Usefulness of Omega-3 Fatty Acids and the Prevention of Coronary Heart Disease
2005; Elsevier BV; Volume: 96; Issue: 11 Linguagem: Inglês
10.1016/j.amjcard.2005.07.071
ISSN1879-1913
AutoresCharles R. Harper, Terry A. Jacobson,
Tópico(s)Diet, Metabolism, and Disease
ResumoClinical trial evidence exists that supports a role for the omega-3 polyunsaturated fatty acids in coronary heart disease prevention. However, the results from these clinical trials have varied and were conducted in diverse population groups using several different types of omega-3 polyunsaturated fatty acids, including eicosapentaenoic acid, docosahexaenoic acid, and alpha-linolenic acid (ALA). Thus, we systematically reviewed previously published reports assessing the different types of omega-3 polyunsaturated fatty acid interventions and cardiovascular outcomes. Fourteen randomized clinical trials were included in the review. Six trials were included with fish oil, with 1 large trial (10,000 patients) dominating the analysis. In aggregate, the fish oil trials demonstrated a reduction in total mortality and sudden death without a clinically significant reduction in nonfatal myocardial infarction. The 6 trials with ALA supplements or an ALA-enriched diet were of poorer design than the fish oil trials and had limited power. Many of the trials with ALA involved other changes in dietary components. In aggregate, the ALA trials demonstrated possible benefits in reducing sudden death and nonfatal myocardial infarction, but with wider confidence intervals than in the fish oil trials. In conclusion, the evidence suggests a role for fish oil (eicosapentaenoic acid, docosahexaenoic acid) or fish in secondary prevention because recent clinical trial data have demonstrated a significant reduction in total mortality, coronary heart disease death, and sudden death. The data on ALA have been limited by studies of smaller sample size and limited quality. Clinical trial evidence exists that supports a role for the omega-3 polyunsaturated fatty acids in coronary heart disease prevention. However, the results from these clinical trials have varied and were conducted in diverse population groups using several different types of omega-3 polyunsaturated fatty acids, including eicosapentaenoic acid, docosahexaenoic acid, and alpha-linolenic acid (ALA). Thus, we systematically reviewed previously published reports assessing the different types of omega-3 polyunsaturated fatty acid interventions and cardiovascular outcomes. Fourteen randomized clinical trials were included in the review. Six trials were included with fish oil, with 1 large trial (10,000 patients) dominating the analysis. In aggregate, the fish oil trials demonstrated a reduction in total mortality and sudden death without a clinically significant reduction in nonfatal myocardial infarction. The 6 trials with ALA supplements or an ALA-enriched diet were of poorer design than the fish oil trials and had limited power. Many of the trials with ALA involved other changes in dietary components. In aggregate, the ALA trials demonstrated possible benefits in reducing sudden death and nonfatal myocardial infarction, but with wider confidence intervals than in the fish oil trials. In conclusion, the evidence suggests a role for fish oil (eicosapentaenoic acid, docosahexaenoic acid) or fish in secondary prevention because recent clinical trial data have demonstrated a significant reduction in total mortality, coronary heart disease death, and sudden death. The data on ALA have been limited by studies of smaller sample size and limited quality. An inverse association between the intake of omega-3 polyunsaturated fatty acids (n-3 PUFAs) and coronary heart disease (CHD) mortality has been demonstrated in several prospective epidemiologic studies, but not in all.1Albert C.M. Campos H. Stampfer M.J. Ridker P.M. Manson J.E. Willett W.C. Ma J. Blood levels of long-chain n-3 fatty acids and the risk of sudden death.N Engl J Med. 2002; 346: 1113-1118Crossref PubMed Scopus (1016) Google Scholar, 2Hu F.B. Bronner L. Willett W.C. Stampfer M.J. Rexrode K.M. Albert C.M. Hunter