Cardiol. 1996;77:31–36[CrossRef][Web of Science][Medline]
  82. Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto Miocardico. GISSI-2: a factorial randomised trial of alteplase versus streptokinase and heparin versus no heparin among 12 490 patients with acute myocardial infarction. Lancet. 1990;336:65–71[Web of Science][Medline]
  83. Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto Miocardico (GISSI). GISSI-3: effects of lisinopril and transdermal glyceryl trinitrate singly and together on 6-week mortality and ventricular function after acute myocardial infarction. Lancet. 1994;343:1115–1122[Web of Science][Medline]
  84. ISIS-4 (Fourth International Study of Infarct Survival) Collaborative Group. ISIS-4: a randomised factorial trial assessing early oral captopril, oral mononitrate, and intravenous magnesium sulphate in 58 050 patients with suspected acute myocardial infarction. Lancet. 1995;345:669–685[CrossRef][Web of Science][Medline]
  85. Krauss RM, Eckel RH, Howard B, et al. AHA Dietary Guidelines Revision 2000: A Statement for Healthcare Professionals from the Nutrition Committee of the American Heart Association. Circulation. 2000;102:2296–2311

Add to CiteULike CiteULike   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us    What's this?



This Article
Right arrow Abstract Freely available
Right arrow FREE Full Text (PDF) Freely available
Right arrow E-letters: Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when E-letters are posted
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrow Disclaimer
Right arrow Request Permissions
Google Scholar
Right arrow Articles by Marchioli, R.
Right arrow Search for Related Content
PubMed
Right arrow Articles by Marchioli, R.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?