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Therapeutic Use of n-3 Fatty Acids for Vascular Disease and Thrombosis
Therapeutic Use of n-3 Fatty Acids for Vascular Disease and Thrombosis Scott H. Goodnight, MD, Chair; and John A. Cairns, MD
T
he n-3 fatty acids are long-chain polyunsaturated fatty acids that are a natural component of marine oils and some plants. Medically important n-3 fatty acids include eicosapentaenoic acid (EPA) (C20:5 n-3), docosahexaenoic acid (C22:6 n-3), and a-linolenic acid (a-LA) (C18:3 n-3). The fatty acids can be ingested as part of the diet or can be administered in more concentrated form as semipurified triglycerides or highly purified ethyl esters. After administration to humans, the n-3 fatty acids are incorporated into cellular lipids where they can exert their biologic effects. The actions of n-3 fatty acids on cellular functions are diverse and include decreases in the production of prostaglandins, interleukin-1, tumor necrosis factor, tissue factor, leukotrienes, and growth factors such as granulocyte, granulocytemacrophage colony-stimulating factor, or platelet-derived growth factor. 1 The end result is reduced platelet-vascular and leukocyte-endothelium interactions, both of which could modify the progression or consequences of human arterial vascular disease. Side effects and toxic reactions generally have been mild even when large doses of n-3 fatty acid have been administered to patients in clinical trials. Despite slight impairment of platelet function, little or no bleeding has been detected, even when fish oil or n-3 fatty acids are combined with aspirin or oral anticoagulants. 2-4 There is no evidence that n-3 fatty acids lead to increased rates of cancer, infections, or clinically significant impairment in immunity. 5 PoPULATION STUDIES
Some epidemiologic studies have suggested that increased consumption of fish is associated with a lower risk of death from coronary heart disease. 6-9 In the study by Kromhout et al,6 the ingestion of 0 to 44 gld of fish was inversely related to the risk of coronary heart disease mortality, with up to 50% decreases in those individuals who consume more than 30 gld. However, a recently published study of almost 45,000 male health professionals in the United States suggested that further increases in dietary fish intake to more than one to two servings per week did not substantially reduce the risk of coronary heart disease. 10 Other studies have failed to find an association between fish consumption and lower rates of heart disease.l 1- 13 SECONDARY PREVENTION TRIALS IN CoRONARY HEART DISEASE
The Diet and Reinfarction Trial (DART) 14 found that an increased consumption of oily fish following a myocardial infarction led to a 29% decrease in all-cause mortality (p<0.05) and a 33% reduction in ischemic heart disease mortality (p<0.01 ) in middle-aged men younger than 70 years of age who were randomized within 41 days following an acute myocardial infarction (level I). There was no benefit of dietary modifications that restricted fat or augmented fiber intakes. 302S
A recently reported prospective randomized trial studied the effects of a diet rich in a-LA compared with a usual postinfarction diet in 600 patients recruited after a first myocardial infarction (level 1). 15 Patients were followed up yearly for 5 years. The experimental group consumed less total and saturated fat, cholesterol, and linoleic acid, but larger amounts of a-LA and oleic acid. After a mean follow-up of 27 months, the risk ratio for cardiac death and nonfatal myocardial infarction fell to 0.27 (p=0.001) in the experimental group. Overall mortality was also reduced (risk ratio, 0.3; p=0.02). Because there were several dietary modifications in the experimental group, it was not clear whether the beneficial effects were mediated by an increase in intake of a-LA. However, both a-LA and EPA were substantially increased in the plasma fatty acids when measured at 52 weeks (p<0.001). THERAPY OF HYPERTENSION
