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 intervention with high doses of n-3 fatty acids (PUFAs) following and acute myocardial infarction. Euro J Clin Nutr. 57 (in press).
5. Guallar E, Hennekens CH, Sacks FM, Willett WC, Stampfer MJ. 1995 A Prospective Study of Plasma Fish Oil Levels and Incidence of Myocardial Infarction in U.S. Male Physicians. J Am Coll Cardiol.25:387-394.
6. Leng GC, Taylor GS, Lee AJ, Fowkes FG, Horrobin D. 1999 Essential fatty acids and cardiovascular disease: the Edinburgh Artery Study. Vasc Med.4:219-226.
7. Lemaitre RN, King IB, Mozaffarian D, Kuller LH, Tracy RP, Siscovick DS. 2002 N-3 polyunsaturated fatty acids, fatal ischemic heart disease and non-fatal myocardial infarction in older adults. The Cardiovascular Health Study. Am J Clin Nutr.76:319-325.

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Secondary Prevention of Coronary Heart Disease Role f Alphalinolenic Acid (LNA 18:3,n-3)

Bruce Holub, Ph.D., University of Guelph, Guelph, Ontario, Canada*

North Americans consume about 1.3 grams of alpha-linolenic acid (LNA or ALA, 18-3, n-3) a n-3 polyunsaturated fatty acid (PUFA), with a wide variability between 1 and 2 grams/day in adult population. Canola oil is 10% by weight LNA, safflower oil, and olive oil are totally devoid of LNA. Non-hydrogenated soybean oil contains about 7% LNA. Eggs, containing LNA and DHA (18:6,n-3) obtained by feeding flaxseed to birds have been launched on the market. Some eggs provide 350 mg or more of n-3 per large (50 gram) serving. Canada and Montana have good food-quality flaxseed, which contains about 22% by weight LNA. Flaxseed oil, contains up to 50-55% LNA. Very few oils have those levels at the low cost of flaxseed oil. Pearl oil, used in Japan, has about 55-60% LNA.

The Mediterranean diet sparked significant interest in the potential cardioprotective effects of LNA on post-myocardial infarction (MI) patients. There is a wide variability in the published literature as to whether LNA, when substituted for linoleic acid (LA, 18:2,n-6), actually has a significant blood cholesterol-lowering effect. A thorough review of the pertinent scientific concluded that dietary LNA is as effective as oleic acid and linoleic acid in lowering blood cholesterol in normal lipidemic men, a more recent study concluded the opposite—replacement of linoleic acid by LNA does not lower cholesterol in normal lipidemic men.These studies have confounding variables. For example, if canola oil is the source of LNA, there is an accompanying intake of oleic acid, which, in most studies, has an LDL cholesterol-lowering effect. But, if a flaxseed oil supplement is used on top of a diet high in the n-6 PUFA linoleic acid, the outcomes could be very different. The basic composition of the diet has to be thoroughly analyzed to reach concrete conclusions from these studies on the possible cholesterol-lowering effect of LNA. Studies intended to correlate the risk of developing coronary heart disease provided statistically insignificant results. 

Arterial complicance

The literature on LNA and arterial compliance, that can now be measured by ultrasound, is important. Arterial compliance could become an important marker for diagnosis of risk of serious cardiovascular disease. Paul Nestle et al., in Australia used daily LNA intake of 20 grams/day from margarine products based on flaxseed oil. They observed a marked rise at least in arterial compliance with LNA and improvement in systemic arterial circulation despite the rise in LDL-oxidation. This is a novel approach to improving arterial function, perhaps independently, from its convertibility to the longer-chain n-3 phospholipids. McFee and others have found similar effects in type-II diabetics. 

Intervention trials

With respect to secondary preventive intervention trials, there are no studies like the GISSI study, using encapsulated flaxseed oil containing LNA. There was a fairly small, randomized, double-blind, placebo-controlled clinical trial on fish oil and mustard oil conducted in patients with suspected acute MI in India. This experiment of infarct survival, studied by Singh et al, found that LNA intervention with mustard seed oil at 2.9 grams/day for one year reduced non-fatal MIs significantly (28%) as compared to the non-supplemented placebo (34.5%). 

Epidemiological studies 

In a Harvard study, results for LNA were promissing. Doses were from 0.7 grams to up to 1.3 grams/day LNA/day (average N. American intake is about 1 gram/day). While for non-fatal CHD there was no significant relationship overall, for fatal CHD there was a significant reduction, approaching 50% at the 1.36 gram level compared with levels of one gram or less. The Harvard study published a few weeks ago shows fatty acids in total blood. Docosahexaenoic acid (DHA, 22:6,n-3) was the strongest protector in terms of a 0.005 p-value. 

LNA is converted to EPA (20:5,n-3) and DHA with low efficiency (3.8% on average to DHA and 10 to 11 % on average to EPA-DPA/day). There is a consistent rise in EPA, and in DPA (22:5,n-3) with no change in DHA. (A note on the rise of DPA: there is epidemiological literature that shows when blood-levels of DPA increase, so does the risk of CHD in some but not all studies. If DHA is provided to patients, a drop in DPA is observed. Thus, excess LNA could be responsible for the rise of DPA in circulation.

Conclusion

Holub et al. performed a study to assess the effects of increasing LNA while increasing LA. When platelet phospholipids were measured, as patients consumed 1 to 7.8 grams of LNA/day, LNA levels went up with no change in EPA, but with some rise in DPA. As the ratio of n-6 to n-3 droped from 7:1 to 6:3 to 3:1, an additional boost was observed in DPA but not in EPA and DHA.

Average intake of LNA in N. American women is about 1.295 grams/day. Conventional risk factor modifications like LDL, HDL, triglycerides, and blood pressure, do not support any superiority of LNA over LA. Athough direct physiological effects of LNA, independent from EPA and DHA formation, cannot be unequivocally excluded at the present time accumulation of EPA and DPA in cells and tissues likely mediates the dietary benefits of LNA, which are independent of blood lipid lowering, Reducing the LA to LNA ratio might be beneficial but additional data is still needed to prove that. A recommendation was made to raise the current Canadian average intake of 1.3 grams LNA to about 2 grams/day, or about 0.7% or 0.8% of energy intake regardless of the consumption of fish.

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Antiarrhythmic Effects Of N-3 Fatty Acids From Fish Oil

William E. Connor, M.D., Oregon Health Sciences University, Portland, Oregon, U.S.A;

Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) from fish oil have many effects upon human and animal physiology (see table 1). Of all of these effects, the one that is most pronounced and active is the antiarrhythmic effect. This effect may reduce the incidence of sudden death from ventricular fibrillation and ventricular tachycardia. The antiarrhythmic effects of EPA and DHA are largely mediated through their influence on the calcium and sodium channels of the hearts, lessening the excitability of heart muscle and thus inhibiting ventricular arrhythmias. Previous clinical trials have explored the effects of fish oil on long-term cardiovascular disorders, such as hyperlipidemia, endothelial function, and hypertension. Any future clinical trial with fish oil must evaluate the endpoint of an abnormal cardiac rhythm, which could cause sudden cardiac death.

Sudden cardiac death occurs in some 250,000 individuals per year. An inexpensive public health measure to prevent sudden death would clearly be in the national interest. However, there has been only one clinical trial, the Italian GISSI trial, has dealt directly with the prevention of sudden death by fish oil fatty acids. This trial compared a placebo versus a fish oil and found a pronounced reduction in the incidence of sudden death in the survivors of myocardial infarction. However, the trial did not measure levels of n-3 polyunsaturated fatty acids (PUFA) in the survivors’ blood, so precise correlations of prevention of sudden death with plasma or red blood cell levels of n-3 fatty acids could not be made. There have been many epidemiological associations with fish consumption and the prevention of sudden death. It should be emphasized that these are associations only. Two recently published publications on endpoint data of The Physician’s Health Study and the Nurse’s Study, discuss these epidemiological associations. In the Physician’s Health Study, the consumption of fish was inversely correlated with the risk of sudden death and also inversely with the amount of n-3 PUFA (EPA + DHA) present in the blood. In the Nurse’s Study, a similar correlation was made but no biochemical measurements took place.Currently, there are three studies in progress that are double-blind and are using various doses of fish oil, from 1.0 to 4.0 grams per day. All of these studies have enrolled defibrillator patients as the basic group, since these patients have already shown a pronounced liability for the development of ventricular arrhythmias. In all three studies double blind studies, patients will receive either a concentrated fish oil preparation or a placebo (usually olive oil). One of the studies, a Dutch study, is just beginning. The Boston study under Dr. Alexander Leaf is nearing conclusion and the McAnulty study at Oregon Health & Science University has one to two years more until completion. In all three of these studies, biochemical measurements of n-3 PUFA in the blood are being carried out, so that appropriate correlations with n-3 fatty acid levels and their beneficial or harmful effects can be made. The mechanism of the effect of EPA and DHA to prevent ventricular arrhythmias and sudden death has been well established in experimental animals and tissue culture studies. The effective substance is the free fatty acid form of EPA and DHA. These free fatty acids may be derived from one of three sources as follows:

Directly from the diet. After the metabolism of chylomicrons, free fatty acids are released and are taken up by the myocardium as well as by other tissues of the body, particularly adipose tissue.

There is a constant efflux of free fatty acids, particularly EPA, from adipose tissue stores, including adipose tissue in the heart. These fatty acids are picked up by the myocardium and could have a direct effect on the heart.

A third source of free fatty acids would be in the myocardium itself from myocardial phospholipids. Under the influence of phospholipase A-2, the fatty acids from the SN-2 position in the phospholipids could be released in the free fatty acid form and could directly affect the rhythm of the heart to prevent ventricular arrhythmias.

Leaf and co-workers hypothesized that the antiarrhythmic effects of EPA and DHA are largely mediated through their influence on the calcium and sodium channels of the heart, lessening the excitability of heart muscle and thus inhibiting ventricular arrhythmias.

Considerations for the design of studies to establish the efficacy of n-3 PUFA from fish oil in populations at high risk for sudden death but which have not yet developed evidence of coronary or other atherosclerotic disease. Such populations would include the following:

Diabetic patients

Patients with the “metabolic syndrome”Patients with a high Framingham risk scorePatients with familial hypercholesterolemia (the same group of patients that was used in the Lipid Research Clinic trial, which was the first trial to really show the effect of active intervention in individuals with very high cholesterol levels)

The primary endpoints of the study would be death, sudden cardiac death, myocardial infarction and stroke. Secondary endpoints include the development of symptoms (angina pectoris or claudication), and the need for bypass surgery or angioplasty.

