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Mortality in Randomized Trials of Antioxidant Supplements for Primary and Secondary PreventionSystematic 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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Table 1. Characteristics of Included Trials With High Risk of Bias
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Table 2. Characteristics of Included Trials With Low Risk of Bias
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Twenty-one trials were primary prevention trials including 164 439 healthy participants; 47 trials were secondary prevention trials including 68 167 participants with gastrointestinal (n=11), cardiovascular (n=9), neurological (n=6), ocular (n=5), dermatological (n=5), rheumatoid (n=2), renal and cardiovascular (n=1), endocrinological (n=1), or unspecified (n=7) diseases. Main outcome measures in the primary prevention trials were cancer and mortality (cause specific and all cause), and in the secondary prevention trials they were progression of disease and mortality (cause specific and all cause; Table 3 and Table 4).
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Table 3. Participants and Outcome Measures of Included Trials With High Risk of Bias
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Table 4. Participants and Outcome Measures of Included Trials With Low Risk of Bias
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All antioxidant supplements were administered orally. The dose and regimen of the antioxidant supplements were: beta carotene 1.2 to 50.0 mg (mean, 17.8 mg) , vitamin A 1333 to 200 000 IU (mean, 20 219 IU), vitamin C 60 to 2000 mg (mean, 488 mg), vitamin E 10 to 5000 IU (mean, 569 IU), and selenium 20 to 200 µg (mean 99 µg) daily or on alternate days for 28 days to 12 years (mean 2.7 years). In one trial40 antioxidants were applied in a single dose and participants were followed up for 3 months thereafter. The mean duration of follow-up in all trials was 3.3 years (range, 28 days-14.1 years).
Beta carotene was tested in 25 trials, vitamin A in 16, vitamin C in 34, vitamin E in 55, and selenium in 21. Beta carotene was tested singly in 6 trials, vitamin A in 2, vitamin E in 24, and vitamin C and selenium in 3 trials each. The antioxidant supplements were given in the following combinations: beta carotene and vitamin A; beta carotene and vitamin E; beta carotene and vitamin C; vitamin A and vitamin C; vitamin C and vitamin E; vitamin E and selenium; selenium and zinc; beta carotene, vitamin C, and vitamin E; beta carotene, vitamin C, vitamin E, and selenium; beta carotene, vitamin C, vitamin E, selenium, and zinc; vitamin A, vitamin C, vitamin E, selenium, and zinc; vitamin A, vitamin C, vitamin E, selenium, methionine, and ubiquinone. In 11 trials, participants were supplemented with different mixtures of antioxidants as well as with vitamins and minerals without antioxidant properties.39, 41-42,45, 51-52,72, 84, 91-92,101
Sixty-three trials used placebo and 5 trials43, 48, 58, 69, 82 used no intervention in the control group. In 9 trials35, 40, 46, 48, 65, 81, 89, 97, 99 the active and placebo (control) groups were supplemented with vitamins and minerals (with or without antioxidant properties). In 6 of the trials, the supplementation was with vitamin E 4 IU,46, 89 vitamin A 1000 IU40; vitamin C 20 and 50 mg48, 81; riboflavin 10 mg35; or niacin 100 mg.65 In the trials with factorial or parallel-group design, the additional interventions tested were multivitamins and minerals (zinc, copper, chromium); ubiquinone; L-methionine; omega-3 polyunsaturated fatty acids; citrus bioflavonoid complex; quercetin, bilberry extract, rutin (bioflavonoids); taurine; N-acetyl cysteine; L-glutathione; aged garlic; deprenyl–selegiline (selective monoamine oxidase B inhibitor); donepezil (acetylcholinesterase inhibitor); riluzole (modulator of glutamatergic neurotransmission); amoxicillin, metronidazole (antibiotics); bismuth subsalicylate; omeprazole (proton-pump inhibitor); aspirin; simvastatin (cholesterol-lowering drug); celecoxib (inhibitor of cyclooxygenase), and ramipril (angiotensin-converting enzyme inhibitor).
In 54 trials (79.4%), the antioxidants were provided at no cost from pharmaceutical companies. In the rest of the trials funding was not reported. The trials were conducted in Europe, North and South America, Asia, and Australia. Six trials came from lower-middle-income countries41-42,47, 62, 67-68 and 62 trials from high-income countries.
Methodological Quality of Included Trials
Forty-seven of the 68 trials (69.1%) had low-bias risk, ie, had adequate generation of the allocation sequence, adequate allocation concealment, blinding, and follow-up.24 The remaining trials had one or more inadequate components.
All Randomized Trials
The pooled effect of all supplements vs placebo or no intervention in all randomized trials was not significant (RR, 1.02; 95% CI, 0.98-1.06). Heterogeneity was not significant (I2 = 18.6%, P = .10). Adjusted-rank correlation test (P = .08), but not the regression asymmetry test (P = .26), suggested bias among the trials. Exploratory analysis adding an imagined trial with one death and 20 000 participants in each study group had no noticeable effect on the result.
Univariate meta-regression analyses revealed significant influences of dose of beta carotene (RR, 1.004; 95% CI, 1.001-1.007; P = .012), dose of vitamin A (RR, 1.000006; 95% CI, 1.000002-1.000009; P = .003), dose of selenium (RR, 0.998; 95% CI, 0.997-0.999; P = .002), and bias-risk (RR, 1.16; 95% CI, 1.05-1.29; P = .004) on mortality. None of the other covariates (dose of vitamin C; dose of vitamin E; single or combined antioxidant regimen; duration of supplementation; and primary or secondary prevention) were significantly associated with mortality.
In multivariate meta-regression analysis including all covariates, dose of selenium was associated with significantly lower mortality (RR, 0.998; 95% CI, 0.997-0.999; P = .005) and low-bias risk trials with significantly higher mortality (RR, 1.16; 1.05-1.29; P = .005). None of the other covariates was significantly associated with mortality.
Bias Risk of Trials
In trials with low-bias risk mortality was significantly increased in the supplemented group (RR, 1.05; 95% CI, 1.02-1.08) without significant heterogeneity (I2 = 7.0%). Exploratory analysis adding an imagined trial with 1 death and 20 000 participants in each study group had no noticeable effect on the result.
In high-bias risk trials (low-methodological quality in  1 of the 4 components) mortality was significantly decreased in the supplemented group (RR, 0.91; 95% CI, 0.83-1.00) without significant heterogeneity (I2 = 4.5%). The difference between the estimate of antioxidants on mortality in low- and high-bias risk trials was statistically significant by test of interaction (z = 2.88, P = .004; Figure 2 and Figure 3).
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Figure 2. Intervention Effect of Antioxidant Supplements vs Placebo on Mortality in Trials With Low Risk of Bias
Error bars indicate 95% confidence intervals (CIs).