D. Manson J.E. Fish and omega-3 fatty acid intake and risk of coronary heart disease in women.JAMA. 2002; 287: 1815-1821Crossref PubMed Scopus (863) Google Scholar, 3Hu F.B. Stampfer M.J. Manson J.E. Rimm E.B. Wolk A. Colditz G.A. Hennekens C.H. Willett W.C. Dietary intake of alpha-linolenic acid and risk of fatal ischemic heart disease among women.Am J Clin Nutr. 1999; 69: 890-897Crossref PubMed Scopus (455) Google Scholar, 4Dolecek T.A. Epidemiological evidence of relationships between dietary polyunsaturated fatty acids and mortality in the Multiple Risk Factor Intervention Trial dietary PUFA and mortality.Proc Soc Experiment Biol Med. 2000; : 177-182Google Scholar Studies have used food diaries and biologic markers of dietary intake (i.e., percentage of serum fatty acids) to estimate dietary exposure and CHD risk. A recent review of prospective cohort epidemiologic studies has suggested that n-3 PUFA consumption correlates with a reduction in CHD death.5He K. Song Y. Daviglus M.L. Liu K. Van Horn L. Dyer A.R. Greenland P. Accumulated evidence on fish consumption and coronary heart disease mortality a meta-analysis of cohort studies.Circulation. 2004; 109: 2705-2711Crossref PubMed Scopus (663) Google Scholar Additionally, clinical trial evidence exists that supports a role for the n-3 PUFA in CHD prevention. The results from these clinical trials have varied and were conducted in several different ethnic groups and with several varieties of omega-3 fatty acids. The purpose of this study was to review published data systematically to assess the different types of randomized controlled clinical trials involving different types of n-3 PUFA interventions and their effects on CHD morbidity and mortality.MethodsSearch strategyStudies were identified by searching MedLine, EMBASE, and Index Medicus from 1966 to June 2004, as well as the Cochrane Library of references and clinical trials. We included all languages. A search was done with key words, including, omega-3 fatty acids, fish oil, eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), alpha-linolenic acid (ALA), gamma-linolenic acid, polyunsaturated fatty acids (PUFAs), flax seed oil, dietary therapy, and cardiovascular disease.Inclusion criteriaWe used several criteria to select the studies. First, the trials had to be randomized, controlled trials, which included a control group or a placebo group. Second, trial end points had to include either significant cardiovascular disease end points, such as fatal myocardial infarction, nonfatal myocardial infarction, cardiovascular mortality, or total mortality. Third, trials were excluded if patients were not followed for ≥1 year. Finally, trials were excluded if they involved >1 intervention unless in a prospective 2 × 2 design.Data extraction and validity assessmentStudy quality was also assessed by a scoring system described by Jadad et al.6Jadad A.R. Moore R.A. Carroll D. Jenkinson C. Reynolds D.J. Gavaghan D.J. McQuay H.J. Assessing the quality of reports of randomized clinical trials is blinding necessary?.Control Clin Trials. 1996; 17: 1-12Abstract Full Text PDF PubMed Scopus (13357) Google Scholar Scoring was based on the following: (1) randomization of patients; (2) blinding of patients and providers and those analyzing the data; (3) complete follow-up of those who withdrew from the study; (4) the presence of concealed randomization; and (5) the presence of double blinding and a placebo group.Data synthesisThe studies were divided into those with plant-based n-3 PUFAs (ALA), fish-based n-3 PUFAs (DHA and EPA), and those that used whole food changes, such as increased fish consumption or increased margarine consumption. The data were organized into tabular form and then divided by more specific cardiac end points. A formal meta-analysis was not performed due to the heterogeneity of the studies, limited number of studies, general poor study quality, and diversity of the interventions.ResultsIdentified studiesOur search identified 2,478 publications with possible relevance. From their structured abstracts, we reviewed 118 for full study analysis. Of these, 14 studies met the inclusion criteria.Study characteristicsThe doses of n-3 PUFA ranged from 0.85 to 4.8 g/day for the studies with EPA and DHA and from 1.0 to 6.3 g/day for the studies with ALA. The Jadad quality scores (Jadad quality rating 0 to 5, with 5 indicating highest quality study) ranged from 1 to 4.6Jadad A.R. Moore R.A. Carroll D. Jenkinson C. Reynolds D.J. Gavaghan D.J. McQuay H.J. Assessing the quality of reports of randomized clinical trials is blinding necessary?.Control Clin Trials. 