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Marine n−3 polyunsaturated fatty acids and coronary heart disease
Thrombosis Research (2005) 115, 257 – 262
intl.elsevierhealth.com/journals/thre
REVIEW
Marine n 3 polyunsaturated fatty acids and coronary heart disease Part II: Clinical trials and recommendations E.B. Schmidta,*, H. Arnesenb, J.H. Christensenc, L.H. Rasmussena, S.D. Kristensend, R. De Caterinae a
˚rhus University Hospitals, Denmark Department of Preventive Cardiology, Aalborg Sygehus, A Department of Cardiology, Ullevaal University Hospital, Oslo, Norway c ˚rhus University Hospitals, Denmark Department of Nephrology, Aalborg Sygehus, A d Department of Cardiology, Skejby University Hospital, Denmark e Institute of Cardiology and Center of Excellence on Aging, bG. dTAnnunzioQ University, Chieti, Italy b
Received 27 August 2004; accepted 13 September 2004 Available online 12 October 2004
Contents Introduction . . . . . . . . . . . . . . . . . . . . . . . . . Clinical trials . . . . . . . . . . . . . . . . . . . . . . . . . Primary prevention of CHD . . . . . . . . . . . . . . . Clinical studies in patients with documented CHD . . Patients admitted with acute coronary syndromes Secondary prevention after myocardial infarction . Restenosis after PTCA. . . . . . . . . . . . . . . . . Coronary artery bypass surgery . . . . . . . . . . . Stable angina pectoris . . . . . . . . . . . . . . . . Arrhythmias and SCD . . . . . . . . . . . . . . . . . Current status and suggestions for future trials . . . . . Recommendations . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . .
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* Corresponding author. Tel.: +45 99323158. E-mail addresses: [email protected], [email protected] (E.B. Schmidt). 0049-3848/$ - see front matter D 2004 Elsevier Ltd. All rights reserved. doi:10.1016/j.thromres.2004.09.007
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Introduction In a previous section of this review, we described the effects of n 3 polyunsaturated fatty acids (PUFA) from fish obtained from epidemiological studies, animal and in vitro experiments, their effects on risk factors for coronary heart disease (CHD) and their safety [1]. Here, we review the results from clinical trials of n 3 PUFA on clinical endpoints, and suggest recommendations for the use of n 3 PUFA in the prevention and treatment of CHD as well as areas where further studies are needed.
Clinical trials Primary prevention of CHD The risk of future acute coronary events was related to the serum concentrations of marine n 3 PUFA in a prospective, population-based cohort study comprising 1871 middle-aged men without overt CHD at baseline. After 10 years of follow-up, a significant 44% reduction in the risk of acute coronary events was observed among men belonging to the highest quintile of the proportion of serum n 3 PUFA compared with men in the lowest quintile [2]. There are no randomized clinically controlled trials of the effect of an increased intake of n 3 PUFA (fish or n 3 PUFA supplements) in healthy subjects published so far. However, a large trial from Japan, including 15,000 hypercholesterolemic subjects free of CHD randomized for 5 years to treatment with a statin or a statin +1.8 g of purified eicosapentaenoic acid (EPA) plus docosahexaenoic acid (DHA), is ongoing [3]. The primary endpoint is the combined number of major coronary events, and the study is scheduled to terminate in 2005. In addition, the Gruppo Italiano per lo Studio della Sopravvivenza nellTinfarto (GISSI) is currently undertaking a primary prevention trial with 1 g/ day of a preparation of purified EPA+DHA in subjects at high risk of CHD (De Caterina R, personal communication).
Clinical studies in patients with documented CHD Patients admitted with acute coronary syndromes In a trial from India, 404 patients with acute coronary syndromes judged likely to have suffered from an acute myocardial infarction (MI) within the
E.B. Schmidt et al. preceding 24 h were randomized to daily supplementation with 1.8 g of EPA+DHA, 2.9 g of alinolenic acid or placebo [4]. Cardiac events were significantly reduced after one year with both active treatments compared to placebo, but cardiac deaths were only reduced in the EPA+DHA group. In a retrospective analysis of 753 patients with an acute MI, infarct size, ascertained by peak values of creatine kinase and lactate dehydrogenase, was significantly lower in patients (n=242) who had used n 3 supplements regularly for at least 4 weeks prior to admission compared to non-users [5]. The n 3 PUFA group differed by having had fewer MIs, smoked less and by containing fewer patients with diabetes mellitus. A prospective study examining the effects of n 3 PUFA on clinical endpoints in patients with acute coronary syndromes treated by current standards would be of interest. Secondary prevention after myocardial infarction Burr et al. [6] randomized 2033 men with a recent MI to various dietary changes, including an increased intake of n 3 PUFA (fatty fish twice weekly or alternatively fish oil capsules) for 2 years in the DART trial. There was a significant 29% reduction in total mortality and in deaths from CHD in the group increasing their dietary intake of n 3 PUFA to 0.5–1 g/day. The number of nonfatal MIs increased, although not significantly, in the group given fish advice. This makes the underlying mechanism of protection in the fish group unlikely to be antithrombotic, and the authors suggested an antiarrhythmic effect of n 3 PUFA as an explanation for their findings. There was apparently no difference between patients who acquired their n 3 PUFA from fish compared to those who received their n 3 PUFA from fish oil capsules [7]. This study was a clinical landmark trial and still provides some of the best evidence for a protective role of n 3 PUFA in CHD. However, a 10-year follow-up study showed that the effect of the initial dietary changes in DART did not confer a sustained survival benefit [8]. In the Lyon Heart Study, the effect of a Mediterranean type of diet with an increased intake of fish, bread, fruit, vegetables and the non-marine n 3 PUFA a-linolenic acid was investigated in 600 patients with a recent MI [9]. There was a 70% reduction in cardiac morbidity and mortality in the patients randomized to the Mediterranean diet after 5 years of observation. However, in this trial, an increased intake of fish was only one of several dietary changes, making it impossible to know what role the (marginally)