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Figure 3. Intervention Effect of Antioxidant Supplements vs Placebo or No Intervention on Mortality in Trials With High Risk of Bias
Error bars indicate 95% confidence intervals (CIs).
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Antioxidant Supplements Given Singly or in Combination
Beta carotene used singly significantly increased mortality (Table 5). This effect was not significant when combined with other supplements. After exclusion of high-bias risk and selenium trials, beta carotene singly or combined significantly increased mortality (Table 5).
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Table 5. Intervention Effects of Different Antioxidant Supplements vs Placebo or No Intervention on Mortality
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Vitamin A given singly or in combination with the other supplements did not significantly affect mortality. After exclusion of high-bias risk and selenium trials, vitamin A singly or combined significantly increased mortality (Table 5).
Vitamin E given singly or in combination with the other supplements did not significantly affect mortality (Table 5). Vitamin E given singly in high (1000 IU) or low dose (<1000 IU) did not significantly affect mortality (RR, 1.07; 95% CI, 0.91-1.25; I2 = 0% and RR, 1.00; 95% CI, 0.94-1.07; I2 = 13.0%, respectively). After exclusion of high-bias risk and selenium trials, vitamin E given singly or combined significantly increased mortality (Table 5).
Vitamin C given singly or in combination with the other supplements was without significant influence on mortality, even after the exclusion of high-bias risk trials and selenium trials (Table 5).
Selenium given singly or in combination with other antioxidant supplements had no significant influence on mortality when analyzed separately (Table 5). Selenium given singly or combined significantly decreased mortality when analyzed together. After exclusion of high-bias risk trials, selenium given singly or with other antioxidants had no significant influence on mortality (Table 5).
COMMENT
Our systematic review contains a number of findings. Beta carotene, vitamin A, and vitamin E given singly or combined with other antioxidant supplements significantly increase mortality. There is no evidence that vitamin C may increase longevity. We lack evidence to refute a potential negative effect of vitamin C on survival. Selenium tended to reduce mortality, but we need more research on this question. We confirm that trials with inadequate bias control overestimate intervention effects.14-15,19, 22-24 Our findings support and extend our previous findings regarding antioxidant supplements and increased mortality.14-15
Our review offers a number of strengths. It follows a published, peer-reviewed Cochrane protocol,18 taking into consideration our previous findings in a systematic review on antioxidant supplements for preventing gastrointestinal cancers.14-15 Our review represents a comprehensive review of the topic, including 68 randomized trials with almost a quarter of a million participants. This increases the precision and power of our analyses.17 Previous meta-analyses of preventive trials of antioxidant supplements have included less information (lung cancer, 4 trials with 109 394 participants103; cardiovascular diseases, 8 trials with 138 113 participants104; gastrointestinal cancers, 14 trials with 170 525 participants14-15; colorectal adenoma, 8 trials with 17 620 participants19; cancer or preinvasive lesions, 7 trials with 5112 participants105; and mortality, 19 trials with 135 967 participants106).
Previous studies either found no beneficial or harmful effect of the supplements19, 103-105,107 or reported a significantly increased mortality.14-15,103-104,106 We conducted a thorough assessment of trial methodology following the recommendations of the Cochrane Collaboration17 and findings of methodological studies.22-24 More than two thirds of the included trials with more than 180 000 participants fall in the group of low-bias risk trials. This highlights the validity of our results.22-24 Antioxidant supplements not only seem to be one of the most researched topics in the world, they also seem to be one of the most adequately researched clinical questions. Only a small proportion of trials use adequate methodologies.108-109 Our meta-analyses had little trial heterogeneity. This increases the trustworthiness of our findings. Our analyses were robust to sensitivity analyses involving different imputations of mortality in the 0-event study groups. We gave full account of all 405 identified trials assessing the supplements having 0 events in both study groups. These trials were mostly assessing short-term supplement administration and surrogate outcome measures. Our results were robust to exploratory analyses adding an imagined trial with 20 000 participants and one death in each intervention group. Accordingly, the increased mortality does not seem to be an artifact created by exclusion of trials with 0 events in both study groups.27-28 Furthermore, all-cause mortality should generally be connected with unbiased estimates.
A large number of unpublished trials on supplements may exist. Their results are more likely to have been either neutral or negative than to have shown beneficial effects.110 Accordingly, our estimates of increased mortality of about 5% is likely to be conservative.
The choice of statistical model for performing meta-analysis of sparse data are important.27-28 Because many methods are based on large sample approximations, they may be unsuitable when events are rare. Bradburn et al28 found that no method gives completely unbiased estimates. At event rates below 1%, the Peto odds-ratio method appears to be the least biased and most powerful method when there is no substantial imbalance in treatment and control group sizes within trials, and treatment effects are not exceptionally large. Bradburn et al28 also demonstrated that the Peto odds ratio works well up to event rates around 10%. The calculation avoids addition of 0.5-event adjustments (or any other adjustment). When we applied Peto odds ratio, we found even stronger support for detrimental effects of the supplements (for all 68 trials: 1.05; 95% CI, 1.02-1.08; for the 47 low-bias risk trials: 1.07; 95% CI, 1.04-1.10; after exclusion of high-bias risk trials and selenium trials, for beta carotene: 1.09; 95% CI, 1.06-1.13; for vitamin A: 1.20; 95% CI, 1.12-1.29; for vitamin C: 1.06; 95% CI, 0.99-1.14; and for vitamin E: 1.06; 95% CI, 1.02-1.10).
Our systematic review has several limitations. As with all systematic reviews, our findings and interpretations are limited by the quality and quantity of available evidence on the effects of specific supplements on mortality. The examined populations varied. The effects of supplements were assessed in the general population or in patients with gastrointestinal, cardiovascular, neurological, skin, ocular, renal, endocrinological, and rheumatoid diseases. These populations mostly came from countries without overt deficiencies of specific supplements. Accordingly, we are unable to assess how antioxidant supplements affect mortality in populations with specific needs.
We have compared antioxidants with different properties, given at different doses and duration, singly or combined. We are aware of the potential risks in assessing the effects of different types of antioxidants together with different mechanisms of action, biotransformation, and bioavailability. There are pros111-113 and cons114 in the literature about vitamin A being antioxidant. We fully acknowledge this. Most trials assessed combinations of different supplements, which reflects the way supplements are marketed, sold, and taken by people.7-10
The methodological quality of some of the trials was assessed using the published reports, which may not reflect the actual design and bias risk of the trials. Some authors responded to our requests for further information.
