Clinical trials and a meta-analysis of the effects of vitamins.

Bleys et al (1) recently published a meta-analysis of randomized controlled trials concerning the possible role of antioxidants and B vitamins in the prevention of the progression of atherosclerosis, as measured by any one of several imaging techniques. This study discusses some of the unresolved issues related to this topic. The corresponding editorial by McCormick (2) is substantially tangential to the evidence and discussion by Bleys et al, and it raises significant issues about the accuracy of his assumptions and their relevance to the meta-analysis. Because of the small number of clinical trials available for inclusion in the meta-analysis, the statistical power to detect intervention effects was small and the outcomes were not significant. The characteristics of the subjects and the vitamin treatments differed considerably from one clinical trial to another. Because of the differences in design, the large heterogeneity of the outcomes was not surprising. For the antioxidant vitamins in trials with subjects with no percutaneous transluminal coronary angioplasty (no-PTCA), the pooled effect across all included clinical trials was 0.94 (P 0.44)—a highly nonsignificant result. Because the results of the individual clinical trials ranged from apparent benefit to apparent harm, a more meaningful identification and comparison of the experimental conditions (baseline characteristics, treatment and duration, follow-up duration, and the technology used to monitor) may be more useful in identifying the factors relevant to benefit, harm, or no effect. Certainly, the low power stemming from the inclusion of only 7 trials, together with the fact that some trials had positive outcomes and others had negative outcomes, makes the nonsignificant outcome of the meta-analysis a foregone conclusion. Furthermore, the present analysis failed to include or mention the findings of the Women’s Health Study (3)—the largest and longest primary prevention trial to have used vitamin E. That study showed that vitamin E supplementation significantly reduced cardiovascular deaths in women, especially older women. Therefore, the conclusion by Bleys et al of the lack of effect of antioxidants and B vitamins on clinical cardiovascular events is not an accurate reflection of the literature. For the B vitamins in no-PTCA clinical trials, the observed effects produced a mean of 0.93 (P 0.12). Because only 5 trials were included, the outcome was, not surprisingly, not significant. Even fewer post-PTCA trials were available for inclusion, and the power was so low that, although the composite treatment effects numerically suggest a benefit, the results were not significant. These points do not suggest that antioxidants or B vitamins benefit, harm, or have no effect on the progression of atherosclerosis. Instead, these points suggest that a meta-analysis is not a useful tool with extant data sets. In contrast, the authors state that their metaanalysis showed no evidence of protective effects of either antioxidants or B vitamins. Although this statement is literally true, it is seemingly misleading because it suggests that the conclusion has significant evidentiary support. Nonetheless, the editorial by McCormick not only endorses the authors’ conclusions but also expounds on the historical basis of the Recommended Dietary Allowances (RDA) as they have related to the classic deficiency diseases and criticizes the consideration of “optimal nutrition. ” McCormick fails to note that neural tube defects (NTDs) are not a classic folic acid deficiency disease (ie, the deficiency does not always lead to NTDs), yet the current RDA for folic acid for women of childbearing age is directly linked to the prevention of NTDs. All nutrition researchers, healthcare providers, and policy makers should recognize that, although there is strong epidemiologic evidence in support of a positive role of the antioxidant and B vitamins in reducing the risk of cardiovascular disease and cancer, the outcomes of clinical trials have generally not supported this finding. There are 2 possible explanations for this lack of support: no benefit has been shown or the clinical trials have not been properly designed or executed to detect the benefit, perhaps by starting too late after the sensitive phases of the diseases had passed. More research and better study designs are needed to address this issue, and misconstruing the data or prejudging the outcomes to disregard the benefits of antioxidants and B vitamins does a tremendous disservice.