The potential beneficial effects of omega-3 polyunsaturated fatty acids on cardiovascular health have become of substantial interest to patients, physicians, researchers, and policy makers. In this issue of American Family Physician, Covington provides a clinical review¹ of omega-3 fatty acids. Recently, the American Heart Association released a scientific statement,² and the Agency for Healthcare Research and Quality (AHRQ) commissioned an evidence report.³ The question of interest is whether increasing the intake of omega-3 fatty acids from foods or supplements can prevent or treat chronic diseases, particularly atherosclerotic cardiovascular disease.

The two principal dietary sources of omega-3 fatty acids are seafood and certain plant oils. Fish (particularly “fatty fish” such as tuna, salmon, and mackerel) and fish oils provide eicosapentaenoic acid (EPA) and doco-sahexaenoic acid (DHA). Some oils, such as canola, walnut, soybean, rapeseed, and flax-seed, are rich in alpha-linolenic acid (ALA). Omega-3 fatty acids are termed “essential” fatty acid, because they are required for normal development and function of the retina and brain. In humans, ALA is inefficiently converted to DHA and EPA.

Over the past several decades, research has fueled interest in omega-3 fatty acids. Initial reports were ecologic studies that documented low rates of ischemic heart disease in populations such as Greenland Inuits that consume large quantities of fatty fish. Subsequently, results of longitudinal, observational studies found an inverse association between consumption of fish or fish oil and ischemic heart disease.

In other studies,³ fish oil suppressed arrhythmias, stabilized atherosclerotic plaque, reducedinflammation, improved endothelial function, lowered triglyceride concentrations, and reduced blood pressure. Hence, there is a reasonably strong biologic basis to believe that an increased intake of omega-3 fatty acids could be cardioprotective.

The most persuasive evidence of cardioprotection comes from randomized trials with clinical cardiovascular outcomes.⁴ To date, more than 10 such trials of the use of omega-3 fatty acids have been conducted in patients with previous cardiovascular disease, but only one trial was conducted in persons without preexisting cardiovascular disease. Many of the trials, including the only primary prevention trial, had a small sample size and, accordingly, were underpowered.

The most salient of the available trials are the Diet and Reinfarction Trial (DART)⁵ and the GISSI Prevenzione trial.⁶ In DART, which enrolled 2,033 men with a previous myocardial infarction, those who received advice to increase their intake of fatty fish had a 29 percent reduced risk of total mortality over two years. However, during a follow-up study of DART participants, the early reduction in risk observed in those assigned to the fish advice group was followed by increased risk over the course of the next three to nine years.⁷

The GISSI trial tested the effects of two types of supplements (omega-3 fatty acid and vitamin E), taken alone or in combination, in 11,324 patients with a previous myocardial infarction. Over the course of three and one-half years, the groups assigned to take an omega-3 fatty acid supplement experienced a nearly 15 percent reduced risk of the primary trial outcome (death, nonfatal myocardial infarction, or stroke), while vitamin E had no effect. Interestingly, the benefit occurred rapidly, within three months of randomization⁸ ; these findings support the hypothesis that the beneficial effects of omega-3 fatty acids result, at least in part, from their antiarrhythmic or antithrombotic properties.

Although the evidence from prospective observational studies and clinical trials led the American Heart Association to issue dietary recommendations for the consumption of fish and omega-3 fatty acids,² it is well recognized that the research data supporting a cardioprotective effect of fish and omega-3 fatty acids is not nearly as robust as the evidence supporting other therapies.

Those familiar with the vitamin E and beta-carotene “sagas” would be hesitant to make firm recommendations for the use of omega-3 supplements without strong and consistent evidence from randomized trials. After a flurry of observational studies documenting an impressive inverse association between the use of vitamin E supplements and ischemic heart disease, large-scale trials showed striking null results.⁶ Trials of beta-carotene documented that supplementation increased, rather than decreased, the risk of lung cancer.⁹

Other concerns pertain to the supply of omega-3 fatty acid supplements, which may be inadequate in the setting of widespread consumption, and the quality of supplements, which is not standardized. While I doubt that moderate consumption of omega-3 fatty acids will prove to be harmful, we need evidence of benefit before we routinely recommend omega-3 fatty acid supplements to the general population. Clinical trials most likely will be initiated but, given the time required to design and conduct such trials, near-term answers are unlikely. In the interim, the American Heart Association guidelines² remain prudent policy.