Patient recruitment for this study would exclude those with a history of fatty fish intake two or more times per week (such as salmon or sardines). Plasma and red cell fatty acids would be measured at the beginning and throughout the study. Adipose tissue fatty acids will be obtained at time 0 and the end of the study. The estimated duration of the study is 24 months. The dose of fish oil administered to patients in the study will be 1 gram to 2 grams per day (EPA and DHA). The intervention will be with fish oil fatty acids. Diabetic control, hypertension, hyperlipidemia, or other medical problems would be carried out as necessary by the family physician.

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Comparison of Primary and Secondary Prevention of CHD: The Statin Experience

Michael B. Clearfield, D.O., University of North Texas Health Science Center, Fort Worth, Texas, U.S.A.

The treatment and prevention of cardiovascular disease has changed dramatically since the 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) became available. The statins have been shown, in long term perspective studies, to significantly reduce the risk of CHD morbidity and mortality in people with or without evidence of established CHD (secondary and primary prevention, respectively). 

There have been six large randomized placebo based perspective trials utilizing statins. Two of these were primary prevention trials (WOSCOPS, AFCAPS/TexCAPS1), three were secondary prevention trials (4S, CARE, LIPID) and the most recent is a hybrid, predominately secondary prevention with a sub-group of high risk primary prevention participants (HPS2). In every trial, the statin significantly reduced the incidence of CHD events when compared to the placebo group. 

In excess of 50,000 people have participated in these statin trials, the majority being middle-aged Caucasian men. However, with the recent data from the Heart Protection Study (HPS), a significant number of women, elderly and diabetics have also been shown to significantly benefit from statin therapy.

The benefit from statins starts early in the treatment process and is maintained over time. As a class the statins appear to be safe, well tolerated and effective in lowering total cholesterol, LDL cholesterol and triglycerides, while modestly raising HDL-C. 

An additional potential benefit of the statins are their pleiotropic effects which influence endothelial function, inflammation and thrombosis. Whether these additional benefits of the statins are additive to the benefit of LDL-C reduction is under investigation.3

The statins have revolutionized the treatment and prevention of cardiovascular disease, however there are still individuals who will manifest symptomatic cardiovascular disease even when treated effectively with a statin. The addition of other therapies including long chain n-3 fatty acids may continue to further the positive impact of the statins on the prevention of cardiovascular disease.4

1 JAMA 1999;282:2340-2346

2 Int J Clin Prac 2002;56(1):53-56

3 NEJM 2001;344:1959-1965.

4 NEJM 2002;346:1113-1118.

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ACE-Inhibitor Use in Cardiovascular Risk Reduction

Byron Hoogwerf, M.D., FACP, FACE, Cleveland Clinic Foundation, Cleveland, Ohio, U.S.A.

Background

Therapy with angiotensin converting enzyme inhibitors (ACE-I) has a well-established role in the treatment of diabetic nephropathy and in the treatment of patients with heart failure. Information from the heart failure studies suggested that there was a reduction in the risk for cardiovascular events (fatal or non-fatal MI) that was independent of any benefit on heart failure. In addition, this benefit appeared to be independent of any blood pressure reduction effect.

Heart Outcomes Prevention (HOPE) Study

The Heart Outcomes Prevention Study (HOPE) was double blind placebo controlled trial designed to assess whether ramipril 10 mg (vs. placebo) would reduce the risk for cardiovascular events in subjects at high risk for coronary disease events. The participants included a population of patients who had evidence of atherosclerotic vascular disease or diabetes with atherosclerotic vascular disease or (in the absence of clinical evidence of cardiovascular disease) one other cardiovascular risk factor. The diabetic population was a subset of patients specified for analyses at the beginning of the trial. The use of ramipril was associated with a significant reduction in the combined endpoint (non-fatal MI, stroke, cardiovascular death) as well as for each of these end-points individually. This was true for all participants in the study as well as for the diabetic patients (see slide sets for event rates/Kaplan Meier curves). Event rates were comparable in the diabetic patients and non-diabetic patients.

Whereas there were slightly lower mean blood pressure levels , most of the beneficial effect on MI and stroke reduction associated with ramipril use was independent of the blood pressure effect.

Event rates were slightly lower in patients without prior coronary heart disease (CHD, all with diabetes) vs. those with prior CHD. The incremental reduction in events with ramipril was comparable in patients both with and without CHD. In subsequent analyses, albuminuria was a continuous and graded risk factor for CHD events in both diabetic and non-diabetic participants. Patients with diabetes and elevated serum creatinine (>1.4 mg/dl) on placebo had higher event rates than those with serum creatinine levels (<1.4 mg/dl). Ramipril use had a greater incremental benefit in patients with creatinine >1.4 than in patients with values <1.4, although the absolute risk with ramipril treatment was higher in the elevated creatinine group.

Finally, the effects of ACE-I are in addition to other strategies associated with a reduction in risk for CHD (e.g. lipid lowering, aspirin use, or beta blocker use).