All available nonenzymatic antioxidants work differently in the human body, and most of them exert effects that are nonantioxidant. We are not able to point to the specific biochemical mechanisms behind the detrimental effects. We found that trials examining the individual supplements singly were rare. It has been suggested that antioxidant supplements may show interdependency and may have effects only if given in combination.115
Most trials investigated the effects of supplements administered at higher doses than those commonly found in a balanced diet, and some of the trials used doses well above the recommended daily allowances and even above the tolerable upper intake levels.116-117 Our meta-regression analyses revealed significant effects of dose of beta carotene, vitamin A, and selenium on mortality. The duration of supplementation and follow-up differed among the trials. However, we found no significant effect of treatment duration on our results.
We only assessed all-cause mortality. We are not able to determine the cause of the increased mortality. It is likely that increased cancer and cardiovascular mortality are the main reasons for the increased all-cause mortality.103-104 Further study of causes of mortality is needed. We fear that its assessment may be difficult due to varying definitions in the included trials. Our results extend previous reviews14-15,19, 103-107 and guidelines,118-120 suggesting that antioxidant supplements may not be beneficial.
Beta carotene, administered singly or in combination with other antioxidants, significantly increased all-cause mortality. Recent studies have suggested that beta carotene may act as a cocarcinogen.121-122 Vitamin A combined with other antioxidants significantly increased mortality. We found that vitamin E given singly or combined with 4 other antioxidants did not significantly influence mortality. After exclusion of high-bias risk trials, however, vitamin E given singly or combined significantly increased mortality. This is in agreement with a recent meta-analysis.106 Dose of vitamin E was without significant effect on mortality in our analysis. The chance that vitamin E may benefit seems low.123-125
The trials in which vitamin C was applied singly or in different combinations with beta carotene, vitamin A, vitamin E, and selenium found no significant effect on mortality. According to the CIs, small beneficial or large harmful effects cannot be excluded. We calculated the proportion of participants who died in the trials in which participants took vitamin C alone. In the control group it was 0.019 and in the vitamin C group it was 0.017. With  set to .05 and power to .90, the required sample size would be 186 000 participants. We are still far from having examined a sufficient sample. Studies have demonstrated that vitamin C may act as both a pro-oxidant and as an antioxidant in vivo,126-127 and trials should be monitored closely for harm.
Selenium given singly or in combination with other supplements seemed to significantly decrease mortality, but after exclusion of high-bias risk trials, the effect disappeared. Results of ongoing randomized trials with selenium will likely increase our understanding of the effects of selenium.128
Our findings contradict the findings of observational studies, claiming that antioxidants improve health.129-132 Considering that 10% to 20% of the adult population (80-160 million people) in North America and Europe may consume the assessed supplements,7-10 the public health consequences may be substantial. We are exposed to intense marketing with a contrary statement, which is also reflected by the high number of publications per included randomized trial found in the present review.
There are several possible explanations for the negative effect of antioxidant supplements on mortality. Although oxidative stress has a hypothesized role in the pathogenesis of many chronic diseases, it may be the consequence of pathological conditions.133 By eliminating free radicals from our organism, we interfere with some essential defensive mechanisms like apoptosis, phagocytosis, and detoxification.134-136 Antioxidant supplements are synthetic and not subjected to the same rigorous toxicity studies as other pharmaceutical agents.137 Better understanding of mechanisms and actions of antioxidants in relation to a potential disease is needed.138
Because we examined only the influence of synthetic antioxidants, our findings should not be translated to potential effects of fruits and vegetables.
CONCLUSION
We did not find convincing evidence that antioxidant supplements have beneficial effects on mortality. Even more, beta carotene, vitamin A, and vitamin E seem to increase the risk of death. Further randomized trials are needed to establish the effects of vitamin C and selenium.
AUTHOR INFORMATION
Corresponding Author: Goran Bjelakovic, MD, DrMedSci, University of Nis, Department of Internal Medicine, Boulevard Dr Zorana Djindjica 81, 18000 Nis, Serbia (goranb{at}junis.ni.ac.yu).
Author Contributions: Dr Bjelakovic had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Study concept and design: Bjelakovic, Nikolova, L. Gluud, Simonetti, C. Gluud.
Acquisition of data: Bjelakovic, Nikolova, C. Gluud.
Analysis and interpretation of data: Bjelakovic, Nikolova, L. Gluud, Simonetti, C. Gluud.
Drafting of the manuscript: Bjelakovic, Nikolova, L. Gluud, Simonetti, C. Gluud.
Critical revision of the manuscript for important intellectual content: Bjelakovic, Nikolova, L. Gluud, C. Gluud.
Statistical analysis: Bjelakovic, L. Gluud, Simonetti, C. Gluud.
Obtained funding: C. Gluud.
Administrative, technical, or material support: Nikolova, C. Gluud.
Study supervision: Bjelakovic, C. Gluud.
Financial Disclosures: None reported.
Funding/Support: Supported by The Copenhagen Trial Unit, Center for Clinical Intervention Research, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.
Role of the Sponsor: The funding source had no role in the conduct of the study, collection of data, management, analysis, interpretation of the data, or preparation of the manuscript.
Acknowledgment: We thank the participants who entered the trials and the investigators who conducted them. We thank authors who kindly responded to our requests for further information on the trials they were involved in. We thank Yan Gong, MD, MIH, Copenhagen Trial Unit, Center for Clinical Intervention Research, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark, for assistance with statistical analyses and Sarah Louise Klingenberg, Cochorane Hepato-Billary Group, Copenhagen Trial Unit, Center for Clinical Intervention Research, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark, for help with paper copies of articles. None has received any money for assistance.
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).
REFERENCES
| |
1. Sies H. Introductory remarks. In: Sies H, ed. Oxidative stress. Orlando, Fla: Academic Press; 1985:1-7.
2. Halliwell B, Gutteridge JMC. Free Radicals. In: Biology and Medicine. 3rd ed. London, England: Oxford University Press; 1999.3. Papas AM. Diet and antioxidant status. In: Papas AM, ed. Antioxidant Status, Diet, Nutrition, and Health. Boca Raton, Fla: CRC Press; 1998:89-94.4. Halliwell B. Antioxidants in human health and disease. Annu Rev Nutr. 1996;16:33-50.
FULL TEXT
|
WEB OF SCIENCE
| PUBMED
5. Halliwell B. Antioxidant defense mechanisms: from the beginning to the end (of the beginning). Free Radic Res. 1999;31:261-272.
WEB OF SCIENCE
| PUBMED
6. Willcox JK, Ash SL, Catignani GL. Antioxidants and prevention of chronic disease. Crit Rev Food Sci Nutr. 2004;44:275-295.
FULL TEXT
|
WEB OF SCIENCE
| PUBMED
7. Balluz LS, Kieszak SM, Philen RM, Mulinare J. Vitamin and mineral supplement use in the United States: results from the third National Health and Nutrition Examination Survey. Arch Fam Med. 2000;9:258-262.