Marine n 3 polyunsaturated fatty acids and coronary heart disease increased intake of marine n 3 PUFA had for the outcome. Since the publication of the DART trial in 1989 [6], a confirmatory study has been eagerly awaited. Such a study, the GISSI-Prevenzione trial, was initiated as a multicenter trial in Italy in 1993 and published in 1999 [10]. In this trial, 11,324 patients with a recent (b3 months) MI were randomized to one of four groups in an open-label 22 factorial design. One group received one daily capsule of 1 g of fish oil containing approximately 0.85 g of EPA+DHA as ethyl esters (Omacor); a second group received one capsule of vitamin E 300 mg/day; a third group received the combination of n 3 PUFA and vitamin E, while the last group received no supplements. The supplements were given in addition to modern standard treatment of patients with a recent MI. Dietary habits did not differ between the groups and 88% received more than one fish serving per week. The patients (mean age 59 years; 15% women) were followed for 3.5 years, and the primary endpoints were the cumulative rate of (1) total death, nonfatal MI and nonfatal stroke or (2) cardiovascular death, nonfatal MI and nonfatal stroke. There were 1017 deaths, 639 cardiovascular deaths, 479 coronary deaths and 286 sudden cardiac deaths (SCD) with a total of 1500 events (13.3%) for the combined primary endpoints. In a four-way, intention-to-treat analysis, there was a significant relative reduction of 15% in the first primary endpoint (all-cause death+nonfatal MI+nonfatal stroke), and a significant 20% reduction in the second primary endpoint (cardiovascular death+nonfatal MI+nonfatal stroke) in patients randomized to n 3 PUFA. In secondary analyses, the reduction in fatal events was entirely due to a 30% reduction in cardiovascular deaths. Nilsen et al. [11] assigned 300 post-MI patients to a supplement with 4 g n 3 PUFA or n 6 PUFA (corn oil) for a median period of 18 months. Triglycerides decreased and HDL increased marginally in the n 3 PUFA group, but major coronary events did not differ between the two groups (42 cases in the n 3 PUFA group vs. 36 cases in the n 6 PUFA group). Restenosis after PTCA The effect of n 3 PUFA on restenosis rate after percutaneous transluminal coronary angioplasty (PTCA) has been evaluated in several trials. The results were initially promising, however, larger trials set up to finally prove an effect of n 3 PUFA on restenosis rate failed to demonstrate significant reductions in restenosis [12–14]. A partial exception to this has been the latest published trial, with a randomized double-blind design and quantitative evaluation of angiographic results [15]. Here the
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authors found a modest reduction in the restenosis rate with a high dose of n 3 PUFA (6 g/day given for 1 month before the procedure and for 1 month thereafter, then 3 g/day up to 6 months), which was of borderline significance in the analysis per vessel and per patient. All these trials were conducted before the recent introduction of coronary stenting, which has significantly reduced the risk of early restenosis by abolishing the early recoil component occurring after PTCA. Studies investigating the possible effect of n 3 PUFA in stented patients, in whom restenosis is entirely due to intimal proliferation (possibly a better target than elastic recoil for the action of n 3 PUFA), have yet to be published. However, the very low restenosis rate after the introduction of drug-eluting stents makes the restenosis model less attractive for studying the effects of any systemic drug, and therefore also of n 3 PUFA. Coronary artery bypass surgery The incidence of late vein graft occlusion after coronary artery bypass surgery did not differ between patients randomized to fish oil or to aspirin in one study [16]. However, in the largest study hitherto performed, 610 patients undergoing coronary artery bypass surgery were supplemented with 3.5 g n 3 PUFA daily as fish oil capsules or no supplement for 1 year. Graft patency for venous, but not for arterial (mammary), grafts was significantly better after 1 year of follow-up in those randomized to fish oil [17]. The trial was not powered to study effects on mortality or major coronary events. Stable angina pectoris Saynor et al. [18] back in 1984 reported a marked symptomatic effect in 12 patients with stable angina pectoris supplemented with 6 g n 3 PUFA/ day for 9 months in an open trial. This effect could not be confirmed in a controlled trial, where 36 patients were randomized to a 12-week treatment with 4.5 g n 3 PUFA/day or matching placebo [19]. In a recent publication comprising 3114 men below 70 years of age with angina pectoris by the investigators of the DART and performed with a similar design—patients advised to eat fatty fish twice a week for 3–9 years had an increased risk of coronary events [20]. Total mortality was increased by 15% ( p=.13), coronary deaths increased by 26% ( p=.047) and SCD increased by 54% ( p=.025) in the fish advice group. The authors offered several explanations for their unexpected findings, the most likely probably being results by chance or by detrimental changes in diet or lifestyle in the fish
260 advice group, because people thought they were protected by their increased intake of n 3 PUFA. Arrhythmias and SCD The importance of SCD for public health is illustrated by a British study reporting that 74% of fatal events among patients with CHD happened outside hospital [21]. In-hospital mortality from CHD is 10– 15%, and even a total elimination of these fatalities will only have a minor effect on total cardiac mortality. Furthermore, many patients die from SCD as their first symptom of CHD [22]. Small studies in humans have reported a reduction in ventricular extrasystoles in patients given n 3 PUFA [23,24]. Heart rate variability (HRV) is, however, a better indicator for the risk of SCD than the number of ventricular extrasystoles [25]. It is therefore of interest that n 3 PUFA may increase HRV in patients with CHD, in several other groups of patients and in healthy subjects [26,27]. The data from clinical intervention trials also lend support to the hypothesis of a beneficial effect of n 3 PUFA on SCD. In the DART trial, patients eating fatty fish had a better survival than non-fish eaters despite the fact that reinfarctions were not reduced [6]. Thus, the n 3 patients had a lower mortality after MI, which might have been due to a decrease in SCD elicited by ventricular tachyarrhythmias. In the Lyon Heart Trial, there were no reports of SCD in the intervention group, whereas eight cases were recorded among controls [9]. However, the intervention group in this study had a complex diet, in which fish intake was only marginally increased and other dietary changes were also introduced. In the Indian trial, there were two deaths from SCD in both active groups compared to eight in the control group, but the differences were not statistically significant [4]. In the GISSI-Prevenzione trial, there was a significant 45% relative reduction in SCD or in absolute terms 0.7% [10]. Total mortality was significantly decreased by 41% already 3 months after the randomization, and SCD was significantly reduced by 53% four months after the initiation of the treatment [28]. Electrophysiological testing of the effects of n 3 PUFA infusions [29] was recently performed in patients with an implanted cardioverter defibrillator (ICD). In five out of seven patients, sustained monomorphic ventricular tachycardia was no longer inducible after infusion of n 3 PUFA. However, in a preliminary report of a clinical trial of patients with implanted cardioverter defibrillators, n 3 PUFA had no favourable effects on arrhythmic events (Raitt M et al.,
E.B. Schmidt et al. Abstract presentation at American Heart Association Scientific Session 2003, Orlando, Fla, Nov 9th 2003). Also, in a comment to reported clinical trials from the same meeting, it was stated that 1.8 g of fish oil supplemented for 2 years had no effect on the incidence of ventricular tachycardia or ventricular fibrillation in 200 patients with a recently implanted ICD and heart failure in the GISSI-CHF trial [30]. In conclusion, an antiarrhythmic effect may be very important for the effect of n 3 PUFA in protection from CHD [27,31], but the final proof for this hypothesis is still pending.
