Mortality after multivitamin supplementation: Nearly 35‐year follow‐up of the randomized Linxian Dysplasia Nutrition Intervention Trial

Background The objective of this study was to update the association between multivitamin supplementation and total or cause‐specific mortality in a population with a high prevalence of undernutrition in China. Methods The Linxian Dysplasia Nutrition Intervention Trial was a randomized, double‐blind, placebo‐controlled trial in which 3318 persons aged 40–69 years with esophageal squamous dysplasia were assigned to receive daily multivitamin supplementation or a placebo for 6 years and were followed for 29 years. The primary outcome was esophageal/gastric cardia cancer mortality. The data were analyzed with Cox proportional hazards regression models. Subgroup analyses were performed by common characteristics such as age and gender. Results The cumulative total mortality was 83.5%. Multivitamin supplementation did not affect total or cause‐specific mortality in the participants as a whole (hazard ratio [HR], 0.96; 95% confidence interval [CI], 0.89–1.03). Subgroup analyses showed that no association between multivitamin supplementation and all‐cause mortality was observed in men (HR, 0.90; 95% CI, 0.81–1.01), women (HR, 1.01; 95% CI, 0.91–1.12), younger participants (HR, 0.97; 95% CI, 0.87–1.08), or older participants (HR, 0.94; 95% CI, 0.85–1.04). Significant reductions in heart disease mortality (HR, 0.64; 95% CI, 0.47–0.87) and cerebrovascular disease mortality (HR, 0.74; 95% CI, 0.56–1.00) were seen in older men. In a subgroup of younger men and a subgroup of moderate or severe dysplasia, subjects receiving multivitamin supplementation had a lower risk of esophageal/cardia cancer mortality (HR for younger men, 0.76; 95% CI, 0.58–0.99; HR for moderate or severe dysplasia, 0.76; 95% CI, 0.58–1.00). No association between multivitamin supplementation and any cause‐specific mortality was observed in a mild dysplasia population. Conclusions Multivitamin supplementation in a population with esophageal squamous dysplasia was not associated with the risk of total mortality in the 35‐year follow‐up of this randomized controlled trial. In light of this and previous trials, multivitamin supplements should be used thoughtfully to improve health status of populations with esophageal squamous dysplasia. Lay summary Multivitamin supplementation is common, yet its effect on mortality is unclear. The aim of this study was to update the long‐term effects of multivitamin supplementation on total and cause‐specific mortality during nearly 35 years of follow‐up in the Linxian Dysplasia Nutrition Intervention Trial in China. Multivitamin supplementation in a population with esophageal squamous dysplasia was not associated with the risk of total mortality in the 35‐year follow‐up of this randomized controlled trial, and this indicates that multivitamin supplements should be used thoughtfully to improve health status.