Another Supplement for CAD Prevention Fails

Abstract & Commentary

By Michael H. Crawford, MD, Editor

Source: Risk and Prevention Study Collaborative Group. n-3 fatty acids in patients with multiple cardiovascular risk factors. N Engl J Med 2013;368: 1800-1808.

N-3 polyunsaturated fatty acids (n-3 FA) from fish have been reputed to prevent the development of cardiovascular disease (CVD) and have demonstrated some benefits in secondary prevention studies. Thus, this community-based investigator group in Italy conducted a double-blind, placebo-controlled trial of subjects with multiple risk factors for CVD (at least four, or one if diabetic) or evidence of atherosclerotic vascular disease, but without myocardial infarction (MI). Subjects were given 1 g of an n-3 FA capsule or an olive oil capsule (placebo) per day. Clinical status of the subjects was assessed yearly. The primary endpoint was the rate of death, MI, and stroke, but after low event rates were noted after 1 year, time to a CVD death and hospital admission for CVD were added. Over about 3 years, 12,513 subjects were enrolled. Almost half had diabetes and 20% had a history of vascular disease. After a median 5-year follow-up, it was noted that the CVD risk profile had improved in both groups. Drug therapy for risk factors increased over time, but to the same extent in both groups. Triglyceride levels fell more in the n-3 FA group (-28 vs -20 mg/dL, P < 0.001), but blood pressure, LDL cholesterol, and glucose were no different between groups. There was a slight increase in HDL cholesterol in the n-3 FA group. The primary endpoint was not different between the two groups (12% for both). At the study’s end, 18% of subjects were no longer taking n-3 FA and 19% had stopped the placebo, but only analyzing the compliant subjects did not affect the outcome. Also, none of the individual endpoints in the composite primary endpoint were significantly different. Of the secondary endpoints, only heart failure admissions were lower in the n-3 FA group (1.5% vs 2.3%, P = 0.04). The primary endpoint occurred less frequently in women and was significantly less in the n-3 FA group women (hazard ratio, 0.82; 95% confidence interval, 0.67-0.99; P = 0.04). Finally, the results were not related to fish consumption or risk-reducing medication differences. Reported adverse events were not different between the two groups. The authors concluded that in patients at high risk for CVD, n-3 FA did not reduce mortality or morbidity over a median follow-up of 5 years.


First vitamin C, then folic acid, then vitamin E, then multivitamins, then niacin, and now fish oil supplements — all proven to be largely worthless for the primary prevention of CVD. This leaves us with the Mediterranean diet, exercise, and moderate alcohol consumption to recommend for our patients who want to go natural. Unfortunately, patients generally want the magic pill, not the hard stuff like diet and exercise. Also, alcohol is hard to calculate because of the narrow therapeutic-to-toxic range and the many variables affecting gastrointestinal absorption rates, so now we have to tell our patients there is no easy way — a hard sell.

The investigators were surprised by the results because the GISSI post-MI and heart failure trials showed a benefit of n-3 FA with reduced morbidity and mortality. One possible reason this trial was negative was the low rate of events (12% for the combined endpoint). One reason for this may be that the major effect in the GISSI trials was on sudden death rates. Arrhythmias are much more common in post MI and heart failure patients (excluded in this trial) and n-3 FA may reduce arrhythmias. The positive secondary endpoints were probably due to chance and they do not recommend n-3 FA for women only. Some will argue that the dose was too low or the ratio of eicosapentaenoic acid to docosahexaenoic acid was wrong, but their dose and formulation avoided adverse effects and significantly lowered triglycerides. n-3 FA probably won’t hurt you and may be safer than pumping up your mercury levels with fish consumption, so I suspect many will keep at it despite this study.