Several clinical studies have suggested that n-3 fatty acids can reduce systolic and diastolic BP in mildly hypertensive patients.l 6- 18 Two recently published meta-analyses of controlled trials showed that relatively high doses of n-3 fatty acids, ie, >3 gld, produced a lowering of BP in patients with hypertension, atherosclerosis, or hypercholesterolemia. 19•20 There was a dose-response relationship of n-3 fatty acid intake to BP reduction, with a decrease of 0.66/0.35 mm Hg for each gram per day of n-3 fatty acids ingested. RESTENOSIS AFTER ANGIOPLASTY
Experimental studies have suggested that high doses of fish oil or purified n-3 fatty acids can inhibit vascular responses to injury in experimental animals. In one study conducted in pigs, deep carotid arterial wall injury by balloon angioplasty was associated with significantly less lll Inlabeled platelet deposition and injury-related vasoconstriction when the animals were fed large doses of cod liver oil. 21 In another study, baboons were given large doses of n-3 fatty acids (composed of two-thirds EPA and one-third decosahexaenoic acid) as an ethyl ester concentrate.22 Bleeding times were prolonged, platelet aggregation was suppressed, and stimulated monocyte tissue factor expression was reduced in the treated animals. Deposition of radiolabeled autologous platelets onto Dacron vascular grafts and endarterectomized homologous aorta was significantly reduced. In addition, decreased vascular thrombus formation at sites of surgical carotid endarterectomy was seen. Importantly, dietary n-3 fatty acids abolished vascular lesion formation at sites of carotid endarterectomy when the animals were assessed 6 weeks after surgery. These and earlier studies suggest that treatment with n-3 fatty acids might reduce restenosis after percutaneous transluminal coronary angioplasty (PTCA) in humans. 23 This procedure is performed on more than 300,000 Americans annually, and yet restenosis recurs in about 40% of them within 6 months. In at least half the patients with restenosis, repeated PTCA or coronary bypass surgery is required. 24 Despite a large number of trials of pharmacologic and mechanical adjuncts to PTCA, the restenosis rate has changed little over the 18 years since the procedure was introduced. 25 Following PTCA, vessel occlusion may occur acutely as the result of intimal flap formation, subsequently as the reFourth ACCP Consensus Conference on Antithrombotic Therapy
Table !-Clinical Trials of n-3 Fatty Acids to Prevent Restenosis Following Coronary Angioplasty
Study, yr
No. of Patients
n-3 FA, gld
Control Oil
Slack et al, 31 1987 Dehmer et al,2 1988 Grigg et al,32 1989 Reis et al,33 1989 Milner et al,34 1989
162 82 108 186 194
2.5 5.4 3.0 6.0 4.5
None None Olive/com Olive None
Nye e t al,35 1990 Bairati et al,36 1992 Leaf et al,4 1994 Cairns et al,30 1994
69 119 551 814
4.0 4.5 6.9 5.4
Olive Olive Com oil Com oil
Patients Assessed for Restenosis, FO vs C.%§ 35 vs 19 VS 34 vs 34 VS 19 VS 22 VS ll vs 31 VS 52 VS 47 vs
Significance, p Value
39 46 33 23 36 35* 30t 48 46 46
NSt 0.026 NS NS <0.008 <0.04 <0.05 =0.05 NS NS
*Intention to treat. IRestenosis by lesion. INS =not significant. §FO=fish oil; C=control.