Current status and suggestions for future trials The use of marine n 3 PUFA in subjects without CHD is mainly supported by data from epidemiological studies, where the intake of even very low amounts of fish seems to be protective, and from beneficial effects of n 3 PUFA on risk factors for CHD [although mainly achieved by relatively high doses of n 3 PUFA] and not from clinical trial data [1,32]. The best documentation for a beneficial effect of marine n 3 PUFA on CHD is derived from studies in patients after an MI. It is worth noting that the effect obtained in DART and GISSIPrevenzione Trial is of a magnitude similar to that seen after treatment with statins. However, one should not ignore that there are many uncertainties and problems with the interpretation of dietary trials. While a subgroup of patients given fish advice and examined for fatty acid levels in the blood in the DART trial did have a higher content of EPA and DHA in serum phospholipids, such data relate to groups and not to individuals. The compliance and individual intake of marine n 3 PUFA (g/day) in the DART was therefore uncertain. Also, dietary habits may change over time in those randomized to an increased intake of n 3 PUFA as well as in controls, who might have been increasingly aware of a beneficial effect of fish consumption on CHD. The majority of patients admitted with an acute coronary syndrome are now treated with percutaneous coronary interventions (PCI) with stenting of the culprit lesion and other significant stenoses. The problem of restenosis is diminished by the use of drug-eluting stents, and there is little indication that n 3 PUFA will affect restenosis rate after PCI. There is only one clinical trial with marine n 3 PUFA in patients treated with coronary bypass
Marine n 3 polyunsaturated fatty acids and coronary heart disease grafting, and despite this trial showing a beneficial effect on the reocclusion rate in venous grafts, more studies would be needed to establish the use of n 3 PUFA for this purpose in these patients. The antiarrhythmic effect of marine n 3 PUFA is currently the scope of several studies both in patients at increased risk for SCD, like patients with heart failure, and in the elegant model of patients treated with an ICD, which allows the direct visualization of the arrhythmias leading to the discharge of the device. The final publication of results from at least four trials is awaited. There are few data and no clear evidence whether n 3 PUFA influence the outcome in patients admitted with acute coronary syndromes. Such type of trials would be of interest because n 3 PUFA possess multiple effects, including anti-inflammatory, antiarrhythmic and antiplatelet effects that might benefit these patients, both in the acute phase and also in the long-term, for example, by reducing infarct size, an important prognostic indicator for future events. Patients with hypertriglyceridemia, including patients with the metabolic syndrome, may be a particularly interesting group to study because of the known effects of marine n 3 PUFA on plasma triglycerides, and clinical trials in such patients are warranted.
Recommendations Several clinical trials with n 3 PUFA are currently under way, but at this time we suggest the following: 1.
2.
Healthy subjects: There is a general agreement that all subjects should be advised to consume fish, preferably fatty fish at least twice a week. This is, however, not based on clinical trial data. There is insufficient evidence to recommend fish oil concentrates to subjects not consuming fish. Patients with CHD: These patients should eat fatty fish at least twice weekly aiming for an intake of 7 g of EPA+DHA weekly. The controversial question is whether patients with CHD not consuming fish should be given fish oil concentrates. In our view, there is sufficient balanced evidence to recommend 1 g of EPA+DHA per day from high-quality products to such patients.
Our recommendations are in line with those from the American Heart Association [33], but clearly more clinical trial data would be desirable [34].
