The results of two randomised, double-blind, placebo-controlled trials presented at the Annual Scientific Sessions of the American Heart Association (AHA) on 15 November have failed to demonstrate any benefit of omega-3 fatty acid (FA) administration in terms of reduced risk of cardiovascular (CV) events. The findings have re-ignited debate surrounding the controversial role of omega-3 FA administration in preventing CV events in at-risk patients. A wide variety of trials have investigated this subject over several decades, with studies often producing conflicting findings. These latest data further undermine confidence in this therapeutic approach, which may impede growth of the omega-3 FA market.

The STRENGTH trial compared the effects of daily administration of Epanova (omega-3-carboxylic acids) with a corn oil placebo. The trial enrolled over 13,000 statin-treated patients who had, or were at high risk for, CV disease. The study’s primary efficacy endpoint—time to occurrence of first CV event—was not met, with no significant differences observed between the Epanova and placebo groups. Further analysis also revealed that there were no significant differences in any of the individual components of the composite endpoint—CV death, myocardial infarction (MI), stroke, coronary revascularisation, and hospitalisation for unstable angina. Consequently, in January 2020, the trial was terminated on the grounds of futility.

The second trial, OMEMI, investigated the effects of omega-3 FA administration in elderly patients (ages 70–82 years) who had recently experienced an MI. Patients received daily treatment with either omega-3 FAs or a corn oil placebo, which were administered as add-on therapies to standard-of-care secondary prevention therapies. Subsequent CV events were recorded during two years of follow-up. In line with the findings of the STRENGTH trial, there were no significant differences in CV events between the treatment groups for the composite primary endpoint (non-fatal MI, unscheduled revascularisation, stroke, hospitalisation for heart failure or all-cause mortality), nor for the individual components of this endpoint.

Additionally, both the STRENGTH and OMEMI trials identified an increased risk of atrial fibrillation in omega-3 FA-treated patients relative to placebo-treated patients (although the difference was not significant in the OMEMI trial). Therefore, these data clearly do not support omega-3 FA administration in these CV patient populations, owing to a high risk-benefit ratio.

For many, these findings will be somewhat surprising. In particular, the data contradict the findings of the recent REDUCE-IT trial, which reported a significant risk reduction in CV events among omega-3 FA-treated patients relative to placebo. Consequently, in December 2019, the study drug, Amarin’s Vascepa (icosapent ethyl), received FDA approval, as an add-on to maximally tolerated statin therapy, for the prevention of CV events in at-risk patients with hypertriglyceridemia. GlobalData estimates that there were 78,697,905 prevalent cases of this condition in the US in 2019.

However, it is possible that the discrepancy between the findings of the trials partially reflect the omega-3 FA preparation administered. Vascepa is a pure eicosapentaenoic acid (EPA) preparation, whereas the STRENGTH and OMEMI trials used combined EPA/docosahexaenoic acid (DHA) combinations. DHA has been proposed to be less biologically active than EPA and may therefore neutralise some of the more favorable effects of EPA. Furthermore, the REDUCE-IT trial used a mineral oil placebo, rather than a corn oil placebo, as used in the STRENGTH and OMEMI trials. According to Dr Michael Lincoff, the lead author of the STRENGTH study, mineral oil likely represents a negative control as it has been associated with adverse effects on lipids and inflammatory markers such as high-sensitivity C-reactive protein (hsCRP). The usage of mineral oil as a placebo in the REDUCE-IT trial may have led to deleterious cardiac effects in this group, therefore exaggerating the efficacy effects observed in the Vascepa group.

Despite the important insights offered by the findings of the STRENGTH and OMEMI trials, there is still a lack of clarity in this area, which is unlikely to be resolved without further research. In particular, a head-to-head trial of Epanova versus Vascepa, using corn oil as a placebo comparator, may help to elucidate some of these contradictions.