Update on the omega-3 fatty acid trial landscape: A narrative review with implications for primary prevention.

Residual risk mediated by hypertriglyceridemia among statin-treated individuals is an important clinical and public health challenge. Niacin, fibrates and omega-3 FA are three classes of non-statin agents with demonstrated TG-lowering effects. Randomized controlled trials of niacin and fibrates have been consistently negative, but the trial landscape for two key sources of omega-3 FAs, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) is more complex. Clinical trials evaluating omega-3 FA can be differentiated into those that studied mixed formulations (EPA + DHA) and those that studied EPA alone. Those assessing the impact of mixed formulations have not consistently demonstrated CVD risk reduction, whereas trials of EPA alone have been successful. Two recent trials of mixed formulations - STRENGTH (Long-Term Outcomes Study to Assess Statin Residual Risk with Epanova in High Cardiovascular Risk Patients with Hypertriglyceridemia) and OMEMI (Omega-3 fatty acids in Elderly patients with Myocardial Infarction) - studied contemporarily treated patients with mixed EPA + DHA formulations at higher doses than before and showed no benefit, thus adding valuable information to our overall understanding of this evolving therapeutic class. In this review, we contextualize the findings of STRENGTH and OMEMI within the existing omega-3 FA clinical trial landscape and look ahead to how future trials can inform existing knowledge gaps, particularly with regards to the applicability of these agents within the primary prevention realm.