1996; 17: 1-12Abstract Full Text PDF PubMed Scopus (13357) Google Scholar The included studies had sample sizes ranging from 59 to >13,000 subjects studied.Characteristics of dietary interventionThe core group of 14 studies included 6 studies with fish oil, 2 studies with fish, 5 studies with ALA supplements, and 2 studies with an ALA-enriched diet. Of the ALA supplement trials, several included supplementation with flaxseed oil, mustard seed oil, soybean oil, or ALA-enhanced margarine.Characteristics of study participantsThe studies had recruited participants from northern Europe, Southern Europe, and India. Participants were recruited from vegan populations and meat-consuming populations. In addition, studies were conducted in low-fish consumption and moderate-to-high fish consumption populations. Table 1 lists the estimated background fish or n-3 PUFA consumption.Table 1Randomized controlled clinical trials of omega-3 fatty acids and cardiovascular outcomesTrialn-3 (Type/Dose)Control (Type/Dose)nMean Follow-up (mo)Previous MI (%)Baseline Fish or n-3 IntakeAll-Cause Mortality RR, 95% CI)CVD Death (RR, 95% CI)Cardiac Death (RR, 95% CI)Sudden Death (RR, 95% CI)Fatal MI (RR, 95% CI)Nonfatal MI(RR, 95% CI)All Strokes (95% CI)All CVD Events (95% CI)Quality ScoreFish OilGISSI Italy, 19997GISSI-Prevenzione InvestigatorsDietary supplementation with n-3 polyunsaturated fatty acids and vitamin E after myocardial infarction results of the GISSI-Prevenzione trial.Lancet. 1999; 354: 447-455Abstract Full Text Full Text PDF PubMed Scopus (3712) Google ScholarEPA + DHA (1:2) 0.85 g/dControl or vitamin E11,2344210073% >1 serving fish/wk0.79 (0.66–0.93)0.70 (0.56–0.86)0.65 (0.51–0.82)0.55 (0.51–0.82)0.68 (0.53–0.88)0.91 (0.68–0.94)1.2 (0.81–1.9)0.80 (0.68–0.94)3Singh, India 19978Singh 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.Cardiovasc Drugs Ther. 1997; 11: 485-491Crossref PubMed Scopus (485) Google ScholarEPA + DHA (1:1) 1.8 g/d100 mg Aluminum hydroxide36012100NDNDND0.52 (0.29–0.95)0.24 (0.05–1.1)ND0.52 (0.3–0.9)ND0.71 (0.48–1.1)4Nilsen, Norway 20019Nilsen 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.Am J Clin Nutr. 2001; 74: 50-56Crossref PubMed Scopus (171) Google ScholarEPA + DHA (1:2) 3.4 g/dCorn oil 4 g/d300181003 servings fish/wk1.0 (0.45–2.2)ND1.0 (0.39–2.6)NDND1.4 (0.75–2.6)ND1.1 (0.84–1.3)4Von Schacky 1999 GermanyEPA + DHA (3:2) 1.85 g/d10von 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.Ann Intern Med. 1999; 130: 554-562Crossref PubMed Scopus (420) Google ScholarVegetable oil blend 1.85 g/d2232457ND0.5 (0–5.5)NDNDND0.5 (0–14.7)0.4 (0.1–2.9)NDND3Leng, UK, 199811Leng G.C. Lee A.J. Fowkes F.G. Jepson R.G. Lowe G.D. Skinner E.R. Mowat B.F. Randomized controlled trial of gamma-linolenic acid and eicosapentaenoic acid in peripheral arterial disease.Clin Nutr. 1998; 17: 265-271Abstract Full Text PDF PubMed Scopus (70) Google ScholarEPA 0.27 g/dSunflower seed oil 3 g/d1202429ND1.0 (0.21–4.8)1.0 (0.15–0.69)NDNDND0.75 (0.18–3.2)3.0 (0.32–28)0.86 (0.43–1.7)5Sacks USA, 199512Sacks F.M. Stone P.H. Gibson C.M. Silverman D.I. Rosner B. Pasternak R.C. the HARP Research GroupControlled trial of fish oil for regression of human coronary atherosclerosis.J Am Coll Cardiol. 