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References [1] Schmidt EB, Arnesen H, Rasmussen LH, De Caterina R, Kristensen SD. Marine n 3 polyunsaturated fatty acids and coronary heart disease. Part I: Background, epidemiology, animal data, effects on risk factors and safety. Thromb Res (in press). [2] Rissanen T, Voutilainen S, Nyyssonen K, Lakka TA, Salonen JT. Fish-oil derived fatty acids, docosahexaenoic acid and docosapentaenoic acid, and the risk of acute coronary events. The Kuopio ischaemic heart disease risk factor study. Circulation 2000;102:2677 – 9. [3] Yokoyama M, Origasa H. Effects of eicosapentaenoic acid on cardiovascular events in Japanese patients with hypercholesterolaemia: rationale, design, and baseline characteristics of the Japan EPA Lipid Intervention Study (JELIS). Am Heart J 2003;146:613 – 20. [4] Singh RB, Niaz MA, Sharma JP, 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 – 91. [5] Landmark K, Abdelnoor M, Urdal P, Kilhovd B, Dorum HP, Borge N, et al. Use of fish oils appears to reduce infarct size as estimated from peak creatine kinase and lactate dehydrogenase activities. Cardiology 1998;89:94 – 102. [6] Burr ML, Fehily AM, Gilbert JF, Rogers S, Holliday RM, Sweetnam PM, et al. Effects of changes in fat, fish, and fibre intakes on death and reinfarction: diet and reinfarction trial (DART). Lancet 1989;2:757 – 61. [7] Burr ML, Sweetnam PM, Fehily AM. Diet and reinfarction. Eur Heart J 1994;15:1152 – 3. [8] Ness AR, Hughes J, Elwood PC, Whitley E, Smith GD, Burr ML. The long-term effect of dietary advice in men with coronary disease: follow-up of the Diet and Reinfarction Trial. Eur J Clin Nutr 2002;56:512 – 8. [9] De Lorgeril M, Renaud S, Mamelle N, Salen P, Martin JL, Monjaud I, et al. Mediterranean alpha-linolenic acid-rich diet in secondary prevention of coronary heart disease. Lancet 1994;343:1454 – 9. [10] 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 – 55. [11] Nilsen DW, 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 – 6. [12] Cairns JA, Gill J, Morton B, Roberts R, Gent M, Hirsh J, et al. Fish oils and low-molecular-weight heparin for the reduction of restenosis after percutaneous transluminal coronary angioplasty. Circulation 1996;94:1553 – 60. [13] Leaf A, Jorgensen MB, Jacobs AK, Cote G, Schoenfeld DA, Scheer J, et al. Do fish oils prevent restenosis after coronary angioplasty? Circulation 1994;90:2248 – 57. [14] Johansen O, Brekke M, Seljeflot I, Abdelnoor M, Arnesen H. n 3 fatty acids do not prevent restenosis after coronary angioplasty: results from the CART study. J Am Coll Cardiol 1999;33:1619 – 26. [15] Maresta A, Balduccelli M, Varani E, Marzilli M, Galli C, Heiman F, et al. Prevention of postcoronary angioplasty restenosis by omega-3 fatty acids: main results of the Esapent for prevention of restenosis Italian Study. Am Heart J 2002;143:e5.
262 [16] Roy L, Meyer F, Gingras L, Auger L. A double-blind randomized controlled study comparing the efficacy of fish oil and low dose ASA to prevent coronary saphenous vein graft obstruction after CABG. Circulation 1991;84:II-285 [suppl]. [17] Eritsland J, Arnesen H, Grønseth 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 – 6. [18] Saynor R, Verel D, Gillott T. The long term effect of dietary supplementation with fish lipid concentrate on serum lipids, bleeding time, platelets and angina. Atherosclerosis 1984;50:3 – 10. [19] Kristensen SD, Schmidt EB, Andersen HR, Dyerberg J. Fish oil in angina pectoris. Atherosclerosis 1987;64:13 – 9. [20] Burr ML, Ashfield-Watt PAL, Dunstan FDJ, Fehily AM, Breay P, Ashton T, et al. Lack of benefit of dietary advice to men with angina: results of a controlled trial. Eur J Clin Nutr 2003;57:193 – 200. [21] Norris RM. Fatality outside hospital from acute coronary events in three British health districts, 1994–5. BMJ 1998;316:1065 – 70. [22] Priori SG, Aliot E, Blomstrom-Lundquist C, Bossaert L, Breithardt G, Brugada P, et al. Task force on sudden cardiac death of the European Society of Cardiology. Eur Heart J 2001;22:1374 – 450. [23] Christensen JH, Gustenhoff P, Ejlersen E, Jessen T, Korup E, Rasmussen K, et al. n 3 fatty acids and ventricular extrasystoles in patients with ventricular tachyarrhythmias. Nutr Res 1995;15:1 – 8. [24] Sellmayer A, Witzgall H, Lorenz RL, Weber PC. Effects of dietary fish oil on ventricular premature complexes. Am J Cardiol 1995;76:974 – 7. [25] Task Force of the European Society of Cardiology and North American Society of Pacing and Electrophysiology. Heart rate variability: standards of measurement, physio-
E.B. Schmidt et al.
[26]
[27]
[28]
[29]
[30]
[31]
[32]
[33]
[34]
logical interpretation and clinical use. Circulation 1996;93:1043 – 65. Christensen JH, Skou HA, Fog L, et al. Marine n 3 fatty acids, wine intake and heart rate variability in patients referred for coronary angiography. Circulation 2001;103: 651 – 7. Christensen JH. n 3 fatty acids and the risk of sudden cardiac death: emphasis on heart rate variability (thesis). Dan Med Bull 2003;50:347 – 67. Marchioli R, Barzi F, Bomba E, Chieffo C, Di Gregorio D, Di Mascio R, et al. Early protection against sudden death by n 3 polyunsaturated fatty acids after myocardial infarction. Circulation 2002;105:1897 – 903. Schrepf R, Limmert T, Weber PC, Theisen K, Sellmeyer A. Immediate effects of n 3 fatty acid infusion on the induction of sustained ventricular tachycardia. Lancet 2004;363:1441 – 2. Cleland JGF, Freemantle N, Kaye G, Nasir M, Velavan P, Lalukota K, et al. Clinical trials update from the American Heart Association meeting: OMega-3 fatty acids and arrhythmia risk in patients with an implantable defibrillator, ACTIV in CHF, VALIANT, the Hanover autologous bone marrow transplantation study, SPORTIF V, ORBIT and PAD and DEFINITE. Eur J Heart Fail 2004;6:109 – 15. De Caterina R, Madonna R, Zucchi R, La Rovere MT. Antiarrhythmic effects of omega-3 fatty acids: from epidemiology to bedside. Am Heart J 2003;146:420 – 30. Kris-Etherton PM, Harris WS, Appel LJ. Scientific statement: fish consumption, fish oil, omega-3 fatty acids and cardiovascular disease. Circulation 2002;106:2747 – 57. Kris-Etherton PM, Harris WS, Appel LJ. Omega-3 fatty acids and cardiovascular disease. New recommendations from the American Heart Association. Arterioscler Thromb Vasc Biol 2003;23:151 – 2. Grundy S. n 3 fatty acids. Priority for post-myocardial infarction clinical trials. Circulation 2003;107:1834 – 6.
