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


METHODS
We included 68 randomized trials with 232 606 participants (385 publications).


RESULTS
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.
Bjelakovic
Goran
G
The Cochrane Hepato-Biliary Group, Copenhagen Trial Unit, Center for Clinical Intervention Research, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark. goranb@junis.ni.ac.yu
Nikolova
Dimitrinka
D
Gluud
Lise Lotte
LL
Simonetti
Rosa G
RG
Gluud
Christian
C
D000328:Adult; D000975:Antioxidants / Q000009:adverse effects; D001205:Ascorbic Acid; D019587:Dietary Supplements / Q000009:adverse effects; D006801:Humans; D016032:Randomized Controlled Trials as Topic / Q000401:mortality*; D012643:Selenium; D014801:Vitamin A; D014810:Vitamin E; D019207:beta Carotene
D000975:Antioxidants; D019207:beta Carotene; D014801:Vitamin A; D014810:Vitamin E; D012643:Selenium; D001205:Ascorbic Acid