1995; 25: 1492-1498Abstract Full Text PDF PubMed Scopus (196) Google ScholarEPA + DHA (3:2) 4.8 g/dOlive oil 12 g/d592856ND0.3 (0.01–7.1)0.3 (0.01–7.1)0.3 (0.01–7.1)ND0.3 (0.01–7.7)0.45 (0.04–4.7)2.7 (0.12–64)ND3FishBurr, UK, 200314Burr M.L. Ashfield-Watt P.A. Dunstan F.D. Fehily A.M. Breay P. Ashton T. Zotos P.C. Haboubi N.A. Elwood P.C. Lack of benefit of dietary advice to men with angina results of a controlled trial.Eur J Clin Nutr. 2003; 57: 193-200Crossref PubMed Scopus (372) Google ScholarEPA 2.65 g/wk"Sensible eating" EPA 0.12 g/wk3,114108500.54–0.67 g/wk1.15 (0.86–1.36)ND1.26 (1.00–1.58)1.54 (1.06–2.23)NDNDNDND1Burr, UK 198913Burr M.L. Fehily A.M. Gilbert J.F. Rogers S. Holliday R.M. Sweetnam P.M. Elwood P.C. Deadman N.M. Effects of changes in fat, fish, and fiber intakes on death and myocardial reinfarction Diet and Reinfarction Trial (DART).Lancet. 1989; 2: 757-761Abstract PubMed Scopus (2306) Google Scholar2.4 g/wkNo fish advice2,033241000.7 g/wk0.73 (0.56–0.93)ND0.67 (0.51–0.89)ND0.7 (0.5–0.9)1.5 (0.97–2.3)NDND2ALA supplementsNatvig, Norway, 196615Natvig H. Borchgrevink C.F. Dedichen J. Owren P.A. Schiotz E.H. Westlund K. A controlled trial of the effect of linolenic acid on incidence of coronary heart disease the Norwegian vegetable oil experiment of 1965–66.Scand J Clin Lab Invest Suppl. 1968; 105: 1-20PubMed Google ScholarALA 5.25 g/d Linseed oil 10 ml/dALA 0.13 g/d Sunflower oil 10 ml/d13,578128ND1.07ND1.0NDNDND1.43ND2Leren, Norway 196616Leren P. The effect of plasma cholesterol lowering diet in male survivors of myocardial infarction.Acta Med Scand. 1966; 466: 1-92Google ScholarALA 1.0–1.9 g/d (soybean oil)Usual diet41260100ND0.75 (0.52–1.06)0.73 (0.50–1.06)ND1.00 (0.61–1.64)0.43 (0.21–0.89)0.77 (0.47–1.27)NDND2MRC Soya-Bean UK, 196817Report of a Research Committee to the Medical Research CouncilControlled trial of soya-bean oil in myocardial infarction.Lancet. 1968; 2: 693-700PubMed Google ScholarALA 5.9 g/d soybean oilUsual diet393 men54100ND0.86 (0.49–1.50)1.06 (0.59–1.9)0.97 (0.54–1.76)ND1.05 (0.49–2.23)0.97 (0.54–1.76)ND0.99 (0.61–1.64)2Bemelmans Netherlands 200218Bemelmans W.J. Broer J. Feskens E.J. Smit A.J. Muskiet F.A. Lefrandt J.D. Bom V.J. May J.F. Meyboom-de Jong B. Effect of an increased intake of alpha-linolenic acid and group nutritional education on cardiovascular risk factors the Mediterranean Alpha-linolenic Enriched Groningen Dietary Intervention (MARGARIN) study.Am J Clin Nutr. 2002; 75: 221-227PubMed Google ScholarALA 6.3 g/d (margarine 15% ALA)Margarine (0.3% ALA) 1 g/d28224ND2.1 servings fish/wk4.3 (0.46–41)1.44 (0.09–23)NDNDND0.16 (0.01–2.9)0.29 (0.01–5.9)0.16 (0.02–1.3)3Singh India 19978Singh 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.Cardiovasc Drugs Ther. 1997; 11: 485-491Crossref PubMed Scopus (485) Google ScholarALA 2.9 g/dAluminum hydroxide3601290NDNDND0.61 (0.34–1.1)0.25 (0.05–1.1)ND0.59 (0.35–1.0)ND0.82 (0.56–1.2)4ALA-enriched diet19Singh R.B. Dubnov G. Niaz M.A. Ghosh S. Singh R. Rastogi S.S. Manor O. Pella D. Berry E.M. Effect of an Indo-Mediterranean diet on progression of coronary artery disease in high risk patients (Indo-Mediterranean Diet Heart Study) a randomised single-blind trial.Lancet. 2002; 360: 1455-1461Abstract Full Text Full Text PDF PubMed Scopus (585) Google ScholarSingh India 2002ALA 1.8 g/d (SD 0.4)ALA 0.8 g/d (SD 0.2)1,00024501.1 g/d (10 g/day MSO)0.63 (0.38–1.04)NDND0.38 (0.15–0.95)0.71 (0.34–1.5)0.49 (0.30–0.81)0.54 (0.22–1.3)ND3De Lorgeril, France 199920de Lorgeril M. Salen P. Martin J.L. Monjaud 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: 779-785Crossref PubMed Scopus (2306) Google ScholarALA-fortified margarine (1.0–1.9 g/d)Usual care605271003 servings fish/wk0.44 (0.21–0.94)ND0.35 (0.15–0.83)0.06 (0.003–1.02)ND0.32 (0.15–0.70)0.11 (0.01–2.1)0.53 (0.38–0.74)4CVD = cardiovascular disease; MI = myocardial infarction; MSO = mustard seed oil; ND = not determined. Open table in a new tab Characteristics of individual fish oil studiesOf the 6 fish oil studies, only 3 were designed and powered to analyze hard cardiac end points. The Gruppo Italiano per 10 Studio della Sopravvienza nell'Infarcto Miocardio (GISSI) trial, which was the largest, had a 2 × 2 factorial design and included fish oil capsules and vitamin E capsules.7GISSI-Prevenzione InvestigatorsDietary supplementation with n-3 polyunsaturated fatty acids and vitamin E after myocardial infarction results of the GISSI-Prevenzione trial.Lancet. 