4. Discussion
stroke
CORONARY DISEASE, CVD, STROKE, SECONDARY, EVENTS, HEART
In the present secondary analysis of the n−3 supplementation arm of the VITAL trial, the present study used a novel win ratio method, which can adequately model the priority of individual components of composite outcomes in the RCT. Marine n−3 fatty acid supplementation of 1 g/day had suggestive but statistically nonsignificant benefits on the primary hierarchical composite major CVD outcome in the overall study population; however, n−3 fatty acid supplementation had significant benefits in the participants with lower dietary fish intake (<1.5 servings/week). The benefit of the n−3 fatty acid supplementation shown with the win ratio method is aligned to the primary findings of VITAL, which included 25,871 participants and had a median follow up of 5.3 years, demonstrating that the principal CVD benefits came from reducing the hierarchical composite CHD outcome, but not from reducing the hierarchical composite stroke outcome. Although our previous publication of the main results of the VITAL study did not consider the priority of the individual components of the composite outcome [Benefits of the marine n−3 fatty acid supplementation on CHD events were more apparent in VITAL participants with lower dietary intake of fish than those with higher intake, congruent with the main VITAL trial results [In the present analyses, the benefit of the n−3 fatty acid supplementation on CVD events was principally influenced by CHD events rather than stroke events; these results are similar to the main VITAL analyses and recent previous meta-analysis of RCTs [Our trial has several notable strengths, including representation of the general population encompassing diverse racial, ethnic, and geographic backgrounds. Additionally, the present study used the new statistical method, win ratio analyses considering priority of individual components of a composite outcome, which allowed us to handle composite outcomes more appropriately than conventional methods including Cox proportional hazard models. Furthermore, the VITAL study achieved high rates of participant follow up and adherence to the present questionnaires and the prescribed study pill regimen. The average response rate to the questionnaire was 93.1%, and participants in both the n−3 group and the placebo group reported an average adherence rate to the trial regimen (defined as taking at least two-thirds of the trial capsules) of 81.6% and 81.5%, respectively during the 5-year follow-up period. Throughout the follow up, personal use of fish-oil supplements from outside sources remained below 3.5% in each group.This trial had several limitations. The duration of the trial intervention, with a median of 5.3 years, could be considered moderate. Moreover, due to the utilization of a single dose level of n−3 fatty acids, the present study was unable to investigate potential dose–response relationships. Nonetheless, it is important to note that the dose employed in our trial aligns with the American Heart Association’s recommendation for cardio-protection in individuals with a history of coronary disease. This recommended dose is at least twice the dosage suggested for cardiovascular protection in healthy populations, which is equivalent to consuming 1 to 2 servings of fish per week. In addition, we performed the subgroup analyses based on the dietary fish intake at baseline. Although analyses based on the plasma n–3 index at baseline would also have been of great interest, measurement of the plasma n–3 index at baseline was limited to 60% of the 25,871 participants, resulting in greatly reduced statistical power. Thus, we decided a priori to stratify the participants based on dietary fish intake at baseline.