Abstracts and Summaries of Presentations

Secondary Prevention Trials with n-3 Fatty Acids in Western Populations Consuming Non-Mediterranean Diets 
Clemens von Schacky, M.D., University of Munich, Munich, Germany 

Conducting large-scale, general population studies of the effects of omega3s (n-3) is important because of the lessons of the Vitamin E trials. Previous epidemiologic studies had proven the efficacy of Vitamin E supplementation against cardiovascular disease (CD) in a secondary prevention setting. In spite of these positive effects, recent large-scale intervention studies failed to demonstrate a protective cardiovascular effect or absence of cardiovascular disease in the general population supplemented with vitamin E in a primary prevention setting. The same issue should be explored in regard to n-3 polyunsaturated fatty acids (PUFA). Will n-3 PUFA lower the incidence of cardiovascular disease in the general population? In light of new accumulating epidemiologic evidence of a positive, even graded association between ingestion of marine n-3 PUFA and reduction in sudden cardiac death in large-scale, secondary intervention studies, we still do not know whether they confer any benefit in the prevention of sudden death in a primary prevention setting or in the population at large. 

Sudden cardiac death has recently been defined as ”Death within one hour of symptom onset or witnessed cardiac arrest or abrupt collapse that occurred within one hour after the onset of symptoms and that resulted in death.” This definition makes sudden death compatible with severe cardiac arrhythmia or large myocardial infarction ultimately resulting in pump failure. In mechanistic studies, n-3 PUFA have been demonstrated to have antiarrhythmic properties, to improve endothelial function, and other effects suitable to mitigate the otherwise catastrophic consequences of a myocardial infarction.In two large-scale intervention studies in patients after a first myocardial infarction, n-3 PUFA reduced overall mortality and cardiovascular mortality largely by reducing the incidence of sudden death by 15–29% within two to three-and a-half years. Dr. von Schacky performed an informal analysis of all other published, randomised, controlled intervention studies of cardiac patients under Western dietary conditions that were aimed at intermediate end points like progression of coronary atherosclerosis or restenosis after balloon angioplasty. Consistent with the large-scale intervention studies, the incidence of fatal myocardial infarction was reduced by 36 % in the n-3 PUFA-treated patients as compared to controls. Current evidence has led the American Heart Association to encourage ingestion of n-3 fatty acids in “Guidelines for preventing heart attack and death of patients with atherosclerotic cardiovascular disease.” Taken together, current evidence demonstrates a need for a large-scale primary intervention trial with marine dietary n-3 fatty acids with fatal myocardial infarction or sudden cardiac death as endpoints.

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Background Diet in the GISSI Prevencione Population
Roberto Marchioli, M.D., Consorzio Mario Negri Sud, Santa Maria Imbaro, Italy;

During the GISSI Prevencione study (started in Italy in 1993 and as published in Lancet in 1999), patients with recent Myocardial Infarction (MI) were given simple dietary advice for using the Mediterranean diet to explore its positive effects. This diet is rich in fish and olive oil, which are excellent sources of omega-3 (n-3) fatty acids. This makes the GISSI database an important source for data on the effects of n-3 Fatty Acid’s on cardiovascular health. The GISSI clinical trial was conducted in 172 cardiological centers all over Italy. The patients in the study had experienced MI within the three months previous to the study. They already had standard dietary recommendations and treatments for MI, including aspirin, beta-blockers, ACE-inhibitors, etc. They were randomized to one of four groups, receiving n-3 fatty acids, Vitamin E, both, or neither.

In addition to the standard dietary advice already given, patients received a simple leaflet underlining risk factors to avoid. GISSI wanted to make sure the leaflet was clear and straightforward enough to be understood and followed by a broad range of patients all over Italy. The leaflet instructed them to refrain from too much, too strenuous exercise, but to be sure to engage in light to moderate exercise. It also advised to increase their intake of fish, fruit, and vegetables and increase their intake of olive oil (especially in comparison to butter). It also explained why these four things were important.

Results of the GISSI Prevencione Study

At the end of the study, out of patients who began the study on standard treatment, 82% were receiving anti-platelet drugs, 38% Beta Blockers, and 49% ACE Inhibitors. Most patients were also taking a cholesterol-lowering drug, and one out of four were hospitalized for angioplasty or coronary artery bypass graft. N-3 Fatty Acids had lowered total mortality by 20%, cardiovascular mortality by 30%, and incidence of sudden death by 45%.