1999; 354: 447-455Abstract Full Text Full Text PDF PubMed Scopus (3712) Google Scholar In that study, 10,000 patients were randomized to fish oil (850 mg EPA plus DHA, EPA/DHA ratio 1:2), with or without vitamin E (300 mg), and followed for 3.5 years. The primary combined end point was death, nonfatal myocardial infarction, and stroke. Fish oil reduced the primary end point by 15% (4-way analysis), and vitamin E had no effect on any end point. When analyzing secondary end points, a relative risk reduction of 20% was seen for total mortality. This effect was seen early and was driven by a 45% reduction in sudden death, suggesting an antiarrhythmic effect.7GISSI-Prevenzione InvestigatorsDietary supplementation with n-3 polyunsaturated fatty acids and vitamin E after myocardial infarction results of the GISSI-Prevenzione trial.Lancet. 1999; 354: 447-455Abstract Full Text Full Text PDF PubMed Scopus (3712) Google Scholar These positive results occurred in a group of patients already on a prototypical heart healthy Mediterranean diet (88% ≥1 fish serving/wk, 88% ≥1 fruit serving/day, 55% ≥1 vegetable serving/day). In addition, patients were receiving standard pharmacologic therapy for secondary prevention of CHD (46% statin, 83% aspirin, and 39% β blockers by study end). This trial was limited by its open-label design and lack of a control group.The Indian Study on Infarct Survival was a randomized, placebo-controlled study of 360 Indian patients <1 day after myocardial infarction.8Singh 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.Cardiovasc Drugs Ther. 1997; 11: 485-491Crossref PubMed Scopus (485) Google Scholar Participants were enrolled into 1 of 3 groups: a group receiving fish oil (1.08 g/day EPA and 0.72 g/day DHA), a group receiving mustard seed oil 20 g/day (ALA content 2.9 g/day), and a placebo group receiving aluminum hydroxide 100 mg/day. The combined primary end point was total cardiac events (sudden cardiac death plus total cardiac deaths plus nonfatal reinfarction). The fish oil group had a 30% reduction in total cardiac events. The study population in this trial had unique features. First, the patients entered the study within 24 hours of their myocardial infarction symptoms, and second, although the investigators did not provide any baseline dietary data, it is known that a high percentage of patients living in that part of India are vegetarians. This baseline diet might have resulted in underestimating the effect of plant-based omega-3 fatty acids. Study limitations included the unique characteristics of the study population (vegetarian south Asians), and that the patients were 1 day after myocardial infarction and not treated aggressively with modern post-myocardial infarction therapies. Only 30% of patients were receiving β blockers and 20% angiotensin-converting enzyme inhibitors; the use of lipid-lowering drugs was not reported.Nilsen et al9Nilsen 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.Am J Clin Nutr. 2001; 74: 50-56Crossref PubMed Scopus (171) Google Scholar studied the effect of omega-3 fatty acids on subsequent cardiac complications in patients recently hospitalized with myocardial infarction. In Norway, 300 patients were enrolled within 1 week of myocardial infarction and followed for 1.5 years. Patients randomized to the treatment group received 4 capsules of 1-g fish oil daily (EPA 2.24 g/day, DHA 1.12 g/day). The placebo control group received 4 g of corn oil (59% linoleic acid, 24% oleic acid, 17% stearic acid, 0% ALA). The primary end point was defined as cardiac death, cardiac resuscitation, recurrent myocardial infarction, or unstable angina. The results of this study did not demonstrate any clinical benefit from fish oil; however, certain important limitations were present. The patients enrolled in this study lived in a coastal area, and the baseline diet was rich in fish containing omega-3 fatty acids. Another potential confounder with this study was the corn oil placebo. Some studies have suggested that corn oil may be antiarrhythmic and thus could potentially reduce sudden death. Also, observational cohort studies seem to suggest a threshold effect with fish-based omega-3 fatty