Mortality in randomized trials of antioxidant supplements for primary and secondary prevention: systematic review and meta-analysis.


Cochrane review of 68 randomized trials. Vitamin A supplementation (20,000 IU) showed an average of 16% increase mortality risk. Beta carotene increased mortality risk by 7% (mean 3 years). No significant increased or decreased mortality from Vitamin C and selenium

TitleMortality in randomized trials of antioxidant supplements for primary and secondary prevention: systematic review and meta-analysis.
Publication TypeJournal Article
Year of Publication2007
AuthorsBjelakovic G, Nikolova D, Gluud LL, Simonetti RG, Gluud C
JournalJAMA : the journal of the American Medical Association
Date Published2007 Feb 28
KeywordsAdult, Antioxidants, Ascorbic Acid, beta Carotene, Dietary Supplements, Humans, Randomized Controlled Trials as Topic, Selenium, Vitamin A, Vitamin E

CONTEXT: Antioxidant supplements are used for prevention of several diseases.

OBJECTIVE: To assess the effect of antioxidant supplements on mortality in randomized primary and secondary prevention trials. DATA SOURCES AND TRIAL SELECTION: We searched electronic databases and bibliographies published by October 2005. All randomized trials involving adults comparing beta carotene, vitamin A, vitamin C (ascorbic acid), vitamin E, and selenium either singly or combined vs placebo or vs no intervention were included in our analysis. Randomization, blinding, and follow-up were considered markers of bias in the included trials. The effect of antioxidant supplements on all-cause mortality was analyzed with random-effects meta-analyses and reported as relative risk (RR) with 95% confidence intervals (CIs). Meta-regression was used to assess the effect of covariates across the trials.

DATA EXTRACTION: We included 68 randomized trials with 232 606 participants (385 publications).

DATA SYNTHESIS: When all low- and high-bias risk trials of antioxidant supplements were pooled together there was no significant effect on mortality (RR, 1.02; 95% CI, 0.98-1.06). Multivariate meta-regression analyses showed that low-bias risk trials (RR, 1.16; 95% CI, 1.04[corrected]-1.29) and selenium (RR, 0.998; 95% CI, 0.997-0.9995) were significantly associated with mortality. In 47 low-bias trials with 180 938 participants, the antioxidant supplements significantly increased mortality (RR, 1.05; 95% CI, 1.02-1.08). In low-bias risk trials, after exclusion of selenium trials, beta carotene (RR, 1.07; 95% CI, 1.02-1.11), vitamin A (RR, 1.16; 95% CI, 1.10-1.24), and vitamin E (RR, 1.04; 95% CI, 1.01-1.07), singly or combined, significantly increased mortality. Vitamin C and selenium had no significant effect on mortality.

CONCLUSIONS: Treatment with beta carotene, vitamin A, and vitamin E may increase mortality. The potential roles of vitamin C and selenium on mortality need further study.

Alternate JournalJAMA
PubMed ID17327526
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