FREE FULL TEXT
8. Radimer K, Bindewald B, Hughes J, Ervin B, Swanson C, Picciano MF. Dietary supplement use by US adults: data from the National Health and Nutrition Examination Survey, 1999-2000. Am J Epidemiol. 2004;160:339-349.
FREE FULL TEXT
9. Millen AE, Dodd KW, Subar AF. Use of vitamin, mineral, nonvitamin, and nonmineral supplements in the United States: the 1987, 1992, and 2000 National Health Interview Survey results. J Am Diet Assoc. 2004;104:942-950.
FULL TEXT
|
WEB OF SCIENCE
| PUBMED
10. Nichter M, Thompson JJ. For my wellness, not just my illness: North Americans' use of dietary supplements. Cult Med Psychiatry. 2006;30:175-222.
FULL TEXT
|
WEB OF SCIENCE
| PUBMED
11. Herbert V. The value of antioxidant supplements vs their natural counterparts. J Am Diet Assoc. 1997;97:375-376.
WEB OF SCIENCE
| PUBMED
12. Stanner SA, Hughes J, Kelly CN, Buttriss J. A review of the epidemiological evidence for the "antioxidant hypothesis." Public Health Nutr. 2004;7:407-422.
FULL TEXT
|
WEB OF SCIENCE
| PUBMED
13. Berger MM. Can oxidative damage be treated nutritionally? Clin Nutr. 2005;24:172-183.
FULL TEXT
|
WEB OF SCIENCE
| PUBMED
14. Bjelakovic G, Nikolova D, Simonetti RG, Gluud C. Antioxidant supplements for preventing gastrointestinal cancers. Cochrane Database Syst Rev. doi: 10.1002/14651858.CD004183.pub2. 2004;(4):CD004183.
PUBMED
15. Bjelakovic G, Nikolova D, Simonetti RG, Gluud C. Antioxidant supplements for prevention of gastrointestinal cancers: a systematic review and meta-analysis. Lancet. 2004;364:1219-1228.
FULL TEXT
|
WEB OF SCIENCE
| PUBMED
16. Forman D, Altman D. Vitamins to prevent cancer: supplementary problems. Lancet. 2004;364:1193-1194.
FULL TEXT
|
WEB OF SCIENCE
| PUBMED
17. Higgins JPT, ed, Green S, ed. Cochrane Handbook for Systematic Reviews of Interventions 4.2.5 [updated May 2005]. http://www.cochrane.org/resources/handbook/hbook.htm. Accessed January 26, 2007.18. Bjelakovic G, Nikolova D, Simonetti R. Antioxidants for preventing gastrointestinal cancers (protocol for a Cochrane Review), The Cochrane Library, Issue 2. Oxford: Update Software; 2003.19. Bjelakovic G, Nagorni A, Nikolova D, Simonetti RG, Bjelakovic M, Gluud C. Meta-analysis: antioxidant supplements for primary and secondary prevention of colorectal adenoma. Aliment Pharmacol Ther. 2006;24:281-291.
FULL TEXT
|
WEB OF SCIENCE
| PUBMED
20. Royle P, Milne R. Literature searching for randomized controlled trials used in Cochrane reviews: rapid vs exhaustive searches. Int J Technol Assess Health Care. 2003;19:591-603.
WEB OF SCIENCE
| PUBMED
21. World Bank list of economies (July 2006). http://siteresources.worldbank.org/DATASTATISTICS/Resources/CLASS.XLS. Accessed August 24, 2006.22. Moher D, Pham B, Jones A, et al. Does quality of reports of randomised trials affect estimates of intervention efficacy reported in meta-analysis. Lancet. 1998;352:609-613.
FULL TEXT
|
WEB OF SCIENCE
| PUBMED
23. Schulz KF, Chalmers I, Hayes RJ, Altman DG. Empirical evidence of bias: dimensions of methodological quality associated with estimates of treatment effects in controlled trials. JAMA. 1995;273:408-412.
FREE FULL TEXT
24. Kjaergard LL, Villumsen J, Gluud C. Reported methodologic quality and discrepancies between large and small randomized trials in meta-analyses. Ann Intern Med. 2001;135:982-989.
FREE FULL TEXT
25. DerSimonian R, Laird N. Meta-analysis in clinical trials. Control Clin Trials. 1986;7:177-188.
FULL TEXT
|
WEB OF SCIENCE
| PUBMED
26. DeMets DL. Methods for combining randomized clinical trials: strengths and limitations. Stat Med. 1987;6:341-350.
WEB OF SCIENCE
| PUBMED
27. Sweeting MJ, Sutton AJ, Lambert PC. What to add to nothing? use and avoidance of continuity corrections in meta-analyses of sparse data. Stat Med. 2004;23:1351-1375.
FULL TEXT
|
WEB OF SCIENCE
| PUBMED
28. Bradburn MJ, Deeks JJ, Berlin JA, Russell Localio A. Much ado about nothing: a comparison of the performance of meta-analytical methods with rare events. Stat Med. 2007;26:53-77.
FULL TEXT
|
WEB OF SCIENCE
| PUBMED
29. Sharp SJ. Metaanalysis regression. STATA Techn Bull. 1998;42:16-22.
30. McAlister FA, Straus SE, Sackett DL, Altman DG. Analysis and reporting of factorial trials: a systematic review. JAMA. 2003;289:2545-2553.
FREE FULL TEXT
31. Higgins JP, Thompson SG. Quantifying heterogeneity in a meta-analysis. Stat Med. 2002;21:1539-1558.
FULL TEXT
|
WEB OF SCIENCE
| PUBMED
32. Altman DG, Bland JM. Interaction revisited: the difference between two estimates. BMJ. 2003;326:219.
FREE FULL TEXT
33. Begg CB, Mazumdar M. Operating characteristics of a rank correlation test for publication bias. Biometrics. 1994;50:1088-1101.
FULL TEXT
|
WEB OF SCIENCE
| PUBMED
34. Egger M, Davey Smith G, Schneider M, Minder C. Bias in meta-analysis detected by a simple, graphical test. BMJ. 1997;315:629-634.
FREE FULL TEXT
35. Gillilan RE, Mondell B, Warbasse JR. Quantitative evaluation of vitamin E in the treatment of angina pectoris. Am Heart J. 1977;93:444-449.
WEB OF SCIENCE
| PUBMED
36. McKeown-Eyssen G, Holloway C, Jazmaji V, Bright-See E, Dion P, Bruce WR. A randomized trial of vitamins C and E in the prevention of recurrence of colorectal polyps. Cancer Res. 1988;48:4701-4705.