acids; thus, consuming more fish than the threshold might have no added benefit.von Schacky and others10von 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.Ann Intern Med. 1999; 130: 554-562Crossref PubMed Scopus (420) Google Scholar evaluated 223 patients with angiographically proven CHD and followed them for 2 years. Patients in the treatment group received 6 g of fish oil daily (3.3 g/day EPA plus DHA, EPA/DHA ratio 3:2) for 3 months and then 3 g/day for 21 months. The placebo controls were treated with capsules containing a blend of oils comparable to that of the typical European diet (placebo capsules 0% ALA, 0% EPA, 0% DHA). Although the primary end point was angiographic (luminal diameter), clinical events were recorded. The loss of luminal diameter was not statistically significant. Seven cardiovascular events occurred in the control group and 2 in the fish oil group (p = 0.10). This difference, however, was not statistically significant.Two small fish oil trials are also listed in Table 1. A study by Leng et al11Leng G.C. Lee A.J. Fowkes F.G. Jepson R.G. Lowe G.D. Skinner E.R. Mowat B.F. Randomized controlled trial of gamma-linolenic acid and eicosapentaenoic acid in peripheral arterial disease.Clin Nutr. 1998; 17: 265-271Abstract Full Text PDF PubMed Scopus (70) Google Scholar included 120 patients with known peripheral vascular disease; cardiac events were a secondary end point. Sacks et al12Sacks F.M. Stone P.H. Gibson C.M. Silverman D.I. Rosner B. Pasternak R.C. the HARP Research GroupControlled trial of fish oil for regression of human coronary atherosclerosis.J Am Coll Cardiol. 1995; 25: 1492-1498Abstract Full Text PDF PubMed Scopus (196) Google Scholar conducted a trial with 59 participants designed to look at angiographic end points and recorded cardiac events. These 2 studies failed to show a reduction in cardiac death, myocardial infarction, or revascularization rates.12Sacks F.M. Stone P.H. Gibson C.M. Silverman D.I. Rosner B. Pasternak R.C. the HARP Research GroupControlled trial of fish oil for regression of human coronary atherosclerosis.J Am Coll Cardiol. 1995; 25: 1492-1498Abstract Full Text PDF PubMed Scopus (196) Google ScholarCharacteristics of individual fish diet studiesThe previously mentioned trials increased omega-3 fatty acid consumption by providing a supplement; however, other investigators have studied the effect of n-3 PUFAs by instructing patients to eat more fish.The first of these trials was the Diet And Reinfarction Trial (DART). In this randomized controlled factorial study, 2,033 men 4 to 6 weeks after myocardial infarction were followed for 2 years.13Burr M.L. Fehily A.M. Gilbert J.F. Rogers S. Holliday R.M. Sweetnam P.M. Elwood P.C. Deadman N.M. Effects of changes in fat, fish, and fiber intakes on death and myocardial reinfarction Diet and Reinfarction Trial (DART).Lancet. 1989; 2: 757-761Abstract PubMed Scopus (2306) Google Scholar Participants were randomized to receive advice on each of the following 3 dietary factors: (1) fat intake (<30% of total calories); (2) fiber intake (≥18 g/day); and (3) fatty fish intake (2 servings of oily fish weekly). The primary end point was total mortality; secondary end points included cardiac death and nonfatal myocardial infarction.Fish advice resulted in a 29% (p <0.05) reduction in mortality; other forms of advice had no effect on mortality. The 2-year incidence of nonfatal myocardial infarction was not reduced by any of the 3 dietary interventions; however, the incidence of cardiac death in the fish group was reduced by 33% (p <0.05). The investigators proposed that the mortality benefit was driven by a reduction in sudden death. More importantly, the results of their study suggest that diets used to prevent mortality from coronary heart disease need to focus on more than just their effects on lipoprotein levels. This concept was underscored by the following facts. First, the 29% reduction in mortality occurred independent of the serum cholesterol levels. Second, the serum cholesterol increased in the fish advice group. Finally, the amount of fish consumed was only 300 g of