Perindopril Protection against Recurrent Stroke Study (PROGRESS)

The PROGRESS trial was a secondary prevention trial designed to assess whether perindopril 4.0 mg (vs. placebo) + indapamide would reduce the risk for stroke in subjects with a prior stroke or transient ischemic attack. There was a 28% reduction in the risk for recurrent stroke with perindopril use. The greatest effect was perindopril use in combination with indapamide (43% reduction) vs. perindopril alone (5% reduction (P=NS). Most of the beneficial effect on stroke reduction appears to be related to blood pressure reduction.

United Kingdom Prospective Diabetes Study (UKPDS)

The blood pressure treatment arm of the UKPDS used the ACE-I, captopril, and the beta blocker, atenolol, in the intensive treatment blood pressure arm. The intensive blood pressure treatment was associated with a reduction in the risk for microvascular and macrovascular diabetes endpoints. However, for comparable blood pressure reduction, there were no differences in clinical endpoints between captopril and atenolol treatment strategies based on intent to treat analyses. When outcomes in this trial were analyzed by in trial blood pressure levels, for every 10 mmHg reduction in blood pressure, there was a 12% reduction in fatal/non-fatal MI. It is not clear whether there was a beneficial effect of either the ACE-I or beta blocker beyond the reduction in blood pressure.

Other trials

There are several other trials that included ACE-I and diabetic patients as a part of the treatment strategy. In general, there is a beneficial effect on cardiovascular endpoints in these studies.

Implications of the ACE-I trials for a prevention trial with omega-3 fatty acids

The ACE-inhibitor trials provide strong evidence that patients with established CHD and cerebrovascular disease benefit from the use of ACE-inhibitors. Furthermore, the HOPE study data indicate that patients with diabetes and other CHD risk factors benefit from ACE-I therapy. Therefore, it is likely that diabetic patients eligible for a primary prevention trial will likely all be candidates for ACE-I therapy based on current clinical trial data and current guidelines. This will have an effect on the event rate calculations for such patients, as the projected event rates will be more than 20% lower than may be derived from other populations of diabetic patients.

There is clearly some benefit of blood pressure reduction with ACE-I on reduction in atherosclerotic disease events. It is not yet clear whether the beneficial effects of ACE-I reported for ramipril in the HOPE study are applicable to all ACE-inhibitors (class effect). Clinical trials currently in progress may help to address this question. Until these clinical trial data are available, any trial design needs to address the blood pressure effects of ACE-I use, as well as the pleiotrophic effects. Until more is known about whether this is class-effect specific, ACE-I type and dose should be carefully recorded for trial participants.

Selected References

The HOPE Study Investigators. Effects of an Angiotensin-Converting-Enzyme Inhibitor, Ramipril, on Death from Cardiovascular Causes, Myocardial Infarction and Stroke in High Risk Patients. New Engl J. Med. 2000;342:145-153

The HOPE Study Investigators. Effects of Ramipril on Cardiovascular and Microvascular Outcomes in People with Diabetes Mellitus: Results of the HOPE and MICRO-HOPE Study. Lancet 2000;355;253-259

Mann JFE, Gerstein HC, Pogue J, Bosch J, Yusuf S for the HOPE Investigators. Renal Insufficiency as a Predictor of Cardiovascular Outcomes and the Impact of Ramipril: The HOPE Randomized Trial. Ann Intern Med 2001;134:629-636

Gerstein HC. Mann JF. Yi Q. Zinman B. Dinneen SF. Hoogwerf B. Halle JP. Young J. Rashkow A. Joyce C. Nawaz S. Yusuf S. HOPE Study Investigators. Albuminuria and risk of cardiovascular events, death, and heart failure in diabetic and nondiabetic individuals. JAMA. 2001;286:421-6

PROGRESS COLLABORATIVE GROUP. Randomised trial of perindopril-base blood-pressure-lowering regimen among 6105 individuals with previous stroke or transient ischaemic attack. Lancet 2001;358:1033-1041

United Kingdom Prospective Diabetes Study Group. Tight blood pressure control and risk of macrovascular and microvascular complications in type 2 diabetes: (UKPDS 38): BMJ 1998;317:703-713

United Kingdom Prospective Diabetes Study Group. Efficacy of atenolol and captopril in reducing risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 39: BMJ 1998;317:713-720

Adler AI, Stratton IM, Neil AW et al on behalf of the UK Prospective Diabetes Study Group Association of systolic blood pressure with macrovascular and microvascular complications of type 2 diabetes (UKPDS 36): prospective observational study BMJ 2000;321:412-419

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Synergy Between Omega-3 Fatty Acids and Cardiovascular Drugs

Peter R. C. Howe, Ph.D., University of Wollongong, Wollongong, North South Wales, Australia 

Potential health benefits of bioactive nutrients such as long-chain omega-3 polyunsaturated fatty acids (n-3) LC-PUFA can be classified as a) health development, b) risk prevention, c) risk factor management or d) treatment of disease, where a) and b) are nutritional and c) and d) are therapeutic. The nutritional role of n-3 LC-PUFA in relation to cardiovascular health has been acknowledged1, although the evidence for this role comes largely from intervention trials demonstrating improvement, not prevention, of pre-existing risk factors for cardiovascular disease (CV) disease, thus highlighting a therapeutic role for n-3 LC-PUFA. Therapeutic applications of nutrients may be equally, if not more, beneficial than nutritional roles, but their exploitation requires more rigorous, hence costly, substantiation. This may be justified in the case of n-3 LC-PUFA supplementation, especially if one considers its additional potential as an adjunct to drug therapy.

