By Michael H. Crawford, MD

Professor of Medicine, Chief of Clinical Cardiology, University of California, San Francisco

Dr. Crawford reports no financial relationships relevant to this field of study.

SYNOPSIS: A meta-analysis of 10 randomized, controlled trials of omega-3 fatty acids for the prevention of coronary heart disease and major vascular events showed no significant effect on fatal and nonfatal coronary heart disease or any major vascular event. These results do not support the use of omega-3 fatty acids supplements in patients with prior coronary heart disease.

SOURCE: Aung T, Halsey J, Kromhout D, et al. Associations of omega-3 fatty acid supplement use with cardiovascular disease risks: Meta-analysis of 10 trials involving 77,917 individuals. JAMA Cardiol 2018;3:225-233.

The authors of observational population studies have reported that increased fish or omega-3 fatty acid (FA) consumption reduces the risk of dying from coronary heart disease (CHD). However, studies in patients with CHD or at high risk for it have shown mixed results.

Thus, the omega-3 treatment trialists collaboration performed a meta-analysis of 10 randomized, controlled trials of omega-3 FA supplements for the prevention of cardiovascular disease. The primary endpoints were fatal CHD, nonfatal myocardial infarction (MI), stroke, major vascular events, and all-cause mortality in prespecified subgroups. Data were obtained directly from the principal investigator in nine of the 10 trials. The prespecified subgroups included age, sex, prior CHD, prior stroke, diabetes, blood lipids, statin use, and trial design (blinded or open-label). A total of 77,917 individuals participated in the 10 trials. Eight trials were blinded and two were open-label. Men comprised 61% of the participants and the mean age was 64 years. Two-thirds reported a prior history of CHD, 28% experienced a prior stroke, and 37% were diabetic. Major vascular events occurred in 16% (3% MI, 3% CHD deaths, 2% stroke, 8% revascularization).

Randomization to omega-3 FA supplementation resulted in no significant associations with CHD death (relative risk [RR], 0.93; 95% confidence interval [CI], 0.83-1.03; P = 0.05), nonfatal MI (RR, 0.97; 95% CI, 0.87-1.08; P = 0.43), any CHD event (RR, 0.96; 95% CI, 0.90-1.01; P = 0.12), or major vascular events (RR, 0.97; 95% CI, 0.93-1.01; P = 0.10) in any subgroups. Also, there was no effect noted on all-cause mortality (RR, 0.96; 95% CI, 0.92-1.01; P = 0.16). The authors concluded that this meta-analysis of 10 randomized, controlled trials of omega-3 FA treatment fails to support the use of these supplements in patients with CHD.

COMMENTARY

Although a properly designed and powered randomized, controlled trial is preferable, a well-conducted meta-analysis of smaller randomized, controlled trials generally is better than observational studies. Given the tremendous public interest in omega-3 FA, this meta-analysis of 10 randomized, controlled trials is of interest. This analysis featured several strengths. First, in all but one trial, study level data were obtained from the principal investigator. For the one exception, the published data were detailed enough for inclusion, and when this study was eliminated the results did not change. Second, Aung et al excluded studies in which the intervention was dietary advice or fish consumption. Third, the authors excluded trials with < 500 participants and with less than one year of follow-up. The mean follow-up for the 10 trials chosen was 4.4 years. Finally, these investigators evaluated prespecified subgroups of clinical importance such as diabetics, statin use, various lipid levels, and prior cardiovascular diseases. All but one trial used a combination of omega-3 FA with doses up to 1,800 mg/day for each ingredient. These doses are not high enough to reliably decrease triglycerides, but there are trials underway to evaluate this. One weakness of this analysis is that there were not prespecified subgroups for smoking and cancer history. However, there was no adverse cancer signal observed. Generally, the trials were markedly consistent. There was some weak heterogeneity in three subgroups. No history of prior stroke favored therapy, as did age > 65 years and an open-label study design. Hopefully, these nuances will be addressed in larger randomized, controlled trials underway. At this time, the European Society of Cardiology does not recommend omega-3 FA supplementation (2016), but the American Heart Association (AHA) does for those with prior CHD or heart failure with reduced left ventricular function (2017). This meta-analysis does not support the AHA recommendation.