fish per week or 2.5 g of EPA per week, an amount too small to effect triglyceride levels. The limitations of this study included a lack of blinding.In another randomized controlled factorial trial by the same investigators, 3,114 men with angina were followed for 9 years. Participants were randomized to 1 of 4 groups and given varying advice: group 1, eat more fish; group 2, eat more fruit; group 3, eat more fish and fruit; and group 4, no advice.14Burr M.L. Ashfield-Watt P.A. Dunstan F.D. Fehily A.M. Breay P. Ashton T. Zotos P.C. Haboubi N.A. Elwood P.C. Lack of benefit of dietary advice to men with angina results of a controlled trial.Eur J Clin Nutr. 2003; 57: 193-200Crossref PubMed Scopus (372) Google Scholar The participants in group 1 were told to eat 2 servings per week of oily fish from the ocean. Those that could not eat fish were given fish oil capsules 3 g/day. Group 2 was told to eat 4 portions of fruit daily and 8 g of fiber. Group 3 received the same advice as groups 1 and 2. Group 4 only received advice on "sensible eating." The end points in this study were total mortality and cardiac mortality. All-cause mortality was not altered by any type of advice, and the risk of cardiac death was higher among those given the fish advice (1.26; 95% confidence interval [CI] 1.00 to 1.58; p = 0.047). The risk of sudden cardiac death was also higher for the fish advice group (1.54; 95% CI 1.06 to 2.23; p = 0.025). The results of this study were unexpected, and its several limitations are discussed.Participants in this study were only required to have a history consistent with angina; however, only 50% of participants had documented CHD, raising uncertainty about the trial being a true secondary prevention study. Also, the study was discontinued for 12 months because of interrupted funding. The effect this interruption had on dietary patterns and n-3 PUFA intake is difficult to determine. When the study was resumed, only 10% of the study participants received dietary questionnaires, making assessment of dietary compliance less reliable. The background fish consumption of group 1 before the trial seemed to be high compared with that in other studies. If a threshold effect exists with fish and omega-3 fatty acids, a benefit from consumption of additional fish would not be expected.Characteristics of patient ALA dietary supplementation trialsIn the Norwegian Vegetable Oil experiment, the largest ALA supplement trial, 13,000 men, mostly without known CHD, aged 50 to 59 years, were followed for 1 year.15Natvig H. Borchgrevink C.F. Dedichen J. Owren P.A. Schiotz E.H. Westlund K. A controlled trial of the effect of linolenic acid on incidence of coronary heart disease the Norwegian vegetable oil experiment of 1965–66.Scand J Clin Lab Invest Suppl. 1968; 105: 1-20PubMed Google Scholar In this double-blind trial, patients were randomized to receive 10 ml of flaxseed oil daily; 10 ml of this rich source of ALA would provide 5.25 g of ALA daily. The control group received sunflower oil, which contains no ALA (0% ALA, 65% linoleic acid, 23% oleic acid, and 12% stearic acid). The end points in this trial included all-cause death, sudden death, and myocardial infarction. The mortality from all causes, as well as from CHD, was the same in the 2 groups. More patients had previous angina pectoris or myocardial infarction in the flaxseed oil group (p <0.02). This trial was limited by several major confounders. Thirty percent of the patients stopped taking the flaxseed oil in the first year because the negative results from another earlier linseed oil trial in Norway were widely reported in the lay press. The omega-6–rich sunflower oil used as a control may have had a cardioprotective effect. Also, the event rate in the study participants was significantly lower than the event rate of the background population. Other limitations, in addition to the short duration of the trial, included a lack of information on the percentage of study participants taking aspirin or other cardioprotective medications.ALA was also studied in the Os
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