Apart from improving a range of recognized CV risk factors, including thrombotic tendency, hypertriglyceridemia, hypertension, reduced arterial compliance and endothelial dysfunction, there is increasing evidence that n-3 LC-PUFA supplementation can augment the efficacy of CV drugs and provide broader risk benefit. An example is the ability of n-3 supplementation to further reduce blood pressure (BP) in hypertensives treated with diuretics or b-blockers and, at the same time, counteract the adverse effects of these drugs on plasma lipids (fig 1)2,3. However, the antihypertensive effect of n-3 LC-PUFA is not additive to that of the drug; it will depend on the class of drug and mechanistic interactions. Interactions with other nutrients may also influence the overall therapeutic effect, e.g. sodium restriction can potentiate the antihypertensive effect of n-3s. 

Another important example of synergy is the use of n-3 LC-PFA with statins. The hypotriglyceridemic effect of n-3s can complement the hypocholesterolemic effect of statins, which has obvious application in the treatment of persistent hypertriglyceridemia or combined hyperlipidemia and may prove a safer alternative to the combination of fibrates with statins. There is a pressing need for large-scale trials to demonstrate the efficacy and safety of this promising therapeutic strategy. An additional benefit awaiting confirmation is the potential for n-3 LC-PUFA supplementation in patients taking statins to further reduce plasma cholesterol (mainly VLDL) and shift LDL toward a less atherogenic profile, effects not seen with n-3 alone (fig 2)4,5. 

Additionally, n-3 LC-PUFA may counteract arterial disease by enhancing endothelial function and counteracting the inflammatory mechanisms mediating end organ damage. There is increasing recognition that such mechanisms are also a major factor in the efficacy of ACE inhibitors, angiotensin receptor blockers and statins in reducing coronary outcomes. Hence prudent combinations of n-3 LC-PUFA with these drugs may have potent effects on cardiac mortality, independent of their effects on risk factor modulation. Combining n-3 with aspirin is another important example. Rather than being redundant (in terms of cyclooxygenase products), it appears that n-3 can be converted into a new array of eicosanoids with potent anti-inflammatory effects in blood vessels6. It has been suggested that such n-3 to drug synergies may account for the impressive reduction of cardiac outcomes seen in recent secondary intervention trials in drug-treated subjects supplemented with n-3 LC-PUFA.

Clearly, prudent combinations of w3 and CV drugs have great therapeutic potential that should be systematically evaluated. As a minimum consideration, such synergies should be considered as possible confounders in attributing benefit for CV risk reduction in intervention trials utilizing n-3 LC-PUFA supplements.

References 

1. American Heart Association. AHA Dietary Guidelines - Revision 2000: A Statement for Healthcare Professionals From the Nutrition Committee of the American Heart Association. Circulation 2000;102:2296-2311.
2. Lungershausen YK, Abbey M, Nestel PJ & Howe PRC. Reduction of blood pressure and plasma triglycerides by omega-3 fatty acids in treated hypertensives. J Hypertens 1994;12:1041-1045.
3. Howe PRC. Dietary fats and hypertension - focus on fish oil. Ann NY Acad Sci 1997;827:339-352.
4. Howe P, Hammervold T, Meyer B, Rustan A, Calvert D. Omega-3 supplementation improves drug-treatment of hyperlipidaemia. Ann Nutr Metab 2001;45(suppl 1):96.
5. Nordoy A, Hansen J, Brox J, Svensson B. Effects of atorvastatin and w3 fatty acids on LDL subfractions and postprandial hyperlipemia in patients with combined hyperlipemia. Nutr Metab Cardiovasc Dis 2001;11:7-16.
6. Serhan CN, Clish CB, Brannon J, et al: Novel functional sets of lipid-derived mediators with antiinflammatory actions generated from omega-3 fatty acids via COX2 nonsteroidal antiinflammatory drugs and transcellular processing. J Exp Med 2000;192:1197-1204.

Fig 1: Omacor (4g/d) potentiates BP reduction and improves lipid profiles in hypertensives treated with diuretics or b-blockers (from reference 2)

Fig 2: Effects of fish oil supplementation (4 or 8 g/day of DHA rich tuna oil) on plasma lipids (averaged values after 3 & 6 mths) in statin-treated subjects (from reference 4)

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Aspirin in Primary and Secondary Prevention of Vascular Disorders: Implications for N-3 Fatty Acids 

Howard R. Knapp, MD, PhD. Deaconess Billings Clinic, Billings Montana, U.S.A.

