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Objectives-For many years, the prevailing concept was that LDL oxidation plays a central role in atherogenesis. As a consequence, supplementation of antioxidants, particularly vitamin E, became very popular. Unfortunately, however, the major randomized clinical trials have yielded disappointing results on the effects of vitamin E on both mortality and morbidity. Moreover, recent meta-analyses have concluded that vitamin E supplementation increases mortality. This conclusion has raised much criticism, most of it relating to three issues: (1) the choice of clinical trials to be included in the meta-analyses; (2) the end point of these meta-analyses (only mortality); and (3) the heterogeneity of the analyzed clinical trials with respect to both population and treatment. Our goal was to bring this controversy to an end by using a Markov-model approach, which is free of most of the limitations involved in using meta-analyses. Methods and Results-We used a Markov model to compare the vitamin E supplemented virtual cohorts with nonsupplemented cohorts derived from published randomized clinical trials that were included in at least one of the major meta-analyses. The difference between the virtual supplemented and nonsupplemented cohorts is given in terms of a composite end point denoted quality-adjusted life year (QALY). The vitamin E supplemented virtual cohort had 0.30 QALY (95%CI 0.21 to 0.39) less than the nontreated virtual cohort. Conclusions-Our study demonstrates that in terms of QALY, indiscriminate supplementation of high doses of vitamin Eis not beneficial in preventing CVD. O n the basis of many lines of indirect evidence, for many years the view of LDL peroxidation playing a central role in atherogenesis was the generally accepted one. 1 Hence, antioxidants in general and vitamin E in particular became widely used, with the aim of reducing the morbidity and mortality associated with cardiovascular disease (CVD). 2 Furthermore, several observational studies indicated that antioxidant supplementation is associated with a relatively low incidence of CVD, 3 which also promoted the popularity of vitamin E supplementation.Unfortunately, as shown in supplemental Table I (available online at http://atvb.ahajournals.org), the results of many large prospective randomized trials were disappointing, showing no justification for high dose vitamin E supplementation either to the general public or to CVD patients. The only indications of any benefit of vitamin E supplementation were in studies of specific groups of individuals in which the rate of nonfatal MI decreased on supplementation of vitamin E, such as male smokers (the Alpha-Tocopherol Beta-Carotene study -ATBC Study), 4 and patients with prevalent atherosclerosis (Cambridge Heart Antioxidant study -CHAOS). 5 Furthermore, Boaz et al showed a 50% reduction in the rate of nonfatal MI in patients undergoing hemodialysis, 6 and a similar trend was apparent in women over 65 in the Women's Health Study (WHS). 7 A significant reduction in intimamedia thickness was ...

For many years, the prevailing concept was that LDL oxidation plays the central role in atherogenesis. As a consequence, supplementation of antioxidants, particularly vitamin E, became very popular. Unfortunately, major randomized clinical trials yielded disappointing results and recent meta-analyses concluded that indiscriminate, high dose vitamin E supplementation results in increased mortality. This conclusion raised (quite reasonable) criticism, much of which referred to the characteristics of meta-analysis. In our recent study, we used a Markov-model approach, which is free of most of the limitations of meta-analyses. Our major finding was that the average quality-adjusted life years (QALY) of vitamin E- supplemented individuals was 0.30 QALY (95%CI 0.21 to 0.39) less than that of untreated people. In our view, this supports the view that indiscriminate supplementation of high dose vitamin E can not be recommended to the general public.In the present communication we address several recent studies that demonstrated negative effects of vitamin E and raise possible mechanisms that may be responsible for the harmful effects of vitamin E supplementation. We also review recent studies conducted with specific groups of patients that gained from vitamin E supplementation, indicating that although, on the average, indiscriminate supplementation of high dose vitamin E is not beneficial, specific populations may gain from vitamin E. The challenge is to establish selection criteria that will predict who is likely to benefit from vitamin E supplementation. Such criteria may be based either on the assumption that antioxidants are likely to be beneficial for people under oxidative stress or on knowledge regarding the benefit of sick people with certain diseases. In short, we adopt the view that vitamin E is a "double-edge sword" that should not be consumed until criteria are defined to predict who is likely to benefit from high dose supplementation of vitamin E.

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