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Mortality in Randomized Trials of Antioxidant Supplements for Primary and Secondary Prevention
Systematic Review and Meta-analysis
Goran Bjelakovic, MD, DrMedSci; Dimitrinka Nikolova, MA; Lise Lotte Gluud, MD, DrMedSci; Rosa G. Simonetti, MD; Christian Gluud, MD, DrMedSci
JAMA. 2007;297:842-857.
ABSTRACT
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| 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, 1.05-1.29) 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.
INTRODUCTION
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 nonmelanoma 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.
Data Sources
We searched The Cochrane Central Register of Controlled Trials (CENTRAL) in 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).20 We scanned bibliographies of relevant articles for additional trials.
Data Extraction
Two of the 3 authors (G.B. and D.N., and R.G.S.) independently assessed trial eligibility. Excluded trials were listed with the reasons for exclusion. Disagreement was resolved by discussion or in consultation with a third author (C.G.). We contacted authors of the trials for missing information.
From each trial we recorded first author; country of origin, country income category (low, middle, high)21; number of participants; characteristics of participants: age range (mean or median) and sex ratio; participation rate; dropout rate; trial design (parallel, factorial, or crossover); type of antioxidant; dose; duration of supplementation; duration of follow-up (ie, treatment duration plus posttreatment follow-up); and cointerventions. We extracted the date, location, sponsor of the trial, and the publication status.
Due to the risk of overestimating intervention effects, analyses were stratified according to the risk of bias (methodological quality).14-15,18-19,22-24 Trials with adequate generation of the allocation sequence, adequate allocation concealment, adequate blinding, and adequate follow-up were considered low-bias risk trials (high methodological quality).24 Trials with one or more unclear or inadequate quality components were classified as high-bias risk trials (low methodological quality).24 Generation of the allocation sequence was considered adequate if the allocation sequence was generated by a computer or random-number table, or similar; allocation concealment was considered adequate if concealed up to the point of treatment by central randomization, sealed envelopes, or similar; blinding was considered adequate if the trial was described as double-blind and using identical placebo; follow-up was considered adequate if the numbers and reasons for dropouts and withdrawals in all intervention groups were described or if it was specified that there were no dropouts or withdrawals. Bias risk was assessed without blinding of 2 authors (G.B. and D.N. or R.G.S.). Consensus was reached through discussion or arbitration by a third author (C.G. or L.L.G.) before data entry. We have found high interrater agreement between blinded and unblinded assessments and also between 2 independent assessors.24
Statistical Analyses
We used The Cochrane Collaboration software (RevMan Analyses 1.0; www.cochrane.org), STATA 8.2 (STATA Corp, College Station, Tex), Sigma Stat 3.0 (SPSS Inc, Chicago, Ill), and StatsDirect (StatsDirect Ltd, Altrincham, England). We analyzed the data with a random-effects model,25 calculating the relative risk (RR) with 95% confidence intervals (CIs). To account for 0 cells in the 2 x 2 tables, we calculated the RR with 3 different continuity corrections (0.5; 0.1; 0.01).26-27 We did not include trials with 0 events in both intervention groups.27-28 Because the number of such trials was large, we performed exploratory analysis adding an imagined trial with 1 death and 20 000 participants in each group.
We used the STATA metareg command for the random-effects metaregression to assess which covariates influenced the intervention effect across trials.29 The included covariates were bias risk, type and dose of supplement, single or combined supplement regimen, duration of supplementation, and primary or secondary prevention. Univariate and multivariate analyses including all covariates were performed. Results are presented with regression coefficients and 95% CI.
All analyses followed the intention-to-treat principle. For trials with factorial design, we based our results on at-margins analysis,30 comparing all groups that received antioxidant supplements with groups that did not. To determine the effect of a single antioxidant, we performed inside-the-table analysis30 in which we compared the group taking a single antioxidant with the group taking placebo or receiving no intervention. In trials with more than 2 groups assessing additional therapy, we compared only groups receiving antioxidants, placebo, or no intervention.
We assessed heterogeneity with I2 that describes the percentage of total variation across trials due to heterogeneity rather than chance.17, 31 I2 can be calculated as I2 = 100% x (Qv –df)/Q, where Q is Cochran's heterogeneity statistics and df the degrees of freedom. Negative values of I2 are put equal to 0, so I2 lies between 0% (no heterogeneity) and 100% (maximal heterogeneity).31 We compared the estimated treatment effects in trials with a low- or high-risk of bias with test of interaction.32 We performed adjusted-rank correlation33 and regression-asymmetry tests34 for detection of bias.
RESULTS
Database searches yielded 16 111 references. Exclusion of duplicates and irrelevant references left 1201 references describing 815 trials. To obtain additional information we wrote to authors of eligible trials. Seventy authors responded. We excluded 816 references (747 trials) due to the following: mortality was 0 in both study groups (n=405 trials, including about 40 000 participants [http://ctu.rh.dk]); did not fulfill inclusion criteria (n=245); was not a randomized trial (n=69); insufficient data (n=24); or still ongoing trial (n=4). We included 385 references describing 68 randomized trials fulfilling our inclusion criteria and able to provide data for our analyses35-6970-102 (Figure 1 [http://ctu.rh.dk]). This corresponds to a median of 6 references per included trial (range, 1-44). Forty trials used parallel-group design, 26 factorial design (23 trials 2 x 2; 2 trials 2 x 2x 2; 1 trial half replicate of 2 x 2x 2x 2), and 2 crossover design.
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Figure 1. Flow Diagram of Identification of Randomized Trials for Inclusion
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A total of 232 606 participants were randomly assigned in the 68 trials. The number of participants in each trial ranged from 24 to 39 876 (Table 1 and Table 2). The mean age was 62 years (range, 18-103 years). The mean proportion of women was 44.5% in the 63 trials reporting sex.
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