intl.elsevierhealth.com/journals/thre
REVIEW
Marine n 3 polyunsaturated fatty acids and coronary heart disease Part II: Clinical trials and recommendations E.B. Schmidta,*, H. Arnesenb, J.H. Christensenc, L.H. Rasmussena, S.D. Kristensend, R. De Caterinae a
˚rhus University Hospitals, Denmark Department of Preventive Cardiology, Aalborg Sygehus, A Department of Cardiology, Ullevaal University Hospital, Oslo, Norway c ˚rhus University Hospitals, Denmark Department of Nephrology, Aalborg Sygehus, A d Department of Cardiology, Skejby University Hospital, Denmark e Institute of Cardiology and Center of Excellence on Aging, bG. dTAnnunzioQ University, Chieti, Italy b
Received 27 August 2004; accepted 13 September 2004 Available online 12 October 2004
Contents Introduction . . . . . . . . . . . . . . . . . . . . . . . . . Clinical trials . . . . . . . . . . . . . . . . . . . . . . . . . Primary prevention of CHD . . . . . . . . . . . . . . . Clinical studies in patients with documented CHD . . Patients admitted with acute coronary syndromes Secondary prevention after myocardial infarction . Restenosis after PTCA. . . . . . . . . . . . . . . . . Coronary artery bypass surgery . . . . . . . . . . . Stable angina pectoris . . . . . . . . . . . . . . . . Arrhythmias and SCD . . . . . . . . . . . . . . . . . Current status and suggestions for future trials . . . . . Recommendations . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . .
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* Corresponding author. Tel.: +45 99323158. E-mail addresses: [email protected], [email protected] (E.B. Schmidt). 0049-3848/$ - see front matter D 2004 Elsevier Ltd. All rights reserved. doi:10.1016/j.thromres.2004.09.007
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Introduction In a previous section of this review, we described the effects of n 3 polyunsaturated fatty acids (PUFA) from fish obtained from epidemiological studies, animal and in vitro experiments, their effects on risk factors for coronary heart disease (CHD) and their safety [1]. Here, we review the results from clinical trials of n 3 PUFA on clinical endpoints, and suggest recommendations for the use of n 3 PUFA in the prevention and treatment of CHD as well as areas where further studies are needed.
Clinical trials Primary prevention of CHD The risk of future acute coronary events was related to the serum concentrations of marine n 3 PUFA in a prospective, population-based cohort study comprising 1871 middle-aged men without overt CHD at baseline. After 10 years of follow-up, a significant 44% reduction in the risk of acute coronary events was observed among men belonging to the highest quintile of the proportion of serum n 3 PUFA compared with men in the lowest quintile [2]. There are no randomized clinically controlled trials of the effect of an increased intake of n 3 PUFA (fish or n 3 PUFA supplements) in healthy subjects published so far. However, a large trial from Japan, including 15,000 hypercholesterolemic subjects free of CHD randomized for 5 years to treatment with a statin or a statin +1.8 g of purified eicosapentaenoic acid (EPA) plus docosahexaenoic acid (DHA), is ongoing [3]. The primary endpoint is the combined number of major coronary events, and the study is scheduled to terminate in 2005. In addition, the Gruppo Italiano per lo Studio della Sopravvivenza nellTinfarto (GISSI) is currently undertaking a primary prevention trial with 1 g/ day of a preparation of purified EPA+DHA in subjects at high risk of CHD (De Caterina R, personal communication).
Clinical studies in patients with documented CHD Patients admitted with acute coronary syndromes In a trial from India, 404 patients with acute coronary syndromes judged likely to have suffered from an acute myocardial infarction (MI) within the
E.B. Schmidt et al. preceding 24 h were randomized to daily supplementation with 1.8 g of EPA+DHA, 2.9 g of alinolenic acid or placebo [4]. Cardiac events were significantly reduced after one year with both active treatments compared to placebo, but cardiac deaths were only reduced in the EPA+DHA group. In a retrospective analysis of 753 patients with an acute MI, infarct size, ascertained by peak values of creatine kinase and lactate dehydrogenase, was significantly lower in patients (n=242) who had used n 3 supplements regularly for at least 4 weeks prior to admission compared to non-users [5]. The n 3 PUFA group differed by having had fewer MIs, smoked less and by containing fewer patients with diabetes mellitus. A prospective study examining the effects of n 3 PUFA on clinical endpoints in patients with acute coronary syndromes treated by current standards would be of interest. Secondary prevention after myocardial infarction Burr et al. [6] randomized 2033 men with a recent MI to various dietary changes, including an increased intake of n 3 PUFA (fatty fish twice weekly or alternatively fish oil capsules) for 2 years in the DART trial. There was a significant 29% reduction in total mortality and in deaths from CHD in the group increasing their dietary intake of n 3 PUFA to 0.5–1 g/day. The number of nonfatal MIs increased, although not significantly, in the group given fish advice. This makes the underlying mechanism of protection in the fish group unlikely to be antithrombotic, and the authors suggested an antiarrhythmic effect of n 3 PUFA as an explanation for their findings. There was apparently no difference between patients who acquired their n 3 PUFA from fish compared to those who received their n 3 PUFA from fish oil capsules [7]. This study was a clinical landmark trial and still provides some of the best evidence for a protective role of n 3 PUFA in CHD. However, a 10-year follow-up study showed that the effect of the initial dietary changes in DART did not confer a sustained survival benefit [8]. In the Lyon Heart Study, the effect of a Mediterranean type of diet with an increased intake of fish, bread, fruit, vegetables and the non-marine n 3 PUFA a-linolenic acid was investigated in 600 patients with a recent MI [9]. There was a 70% reduction in cardiac morbidity and mortality in the patients randomized to the Mediterranean diet after 5 years of observation. However, in this trial, an increased intake of fish was only one of several dietary changes, making it impossible to know what role the (marginally)