FREE FULL TEXT
37. Greenberg ER, Baron JA, Stukel TA, et al, Skin Cancer Prevention Study Group. A clinical trial of beta carotene to prevent basal-cell and squamous-cell cancers of the skin. N Engl J Med. 1990;323:789-795.
ABSTRACT
38. Penn ND, Purkins L, Kelleher J, Heatley RV, Mascie-Taylor BH, Belfield PW. The effect of dietary supplementation with vitamins A, C and E on cell-mediated immune function in elderly long-stay patients: a randomized controlled trial. Age Ageing. 1991;20:169-174.
FREE FULL TEXT
39. Chandra RK. Effect of vitamin and trace-element supplementation on immune responses and infection in elderly subjects. Lancet. 1992;340:1124-1127.
FULL TEXT
|
WEB OF SCIENCE
| PUBMED
40. Murphy S, West KP Jr, Greenough WB III, Cherot E, Katz J, Clement L. Impact of vitamin A supplementation on the incidence of infection in elderly nursing-home residents: a randomized controlled trial. Age Ageing. 1992;21:435-439.
FREE FULL TEXT
41. Blot WJ, Li JY, Taylor PR, et al. Nutrition intervention trials in Linxian, China: supplementation with specific vitamin/mineral combinations, cancer incidence, and disease-specific mortality in the general population. J Natl Cancer Inst. 1993;85:1483-1492.
FREE FULL TEXT
42. Li JY, Taylor PR, Li B, et al. Nutrition intervention trials in Linxian, China: multiple vitamin/mineral supplementation, cancer incidence, and disease-specific mortality among adults with esophageal dysplasia. J Natl Cancer Inst. 1993;85:1492-1498.
FREE FULL TEXT
43. Wenzel G, Kuklinski B, Ruhlmann C, Ehrhardt D. Alkoholtoxische Hepatitis—eine "freie Radikale" assoziierte Erkrankung Letalitatssenkung durch adjuvante Antioxidantientherapie. Z Gesamte Inn Med. 1993;48:490-496.
PUBMED
44. Greenberg ER, Baron JA, Tosteson TD, et al, Polyp Prevention Study Group. A clinical trial of antioxidant vitamins to prevent colorectal adenoma. N Engl J Med. 1994;331:141-147.
FREE FULL TEXT
45. Pike J, Chandra RK. Effect of vitamin and trace element supplementation on immune indices in healthy elderly. Int J Vitam Nutr Res. 1995;65:117-121.
WEB OF SCIENCE
| PUBMED
46. Takamatsu S, Takamatsu M, Satoh K, et al. Effects on health of dietary supplementation with 100 mg d-alpha-tocopheryl acetate, daily for 6 years. J Int Med Res. 1995;23:342-357.
WEB OF SCIENCE
| PUBMED
47. de la Maza MP, Petermann M, Bunout D, Hirsch S. Effects of long-term vitamin E supplementation in alcoholic cirrhotics. J Am Coll Nutr. 1995;14:192-196.
ABSTRACT
48. ter Riet G, Kessels AG, Knipschild PG. Randomized clinical trial of ascorbic acid in the treatment of pressure ulcers. J Clin Epidemiol. 1995;48:1453-1460.
FULL TEXT
|
WEB OF SCIENCE
| PUBMED
49. Clark LC, Combs GF Jr, Turnbull BW, et al. Effects of selenium supplementation for cancer prevention in patients with carcinoma of the skin: a randomized controlled trial. JAMA. 1996;276:1957-1963.
FREE FULL TEXT
50. Hennekens CH, Buring JE, Manson JE, et al. Lack of effect of long-term supplementation with beta carotene on the incidence of malignant neoplasms and cardiovascular disease. N Engl J Med. 1996;334:1145-1149.
FREE FULL TEXT
51. Hogarth MB, Marshall P, Lovat LB, et al. Nutritional supplementation in elderly medical in-patients: a double-blind placebo-controlled trial. Age Ageing. 1996;25:453-457.
FREE FULL TEXT
52. Richer S. Multicenter ophthalmic and nutritional age-related macular degeneration study, II: antioxidant intervention and conclusions. J Am Optom Assoc. 1996;67:30-49.
PUBMED
53. Stephens NG, Parsons A, Schofield PM, Kelly F, Cheeseman K, Mitchinson MJ. Randomised controlled trial of vitamin E in patients with coronary disease: Cambridge Heart Antioxidant Study (CHAOS). Lancet. 1996;347:781-786.
FULL TEXT
|
WEB OF SCIENCE
| PUBMED
54. Girodon F, Lombard M, Galan P, et al. Effect of micronutrient supplementation on infection in institutionalized elderly subjects: a controlled trial. Ann Nutr Metab. 1997;41:98-107.
WEB OF SCIENCE
| PUBMED
55. Moon TE, Levine N, Cartmel B, et al. Effect of retinol in preventing squamous cell skin cancer in moderate-risk subjects: a randomized, double-blind, controlled trial. Southwest Skin Cancer Prevention Study Group. Cancer Epidemiol Biomarkers Prev. 1997;6:949-956.
ABSTRACT
56. Sano M, Ernesto C, Thomas RG, et al. A controlled trial of selegiline, alpha-tocopherol, or both as treatment for Alzheimer's disease: the Alzheimer's Disease Cooperative Study. N Engl J Med. 1997;336:1216-1222.
FREE FULL TEXT
57. Bonelli L, Camoriano A, Ravelli P, Missale G, Bruzzi P, Aste H. Reduction of the incidence of metachronous adenomas of the large bowel by means of antioxidants. In: Palmieri Y, ed. Proceedings of International Selenium Tellurium Development Association. Brussels, Belgium: Se-Te Press; 1998:91-94.58. Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto miocardico (GISSI). Dietary supplementation with N-3 polyunsaturated fatty acids and vitamin E after myocardial infarction: results of the GISSI-Prevenzione trial. Lancet. 1999;354:447-455.
FULL TEXT
|
WEB OF SCIENCE
| PUBMED
59. Girodon F, Galan P, Monget AL, et al, MIN VIT AOX Geriatric Network. Impact of trace elements and vitamin supplementation on immunity and infections in institutionalized elderly patients: a randomized controlled trial. Arch Intern Med. 1999;159:748-754.
FREE FULL TEXT
60. Green A, Williams G, Neale R, et al. Daily sunscreen application and beta-carotene supplementation in prevention of basal-cell and squamous-cell carcinomas of the skin: a randomised controlled trial. Lancet. 1999;354:723-729.
FULL TEXT
|
WEB OF SCIENCE
| PUBMED
61. Boaz M, Smetana S, Weinstein T, et al. Secondary prevention with antioxidants of cardiovascular disease in endstage renal disease (SPACE): randomised placebo-controlled trial. Lancet. 2000;356:1213-1218.
