Randomized Trial for Evaluation in Secondary Prevention Efficacy of Combination Therapy-Statin and Eicosapentaenoic Acid (RESPECT-EPA)

RESPECT-EPA enrolled Japanese patients with coronary artery disease, low EPA/arachidonic acid (AA) ratio, and statin therapy — asking whether adding icosapent ethyl (pure EPA) reduced cardiovascular events in a targeted population selected for EPA deficiency.

The primary endpoint — a composite of cardiovascular events — was numerically lower in the EPA group (9.1% vs 12.6%, HR 0.79, p=0.055), falling just short of statistical significance. A prespecified secondary coronary endpoint achieved significance (6.6% vs 9.7%, HR 0.73, p<0.05). The EPA/AA ratio at baseline was very low in the enrolled population, enriching for patients most likely to benefit.

The trial’s near-miss on its primary endpoint complicates interpretation. In the context of REDUCE-IT (which found significant benefit) and STRENGTH (which found no benefit with EPA+DHA), RESPECT-EPA’s result is consistent with icosapent ethyl having a genuine but modest coronary benefit that REDUCE-IT was powered to detect and RESPECT-EPA was not quite. The biomarker-selected design is a methodologically interesting approach to precision medicine in this area.

We rate the evidence moderate. A well-designed RCT in a biomarker-selected population that produced directionally consistent but statistically inconclusive results — adding nuance to the EPA outcomes literature without definitively resolving it.