Marine n 3 polyunsaturated fatty acids and coronary heart disease increased intake of marine n 3 PUFA had for the outcome. Since the publication of the DART trial in 1989 [6], a confirmatory study has been eagerly awaited. Such a study, the GISSI-Prevenzione trial, was initiated as a multicenter trial in Italy in 1993 and published in 1999 [10]. In this trial, 11,324 patients with a recent (b3 months) MI were randomized to one of four groups in an open-label 22 factorial design. One group received one daily capsule of 1 g of fish oil containing approximately 0.85 g of EPA+DHA as ethyl esters (Omacor); a second group received one capsule of vitamin E 300 mg/day; a third group received the combination of n 3 PUFA and vitamin E, while the last group received no supplements. The supplements were given in addition to modern standard treatment of patients with a recent MI. Dietary habits did not differ between the groups and 88% received more than one fish serving per week. The patients (mean age 59 years; 15% women) were followed for 3.5 years, and the primary endpoints were the cumulative rate of (1) total death, nonfatal MI and nonfatal stroke or (2) cardiovascular death, nonfatal MI and nonfatal stroke. There were 1017 deaths, 639 cardiovascular deaths, 479 coronary deaths and 286 sudden cardiac deaths (SCD) with a total of 1500 events (13.3%) for the combined primary endpoints. In a four-way, intention-to-treat analysis, there was a significant relative reduction of 15% in the first primary endpoint (all-cause death+nonfatal MI+nonfatal stroke), and a significant 20% reduction in the second primary endpoint (cardiovascular death+nonfatal MI+nonfatal stroke) in patients randomized to n 3 PUFA. In secondary analyses, the reduction in fatal events was entirely due to a 30% reduction in cardiovascular deaths. Nilsen et al. [11] assigned 300 post-MI patients to a supplement with 4 g n 3 PUFA or n 6 PUFA (corn oil) for a median period of 18 months. Triglycerides decreased and HDL increased marginally in the n 3 PUFA group, but major coronary events did not differ between the two groups (42 cases in the n 3 PUFA group vs. 36 cases in the n 6 PUFA group). Restenosis after PTCA The effect of n 3 PUFA on restenosis rate after percutaneous transluminal coronary angioplasty (PTCA) has been evaluated in several trials. The results were initially promising, however, larger trials set up to finally prove an effect of n 3 PUFA on restenosis rate failed to demonstrate significant reductions in restenosis [12–14]. A partial exception to this has been the latest published trial, with a randomized double-blind design and quantitative evaluation of angiographic results [15]. Here the
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authors found a modest reduction in the restenosis rate with a high dose of n 3 PUFA (6 g/day given for 1 month before the procedure and for 1 month thereafter, then 3 g/day up to 6 months), which was of borderline significance in the analysis per vessel and per patient. All these trials were conducted before the recent introduction of coronary stenting, which has significantly reduced the risk of early restenosis by abolishing the early recoil component occurring after PTCA. Studies investigating the possible effect of n 3 PUFA in stented patients, in whom restenosis is entirely due to intimal proliferation (possibly a better target than elastic recoil for the action of n 3 PUFA), have yet to be published. However, the very low restenosis rate after the introduction of drug-eluting stents makes the restenosis model less attractive for studying the effects of any systemic drug, and therefore also of n 3 PUFA. Coronary artery bypass surgery The incidence of late vein graft occlusion after coronary artery bypass surgery did not differ between patients randomized to fish oil or to aspirin in one study [16]. However, in the largest study hitherto performed, 610 patients undergoing coronary artery bypass surgery were supplemented with 3.5 g n 3 PUFA daily as fish oil capsules or no supplement for 1 year. Graft patency for venous, but not for arterial (mammary), grafts was significantly better after 1 year of follow-up in those randomized to fish oil [17]. The trial was not powered to study effects on mortality or major coronary events. Stable angina pectoris Saynor et al. [18] back in 1984 reported a marked symptomatic effect in 12 patients with stable angina pectoris supplemented with 6 g n 3 PUFA/ day for 9 months in an open trial. This effect could not be confirmed in a controlled trial, where 36 patients were randomized to a 12-week treatment with 4.5 g n 3 PUFA/day or matching placebo [19]. In a recent publication comprising 3114 men below 70 years of age with angina pectoris by the investigators of the DART and performed with a similar design—patients advised to eat fatty fish twice a week for 3–9 years had an increased risk of coronary events [20]. Total mortality was increased by 15% ( p=.13), coronary deaths increased by 26% ( p=.047) and SCD increased by 54% ( p=.025) in the fish advice group. The authors offered several explanations for their unexpected findings, the most likely probably being results by chance or by detrimental changes in diet or lifestyle in the fish
260 advice group, because people thought they were protected by their increased intake of n 3 PUFA. Arrhythmias and SCD The importance of SCD for public health is illustrated by a British study reporting that 74% of fatal events among patients with CHD happened outside hospital [21]. In-hospital mortality from CHD is 10– 15%, and even a total elimination of these fatalities will only have a minor effect on total cardiac mortality. Furthermore, many patients die from SCD as their first symptom of CHD [22]. Small studies in humans have reported a reduction in ventricular extrasystoles in patients given n 3 PUFA [23,24]. Heart rate variability (HRV) is, however, a better indicator for the risk of SCD than the number of ventricular extrasystoles [25]. It is therefore of interest that n 3 PUFA may increase HRV in patients with CHD, in several other groups of patients and in healthy subjects [26,27]. The data from clinical intervention trials also lend support to the hypothesis of a beneficial effect of n 3 PUFA on SCD. In the DART trial, patients eating fatty fish had a better survival than non-fish eaters despite the fact that reinfarctions were not reduced [6]. Thus, the n 3 patients had a lower mortality after MI, which might have been due to a decrease in SCD elicited by ventricular tachyarrhythmias. In the Lyon Heart Trial, there were no reports of SCD in the intervention group, whereas eight cases were recorded among controls [9]. However, the intervention group in this study had a complex diet, in which fish intake was only marginally increased and other dietary changes were also introduced. In the Indian trial, there were two deaths from SCD in both active groups compared to eight in the control group, but the differences were not statistically significant [4]. In the GISSI-Prevenzione trial, there was a significant 45% relative reduction in SCD or in absolute terms 0.7% [10]. Total mortality was significantly decreased by 41% already 3 months after the randomization, and SCD was significantly reduced by 53% four months after the initiation of the treatment [28]. Electrophysiological testing of the effects of n 3 PUFA infusions [29] was recently performed in patients with an implanted cardioverter defibrillator (ICD). In five out of seven patients, sustained monomorphic ventricular tachycardia was no longer inducible after infusion of n 3 PUFA. However, in a preliminary report of a clinical trial of patients with implanted cardioverter defibrillators, n 3 PUFA had no favourable effects on arrhythmic events (Raitt M et al.,
E.B. Schmidt et al. Abstract presentation at American Heart Association Scientific Session 2003, Orlando, Fla, Nov 9th 2003). Also, in a comment to reported clinical trials from the same meeting, it was stated that 1.8 g of fish oil supplemented for 2 years had no effect on the incidence of ventricular tachycardia or ventricular fibrillation in 200 patients with a recently implanted ICD and heart failure in the GISSI-CHF trial [30]. In conclusion, an antiarrhythmic effect may be very important for the effect of n 3 PUFA in protection from CHD [27,31], but the final proof for this hypothesis is still pending.