When making decisions about preventive pharmacotherapy for vascular disease considering primary and secondary prevention is very important. These days patients entering clinical trials are likely to have been engaging in primary prevention—doing things like ingesting omega-3 or taking aspirin before entering a study, even before onset of cardiovascular dysfunction, because they were considered to be at high risk of vascular disease.Vascular disease endpoints (i.e. definite events) can result from several different biological actions, and specific drugs, such as aspirin, may influence only part of the disease process. We wanted to explore the safety of giving aspirin to cardiac patients already ingesting omega-3s.Platelet aggregation is slowed by aspirin (ASA) and is certainly involved in thrombotic events, but ASA may have little or no influence on atherogenesis per se. New recommendations for the treatment of high cholesterol (NCEP-III study) and blood pressure (JNC VI study) to prevent vascular events are now being based more on quantitative estimates of the risk of future events, rather than whether or not an individual patient has already had an event. We can now justify cholesterol-lowering with statins for patients with a predicted event-rate over 2% per year, for example. Similar recommendations for the preventive use of ASA are a logical progression of evidence-based practice guidelines. The Antiplatlet Trialists Collaboration has updated its recommendations based upon results from 287 studies involving over 212,000 patients (BMJ 324:71-86, 2002). Their conclusion was that “high risk” groups with >2%/year event rates would benefit from aspirin, including patients with stable angina, claudication, or asymptomatic carotid disease. The USPS Task force (Annals Int Med 136:157-176, 2002) suggests that patients with >1%/year vascular risk would benefit from aspirin therapy. They did take care to note that benefits are not seen in patients with sub-optimally treated blood pressure, that women likely have less benefit than men, and that the chance of a serious/fatal G.I. bleed from even low-dose ASA is two to three times greater in patients over age 70.We expect that most patients at vascular risk will be treated with aspirin in future studies, so the question arises as to what influence this might have on the risk or benefit of omega-3 PUFA in clinical studies. Interestingly, aspirin therapy has been shown, in at least four studies (>1600 patients), to increase bleeding during CABG, while three studies in which patients received omega-3 PUFA (>4.4g/d for 4 weeks) before CABG failed to detect any bleeding problems. Added effects of omega-3 PUFA and ASA on prolongation of template bleeding time has been noted in three papers, but safety of the combination can be inferred from three sets of observations: 

All patients in angioplasty studies involving omega-3 PUFA were also taking aspirin, and in the 7 largest such studies involving 1309 patients, there was no evidence of problems with bleeding during angioplasty or in those patients requiring CABG (Table 1).

Large studies of omega-3 PUFA levels in women with pregnancy-induced hypertension who were also given ASA did not find any increase in blood loss at parturition.

Women in the Faroe Islands, Greenland, and Northern Canada, where daily omega-3 PUFA intakes range from 1.5-8g/day have no problems with bleeding at delivery, nor did those in a Danish study of 535 women given 2.8g/day omega-3 PUFA from their 30th week of pregnancy onward. 

Overall, we can make a strong case for the essential safety of providing omega-3 PUFA at low doses (<2g/day) to patients at vascular risk who are taking aspirin.

Table 1: Combined Use Of ASA & N-3 PUFA In Angioplasty Trials

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Markers and Surrogate Parameters

Trevor A. Mori, Ph.D., et al., University of Western Australia, Perth, Australia

Effects of the long chain omega-3 polyunsaturated fatty acids (n-3 LC-PUFA), eicosapentaenoic acid (EPA, 20:5n-3) and docosahexaenoic acid (DHA, 22:6n-3) on factors for cardiovascular disease (CVD), such as systolic and diastolic blood pressure, overweight and obesity, dislipidemia, insulin resistance, platelett aggregation, thrombolysis, C-reactive protein and oxidative stress were discussed. Recently published results of two studies by Mori et al. were used to illustrate these effects. The main purpose of the presentation was not to be all encompassing or to establish priorities, but rather to stimulate discussion.

One study1,2 examined the potential effects of both dietary fish rich in n-3 LC-PUFA and a weight loss regimen on 24-hour blood pressure (BP) levels (systolic/diastolic or S/D), on 24-hour heart rate (beats/min or bpm), fasting insulin and glucose levels, HDL and LDL cholesterol, total cholesterol and fasting triacylglycerols (Tg). A factorial design was used and 69 obese and hypertensive subjects on single or dual therapy with ACE inhibitors or beta-blockers were randomized to a daily fish meal (3.65 g n-3 LC-PUFA), weight reduction, a combination of both or a control regimen for 16 weeks. Sixty three subjects completed the study. Weight fell by 5.6 kgs in the reduced energy intake groups. Both dietary fish and weight loss had independent and additive effects on ambulatory 24-hour BP (S/D=6.0/3.0 mm Hg reduction with dietary fish alone, 5.5/2.2 mm Hg with weight reduction alone and 13.0/9.3 mm Hg with both combined). Dietary fish reduced 24-hour ambulatory and daytime heart rates (HR) by 3.1 bpm and 4.2 bpm respectively. Weight reduction had an HR-lowering effect during night only (3.2 bpm). Thus, a combination of dietary fish intake and weight-reducing program could have additive positive effects suggesting reduced cardiovascular risks and a potential reduced need for antihypertensive medication. Fasting insulin levels decreased in the weight loss group with an even greater decrease in both insulin and glucose levels (the area under curve during a glucose tolerance test) in the combined fish + weight loss group. The fish meal group alone showed no reduction in fasting insulin and glucose levels. Fish increased HDL2 cholesterol and decreased HDL3 cholesterol. It did not alter total cholesterol, LDL or HDL cholesterol. Weight loss had no effect on these variables. Fish meals lowered fasting Tg levels significantly by 29% and weight loss lowered fasting Tg levels by 26%. The fish + weight loss group showed the greatest improvements in lipids: Tg decreased by 38% and HDL cholesterol increased by 24% compared with the control group. 