Dietary results were analyzed based on a food frequency questionnaire. A pooled logistic regression was used to estimate the ratio for each individual food then adjusted for potential confounders like age, sex, smoking, hypertension, diabetes, left ventricle dysfunction and drug use (e.g., aspirin, Beta Blockers, ACE-Inhibitors, and experimental treatments). Dietary habits as a whole were assessed with a novel dietary score. 

At the beginning of the study, the baseline intake for fish was two portions per week for about 35% of patients. At the end of the study more than 50% were eating fish two times per week. This was maintained during follow-up. Intake of fresh fruits, fresh vegetables, cooked vegetables, and olive oil (which already had a high baseline in this population) increased during the study, and increased further during follow-up. Multivariable analysis revealed correlations between food type and reduction in mortality as summarized in the table below:

A summary score of dietary habits calculated from the above data indicated a strong association between diet and mortality. The best dietary habits produced the lowest rates of mortality. Mortality was 90% in the quartile with the patients with the worst diets and 10% in the quartile with the patients with the best diets. These results were similar in all subgroups. 

Patients who were given n-3 fatty acid capsules experienced similar effects to patients with high intake of fruit, uncooked and cooked vegetables, olive oil, and fish. There was no difference in the quartile results of patients whose n-3 intake was through diet and those who ingested n-3 fatty acids as supplements. 

The difference between dietary scores for patients compliant to their drug regimens and those who were non-compliant was statistically significant for modifying patient prognosis after MI. The compliant patients also had the best dietary scores. Non-compliant subjects were those who had the worst diets, had higher triglycerides, and were younger, more educated, more likely to be diabetic, and more likely to continue to smoke after MI.

The main results of this study were that diet is extremely important for lowering cholesterol and lowering mortality in post-MI patients. For absolute levels of blood cholesterol, the risk of coronary heart disease (CHD) is completely different from one region of the world to another. Regional dietary habits correspond to different rates of CHD. This supports the conclusion that the GISSI data can be explained by different dietary habits or lifestyle habits.

Additional supporting data 

Patients' compliance with experimental treatments and adherance to dietary habits was assessed. The patients with the best diets were also most compliant to drug treatments. This could indicate that patients with low mortality rates during follow-up were carefully following their diets and drug regimens, while those with high mortality rates were not.

The Lyon dietary study looked at Mediterranean subjects after MI who followed either a Mediterranean or a Western style diet. They found two kinds of fats to be better for lowering cholesterol: olive oil and canola oil—they both have a low proportion of saturated fatty acids and a limited proportion of n-6 fatty acids. The proportion of n-6 to n-3 fatty acids was 6.6 in the medicated group and 7.5 in the control group. This shows that the composition of fats consumed by patients after MI is important.  Membrane composition data was collected outside the GISSI study. Membrane phospholipid composition data was measured in 36 Italian volunteers (mainly young doctors) and found to be roughly the same as the medicated group in the Lyon study: the proportion of n-6 to n-3 fatty acids was about 7.0 vs. 7.2. The subjects were randomized to get 1.0, 2.0 or 4.0 grams of n-3. There was an early increase in the level of n-3 in plasma phospholipids in all groups. Then the levels reached a plateau. The same thing happened with platelets, mononuclear cells, and DHA. The baseline ratio of n-6 to n-3 was about 7.0. The ratio went down to less than 5 with 1.0 g n-3 and to 0.5 with 4.0 g n-3. Note that the results are in Mediterranean countries, where most fat consumption is from olive oil (75%). Regional baseline diets and the issue of patient compliance must be considered when examining data from any n-3 studies.

Conclusion

While proper diet and lifestyle habits are associated with lower mortality after MI, n-3 fatty acids given in capsule form in addition to lifestyle advice further decreased the risk of death. Patients complying with dietary recommendation are also more likely to be compliant with lifestyle and pharmacological recommendations. A corrective Mediterranean diet can be adopted after MI and maintained in the long run to reduce mortality rates.

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Effects of a High-Dose Concentrate of n-3 Fatty Acids or Corn Oil Introduced Early After an Acute Myocardial Infarction on Serum Lipids and Clinical Outcome: Dietary Considerations

Dennis W. Nilsen, Central Hospital in Rogaland, Stavanger Norway, et al.,

Introduction 

The choice of an optimal dose of n-3 fatty acids may be crucial for demonstration of improved outcome in clinical trials. Clinical studies indicate that doses of n-3 fatty acids up to 1 gram a day administered after an acute myocardial infarction (MI) may have a considerable impact on prognosis, essentially by reducing the incidence of cardiovascular death (1, 2. 3). Their main effect on clinical outcome has been attributed to their anti-arrhythmic properties (2, 3). However, they also exert impressive anti-atherothrombogenic properties (4), but it has not been clearly shown whether these effects translate into an improved prognosis. Increasing the doses of n-3 fatty acids beyond 1 gram a day improves serum lipids (5), but the clinical impact of these beneficial changes may be counterbalanced by unwarranted effects, such as increased lipid peroxidation. Moreover, substances, such as corn oil, given to controls in double-blind studies may also be biologically active, which may influence the results. For more references, see AJCN (1).