FULL TEXT
|
WEB OF SCIENCE
| PUBMED
62. Correa P, Fontham ET, Bravo JC, et al. Chemoprevention of gastric dysplasia: randomized trial of antioxidant supplements and anti-helicobacter pylori therapy. J Natl Cancer Inst. 2000;92:1881-1888.
FREE FULL TEXT
63. Jacobson JS, Begg MD, Wang LW, et al. Effects of a 6-month vitamin intervention on DNA damage in heavy smokers. Cancer Epidemiol Biomarkers Prev. 2000;9:1303-1311.
FREE FULL TEXT
64. AREDS. A randomized, placebo-controlled, clinical trial of high-dose supplementation with vitamins C and E and beta carotene for age-related cataract and vision loss: AREDS report no. 9. Arch Ophthalmol. 2001;119:1439-1452.
FREE FULL TEXT
65. Brown BG, Zhao XQ, Chait A, et al. Simvastatin and niacin, antioxidant vitamins, or the combination for the prevention of coronary disease. N Engl J Med. 2001;345:1583-1592.
FREE FULL TEXT
66. Desnuelle C, Dib M, Garrel C, Favier A, ALS riluzole-tocopherol Study Group. A double-blind, placebo-controlled randomized clinical trial of alpha-tocopherol (vitamin E) in the treatment of amyotrophic lateral sclerosis. Amyotroph Lateral Scler Other Motor Neuron Disord. 2001;2:9-18.
FULL TEXT
|
WEB OF SCIENCE
| PUBMED
67. Stevic Z, Nicolic A, Blagojevic D, et al. A controlled trial of combination of methionine and antioxidants in ALS patients. Jugoslov Med Biohem. 2001;20:223-228.
68. You WC, Chang YS, Heinrich J, et al. An intervention trial to inhibit the progression of precancerous gastric lesions: compliance, serum micronutrients and S-allyl cysteine levels, and toxicity. Eur J Cancer Prev. 2001;10:257-263.
FULL TEXT
|
WEB OF SCIENCE
| PUBMED
69. de Gaetano G, Collaborative Group of the Primary Prevention Project. Low-dose aspirin and vitamin E in people at cardiovascular risk: a randomised trial in general practice. Lancet. 2001;357:89-95.
FULL TEXT
|
WEB OF SCIENCE
| PUBMED
70. de Waart FG, Kok FJ, Smilde TJ, Hijmans A, Wollersheim H, Stalenhoef AF. Effect of glutathione S-transferase M1 genotype on progression of atherosclerosis in lifelong male smokers. Atherosclerosis. 2001;158:227-231.
FULL TEXT
|
WEB OF SCIENCE
| PUBMED
71. Chylack LT Jr, Brown NP, Bron A, et al. The Roche European American Cataract Trial (REACT): a randomized clinical trial to investigate the efficacy of an oral antioxidant micronutrient mixture to slow progression of age-related cataract. Ophthalmic Epidemiol. 2002;9:49-80.
FULL TEXT
|
WEB OF SCIENCE
| PUBMED
72. Graat JM, Schouten EG, Kok FJ. Effect of daily vitamin E and multivitamin-mineral supplementation on acute respiratory tract infections in elderly persons: a randomized controlled trial. JAMA. 2002;288:715-721.
FREE FULL TEXT
73. Heart Protection Study. MRC/BHF Heart Protection Study of antioxidant vitamin supplementation in 20,536 high-risk individuals: a randomised placebo-controlled trial. Lancet. 2002;360:23-33.
FULL TEXT
|
WEB OF SCIENCE
| PUBMED
74. Hodis HN, Mack WJ, LaBree L, et al, VEAPS Research Group. Alpha-tocopherol supplementation in healthy individuals reduces low-density lipoprotein oxidation but not atherosclerosis: the Vitamin E Atherosclerosis Prevention Study (VEAPS). Circulation. 2002;106:1453-1459.
FREE FULL TEXT
75. Waters DD, Alderman EL, Hsia J, et al. Effects of hormone replacement therapy and antioxidant vitamin supplements on coronary atherosclerosis in postmenopausal women: a randomized controlled trial. JAMA. 2002;288:2432-2440.
FREE FULL TEXT
76. White KLM, Chalmers DM, Martin IG, et al. Dietary antioxidants and DNA damage in patients on long-term acid suppression therapy: a randomized controlled study. Br J Nutr. 2002;88:265-271.
FULL TEXT
|
WEB OF SCIENCE
| PUBMED
77. Wluka AE, Stuckey S, Brand C, Cicuttini FM. Supplementary vitamin E does not affect the loss of cartilage volume in knee osteoarthritis: a 2 year double blind randomized placebo controlled study. J Rheumatol. 2002;29:2585-2591.
FREE FULL TEXT
78. Collins EG, Edwin Langbein W, Orebaugh C, et al. PoleStriding exercise and vitamin E for management of peripheral vascular disease. Med Sci Sports Exerc. 2003;35:384-393.
FULL TEXT
|
WEB OF SCIENCE
| PUBMED
79. Prince MI, Mitchison HC, Ashley D, et al. Oral antioxidant supplementation for fatigue associated with primary biliary cirrhosis: results of a multicentre, randomized, placebo-controlled, cross-over trial. Aliment Pharmacol Ther. 2003;17:137-143.
FULL TEXT
|
WEB OF SCIENCE
| PUBMED
80. Salonen RM, Nyyssonen K, Kaikkonen J, et al. Antioxidant supplementation in atherosclerosis prevention study: six-year effect of combined vitamin C and E supplementation on atherosclerotic progression: the Antioxidant Supplementation in Atherosclerosis Prevention (ASAP) Study. Circulation. 2003;107:947-953.
FREE FULL TEXT
81. Sasazuki S, Sasaki S, Tsubono Y, et al. The effect of 5-year vitamin C supplementation on serum pepsinogen level and Helicobacter pylori infection. Cancer Sci. 2003;94:378-382.
FULL TEXT
| PUBMED
82. Takagi H, Kakizaki S, Sohara N, et al. Pilot clinical trial of the use of alpha-tocopherol for the prevention of hepatocellular carcinoma in patients with liver cirrhosis. Int J Vitam Nutr Res. 2003;73:411-415.
FULL TEXT
|
WEB OF SCIENCE
| PUBMED
83. Virtamo J, Pietinen P, Huttunen JK, et al, ATBC Study Group. Incidence of cancer and mortality following alpha-tocopherol and beta-carotene supplementation: a postintervention follow-up. JAMA. 2003;290:476-485.
FREE FULL TEXT
84. Allsup SJ, Shenkin A, Gosney MA, et al. Can a short period of micronutrient supplementation in older institutionalized people improve response to influenza vaccine? a randomized, controlled trial. J Am Geriatr Soc. 2004;52:20-24.