suit of thrombosis, or over the next 1 to 6 months as the result of neointimal proliferation. 26 ·27 Smooth muscle cells migrate from the media to the intima, presumably in response to mitogens derived from platelets, endothelial cells, and activated macrophages . There has been considerable interest in the evaluation of n-3 fatty acids and the prevention of PICA restenosis, since they might exert a favorable influence by altering the synthesis of arachidonic acid and leukotriene derivatives, the level of serum lipids, and the synthesis and actions of various smooth muscle cell mitigens. Important considerations in the evaluation of clinical trials of n-3 fatty acids in PICA include the dose of n-3 fatty acids (relatively large doses are required for full incorporation of n-3 fatty acids into platelet and other cell membranes) and blinding (the potential for bias in follow-up and designation of outcomes). The only truly reliable outcomes are angiographic, and quantitative approaches are required for precision and objectivity. Angiography must be obtained in a high percentage of subjects and study sample size must be sufficiently large to detect clinically important reductions in the incidence of restenosis. Published clinical trials of n-3 fatty acids to prevent restenosis following coronary angioplasty are listed in Table 1. Seven trials were available at the time of the previous edition of this chapter, four of them showing statistically significant reductions in restenosis, one showing a favorable trend, one showing no impact, and one showing a deleterious effect. A meta-analysis of the available trials at that time yielded a typical odds reduction of 26.7% (p
Cairns et al 30 randomized 814 patients to 5.4 g!d of n-3 fatty acids (max-EPA) or matching placebo for approximately 1 week pre-PTCA and for 18 weeks thereafter (level 1). The trial employed a 2x2 factorial design whereby patients were also randomized to low molecular weight heparin or control. Restenosis was determined by quantitative coronary angiography performed at 18 weeks. Restenosis rates were 47% with max-EPA and 46% with placebo. A meta-analysis of the data from eight of the nine trials is heavily influenced by the two large trials and reveals no benefit of n-3 fatty acids for the reduction of restenosis in the 6 months following PTCA. RECOMMENDATIONS
1. The ingestion of 30 to 40 gld of fish (eg, two meals a week) in the diet, especially as a substitute for foods containing saturated fatty acids, can be recommended for the possible primary or secondary prevention of coronary artery disease. This grade B recommendation is based on one level I trial for the secondary prevention of coronary artery disease, several epidemiologic studies, and the low risk of side effects of this dietary regimen. There is no evidence to support the use of concentrated n-3 fatty acids in fish oil or as ethyl esters for the prevention or treatment of coronary artery disease. · . 2. Two level I trials and a meta-analysis of nine trials have now demonstrated the lack of benefit of n-3 fatty acids in the prevention of restenosis after coronary angioplasty. Therefore, the use of these agents is not recommended (grade A). 3. Large doses of n-3 fatty acids have been shown to produce short-term reductions in systolic and diastolic BP in patients with mild essential hypertension (two level I trials, two meta-analyses of controlled trials). However, future studies are needed before n-3 fatty acids can be recommended for treatment of hypertension. The doses of fatty acids required are high and alternative medications are readily available. 4. Based on the population studies and two trials in secondary prevention of myocardial infarction, the possibility remains that small amoU:nts of fish, fish oil, or other n-3 fatty acids may have benefit in reducing progression of atherosclerosis or the prevention of myocardial infarction. Additional studies are warranted to explore this possibility. CHEST /108/4/ OCTOBER, 1995/ Supplement
303S
REFERENCES
