BACKGROUND:

Coronary heart disease (CHD) is the major cause of morbidity and mortality in western societies. A major, unresolved question in preventive cardiology is whether dietary omega-3 polyunsaturated fatty acids are causally related to coronary heart disease. Essential omega-3 fatty acids are eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), along with their parent compound alpha-linolenic acid (ALA). EPA and DHA are almost exclusively derived from fatty fish such as mackerel and salmon. ALA is derived from various dietary sources including soy and rapeseed oil, whole grain, vegetables and fruits, and meats. The human body can convert ALA into EPA, but only to a very limited extent; although adequate dietary intake of very-longchain omega-3 fatty acids is crucial, it is well below recommended levels in most western populations. A recent meta-analysis of prospective cohort studies show a decrease in CHD mortality by 15% for fish consumption once per week, by 23% for fish consumption 2-4 times per week, and by 38% for fish consumption 5 or more times per week, compared to fish intake less than once per month.

DESIGN NARRATIVE:

The trial is a randomized, placebo-controlled, double-blind multicenter dietary intervention study of the effect of low-dose supplementation of ALA and/or a combination of EPA and DHA on coronary heart disease mortality among 4,000 Dutch men and women who are 60 to 80 years of age and had a myocardial infarction in the past 10 years. The trial increases intake of omega-3 fatty acids through daily use of 20 g of margarine on bread by randomizing subjects to 1 of 4 margarine groups: 2 g of ALA + placebo-EPA/DHA, 400 mg of EPA/DHA (which is equivalent to an additional serving [100- 150 grams] of fatty fish per week) + placebo-ALA, 2 g ALA + 400 mg EPA/DHA, or placebo-ALA + placebo EPA/DHA for 3 years. The trial started in May 2002 with 400 subjects in a pilot study; as of October 21, 2004, a total of 1,849 subjects (or 46% of total study population) has been enrolled.

The trial is a joint initiative of the Division of Human Nutrition at Wageningen University, the National Institute for Public Health and the Environment, and the Netherlands Heart Foundation. Patients are enrolled by Dutch cardiologists. The primary outcome of the trial is fatal coronary heart disease; secondary outcomes are cardiovascular disease mortality, sudden cardiac death and all-cause mortality. Complete follow-up for vital status is achieved. Physical examination, blood sampling and data collection on diet and lifestyle are performed in all subjects at baseline and after 3 years, and in 800 randomly selected subjects after 1.5 years of intervention. Yearly telephone interviews are used to monitor cardiovascular health, serious adverse events, lifestyle, fish intake and margarine use in all subjects. Compliance is continuously monitored by return of unopened margarine tubs; an objective biomarker of compliance in the form of plasma omega-3 fatty acids is obtained in 800 randomly selected subjects at baseline and after 1.5 and 3 years of the intervention. The trial has sufficient power to detect a 25% decreased risk of coronary heart disease mortality.