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.

National Recommendations Regarding Omega 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. 


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. 

  2. Krauss et al. Revision 2000: A Statement for Healthcare Professionals from the Nutrition Committee of the AHA. Circulation 2000;102:2284-2299.



Different sources of Omega 3 and subsequent weights required to reach 0.9g DHA + EPA.

Different sources of Omega 3 and subsequent weights required to reach 0.9g DHA + EPA.




Data from USDA Nutrient Data Laboratory. 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.