1 Goodnight SH. The effects of n-3 fatty acids on atherosclerosis and the vascular response to injury. Arch Pathol Lab Med 1993; 117:102-06 2 Dehmer GJ, Popma J, Van den Berg EK, et al. Reduction in the rate of early restenosis after coronary angioplasty by a diet supplemented with n-3 fatty acids. N Engl J Med 1988; 319:733-40 3 Smith P, Arnesen H, Opstad T, et al. Influence of highly concentrated n-3 fatty acids on serum lipids and hemostatic variables in survivors of myocardial infarction receiving either oral anticoagulants or matching placebo. Thromb Res 1989; 53:467-74 4 Leaf A, Jorgensen MB, Jacobs AK, et al. Do fish oils prevent restenosis aftercoronaryangioplasty. Circulation 1994; 90:2248-57 5 Saynor R, Gillott T. Changes in blood lipids and fibrinogen with a note on safety in a long-term study on the effects of n-3 fatty acids in subjects receiving fish oil supplements and followed for 7 years. Lipids 1992; 27:533-38 6 Kromhout D, Bosschieter EB, Coulander CDL. The inverse relation between fish consumption and 20-year mortality from coronary heart disease. N Engl J Med 1985; 312:1205-09 7 Shekell RB, Missell LV, Paul 0, et al. Fish consumption and mortality from coronary heart disease. N Engl J Med 1985; 313:820 8 Norell SE, Ahlborn A, Feychting M, et al. Fish consumption and mortality from coronary heart disease. BMJ 1986; 293:426 9 Dolecek T A.Epidemiological evidence of relationships between dietary polyunsaturated fatty acids and mortality in the Multiple Risk Factor Intervention Trial. Proc Soc Exp Bioi Med 1992; 200:177-82 10 Ascherio A, Rimm EB, Stampfer MJ, 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; 332:977-82 11 Vollset SE, Heuch I, Bjelke E. Fish consumption and mortality from coronary heart disease. N Engl J Med 1985; 313:820-21 12 Curb JD, Reed DM. Fish consumption and mortality from coronary heart disease. N Engl J Med 1985; 313:821 13 Simonsen T, Vartun A, Lyngmo V, et al. Coronary heart disease, serum lipids, platelets, and dietary fish in two communities in northern Norway. Acta Med Scand 1987; 222:237-45 14 Burr ML, Gilbert JF, Holliday RM, et al. Effects of changes in fat: intakes on death and myocardial reinfarction: diet and reinfaction trial (DART). Lancet 1989; 2:757-61 15 De Lorgeril M, Renaud S, Mamelle N, et al. Mediterranean alpha-linolenic acid-rich diet in secondary prevention of coronary heart disease. Lancet 1994; 343:1454-59 16 Knapp HR, FitzGerald GA. The antihypertensive effects of fish oil: a controlled study of polyunsaturated fatty acid supplements in essential hypertension. N Engl J Med 1989; 320:1037-43 17 Bonaa KH, Bjerve KS, Straume B, et al. Effect of eicosapentaenoic and docosahexaenoic acids on blood pressure in hypertension: a population-based intervention trial from the Tromso study. N Engl J Med 1990; 322:795-801 18 Radack K, Deck C, Huster G. The effects oflow doses of n-3 fatty acid supplementation on blood pressure in hypertensive subjects: a randomized controlled trial. Arch Intern Med 1991; 151:1173-80 19 Appel LJ, Miller ER III, Seidler AJ, et al. Does supplementation of diet with 'fish oil' reduce blood pressure?: a meta-analysis of
304S
controlled clinical trials. Arch Intern Med 1993; 153:1429-38 20 Morris MC, Sacks F, Rosner B. Does fish oil lower blood pressure?: a meta-analysis of controlled trials. Circulation 1993; 88: 523-33 21 Lam JYf, Badimon JJ, Ellefson RD, et al. Cod liver oil alters platelet-arterial wall response to injury in pigs. Circ Res 1992; 71: 769-75 22 Harker LA, Kelly AB, Hanson SR, et al. Interruption of vascular thrombus formation and vascular lesion formation by dietary n-3 fatty acids in fish oil in nonhuman primates. Circulation 1993; 87:1017-29 23 Goodnight SH, Cairns JA, Fisher M, et al. Assessment of the therapeutic use of n-3 fatty acids in vascular disease and thrombosis. Chest 1992; 102:374 24 Ryan TJ, Bauman WB, Kennedy JW, et al. Guidelines for percutaneous transluminal coronary angioplasty: a report of the American College of Cardiology/American Heart Association Task Force on assessment of diagnostic and therapeutic cardiovascular procedures. Circulation 1993; 88:2987-3007 25 Hillegass WB, Ohman EM, Califf RM. Restenosis: the clinical issues. In: Topol EJ, ed. Textbook of interventional cardiology. Philadelphia: WB Saunders, 1993; 415-35 26 Ip JH, Fuster V, Israel D, et al. The role of platelets, thrombin and hyperplasia in restenosis after coronary angioplasty. JAm Coli Cardiol1991; 17:77B-88B 27 Landau C, Lange RA, Hillis LD. Percutaneous transluminal coronary angioplasty. N Engl J Med 1994; 330:981-93 28 Gapinski JP, VanRuiswyk JV, Heudebert GR, et