The second study3,4 was aimed at identifying the potential significant differences between EPA and DHA in regard to their physiological effects on the above risk factors. Fifty-nine overweight and mildly hyperlipidemic men were randomized to 4.0 g/day of purified EPA and DHA, or olive oil (as placebo) for 6 weeks in a parallel design, double blind, placebo-controlled trial. Fifty six subjects completed the study. When compared with the placebo group DHA reduced 24 hour and daytime ambulatory BP (S/D) by 5.8/3.3 and 3.5/2.0 mm. Hg respectively; decreased 24-hour HR, daytime and nighttime HR by 5 bpm, 3.7 bpm and 2.8 bpm respectively. EPA had no significant effect on either of these parameters. Both DHA and EPA reduced Tg levels by 20% and 18% respectively, Neither EPA, nor DHA had any effect on total cholesterol. EPA reduced HDL3 cholesterol only (by 6.7%) and had no effect on LDL, HDL and HDL2. DHA increased HDL2 significantly (by 29%). DHA increased LDL cholesterol by 8% but also increased LDL cholesterol particle sizes by 0.25 nm. EPA had no effect on particle size. Both EPA and DHA increased fasting insulin levels significantly.

These results indicate that EPA and DHA have differential effects on the above risk factors and that these differences should be taken into account. They also emphasise the importance of connecting omega-3 LC-PUFA consumption with life style changes for a potentially optimal CV benefit.

In regard to vascular effects, DHA appears to have significant vasodilatory effects, while EPA does not. Similarly, DHA reduces platelet aggregation and thrombolitic effects while EPA does not appear to do so in a significant fashion. Presently, C-reactive protein appears non-reactive to n-3 LC-PUFA. Effects due to the presence or absence of oxidative stress are difficult to evaluate due to limitations in measuring methodologies. The increasing importance of measuring urinary F(2)-isoprostanes5 as markers of in vivo lipid peroxidation was emphasised. Diabetes, especially type 2 diabetes should be included in considerations of any long-term primary prevention trial.

References

1. Bao D.Q. et al, Effect of dietary fish and weight reduction on ambulatory blood pressure in overweight hypertensives, Hypertension, 1998; 32, 710-7
2. Mori T.A., et al., Dietary fish as a major component of weight-loss: effect on serum lipids, glucose, and insulin metabolism in overweight hypertensive subjects, Am J Clin Nutr. 1999; 70(5), 817-25
3. Mori T.A. et al., Docosahexaenoic acid but not eicosapentaenoic acid lowers ambulatory blood pressure and heart rate in humans, Hypertension, 1999; 34 (2), 253-60
4. Mori T.A. et al., Purified eicosapentaenoic and docosahexaenoic acids have differential effects on serum lipids and lipoproteins, LDL particle size, glucose, and insulin in mildly hyperlipidemic men, Am J Clin Nutr. 2000; 71 (5): 1085-94
5. Proudfoot J., et al., Measurement of urinary F(2)-isoprostanes as markers of in vivo lipid peroxidation-A comparison of enzyme immunoassay with gas chromatography/mass spectrometry, Anal Biochem. 1999; 272(2), 209-15

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Patient Populations and Clinical Endpoints for an Omega 3 Fatty Acid Cardioprotection Study

Ernst J. Schaefer, M.D., Tufts University, Boston, Massachusetts, U.S.A.

In the Diet and Reinfarction Trial (DART), fish or two fish oil capsules per day were administered to 2033 men with coronary heart disease (CHD). This reduced risk of CHD mortality by 29% (Lancet 2:757-761, 1989). No other dietary advice or practice (e.g. high fiber, low saturated fat) had any significant effect. In the large Italian study know as GISSI, 11324 men and women with CHD took 0.850 gram per day of long chain omega-3 polyunsaturated fatty acids (n-3 LC-PUFA). This reduced CHD mortality 15% (Lancet 345:447-455, 1999). 

Death rates from CHD in United States (U.S.) for men ages 65-74 are approximately 898 out of 100,000 per year. In men ages 75-84 the death rate was 2130 out of 100,000 per year. Therefore, over five years, the projected number of deaths would be 4490 out of 100,000 for the younger age group, and 10650 out of 100,000 for the older group, or 449 out of 10,000 in the younger group and 1065 out of 10,000 for the older group. Death rates of women in the U.S. was 415 and 1288/100,000 or 42 and 128/10,000 per year in the 65-74 and 75-84 age groups respectively or 210 and 640/10,000 over 5 years. The over-75 age group is the fastest growing segment of society in the United States (National Center for Health Statistics, US, 2000), so considering the elderly in cardioprotection studies is of growing importance.

If we consider people who are being treated for hypertension the death rate increases by a factor of 1.66 for men and 2.75 for women. (National Cholesterol Education Program Adult Treatment Panel III guidelines JAMA 285: 2486-2497, 2001). Selecting people for total cholesterol over 200 mg/dl adds no increased risk for men and very little increased risk for women. Selecting for patients with HDL cholesterol below 40 mg/dl would add risk, but it would be difficult to recruit women for such a trial. Age is the overwhelmingly important CHD risk factor, therefore selecting subjects 75 years of age or older greatly increases the risk of CHD death versus younger groups, especially in women. 

