title: Antioxidant supplements for prevention of mortality in healthy participants and patients with various diseases.
abstract: BACKGROUND
  Animal and physiological research as well as observational studies suggest that antioxidant supplements may improve survival.
  
  
  OBJECTIVE
  To assess the effect of antioxidant supplements on mortality in primary or secondary prevention randomised clinical trials.
  
  
  METHODS
  We 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). We scanned bibliographies of relevant publications and wrote to pharmaceutical companies for additional trials.
  
  
  METHODS
  We included all primary and secondary prevention randomised clinical trials on antioxidant supplements (beta-carotene, vitamin A, vitamin C, vitamin E, and selenium) versus placebo or no intervention. Included participants were either healthy (primary prevention trials) or had any disease (secondary prevention trials).
  
  
  METHODS
  Three authors extracted data. Trials with adequate randomisation, 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.
  
  
  RESULTS
  Sixty-seven randomised trials with 232,550 participants were included. Forty-seven trials including 180,938 participants had low risk of bias. Twenty-one trials included 164,439 healthy participants. Forty-six trials included 68111 participants with various diseases (gastrointestinal, cardiovascular, neurological, ocular, dermatological, rheumatoid, renal, endocrinological, 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 by 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), but no significant detrimental effect of 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).
  
  
  CONCLUSIONS
  We found no evidence to support antioxidant supplements for primary or secondary prevention. Vitamin A, beta-carotene, and vitamin E may increase mortality. Future randomised 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. Antioxidant supplements need to be considered medicinal products and should undergo sufficient evaluation before marketing.
authors.affiliation: Copenhagen University Hospital, Rigshospitalet, Department 3344,Copenhagen Trial Unit, Centre for Clinical Intervention Research, Blegdamsvej 9, Copenhagen, Denmark, DK-2100. goranb@junis.ni.ac.yu
authors.forename: G
authors.initials: G
authors.lastname: Bjelakovic
authors.forename: D
authors.initials: D
authors.lastname: Nikolova
authors.forename: L L
authors.initials: LL
authors.lastname: Gluud
authors.forename: R G
authors.initials: RG
authors.lastname: Simonetti
authors.forename: C
authors.initials: C
authors.lastname: Gluud
mesh_terms: D000975:Antioxidants / Q000008:administration & dosage* / Q000009:adverse effects; D001205:Ascorbic Acid / Q000008:administration & dosage / Q000009:adverse effects; D006304:Health Status; D006801:Humans; D009026:Mortality; D011322:Primary Prevention / Q000379:methods*; D016032:Randomized Controlled Trials as Topic; D012643:Selenium / Q000008:administration & dosage / Q000009:adverse effects; D014801:Vitamin A / Q000008:administration & dosage / Q000009:adverse effects; D014810:Vitamin E / Q000008:administration & dosage / Q000009:adverse effects; D019207:beta Carotene / Q000008:administration & dosage / Q000009:adverse effects
chemical_list: D000975:Antioxidants; D019207:beta Carotene; D014801:Vitamin A; D014810:Vitamin E; D012643:Selenium; D001205:Ascorbic Acid