al. Preventing restenosis with fish oils following coronary angioplasty: a metaanalysis. Arch Intern Med 1993; 153:1595-1601 29 O'Connor GT, Malenka DJ, Olmstead EM, et al. A meta-analysis of randomized trials of fish oil in prevention of restenosis following angioplasty. Am J Prev Med 1992; 8:186-92 30 Cairns JA, Gill JB, Morton B, et al. Enoxaparine and Maxepa for the prevention of angioplasty restenosis (EMPAR). Circulation 1994; 90(suppl1):651 31 Slack JD, Pinkerton CA, Van Tassel J. Can oral fish oil supplement minimize restenosis after percutaneous transluminal angioplasty [abstract]? JAm Coli Cardiol1987; 9:64a 32 Grigg LE, Kay 1WH, Valentine PA, et al. Determinants of restenosis and lack of effect of dietary supplementation with eicosapentaenoic acid on the incidence of coronary artery restenosis after angioplasty. J Am Coli Cardiol 1989; 13:665-72 33 Reis GJ, BoucherTM, Sipperly ME, et al. Randomised trial of fish oil for prevention of restenosis after coronary angioplasty. Lancet 1989; 2:177-81 34 Milner MR, Gallino RA, Leffingwell A, et al. Usefulness of fish oil supplements in preventing clinical evidence of restenosis after percutaneous transluminal coronary angioplasty. Am J Cardiol 1989; 62:294-99 35 Nye ER, Iisley CDJ, Ablett MB, et al. Effect of eicosapentaenoic acid on restenosis rate, clinical course and blood lipids in patients after percutaneous transluminal coronary angioplasty. Aust NZ J Med 1990; 20:549-52 36 Bairati I, Roy L, Meyer F. Double-blind, randomized, controlled trial of fish oil supplements in prevention of recurrence of stenosis after coronary angioplasty. Circulation 1992; 85:950-56
Fourth ACCP Consensus Conference on Antithrombotic Therapy
T
he n-3 fatty acids are long-chain polyunsaturated fatty acids that are a natural component of marine oils and some plants. Medically important n-3 fatty acids include eicosapentaenoic acid (EPA) (C20:5 n-3), docosahexaenoic acid (C22:6 n-3), and a-linolenic acid (a-LA) (C18:3 n-3). The fatty acids can be ingested as part of the diet or can be administered in more concentrated form as semipurified triglycerides or highly purified ethyl esters. After administration to humans, the n-3 fatty acids are incorporated into cellular lipids where they can exert their biologic effects. The actions of n-3 fatty acids on cellular functions are diverse and include decreases in the production of prostaglandins, interleukin-1, tumor necrosis factor, tissue factor, leukotrienes, and growth factors such as granulocyte, granulocytemacrophage colony-stimulating factor, or platelet-derived growth factor. 1 The end result is reduced platelet-vascular and leukocyte-endothelium interactions, both of which could modify the progression or consequences of human arterial vascular disease. Side effects and toxic reactions generally have been mild even when large doses of n-3 fatty acid have been administered to patients in clinical trials. Despite slight impairment of platelet function, little or no bleeding has been detected, even when fish oil or n-3 fatty acids are combined with aspirin or oral anticoagulants. 2-4 There is no evidence that n-3 fatty acids lead to increased rates of cancer, infections, or clinically significant impairment in immunity. 5 PoPULATION STUDIES
Some epidemiologic studies have suggested that increased consumption of fish is associated with a lower risk of death from coronary heart disease. 6-9 In the study by Kromhout et al,6 the ingestion of 0 to 44 gld of fish was inversely related to the risk of coronary heart disease mortality, with up to 50% decreases in those individuals who consume more than 30 gld. However, a recently published study of almost 45,000 male health professionals in the United States suggested that further increases in dietary fish intake to more than one to two servings per week did not substantially reduce the risk of coronary heart disease. 10 Other studies have failed to find an association between fish consumption and lower rates of heart disease.l 1- 13 SECONDARY PREVENTION TRIALS IN CoRONARY HEART DISEASE
The Diet and Reinfarction Trial (DART) 14 found that an increased consumption of oily fish following a myocardial infarction led to a 29% decrease in all-cause mortality (p<0.05) and a 33% reduction in ischemic heart disease mortality (p<0.01 ) in middle-aged men younger than 70 years of age who were randomized within 41 days following an acute myocardial infarction (level I). There was no benefit of dietary modifications that restricted fat or augmented fiber intakes. 302S
A recently reported prospective randomized trial studied the effects of a diet rich in a-LA compared with a usual postinfarction diet in 600 patients recruited after a first myocardial infarction (level 1). 15 Patients were followed up yearly for 5 years. The experimental group consumed less total and saturated fat, cholesterol, and linoleic acid, but larger amounts of a-LA and oleic acid. After a mean follow-up of 27 months, the risk ratio for cardiac death and nonfatal myocardial infarction fell to 0.27 (p=0.001) in the experimental group. Overall mortality was also reduced (risk ratio, 0.3; p=0.02). Because there were several dietary modifications in the experimental group, it was not clear whether the beneficial effects were mediated by an increase in intake of a-LA. However, both a-LA and EPA were substantially increased in the plasma fatty acids when measured at 52 weeks (p<0.001). THERAPY OF HYPERTENSION
Several clinical studies have suggested that n-3 fatty acids can reduce systolic and diastolic BP in mildly hypertensive patients.l 6- 18 Two recently published meta-analyses of controlled trials showed that relatively high doses of n-3 fatty acids, ie, >3 gld, produced a lowering of BP in patients with hypertension, atherosclerosis, or hypercholesterolemia. 19•20 There was a dose-response relationship of n-3 fatty acid intake to BP reduction, with a decrease of 0.66/0.35 mm Hg for each gram per day of n-3 fatty acids ingested. RESTENOSIS AFTER ANGIOPLASTY
Experimental studies have suggested that high doses of fish oil or purified n-3 fatty acids can inhibit vascular responses to injury in experimental animals. In one study conducted in pigs, deep carotid arterial wall injury by balloon angioplasty was associated with significantly less lll Inlabeled platelet deposition and injury-related vasoconstriction when the animals were fed large doses of cod liver oil. 21 In another study, baboons were given large doses of n-3 fatty acids (composed of two-thirds EPA and one-third decosahexaenoic acid) as an ethyl ester concentrate.22 Bleeding times were prolonged, platelet aggregation was suppressed, and stimulated monocyte tissue factor expression was reduced in the treated animals. Deposition of radiolabeled autologous platelets onto Dacron vascular grafts and endarterectomized homologous aorta was significantly reduced. In addition, decreased vascular thrombus formation at sites of surgical carotid endarterectomy was seen. Importantly, dietary n-3 fatty acids abolished vascular lesion formation at sites of carotid endarterectomy when the animals were assessed 6 weeks after surgery. These and earlier studies suggest that treatment with n-3 fatty acids might reduce restenosis after percutaneous transluminal coronary angioplasty (PTCA) in humans. 23 This procedure is performed on more than 300,000 Americans annually, and yet restenosis recurs in about 40% of them within 6 months. In at least half the patients with restenosis, repeated PTCA or coronary bypass surgery is required. 24 Despite a large number of trials of pharmacologic and mechanical adjuncts to PTCA, the restenosis rate has changed little over the 18 years since the procedure was introduced. 25 Following PTCA, vessel occlusion may occur acutely as the result of intimal flap formation, subsequently as the reFourth ACCP Consensus Conference on Antithrombotic Therapy
Table !-Clinical Trials of n-3 Fatty Acids to Prevent Restenosis Following Coronary Angioplasty
Study, yr
No. of Patients
n-3 FA, gld
Control Oil
Slack et al, 31 1987 Dehmer et al,2 1988 Grigg et al,32 1989 Reis et al,33 1989 Milner et al,34 1989
162 82 108 186 194
2.5 5.4 3.0 6.0 4.5
None None Olive/com Olive None
Nye e t al,35 1990 Bairati et al,36 1992 Leaf et al,4 1994 Cairns et al,30 1994
69 119 551 814
4.0 4.5 6.9 5.4
Olive Olive Com oil Com oil
Patients Assessed for Restenosis, FO vs C.%§ 35 vs 19 VS 34 vs 34 VS 19 VS 22 VS ll vs 31 VS 52 VS 47 vs
Significance, p Value
39 46 33 23 36 35* 30t 48 46 46
NSt 0.026 NS NS <0.008 <0.04 <0.05 =0.05 NS NS
*Intention to treat. IRestenosis by lesion. INS =not significant. §FO=fish oil; C=control.