In a primary prevention study for CHD mortality, comprised of a total of 10,000 people with equal numbers of men and women all 75 years of age and older with treated hypertension one could assume the following: 

• 426 CHD deaths over 5 years in the 5000 randomized to the placebo group 
• 30% reduction in CHD mortality 
• 298 deaths in the 5000 placed in the fish oil group. 

Power calculations assuming an 8.52% death rate in the placebo group and a 5.97% death rate in the treatment group indicate that about 2300 subjects per group would be sufficient to detect this difference. Therefore 5000 per group should be more than sufficient to show that fish oil supplementation has a significantly beneficial effect in reducing CHD mortality in the primary prevention setting in the elderly. The concept of what constitutes "general population" was discussed in great detail.

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National Recommendations Regarding N-3 Fatty Acids

William S. Harris, PhD., University of Missouri-Kansas City, MO, and the Mid America Heart Institute, Kansas City, Missouri, U.S.A.

Both the National Cholesterol Education Program (NCEP) Adult Treatment Panel (ATP)-III and the American Heart Association (AHA) have issued recommendations regarding the role of diets in reducing risk for coronary heart disease (CHD). Both groups specifically addressed n-3 fatty acids (FA). 

The NCEP ATP-III report1 first discusses n-3 FA under Other factors that may reduce baseline risk for CHD. The Evidence Statement of this report is, “The mechanisms whereby n-3 fatty acids might reduce coronary events are unknown and may be multiple. Prospective data and clinical trial evidence in secondary CHD prevention suggests that higher intakes of n-3 fatty acids reduce risk for coronary events or coronary mortality.” The NCEP ATP-III report recommends that, “higher dietary intakes of n-3 fatty acids in the form of fatty fish or vegetable oils are an option for reducing risk for CHD,” but also states that, “this recommendation is optional because the strength of the evidence is only moderate at present. ATP-III supports the AHA recommendation that fish be included as part of a CHD risk-reduction diet… a dietary recommendation for a specific amount of n-3 fatty acids is not being made,” because of the lack of understanding of the actual mechanisms of n-3 fatty acids.In the section entitled, “Other Drugs” the NCEP ATP also mentions n-3 FA.“N-3 FA have two potential uses. In higher doses (3-12 g/d), EPA and DHA lower serum triglycerides. They represent alternatives to fibrates or nicotinic acid for the treatment of hypertriglyceridemia, especially chylomicronemia. Recent clinical trials also suggest that relatively high intakes of n-3 FA (1.0-2.0 g/d) in the form of fish, fish oils, or high linolenic acid oils will reduce risk for major coronary events in persons with established CHD. Although this usage falls outside the realm of “cholesterol management,” the ATP-III panel recognizes that n-3 FA can be a therapeutic option in secondary prevention. In the view of the ATP-III panel, more definitive clinical trials are required before relatively high intakes (1.0-2.0 g/d) can be strongly recommended for either primary or secondary prevention.”In the AHA Dietary Guidelines1 n-3 FA are first mentioned under Specific Guidelines. “Because of the beneficial effects of omega-3 fatty acids on risk of coronary artery disease as well as other diseases such as inflammatory and autoimmune diseases, the current intake, which is generally low, should be increased. Food sources of omega-3 fatty acids include fish, especially fatty fish such as salmon, as well as plant sources such as flaxseed and flaxseed oil, canola oil, soybean oil and nuts. At least 2 servings of fish per week are recommended to confer cardioprotective effects.”Another reference is found in the section entitled Issues that Merit Further Research. “Consumption of one fatty fish meal per day (or alternatively a fish oil supplement) could result in an omega-3 fatty acid intake (i.e., EPA and DHA) of about 900 mg/d, an amount shown to beneficially affect coronary heart disease mortality rates in patients with coronary disease.”The Table in this abstract lists the approximate amount of EPA and DHA contained in a variety of common fish and fish oils, as well as how much of each one would need to consume in order to obtain 900 mg of these two n-3 FA daily. 

Summary

Obtaining 900 mg a day of EPA and DHA from fish is practically impossible for most people consuming a Western diet as it would require the daily consumption of at least 1.5 oz of oily fish like sardines, mackerel or herring per day. Capsules may be the only practical way for patients with CHD who are unwilling or unable to consume a more Mediterranean-style diet to consistently achieve this intake. Both the AHA and the NCEP generally endorse the consumption of 2 fish meals per week [(preferably oily fish (AHA)] for cardioprotection. This amount is inferred from epidemiological studies, not randomized trials. NCEP believes “strong recommendations for either primary or secondary prevention” must await further clinical trials evidence. AHA suggests daily fatty fish (or n-3 FA capsule) intake for secondary prevention in the context Issues that merit further study, but does not extend these recommendations to the primary prevention setting. 

1. http://www.nhlbi.nih.gov/guidelines/cholesterol/atp3_rpt.htm
2. Krauss et al. Revision 2000: A Statement for Healthcare Professionals from the Nutrition Committee of the AHA. Circulation 2000;102:2284-2299.

Data from USDA Nutrient Data Laboratory,  http://www.nalusda.gov/fnic/foodcomp/   The intakes of fish given above are rough estimates since oil content can vary markedly (>300%) with species, season, diet, and packaging and cooking methods. 

^† This intake of cod liver oil would provide about the Recommended Dietary Allowance of vitamins A and D.

‡ Not currently available in the USA.

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