What’s Going on with Fish Oil and Heart Disease?

By Alan R. Gaby, MD

The omega-3 fatty acids present in fish oil (eicosapentaenoic acid [EPA] and docosahexaenoic acid [DHA]) have many effects that might be useful for preventing and treating cardiovascular disease. One or both of these fatty acids can lower triglyceride levels, inhibit platelet aggregation, decrease blood pressure and blood viscosity, exert an anti-inflammatory and an antiarrhythmic effect, and improve endothelial function.¹

Most of the early randomized controlled trials on fish oil and heart disease produced positive results, which led to the consensus opinion that eating fatty fish or supplementing with fish oil is worthwhile for both primary and secondary prevention of cardiovascular disease. However, more recent clinical trials have been mostly negative, leading many investigators to question the value of fish oil. It could be argued that these negative results were due in part to the more widespread use of statin drugs since the mid-1990s. A subgroup analysis of a secondary prevention trial suggested that omega-3 fatty acids are less effective in people using statin drugs than in those not using these medications.² That suggestion is biologically plausible, since statins and omega-3 fatty acids work in part by a similar mechanism (an anti-inflammatory effect). In addition, because fish oil inhibits platelet aggregation, it is possible that more widespread use of antiplatelet drugs in recent years has blunted the beneficial effect of fish oil.

Three large-scale clinical trials recently published in the New England Journal of Medicine have provided additional data regarding the effectiveness of omega-3 fatty acids. Unfortunately, even though each of these trials enrolled many thousands of participants, none of them were able to provide definitive evidence.

The VITAL Trial

In the Vitamin D and Omega-3 Trial (VITAL) 25,871 men and women (mean age, 67 years) in the United States who did not have cardiovascular disease at baseline were randomly assigned to receive, in double-blind fashion, 2,000 IU per day of vitamin D, 1 g per day of fish oil (Omacor; providing daily 460 mg of EPA and 380 mg of DHA), both treatments, or placebo (olive oil) for a median duration of 5.3 years. This article reported the results of the omega-3 fatty acid arm of the study.³ The primary endpoint was major cardiovascular events (a composite of myocardial infarction, stroke, or death from cardiovascular causes). The incidence of the primary endpoint was nonsignificantly lower by 8% in the omega-3 group than in the placebo group (p = 0.24).

The ASCEND Trial

In the ASCEND trial (A Study of Cardiovascular Events in Diabetes), 15,480 patients over age 40 (mean age, 63 years) with type 1 or type 2 diabetes who had no evidence of atherosclerotic cardiovascular were randomly assigned to receive omega-3 fatty acids (460 mg per day of EPA and 380 mg per day of DHA) or placebo (1 g per day of olive oil). During a mean follow-up period of 7.4 years, compared with placebo, omega-3 fatty acids nonsignificantly decreased the incidence of a serious vascular event (nonfatal myocardial infarction or stroke, transient ischemic attack, or vascular death excluding intracranial hemorrhage) by 3%, and nonsignificantly decreased all-cause mortality by 5%.⁴

The REDUCE-IT Trial

The Reduction of Cardiovascular Events with Icosapent Ethyl-Intervention Trial (REDUCE-IT) enrolled 8,179 patients (median age, 64 years) with cardiovascular disease or with diabetes and other cardiovascular disease risk factors, who had been receiving statin therapy and who had a fasting triglyceride level of 135-499 mg/dl and an LDL-cholesterol level of 41-100 mg/dl. The patients were randomly assigned to receive, in double-blind fashion, an ethyl ester of EPA (icosapent ethyl) at a dose of 2 g twice a day with food or placebo (mineral oil) for a median duration of 4.9 years. The primary endpoint was a composite of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, coronary revascularization, or unstable angina. The proportion of patients who had a primary endpoint event was significantly lower by 25% in the icosapent ethyl group than in the placebo group (p < 0.001).

Making Sense of the New Studies

The authors of the VITAL and ASCEND trials concluded that omega-3 fatty acids did not decrease the incidence of serious cardiovascular events. In contrast, the authors of the REDUCE-IT trial concluded that a relatively large dose of a highly purified EPA ethyl ester substantially decreased serious cardiovascular events in a specific type of patient (i.e., individuals with cardiovascular disease or with diabetes and other cardiovascular disease risk factors who had hypertriglyceridemia despite receiving statin therapy). However, each of these conclusions should be interpreted with caution. In both the VITAL and ASCEND trials, omega-3 fatty acids decreased the incidence of various endpoints by 3-8% compared with placebo. While these decreases were not statistically significant, the results were consistent with previous studies that demonstrated a modest benefit. In addition, in both of these studies, the “placebo” was olive oil, which has been shown to help prevent cardiovascular disease. The dosage of olive oil was only 1 g per day, so the effect was likely very small. Nevertheless, the use of an active placebo may have made omega-3 fatty acids appear slightly less effective than they actually were.

The mineral oil “placebo” in the REDUCE-IT trial, on the other hand, may have had adverse effects, and thereby made the active treatment appear to be more effective than it really was. Treatment with mineral oil was associated with an increase in the median concentration of LDL cholesterol (p < 0.001 compared with the change in the icosapent ethyl group), an increase in the median C-reactive protein concentration (p < 0.001 compared with baseline and compared with the change in the icosapent ethyl group), and an increase in the incidence of anemia (p = 0.03 compared with icosapent ethyl). Based on what is currently known about the biochemical actions of mineral oil and EPA (for example, mineral oil inhibits the absorption of fat-soluble vitamins), each of these findings was more likely due to an adverse effect of mineral oil than to a beneficial effect of icosapent ethyl.

As an aside, the $300 million REDUCE-IT trial was funded by Amarin Pharma, which hopes to make billions of dollars by persuading doctors to prescribe its $10-a-day drug, Vascepa (icosapent ethyl). Cardiologists were initially excited about what appeared to be impressive results in the REDUCE-IT trial, but when they discovered that the placebo was potentially harmful their enthusiasm for prescribing Vascepa waned considerably.

Conclusion

There have been many randomized controlled trials on the use of EPA or EPA+DHA in patients who had or were at risk of developing cardiovascular disease. While the results have been conflicting, they are consistent with a modest benefit from taking fish oil or the omega-3 fatty acids present in fish oil. Cardiovascular disease is a complex, multifactorial disease, of which nutrition is only one of many components. Furthermore, omega-3 fatty acids are only one of many dietary factors and nutrients that play a role in the prevention and treatment of heart disease. Eating fish or taking omega-3 capsules is not the “magic bullet” answer to heart disease. But we should not ignore the evidence that omega-3 fatty acids can provide a modest benefit. These fatty acids should be viewed as just one component of a comprehensive program that includes diet, exercise, micronutrient supplementation, stress reduction, and avoidance of toxic exposures.