Current status and suggestions for future trials The use of marine n 3 PUFA in subjects without CHD is mainly supported by data from epidemiological studies, where the intake of even very low amounts of fish seems to be protective, and from beneficial effects of n 3 PUFA on risk factors for CHD [although mainly achieved by relatively high doses of n 3 PUFA] and not from clinical trial data [1,32]. The best documentation for a beneficial effect of marine n 3 PUFA on CHD is derived from studies in patients after an MI. It is worth noting that the effect obtained in DART and GISSIPrevenzione Trial is of a magnitude similar to that seen after treatment with statins. However, one should not ignore that there are many uncertainties and problems with the interpretation of dietary trials. While a subgroup of patients given fish advice and examined for fatty acid levels in the blood in the DART trial did have a higher content of EPA and DHA in serum phospholipids, such data relate to groups and not to individuals. The compliance and individual intake of marine n 3 PUFA (g/day) in the DART was therefore uncertain. Also, dietary habits may change over time in those randomized to an increased intake of n 3 PUFA as well as in controls, who might have been increasingly aware of a beneficial effect of fish consumption on CHD. The majority of patients admitted with an acute coronary syndrome are now treated with percutaneous coronary interventions (PCI) with stenting of the culprit lesion and other significant stenoses. The problem of restenosis is diminished by the use of drug-eluting stents, and there is little indication that n 3 PUFA will affect restenosis rate after PCI. There is only one clinical trial with marine n 3 PUFA in patients treated with coronary bypass
Marine n 3 polyunsaturated fatty acids and coronary heart disease grafting, and despite this trial showing a beneficial effect on the reocclusion rate in venous grafts, more studies would be needed to establish the use of n 3 PUFA for this purpose in these patients. The antiarrhythmic effect of marine n 3 PUFA is currently the scope of several studies both in patients at increased risk for SCD, like patients with heart failure, and in the elegant model of patients treated with an ICD, which allows the direct visualization of the arrhythmias leading to the discharge of the device. The final publication of results from at least four trials is awaited. There are few data and no clear evidence whether n 3 PUFA influence the outcome in patients admitted with acute coronary syndromes. Such type of trials would be of interest because n 3 PUFA possess multiple effects, including anti-inflammatory, antiarrhythmic and antiplatelet effects that might benefit these patients, both in the acute phase and also in the long-term, for example, by reducing infarct size, an important prognostic indicator for future events. Patients with hypertriglyceridemia, including patients with the metabolic syndrome, may be a particularly interesting group to study because of the known effects of marine n 3 PUFA on plasma triglycerides, and clinical trials in such patients are warranted.
Recommendations Several clinical trials with n 3 PUFA are currently under way, but at this time we suggest the following: 1.
2.
Healthy subjects: There is a general agreement that all subjects should be advised to consume fish, preferably fatty fish at least twice a week. This is, however, not based on clinical trial data. There is insufficient evidence to recommend fish oil concentrates to subjects not consuming fish. Patients with CHD: These patients should eat fatty fish at least twice weekly aiming for an intake of 7 g of EPA+DHA weekly. The controversial question is whether patients with CHD not consuming fish should be given fish oil concentrates. In our view, there is sufficient balanced evidence to recommend 1 g of EPA+DHA per day from high-quality products to such patients.
Our recommendations are in line with those from the American Heart Association [33], but clearly more clinical trial data would be desirable [34].
