Marine n−3 Fatty Acids and Prevention of Cardiovascular Disease: A Novel Analysis of the VITAL Trial Using Win Ratio and Hierarchical Composite Outcomes

Abstract

This study aimed to investigate whether n−3 fatty acid supplementation reduced cardiovascular disease (CVD) events in a novel analysis using hierarchical composite CVD outcomes based on win ratio in the VITamin D and OmegA-3 TriaL (VITAL). This was a secondary analysis of our VITAL randomized trial, which assessed the effects of marine n−3 fatty acids (1 g/day) and vitamin D3 on incident CVD and cancer among healthy older adults (n = 25,871). The primary analysis estimated win ratios of a composite of major CVD outcomes prioritized as fatal coronary heart disease, other fatal CVD including stroke, non-fatal myocardial infarction (MI), and non-fatal stroke, comparing n−3 fatty acids to placebo. The primary result was a nonsignificant benefit of this supplementation for the prioritized primary CVD outcome (reciprocal win ratio [95% confidence interval]: 0.90 [0.78–1.04]), similar to the 0.92 (0.80–1.06) hazard ratio in our original time-to-first event analysis without outcome prioritization. Its benefits came from reducing MI (0.71 [0.57–0.88]) but not stroke (1.01 [0.80 to 1.28]) components. For the primary CVD outcome, participants with low fish consumption at baseline benefited (0.79 [0.65–0.96]) more than those with high consumption (1.05 [0.85–1.30]). These results are consistent with, but slightly stronger than, those without outcome prioritization.