Systematic Review and Meta-analysis
Goran Bjelakovic, MD, DrMed Sci
Dimitrinka Nikolova, MA
Lise Lotte Gluud, MD, DrMedSci
Rosa G. Simonetti, MD
Christian Gluud, MD, DrMedSci
OXIDATIVE STRESS IS IMPLICATED in most human diseases.1,2 Antioxidants may decrease the oxidative damage and its alleged harmful effects. 3-6 Many people are taking antioxidant supplements, believing to improve their health and prevent diseases.7-10 Whether antioxidant supplements are beneficial or harmful is uncertain.11-15 Many primary or secondary prevention trials of antioxidant supplements have been conducted to prevent several diseases.
We found that antioxidant supplements, with the potential exception of selenium, were without significant effects on gastrointestinal cancers and increased all-cause mortality.14,15 We did not examine the effect of antioxidant supplements on all-cause mortality in all randomized prevention trials.16 Our aim with the present systematic review was to analyze the effects of antioxidant supplements (beta carotene, vitamins A and E, vitamin C [ascorbic acid], and selenium) on all-cause mortality of adults included in primary and secondary prevention trials.
METHODS:
The present review follows the Cochrane Collaboration method17 and is based on the principles of our peer-reviewed protocol and review on antioxidant supplements for gastrointestinal cancer prevention.14,15,18,19 We included all primary and secondary prevention trials in adults randomized to receive beta carotene, vitamin A, vitamin C, vitamin E, or selenium vs placebo or no intervention. Parallel-group randomized trials and the first period of crossover randomized trials were included.17 Trials including general or healthy populations were classified as primary prevention. Trials including participants with specific disease were classified as secondary prevention. We excluded tertiary prevention(treatment) trials, like trials on acute, infectious, or malignant diseases except non melanoma skin cancer. We included antioxidant supplements at any dose, duration, and route of administration. We analyzed the antioxidants administered singly, in combination with other antioxidants, or with other vitamins or trace elements. Trials with collateral interventions were included if the interventions were used equally in the trial groups. Subgroup analyses without high-bias risk trials and selenium trials were preconceived.
Our outcome measure was all-cause mortality at maximum follow-up.
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 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
Conclusions: Treatment with (SYNTHETIC-SK) beta carotene, vitamin A, and vitamin E may increase mortality.
JAMA. 2007;297:842-857 www.jama.com
842 JAMA, February 28, 2007—Vol 297, No. 8 (Reprinted) ©2007 American Medical Association. All rights reserved.
Author Affiliations: The Cochrane Hepato-Biliary Group, Copenhagen Trial Unit, Center for Clinical Intervention Research, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark (Drs Bjelakovic,
L. L. Gluud, Simonetti, and C. Gluud and Ms Nikolova); Department of Internal Medicine, Gastroenterology and Hepatology, University of Nis, Nis, Serbia
(Dr Bjelakovic); and Divisione di Medicina, Ospedale V. Cervello, Palermo, Italy (Dr Simonetti).
Corresponding Author: Goran Bjelakovic, MD, DrMedSci, University of Nis, Department of Internal Medicine, Boulevard Dr Zorana Djindjica 81, 18000 Nis, Serbia (goranb@junis.ni.ac.yu).
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