Objectives 

The primary objective of this study was to evaluate the effect of a high-dose ethylester concentrate of n-3 fatty acids administered early after an acute MI on subsequent cardiac events and serum lipids. The clinical issues have previously been accounted for (1). In this presentation we present the background diet of the study. 

Design 

Three hundred patients with acute MI were randomly assigned to a daily dose of either 4 g highly concentrated n-3 fatty acids or corn oil, introduced 4-6 days after the MI and administered in a double blind manner over 12-24 mo. Median follow-up time was 1.5 y. Clinical follow-up, including the drawing of blood samples, was performed after 6 wk of treatment and later at 0.5-year intervals.

Results 

Forty-two (28%) patients in the n-3 group and 36 (24%) in the corn oil group experienced at least one cardiac event (cardiac death, resuscitation, recurrent MI, or unstable angina). No significant difference in prognosis was observed between groups for single or combined cardiac endpoints. Event-free survival curves by treatment group are depicted in Figure 1. Total cholesterol concentrations decreased significantly in both groups, with no significant inter-group difference. On average, the monthly increase in HDL cholesterol was 1.11% in the n-3 group and 0.55% in the corn oil group (p=0.0016). Triacylglycerol concentrations decreased by 1.3%/mo in the n-3 group and increased by 0.35%/mo in the corn oil group (p<0.0001). No clinical benefit of a high-dose concentrate of n-3 fatty acids compared with corn oil was found despite a favorable effect on serum lipids.

Dietary considerations 

Thirty percent in the n-3 group and 25 per cent in the corn oil group of patients were taking fish oil supplements prior to inclusion, comparable to a daily dose of about 1 g of n-3 fatty acids. Patients agreed to abstain from dietary supplements of fish oil during treatment intervention. 

Fatty acids in serum phospholipids were measured in 63 patients randomly allocated from the study population. The distribution of fatty acids in serum phospholipids at baseline is depicted in Table 1 as per cent of total fatty acids. Basal levels of total n-3 fatty acids were reasonably high, as previously seen in a coastal population (4). Patients consuming fish oil supplements had a 25 % higher serum concentration of eicosapentaenoic acid (EPA) at inclusion than patients with no dietary supplementation (p=0.047). Patients’ diets were monitored at 6 wk and later at 0.5-year intervals. The weekly consumption of fish was 2 meals or less in the lower quartile and 3 meals or more in the upper quartile. The median intake consisted of 3 fish meals per week. The dietary habits of the patients were essentially unchanged throughout the study.At 12 months follow-up there was a threefold increase of EPA (p<0.001) in serum phospholipids in patients treated with n-3 fatty acids. Total n-3 fatty acids increased by 61 % as compared to 11.2% in the corn oil group of patients (p<0.001) (Table 2).

Discussion 

No clinical benefit of a high-dose concentrate of n-3 fatty acids compared with corn oil was found despite a favorable effect on serum lipids. The lack of a beneficial effect on clinical outcome may be due to at least one of several possibilities:

1) a dose optimum below the chosen dose in this study, 2) undesirable effects, such as increased lipid peroxidation, of a high-dose concentrated compound of n-3 fatty acids. 3) a background diet rich in n-3 fatty acids, masking the effect of intervention, and sufficient to induce the desirable membrane stabilizing, anti-arrhythmic effects, 4) protective effects of corn oil in controls, 5) use of competing interventions, such as aspirin, but this explanation seems less likely, as the background medication was very similar to that of the GISSI Prevention study (3).

Conclusions 

A diet rich in fish oil may be sufficient to obtain the desirable antiarrhythmic properties of n-3 fatty acids, and a further increase in dose may not exert additional cardioprotection. Dose-dependent unwarranted effects should be considered and biologically active substances should be avoided in control patients. 

REFERENCES 

1. Burr ML, Fehily AM, Gilbert JF, Rogers S, Holliday RM, Sweetham PM, Elwood PC, Deadman NM. Effects of changes in fat, fish, and fibre intakes on death and myocardial reinfarction: diet and reinfarction trial (DART).Lancet 1989; 2: 757-61.
2. de Lorgeril M, Renaud S, Mamelle N, Salen P, Martin J-L, Monjaud I, Guidollet J, Touboul P, Delaye J. Mediterranean alpha-linolenic acid-rich diet in secondary prevention of coronary heart disease. Lancet 1994; 343: 1454-59.
3. GISSI-Prevenzione Investigators. Dietary supplementation with n-3 fatty polyunsaturated fatty acids and vitamin E after myocardial infarction: results of the GISSI Prevenzione trial. Lancet 1999; 354:447-55.
4. Grundt H, Nilsen DWT, Hetland Ø, Aarsland T, Baksaas I, Grande T, Woie L. Improvement of serum lipids and blood pressure during intervention with n-3 fatty acids was not associated with changes in insulin levels in subjects with combined hypertriglyceridaemia. J Int Med 1995; 237(3): 249-59.
5. Nilsen DWT, 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 concentration. Am J Clin Nutr 2001; 74(1): 50-6.

Figure 1.

Significance of difference from baseline: *p<0.001, **p=0.011 

May 22, 2003

Charles H. Halsted, MD
Editor, American Journal of Clinical Nutrition
3247 Meyer Hall
University of California
One Shields Avenue

Davis, CA 95616-8790

Dear Dr. Halsted

One of us (DWTN) previously reported the results of a study carried out in Stavanger, Norway in which the effects on clinical coronary heart disease (CHD) endpoints of 3.4 g per day of eicosapentaenoic and docosahexaenoic acids (EPA+DHA) vs. a corn oil placebo were presented (1). Post-MI patients (n=300) were followed after randomization for 18 months. In contrast to observations in the Diet and Reinfarction Trial (2) and the GISSI Prevenzione study (3), increased omega-3 fatty acid intakes had no beneficial effect in this study. It was suggested that perhaps the background dietary intake of omega-3 fatty acids in this Norwegian population may have produced sufficiently high blood levels of these fatty acids such that no further benefit from supplementation could have been achieved. 

Further data from that trial have now been published (4). In a subset of 28 patients from each treatment group, the frequency of fish consumption, the proportion of patients taking fish oil supplements pre-study, and the serum phospholipid EPA+DHA levels were assessed (Table). Since some of the patients had been taking supplements in the pre-study period, baseline values in the Table may misrepresent the impact of the Norwegian background diet alone on EPA+DHA levels. To address this question, serum from patients not taking supplements pre-study were analyzed. They contained a mean of 6.3% EPA+DHA in the phospholipid fraction. This was not materially different from the baseline values in the Table, therefore, supplement consumption did not have a significant effect on baseline levels.

The EPA+DHA content of the phospholipids in the Stavanger study may be compared to those levels reported in epidemiological studies on fish intake and CHD risk (Table). It is immediately obvious that the patients in the Stavanger Study had levels approximately twice as high as those reported by others, not only after treatment, but more importantly, before treatment began. These data support the original suggestion that the failure of supplemental omega-3 fatty acids to alter future risk for CHD was likely to have been due to the presence of high omega-3 levels in the background diet. More importantly, they also imply that there may be an upper limit of tissue omega-3 fatty acid levels above which further CHD benefit will not be realized. 

Table. Serum phospholipid (PL) eicosapentaenoic (EPA) and docosahexaenoic Acid (DHA) levels in the Stavanger study and in controls and cases from published epidemiological investigations (adapted from (4) with permission)

Reference List

1. Nilsen DWT, Albrektsen G, Landmark K, Moen S, Aarsland T, Woie L. 2001 Effects of a high-dose concentrate of n-3 fatty acids or corn oil introduced early after acute myocardial infarction on serum triacylglycerol and HDL cholesterol. Am J Clin Nutr.74:50-56.
2. Burr ML, Fehily AM, Gilbert JF, et al. 1989 Effects of changes in fat, fish, and fibre intakes on death and myocardial reinfarction: diet and reinfarction trial (DART). Lancet.2:757-761.
3. GISSI-Prevenzione Investigators. 1999 Dietary supplementation with n-3 polyunsaturated fatty acids and vitamin E in 11,324 patients with myocardial infarction: Results of the GISSI-Prevenzione trial. Lancet.354:447-455.
4. Grundt H, Nilsen DWT, Mansoor MA, Nordoy A. 2003 Increased lipid peroxidation during long-term inter