Cochrane Abstract

Background: Animal and physiologic research, as well as observational studies, suggest that antioxidant supplements may Improve survival.

Objectives: To assess the effect of antioxidant supplements on mortality in primary or secondary prevention randomized clinical trials.

Search Strategy: The authors searched The Cochrane Library (Issue 3, 2005), Medline (1966 to October 2005), EMBASE (1985 to October 2005), and the Science Citation Index Expanded (1945 to October 2005). They scanned bibliographies of relevant publications and wrote to pharmaceutical companies for additional trials.

Selection Criteria: The authors included all primary and secondary prevention randomized clinical trials on antioxidant supplements (beta-carotene, vitamins A, C, and E, and selenium) versus placebo or no intervention. Included participants were healthy (primary prevention trials) or had any disease (secondary prevention trials).

Data Collection and Analysis: Three authors extracted data. Trials with adequate randomization, blinding, and follow-up were classified as having a low risk of bias. Random-effects and fixed-effect meta-analyses were performed. Random-effects meta-regression analyses were performed to assess sources of intertrial heterogeneity.

Main Results: Included were 67 randomized trials with 232,550 participants. Forty-seven trials including 180,938 participants had a low risk of bias. Twenty-one trials included 164,439 healthy participants. Forty-six trials included 68,111 participants with various diseases (gastrointestinal, cardiovascular, neurologic, ocular, dermatologic, rheumatoid, renal, endocrinologic, or unspecified). Overall, the antioxidant supplements had no significant effect on mortality in a random-effects meta-analysis (relative risk [RR] = 1.02; 95% confidence interval [CI], 0.99 to 1.06), but significantly increased mortality in a fixed-effect model (RR = 1.04; 95% CI, 1.02 to 1.06).

In meta-regression analysis, the risk of bias and type of antioxidant supplement were the only significant predictors of intertrial heterogeneity. In the trials with a low risk of bias, the antioxidant supplements significantly increased mortality (RR = 1.05; 95% CI, 1.02 to 1.08). When the different antioxidants were assessed separately, analyses including trials with a low risk of bias and excluding selenium trials found significantly increased mortality with vitamin A (RR = 1.16; 95% CI, 1.10 to 1.24), beta-carotene (RR = 1.07; 95% CI, 1.02 to 1.11), and vitamin E (RR = 1.04; 95% CI, 1.01 to 1.07) supplementation, but no significant detrimental effect with vitamin C (RR = 1.06; 95% CI, 0.94 to 1.20). Low-bias risk trials on selenium found no significant effect on mortality (RR = 0.91; 95% CI, 0.76 to 1.09).

Authors' Conclusions: The authors found no evidence to support antioxidant supplements for primary or secondary prevention. Vitamins A and E, and beta-carotene may increase mortality. Future randomized trials could evaluate the potential effects of vitamin C and selenium for primary and secondary prevention. Such trials should be closely monitored for potential harmful effects. Anti-oxidant supplements need to be considered medicinal products and should undergo sufficient evaluation before marketing.