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.