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References [1] Schmidt EB, Arnesen H, Rasmussen LH, De Caterina R, Kristensen SD. Marine n 3 polyunsaturated fatty acids and coronary heart disease. Part I: Background, epidemiology, animal data, effects on risk factors and safety. Thromb Res (in press). [2] Rissanen T, Voutilainen S, Nyyssonen K, Lakka TA, Salonen JT. Fish-oil derived fatty acids, docosahexaenoic acid and docosapentaenoic acid, and the risk of acute coronary events. The Kuopio ischaemic heart disease risk factor study. Circulation 2000;102:2677 – 9. [3] Yokoyama M, Origasa H. Effects of eicosapentaenoic acid on cardiovascular events in Japanese patients with hypercholesterolaemia: rationale, design, and baseline characteristics of the Japan EPA Lipid Intervention Study (JELIS). Am Heart J 2003;146:613 – 20. [4] Singh RB, Niaz MA, Sharma JP, 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 – 91. [5] Landmark K, Abdelnoor M, Urdal P, Kilhovd B, Dorum HP, Borge N, et al. Use of fish oils appears to reduce infarct size as estimated from peak creatine kinase and lactate dehydrogenase activities. Cardiology 1998;89:94 – 102. [6] Burr ML, Fehily AM, Gilbert JF, Rogers S, Holliday RM, Sweetnam PM, et al. Effects of changes in fat, fish, and fibre intakes on death and reinfarction: diet and reinfarction trial (DART). Lancet 1989;2:757 – 61. [7] Burr ML, Sweetnam PM, Fehily AM. Diet and reinfarction. Eur Heart J 1994;15:1152 – 3. [8] Ness AR, Hughes J, Elwood PC, Whitley E, Smith GD, Burr ML. The long-term effect of dietary advice in men with coronary disease: follow-up of the Diet and Reinfarction Trial. Eur J Clin Nutr 2002;56:512 – 8. [9] De Lorgeril M, Renaud S, Mamelle N, Salen P, Martin JL, Monjaud I, et al. Mediterranean alpha-linolenic acid-rich diet in secondary prevention of coronary heart disease. Lancet 1994;343:1454 – 9. [10] 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 – 55. [11] Nilsen DW, 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 – 6. [12] Cairns JA, Gill J, Morton B, Roberts R, Gent M, Hirsh J, et al. Fish oils and low-molecular-weight heparin for the reduction of restenosis after percutaneous transluminal coronary angioplasty. Circulation 1996;94:1553 – 60. [13] Leaf A, Jorgensen MB, Jacobs AK, Cote G, Schoenfeld DA, Scheer J, et al. Do fish oils prevent restenosis after coronary angioplasty? Circulation 1994;90:2248 – 57. [14] Johansen O, Brekke M, Seljeflot I, Abdelnoor M, Arnesen H. n 3 fatty acids do not prevent restenosis after coronary angioplasty: results from the CART study. J Am Coll Cardiol 1999;33:1619 – 26. [15] Maresta A, Balduccelli M, Varani E, Marzilli M, Galli C, Heiman F, et al. Prevention of postcoronary angioplasty restenosis by omega-3 fatty acids: main results of the Esapent for prevention of restenosis Italian Study. Am Heart J 2002;143:e5.
262 [16] Roy L, Meyer F, Gingras L, Auger L. A double-blind randomized controlled study comparing the efficacy of fish oil and low dose ASA to prevent coronary saphenous vein graft obstruction after CABG. Circulation 1991;84:II-285 [suppl]. [17] Eritsland J, Arnesen H, Grønseth 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 – 6. [18] Saynor R, Verel D, Gillott T. The long term effect of dietary supplementation with fish lipid concentrate on serum lipids, bleeding time, platelets and angina. Atherosclerosis 1984;50:3 – 10. [19] Kristensen SD, Schmidt EB, Andersen HR, Dyerberg J. Fish oil in angina pectoris. Atherosclerosis 1987;64:13 – 9. [20] Burr ML, Ashfield-Watt PAL, Dunstan FDJ, Fehily AM, Breay P, Ashton T, et al. Lack of benefit of dietary advice to men with angina: results of a controlled trial. Eur J Clin Nutr 2003;57:193 – 200. [21] Norris RM. Fatality outside hospital from acute coronary events in three British health districts, 1994–5. BMJ 1998;316:1065 – 70. [22] Priori SG, Aliot E, Blomstrom-Lundquist C, Bossaert L, Breithardt G, Brugada P, et al. Task force on sudden cardiac death of the European Society of Cardiology. Eur Heart J 2001;22:1374 – 450. [23] Christensen JH, Gustenhoff P, Ejlersen E, Jessen T, Korup E, Rasmussen K, et al. n 3 fatty acids and ventricular extrasystoles in patients with ventricular tachyarrhythmias. Nutr Res 1995;15:1 – 8. [24] Sellmayer A, Witzgall H, Lorenz RL, Weber PC. Effects of dietary fish oil on ventricular premature complexes. Am J Cardiol 1995;76:974 – 7. [25] Task Force of the European Society of Cardiology and North American Society of Pacing and Electrophysiology. Heart rate variability: standards of measurement, physio-
E.B. Schmidt et al.
[26]
[27]
[28]
[29]
[30]
[31]
[32]
[33]
[34]
logical interpretation and clinical use. Circulation 1996;93:1043 – 65. Christensen JH, Skou HA, Fog L, et al. Marine n 3 fatty acids, wine intake and heart rate variability in patients referred for coronary angiography. Circulation 2001;103: 651 – 7. Christensen JH. n 3 fatty acids and the risk of sudden cardiac death: emphasis on heart rate variability (thesis). Dan Med Bull 2003;50:347 – 67. Marchioli R, Barzi F, Bomba E, Chieffo C, Di Gregorio D, Di Mascio R, et al. Early protection against sudden death by n 3 polyunsaturated fatty acids after myocardial infarction. Circulation 2002;105:1897 – 903. Schrepf R, Limmert T, Weber PC, Theisen K, Sellmeyer A. Immediate effects of n 3 fatty acid infusion on the induction of sustained ventricular tachycardia. Lancet 2004;363:1441 – 2. Cleland JGF, Freemantle N, Kaye G, Nasir M, Velavan P, Lalukota K, et al. Clinical trials update from the American Heart Association meeting: OMega-3 fatty acids and arrhythmia risk in patients with an implantable defibrillator, ACTIV in CHF, VALIANT, the Hanover autologous bone marrow transplantation study, SPORTIF V, ORBIT and PAD and DEFINITE. Eur J Heart Fail 2004;6:109 – 15. De Caterina R, Madonna R, Zucchi R, La Rovere MT. Antiarrhythmic effects of omega-3 fatty acids: from epidemiology to bedside. Am Heart J 2003;146:420 – 30. Kris-Etherton PM, Harris WS, Appel LJ. Scientific statement: fish consumption, fish oil, omega-3 fatty acids and cardiovascular disease. Circulation 2002;106:2747 – 57. Kris-Etherton PM, Harris WS, Appel LJ. Omega-3 fatty acids and cardiovascular disease. New recommendations from the American Heart Association. Arterioscler Thromb Vasc Biol 2003;23:151 – 2. Grundy S. n 3 fatty acids. Priority for post-myocardial infarction clinical trials. Circulation 2003;107:1834 – 6.