FULL TEXT
|
WEB OF SCIENCE
| PUBMED
85. Goodman GE, Thornquist MD, Balmes J, et al. The Beta-Carotene and Retinol Efficacy Trial: incidence of lung cancer and cardiovascular disease mortality during 6-year follow-up after stopping beta-carotene and retinol supplements. J Natl Cancer Inst. 2004;96:1743-1750.
FREE FULL TEXT
86. Hercberg S, Galan P, Preziosi P, et al. The SU.VI.MAX Study: a randomized, placebo-controlled trial of the health effects of antioxidant vitamins and minerals. Arch Intern Med. 2004;164:2335-2342.
FREE FULL TEXT
87. Manuel-y-Keenoy B, Vinckx M, Vertommen J, Van Gaal L, De Leeuw I. Impact of vitamin E supplementation on lipoprotein peroxidation and composition in type 1 diabetic patients treated with atorvastatin. Atherosclerosis. 2004;175:369-376.
FULL TEXT
|
WEB OF SCIENCE
| PUBMED
88. McNeil JJ, Robman L, Tikellis G, Sinclair MI, McCarty CA, Taylor HR. Vitamin E supplementation and cataract: randomized controlled trial. Ophthalmology. 2004;111:75-84.
FULL TEXT
|
WEB OF SCIENCE
| PUBMED
89. Meydani SN, Leka LS, Fine BC, et al. Vitamin E and respiratory tract infections in elderly nursing home residents: a randomized controlled trial. JAMA. 2004;292:828-836.
FREE FULL TEXT
90. Mezey E, Potter JJ, Rennie-Tankersley L, Caballeria J, Pares A. A randomized placebo controlled trial of vitamin E for alcoholic hepatitis. J Hepatol. 2004;40:40-46.
WEB OF SCIENCE
| PUBMED
91. Richer S, Stiles W, Statkute L, et al. Double-masked, placebo-controlled, randomized trial of lutein and antioxidant supplementation in the intervention of atrophic age-related macular degeneration: the Veterans LAST study (Lutein Antioxidant Supplementation Trial). Optometry. 2004;75:216-230.
PUBMED
92. Avenell A, Campbell MK, Cook JA, et al. Effect of multivitamin and multimineral supplements on morbidity from infections in older people (MAVIS trial): pragmatic, randomised, double blind, placebo controlled trial. BMJ. 2005;331:324-329.
FREE FULL TEXT
93. Graf M, Ecker D, Horowski R, et al. High dose vitamin E therapy in amyotrophic lateral sclerosis as add-on therapy to riluzole: results of a placebo-controlled double-blind study. J Neural Transm. 2005;112:649-660.
FULL TEXT
|
WEB OF SCIENCE
| PUBMED
94. Lee IM, Cook NR, Gaziano JM, et al. Vitamin E in the primary prevention of cardiovascular disease and cancer: the Women's Health Study: a randomized controlled trial. JAMA. 2005;294:56-65.
FREE FULL TEXT
95. Limburg PJ, Wei W, Ahnen DJ, et al. Randomized, placebo-controlled, esophageal squamous cell cancer chemoprevention trial of selenomethionine and celecoxib. Gastroenterology. 2005;129:863-873.
FULL TEXT
|
WEB OF SCIENCE
| PUBMED
96. Lonn E, Bosch J, Yusuf S, et al, HOPE and HOPE-TOO Trial Investigators. Effects of long-term vitamin E supplementation on cardiovascular events and cancer: a randomized controlled trial. JAMA. 2005;293:1338-1347.
FREE FULL TEXT
97. Marras C, McDermott MP, Rochon PA, et al. Parkinson Study Group. Survival in Parkinson disease: thirteen-year follow-up of the DATATOP cohort. Neurology. 2005;64:87-93.
FREE FULL TEXT
98. Mooney LA, Madsen AM, Tang D, et al. Antioxidant vitamin supplementation reduces benzo(a)pyrene-DNA adducts and potential cancer risk in female smokers. Cancer Epidemiol Biomarkers Prev. 2005;14:237-242.
FREE FULL TEXT
99. Petersen RC, Thomas RG, Grundman M, et al, Alzheimer's Disease Cooperative Study Group. Vitamin E and donepezil for the treatment of mild cognitive impairment. N Engl J Med. 2005;352:2379-2388.
FREE FULL TEXT
100. Tam LS, Li EK, Leung VY, et al. Effects of vitamins C and E on oxidative stress markers and endothelial function in patients with systemic lupus erythematosus: a double blind, placebo controlled pilot study. J Rheumatol. 2005;32:275-282.
FREE FULL TEXT
101. Witte KK, Nikitin NP, Parker AC, et al. The effect of micronutrient supplementation on quality-of-life and left ventricular function in elderly patients with chronic heart failure. Eur Heart J. 2005;26:2238-2244.
FREE FULL TEXT
102. Rayman M, Thompson A, Warren-Perry M, et al. Impact of selenium on mood and quality of life: a randomized, controlled trial [published online September 21, 2005]. Biol Psychiatry. 2006;59:147-154.
FULL TEXT
|
WEB OF SCIENCE
| PUBMED
103. Caraballoso M, Sacristan M, Serra C, Bonfill X. Drugs for preventing lung cancer in healthy people. Cochrane Database Syst Rev. doi: 10.1002/14651858.CD002141. 2003;(2):CD002141.
PUBMED
104. Vivekananthan DP, Penn MS, Sapp SK, Hsu A, Topol EJ. Use of antioxidant vitamins for the prevention of cardiovascular disease: meta-analysis of randomised trials. Lancet. 2003;361:2017-2023.
FULL TEXT
|
WEB OF SCIENCE
| PUBMED
105. Davies AA, Davey Smith G, Harbord R, et al. Nutritional interventions and outcome in patients with cancer or preinvasive lesions: systematic review. J Natl Cancer Inst. 2006;98:961-973.
FREE FULL TEXT
106. Miller ER III, Pastor-Barriuso R, Dalal D, Riemersma RA, Appel LJ, Guallar E. Meta-analysis: high-dosage vitamin E supplementation may increase all-cause mortality. Ann Intern Med. 2005;142:37-46.
FREE FULL TEXT
107. Huang HY, Caballero B, Chang S, et al. The efficacy and safety of multivitamin and mineral supplement use to prevent cancer and chronic disease in adults: a systematic review for a National Institutes of Health state-of-the-science conference. Ann Intern Med. 2006;145:372-385.
