In 25,871 US adults followed a median 5.3 years, 1 g/day of marine omega-3 fatty acids missed its primary endpoint: major cardiovascular events fell a non-significant 8% (HR 0.92, 0.80-1.06). Yet total myocardial infarction dropped 28% (HR 0.72), fatal MI 50%, percutaneous coronary intervention 22%, and recurrent heart failure hospitalization 14%. Cancer incidence, atrial fibrillation, and all-cause mortality were unchanged; autoimmune disease fell 18% (HR 0.82). Benefits clustered in Black participants and in people with low fish intake.
The pattern is more nuanced than the headline null result implies. A trial that misses its primary endpoint but shows a strong signal in a prespecified secondary outcome deserves caution: multiple comparisons inflate false positives, and several confidence intervals sit close to 1.0 (the heart failure and autoimmune results barely clear it). The coronary signal does echo REDUCE-IT and JELIS, which used much higher or purified EPA doses, yet ASCEND and STRENGTH were neutral, so the literature remains split. The subgroup findings, including greater benefit with low baseline fish intake, are biologically sensible but hypothesis-generating, and sex differences were inconsistent. The absence of an AF signal at 1 g/day is reassuring, since higher doses have raised AF risk in other trials. For adults who eat fish twice weekly, supplements add little. For those who rarely eat fish and carry cardiovascular risk factors, discussing omega-3s with a clinician is reasonable, though dietary fish remains the better first step. Confirmatory rather than paradigm-shifting.