In this primary prevention trial with a median follow-up of 5.3 years, supplementation with n−3 fatty acids at a dose of 1 g per day did not lead to a significantly lower incidence of the primary end points of major cardiovascular events (a composite of myocardial infarction, stroke, and death from cardiovascular causes) or invasive cancer than placebo. Analyses of the components of the primary composite cardiovascular end point suggested that the risk of myocardial infarction was lower in the n−3 group than in the placebo group and that there was no significant difference in the incidence of death from cardiovascular causes or stroke. Exploratory analyses that excluded the first 2 years of follow-up suggested a nonsignificantly higher incidence of cancer in the n−3 group than in the placebo group but not a higher incidence of death from cancer.

Meta-analyses of n−3 supplementation trials involving adults who had cardiovascular disease or who were at high risk for cardiovascular disease have shown that supplementation has no, or at most a weak, preventive effect on cardiovascular outcomes, including major cardiovascular events, major coronary events, myocardial infarction, stroke, and revascularization.14-16 The recent ASCEND (A Study of Cardiovascular Events in Diabetes) trial,17 which tested n−3 supplementation (at a dose of 1 g per day) in adults with diabetes in the United Kingdom, also showed generally null results. Thus, the possible benefit of the intervention with respect to the secondary end points of myocardial infarction and PCI in our trial, which tested n−3 fatty acids for primary prevention in a usual-risk population, raises the question of potential differences between results from primary and secondary prevention trials. Neither our trial nor the secondary prevention trials indicate a benefit of n−3 supplementation with respect to stroke or composite cardiovascular end points. Our finding of a possible lower incidence of the primary cardiovascular end point with n−3 supplementation than with placebo among participants with low fish consumption — a characteristic that has rarely been examined as an effect modifier in previous trials — is hypothesis-generating.

Two early, large, open-label trials that involved more than 10,000 participants6,18 and tested doses of 1 g or more of n−3 fatty acids per day showed significant protection against coronary events. However, all but one19 of the subsequent placebo-controlled trials17,19-24 (some with smaller sample sizes19-22 and lower doses20,22) did not. The finding of a lower risk of coronary events with n−3 fatty acids than with placebo in our trial may be attributable in part to these design differences. Also, the prevalence of the use of medications for cardiovascular disease, including statins, beta-blockers, and anticoagulants, was higher in recent trials than in our trial, perhaps reducing the opportunity to detect incremental benefit. Although a recent meta-analysis15 of n−3 trials showed no variation in results according to statin use, the dilution of a potential effect of n−3 supplementation by other medications cannot be ruled out. Such a dilution would probably be greater in the context of secondary prevention, in which medication use is more prevalent than in the context of primary prevention. In addition, participants in secondary prevention trials generally have more advanced atherosclerosis than those in primary prevention trials, which may necessitate the use of more powerful interventions than n−3 fatty acids (or higher doses of n−3 fatty acids) to avert clinical events. Indeed, a greater benefit of n−3 supplementation on major cardiovascular events was observed among participants without a history of stroke in a recent meta-analysis15 and among those without a history of cardiovascular disease in a trial involving patients with macular degeneration25 than among those with such histories. Differences in fish consumption across study populations may have also influenced findings. Finally, there were few black participants in the secondary prevention trials, and our trial suggests that there is a greater coronary benefit of supplemental n−3 fatty acids in this racial group than in others.

The finding in subgroup analyses of the secondary end point of myocardial infarction that suggested possible greater cardiovascular benefits of n−3 supplementation in blacks than in non-Hispanic whites was unexpected, especially given that both these racial and ethnic groups had similar blood levels of EPA and DHA at baseline and similar fish intake. It may be a chance finding that would require corroboration in future trials. Recent observational studies have shown racial variation in associations of both marine and plant-derived n−3 biomarkers with the incidence of coronary disease.26 Gene variants influence metabolism and the bioavailability of n−3 fatty acids, as has been observed in Greenland Inuits,27 and may influence coronary risk.28 Other racial and ethnic differences in clinical, dietary, or environmental factors may also account for this finding.29 Finally, blacks have a higher prevalence of coexisting conditions such as diabetes and hypertension than do non-Hispanic whites. However, treatment-associated hazard ratios for myocardial infarction were lower across cardiovascular-risk strata among blacks, with lower hazard ratios than among non-Hispanic whites (Table S3 in the Supplementary Appendix).

The hypothesis that supplemental n−3 fatty acids confer coronary protection is biologically plausible. Data from laboratory studies and from studies in animals, as well as from small trials of intermediate cardiovascular end points in humans, support mechanisms including antithrombotic, hypotriglyceridemic, blood-pressure–lowering, and antiinflammatory effects; impeded growth of atherosclerotic plaques; slowing of heart rate; reduced susceptibility to cardiac arrhythmias; and the promotion of nitric oxide–induced endothelial relaxation whereby n−3 fatty acids may reduce risk.1,8 Data from experimental studies provide support for relevant molecular and gene-regulatory effects.1 The dose–response curve for most effects plateaus at 1 g or less of n−3 fatty acids per day.30 Observational studies suggest significant inverse associations between fish intake or n−3 fatty acid biomarkers and coronary outcomes — findings that are compatible with these mechanisms.26,31-33

With regard to cancer, our findings are consistent with the results of secondary prevention trials of n−3 fatty acids for cardiovascular disease, which have mostly shown neutral effects or slight (but nonsignificant) elevations in cancer incidence with n−3 fatty acids.6,17,18,23,24,34,35 A 2014 meta-analysis of 10 trials of n−3 fatty acids showed a risk of cancer that was nonsignificantly higher, by 10%, with the n−3 fatty acids than with placebo (P=0.12).36 A 2018 meta-analysis of n−3 trials of cardiovascular disease15 also showed no significant association between supplementation and incidence of cancer but did not provide an effect estimate. Our finding of a more favorable effect regarding the incidence of cancer among women contrasts with the results of a European trial of n−3 fatty acids,34 which showed a higher risk of cancer with n−3 fatty acids than with placebo among women but not among men. Among three trials investigating cancer mortality, two have shown a neutral treatment effect on the rate of death from cancer17,19 and one has shown a possible benefit.35 The lack of a significant treatment effect of n−3 supplementation on all-cause mortality in the present trial is consistent with the results of meta-analyses of earlier trials14,16 and with the results of ASCEND.17

The strengths of our trial include a large general population sample with racial, ethnic group, and geographic diversity; high rates of follow-up and adherence to the pill regimen; high rates of obtaining blood samples; validated biomarkers of adherence to the regimen; dietary assessments; and rigorously adjudicated end points. Ancillary studies examining diabetes, atrial fibrillation, cognition, autoimmune disorders, and other outcomes in our trial are in progress and may inform the overall benefit–risk balance of n−3 supplementation.

Our trial also has certain limitations. The median duration of the trial intervention was 5.3 years. The single dose level of n−3 fatty acids that was used in this trial did not permit exploration of dose–response relationships. However, the dose that we used has been recommended by the American Heart Association for cardioprotection in persons with a history of coronary disease5,37 and is at least twice the dose that has been recommended for cardiovascular protection in healthy populations (equivalent to 1 to 2 servings of fish per week).31,37 The results of ongoing trials38,39 that are testing higher doses in high-risk populations will be informative but may not apply to primary prevention. Some of our subgroup analyses are based on small numbers of events.

In conclusion, supplementation with n−3 fatty acids did not result in a lower incidence than placebo of the primary end points of major cardiovascular events (a composite of myocardial infarction, stroke, or death from cardiovascular causes) and invasive cancer of any type.