FREE FULL TEXT
108. Gluud LL. Bias in clinical intervention research. Am J Epidemiol. 2006;163:493-501.
FREE FULL TEXT
109. Gluud C. The culture of designing hepato-biliary randomised trials. J Hepatol. 2006;44:607-615.
FULL TEXT
|
WEB OF SCIENCE
| PUBMED
110. Dickersin K, Rennie D. Registering clinical trials. JAMA. 2003;290:516-523.
FREE FULL TEXT
111. Vertuani S, Angusti A, Manfredini S. The antioxidants and pro-antioxidants network: an overview. Curr Pharm Des. 2004;10:1677-1694.
FULL TEXT
|
WEB OF SCIENCE
| PUBMED
112. Kawanishi S, Oikawa S, Murata M. Evaluation for safety of antioxidant chemopreventive agents. Antioxid Redox Signal. 2005;7:1728-1739.
FULL TEXT
|
WEB OF SCIENCE
| PUBMED
113. Palace VP, Khaper N, Qin Q, Singal PK. Antioxidant potentials of vitamin A and carotenoids and their relevance to heart disease. Free Radic Biol Med. 1999;26:746-761.
FULL TEXT
|
WEB OF SCIENCE
| PUBMED
114. Maxwell SR. Antioxidant vitamin supplements: update of their potential benefits and possible risks. Drug Saf. 1999;21:253-266.
FULL TEXT
|
WEB OF SCIENCE
| PUBMED
115. Hercberg S, Galan P, Preziosi P, Alfarez MJ, Vazquez C. The potential role of antioxidant vitamins in preventing cardiovascular diseases and cancers. Nutrition. 1998;14:513-520.
FULL TEXT
|
WEB OF SCIENCE
| PUBMED
116. Panel on Micronutrients: Subcommittees on Upper Reference Levels of Nutrients and of Interpretation and Use of Dietary Reference Intakes, and the Standing Committee on the Scientific Evaluation of Dietary Reference Intakes. Institute of Medicine, Food and Nutrition Board: Dietary Reference Intakes for Vitamin A, Vitamin K, Arsenic, Boron, Chromium, Copper, Iodine, Iron, Manganese, Molybdenum, Nickel, Silicon, Vanadium, and Zinc. Washington, DC: National Academy Press; 2000:1-800.117. Panel on Dietary Antioxidants and Related Compounds: Subcommittees on Upper Reference Levels of Nutrients and Interpretation and Uses of DRIs, Standing Committee on the Scientific Evaluation of Dietary Reference Intakes, Food and Nutrition Board. Institute of Medicine: Dietary Reference Intakes for Vitamin C, Vitamin E, Selenium, and Carotenoids. Washington, DC: National Academy Press; 2000:1-529.118. Ritenbaugh C, Streit K, Helfand M. Routine vitamin supplementation to prevent cancer: summary of evidence from randomized controlled trials. http://www.ahrq.gov/clinic/3rduspstf/vitamins/vitasum.htm. Accessed December 30, 2006.119. Atkins D, Shetty P. Update of the evidence from randomized controlled trials, 1999 - 2002. Routine vitamin supplementation to prevent cancer. http://www.ahrq.gov/clinic/3rduspstf/vitamins/vitupdate.htm. Accessed December 30, 2006.120. McKevith B, Kelly C, Stanner S, Hughes J, Buttriss J. The Food Standards Agency's antioxidants in food programme—a summary. J Hum Nutr Diet. 2003;16:257-263.
FULL TEXT
|
WEB OF SCIENCE
| PUBMED
121. Paolini M, Abdel-Rahman SZ, Sapone A, et al. Beta-carotene: a cancer chemopreventive agent or a co-carcinogen? Mutat Res. 2003;543:195-200.
FULL TEXT
|
WEB OF SCIENCE
| PUBMED
122. Lee BM, Park KK. Beneficial and adverse effects of chemopreventive agents. Mutat Res. 2003;523-524:265-278.
123. Brown BG, Crowley J. Is there any hope for vitamin E? JAMA. 2005;293:1387-1390.
FREE FULL TEXT
124. Devaraj S, Jialal I. Failure of vitamin E in clinical trials: is gamma-tocopherol the answer? Nutr Rev. 2005;63:290-293.
FULL TEXT
|
WEB OF SCIENCE
| PUBMED
125. Guallar E, Hanley DF, Miller ER III. Annus horribilis for vitamin E. Ann Intern Med. 2005;143:143-145.
FREE FULL TEXT
126. Duarte TL, Lunec J. When is an antioxidant not an antioxidant? a review of novel actions and reactions of vitamin C. Free Radic Res. 2005;39:671-686.
FULL TEXT
|
WEB OF SCIENCE
| PUBMED
127. Podmore ID, Griffiths HR, Herbert KE, Mistry N, Mistry P, Lunec J. Vitamin C exhibits pro-oxidant properties. Nature. 1998;392:559.
FULL TEXT
| PUBMED
128. Klein EA, Thompson IM, Lippman SM, et al. SELECT: the selenium and vitamin E cancer prevention trial. Urol Oncol. 2003;21:59-65.
WEB OF SCIENCE
| PUBMED
129. Machlin LJ, Bendich A. Free radical tissue damage: protective role of antioxidant nutrients. FASEB J. 1987;1:441-445.
ABSTRACT
130. Diplock AT. Antioxidants and disease prevention. Mol Aspects Med. 1994;15:293-376.
FULL TEXT
|
WEB OF SCIENCE
| PUBMED
131. van Poppel G, van den Berg H. Vitamins and cancer. Cancer Lett. 1997;114:195-202.
FULL TEXT
|
WEB OF SCIENCE
| PUBMED
132. Diplock AT, Charleux JL, Crozier-Willi G, et al. Functional food science and defence against reactive oxidative species. Br J Nutr. 1998;80(suppl 1):S77-S112.
PUBMED
133. Halliwell B. Free radicals, antioxidants, and human disease: curiosity, cause, or consequence? Lancet. 2000;344:721-724.
134. Salganik RI. The benefits and hazards of antioxidants: controlling apoptosis and other protective mechanisms in cancer patients and the human population. J Am Coll Nutr. 2001;20(suppl):464S-472S.
FREE FULL TEXT
135. Simon HU, Haj-Yehia A, Levi-Schaffer F. Role of reactive oxygen species (ROS) in apoptosis induction. Apoptosis. 2000;5:415-418.
FULL TEXT
|
WEB OF SCIENCE
| PUBMED
136. Kimura H, Sawada T, Oshima S, Kozawa K, Ishioka T, Kato M. Toxicity and roles of reactive oxygen species. Curr Drug Targets Inflamm Allergy. 2005;4:489-495.
FULL TEXT
| PUBMED
137. Bast A, Haenen GR. The toxicity of antioxidants and their metabolites. Environ Toxicol Pharmacol. 2002;11:251-258.
FULL TEXT
138. Ratnam DV, