We agree with Dr Simon that our study suggests a different result when we analyze the data according to CVD risk status. Specifically, among those without major CVD risk factors, there appears to be a 28% to 41% reduction in total CVD and CHD mortality. This association appears strongest for those taking both vitamin E and C. However, this exposure group is small, and thus confidence bounds are wide. We also found this result intriguing. The subgroup without major CVD risk factors represented 56% of the study population but contributed only 25% of the cardiovascular mortality. As is the case with all subgroup analyses, it remains possible that the finding in this subgroup was due to chance, so we believed that a cautious interpretation of the results was warranted. However, this subgroup analysis was stimulated by the conflicting data from large-scale trials and observational studies. Completed large-scale trials have been among those with CVD or at high risk and have been generally negative. In contrast, many observational studies among those at usual or low risk of CVD suggest a benefit of these vitamins. These findings from our study as well as the conflicting data from trials and observational studies raise the possibility that vitamins E and C are most effective in the earliest stages of atherosclerosis. This underscores the need to complete ongoing trials of vitamins E and C among those at low and usual risk. Three such trials, 2 in the United States (Physicians' Health Study II and Women's Health Study) and 1 in France (Supplementation with Antioxidant Vitamins and Minerals [SU.VI.M.AX]), are testing these agents in low- or usual-risk men and women.
Gaziano JM, Muntwyler J. Combined Vitamin E and Vitamin C Supplement Use and Risk of Cardiovascular Disease Mortality—Reply. Arch Intern Med. 2002;162(22):2630. doi: