n−3 Fatty Acids in Patients With Multiple Cardiovascular Risk Factors

Study Questions:

Is intake of n-3 polyunsaturated fatty acids associated with cardiovascular disease (CVD) risk among patients with multiple CV risk factors or atherosclerotic vascular disease who had not had a myocardial infarction?


The Risk and Prevention Study was a double-blind, placebo-controlled clinical trial, which included patients cared for by a network of 860 general practitioners in Italy. Eligible patients included men and women with multiple CV risk factors or atherosclerotic vascular disease, but not myocardial infarction. The criterion of multiple CV risk factors was defined as at least four of the following (or, for patients with diabetes, at least one of the following): age of 65 years or older, male sex, hypertension (clinical history of hypertension or use of antihypertensive treatment), hypercholesterolemia (clinical history of hypercholesterolemia or use of lipid-lowering treatment), status as a current smoker, obesity (a body mass index of 30 or more), or a family history of premature CVD (defined as cardiovascular disease at <55 years of age in the patient’s father or a brother or at <65 years of age in the patient’s mother or a sister). Patients were randomly assigned to n−3 fatty acids (1 g daily) or placebo (olive oil). The predefined specified primary endpoint was the cumulative rate of death, nonfatal myocardial infarction, and nonfatal stroke. At 1 year, after the event rate was found to be lower than anticipated, the primary endpoint was revised as time to death from CV causes or admission to the hospital for CV causes.


A total of 12,513 patients (mean age 64 years, 61.% men) were enrolled, of which 6,244 were randomly assigned to n−3 fatty acids and 6,269 to placebo. The most common inclusion criterion was diabetes mellitus plus one or more cardiovascular risk factors, present in 5,986 patients (47.9%); 3,691 patients (29.5%) had a history of atherosclerotic disease, 2,602 (20.8%) had at least four cardiovascular risk factors excluding diabetes, and 226 (1.8%) had an increased CV risk according to the judgment of the general practitioner. Over a median of 5 years of follow-up, the primary endpoint occurred in 1,478 of 12,505 patients included in the analysis (11.8%), of whom 733 of 6,239 (11.7%) had received n−3 fatty acids and 745 of 6,266 (11.9%) had received placebo (adjusted hazard ratio with n−3 fatty acids, 0.97; 95% confidence interval, 0.88-1.08; p = 0.58). The same null results were observed for all the secondary endpoints.


The investigators concluded that in a large general-practice cohort of patients with multiple CV risk factors, daily treatment with n−3 fatty acids did not reduce CV mortality and morbidity.


Despite prior observation data suggesting benefits of n-3 fatty acids related to CV risk among patients without CVD, these data from a large randomized controlled trial do no support the use of n-3 fatty acids in primary prevention. This does not mean that a healthy diet—which includes polyunsaturated fats including n-3 fatty acids—would not be prudent among patients, particularly those with multiple risk factors.

Clinical Topics: Dyslipidemia, Prevention, Homozygous Familial Hypercholesterolemia, Lipid Metabolism, Nonstatins, Diet, Hypertension

Keywords: Myocardial Infarction, Stroke, Follow-Up Studies, Atherosclerosis, Dietary Fats, Unsaturated, Risk Factors, Hypercholesterolemia, Primary Prevention, Italy, Incidence, Body Mass Index, Fatty Acids, Omega-3, Plant Oils, Cardiovascular Diseases, Obesity, Diet, Hypertension, Diabetes Mellitus

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