suit of thrombosis, or over the next 1 to 6 months as the result of neointimal proliferation. 26 ·27 Smooth muscle cells migrate from the media to the intima, presumably in response to mitogens derived from platelets, endothelial cells, and activated macrophages . There has been considerable interest in the evaluation of n-3 fatty acids and the prevention of PICA restenosis, since they might exert a favorable influence by altering the synthesis of arachidonic acid and leukotriene derivatives, the level of serum lipids, and the synthesis and actions of various smooth muscle cell mitigens. Important considerations in the evaluation of clinical trials of n-3 fatty acids in PICA include the dose of n-3 fatty acids (relatively large doses are required for full incorporation of n-3 fatty acids into platelet and other cell membranes) and blinding (the potential for bias in follow-up and designation of outcomes). The only truly reliable outcomes are angiographic, and quantitative approaches are required for precision and objectivity. Angiography must be obtained in a high percentage of subjects and study sample size must be sufficiently large to detect clinically important reductions in the incidence of restenosis. Published clinical trials of n-3 fatty acids to prevent restenosis following coronary angioplasty are listed in Table 1. Seven trials were available at the time of the previous edition of this chapter, four of them showing statistically significant reductions in restenosis, one showing a favorable trend, one showing no impact, and one showing a deleterious effect. A meta-analysis of the available trials at that time yielded a typical odds reduction of 26.7% (p
Cairns et al 30 randomized 814 patients to 5.4 g!d of n-3 fatty acids (max-EPA) or matching placebo for approximately 1 week pre-PTCA and for 18 weeks thereafter (level 1). The trial employed a 2x2 factorial design whereby patients were also randomized to low molecular weight heparin or control. Restenosis was determined by quantitative coronary angiography performed at 18 weeks. Restenosis rates were 47% with max-EPA and 46% with placebo. A meta-analysis of the data from eight of the nine trials is heavily influenced by the two large trials and reveals no benefit of n-3 fatty acids for the reduction of restenosis in the 6 months following PTCA. RECOMMENDATIONS
1. The ingestion of 30 to 40 gld of fish (eg, two meals a week) in the diet, especially as a substitute for foods containing saturated fatty acids, can be recommended for the possible primary or secondary prevention of coronary artery disease. This grade B recommendation is based on one level I trial for the secondary prevention of coronary artery disease, several epidemiologic studies, and the low risk of side effects of this dietary regimen. There is no evidence to support the use of concentrated n-3 fatty acids in fish oil or as ethyl esters for the prevention or treatment of coronary artery disease. · . 2. Two level I trials and a meta-analysis of nine trials have now demonstrated the lack of benefit of n-3 fatty acids in the prevention of restenosis after coronary angioplasty. Therefore, the use of these agents is not recommended (grade A). 3. Large doses of n-3 fatty acids have been shown to produce short-term reductions in systolic and diastolic BP in patients with mild essential hypertension (two level I trials, two meta-analyses of controlled trials). However, future studies are needed before n-3 fatty acids can be recommended for treatment of hypertension. The doses of fatty acids required are high and alternative medications are readily available. 4. Based on the population studies and two trials in secondary prevention of myocardial infarction, the possibility remains that small amoU:nts of fish, fish oil, or other n-3 fatty acids may have benefit in reducing progression of atherosclerosis or the prevention of myocardial infarction. Additional studies are warranted to explore this possibility. CHEST /108/4/ OCTOBER, 1995/ Supplement
303S
REFERENCES
1 Goodnight SH. The effects of n-3 fatty acids on atherosclerosis and the vascular response to injury. Arch Pathol Lab Med 1993; 117:102-06 2 Dehmer GJ, Popma J, Van den Berg EK, et al. Reduction in the rate of early restenosis after coronary angioplasty by a diet supplemented with n-3 fatty acids. N Engl J Med 1988; 319:733-40 3 Smith P, Arnesen H, Opstad T, et al. Influence of highly concentrated n-3 fatty acids on serum lipids and hemostatic variables in survivors of myocardial infarction receiving either oral anticoagulants or matching placebo. Thromb Res 1989; 53:467-74 4 Leaf A, Jorgensen MB, Jacobs AK, et al. Do fish oils prevent restenosis aftercoronaryangioplasty. Circulation 1994; 90:2248-57 5 Saynor R, Gillott T. Changes in blood lipids and fibrinogen with a note on safety in a long-term study on the effects of n-3 fatty acids in subjects receiving fish oil supplements and followed for 7 years. Lipids 1992; 27:533-38 6 Kromhout D, Bosschieter EB, Coulander CDL. The inverse relation between fish consumption and 20-year mortality from coronary heart disease. N Engl J Med 1985; 312:1205-09 7 Shekell RB, Missell LV, Paul 0, et al. Fish consumption and mortality from coronary heart disease. N Engl J Med 1985; 313:820 8 Norell SE, Ahlborn A, Feychting M, et al. Fish consumption and mortality from coronary heart disease. BMJ 1986; 293:426 9 Dolecek T A.Epidemiological evidence of relationships between dietary polyunsaturated fatty acids and mortality in the Multiple Risk Factor Intervention Trial. Proc Soc Exp Bioi Med 1992; 200:177-82 10 Ascherio A, Rimm EB, Stampfer MJ, 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; 332:977-82 11 Vollset SE, Heuch I, Bjelke E. Fish consumption and mortality from coronary heart disease. N Engl J Med 1985; 313:820-21 12 Curb JD, Reed DM. Fish consumption and mortality from coronary heart disease. N Engl J Med 1985; 313:821 13 Simonsen T, Vartun A, Lyngmo V, et al. Coronary heart disease, serum lipids, platelets, and dietary fish in two communities in northern Norway. Acta Med Scand 1987; 222:237-45 14 Burr ML, Gilbert JF, Holliday RM, et al. Effects of changes in fat: intakes on death and myocardial reinfarction: diet and reinfaction trial (DART). Lancet 1989; 2:757-61 15 De Lorgeril M, Renaud S, Mamelle N, et al. Mediterranean alpha-linolenic acid-rich diet in secondary prevention of coronary heart disease. Lancet 1994; 343:1454-59 16 Knapp HR, FitzGerald GA. The antihypertensive effects of fish oil: a controlled study of polyunsaturated fatty acid supplements in essential hypertension. N Engl J Med 1989; 320:1037-43 17 Bonaa KH, Bjerve KS, Straume B, et al. Effect of eicosapentaenoic and docosahexaenoic acids on blood pressure in hypertension: a population-based intervention trial from the Tromso study. N Engl J Med 1990; 322:795-801 18 Radack K, Deck C, Huster G. The effects oflow doses of n-3 fatty acid supplementation on blood pressure in hypertensive subjects: a randomized controlled trial. Arch Intern Med 1991; 151:1173-80 19 Appel LJ, Miller ER III, Seidler AJ, et al. Does supplementation of diet with 'fish oil' reduce blood pressure?: a meta-analysis of
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Fourth ACCP Consensus Conference on Antithrombotic Therapy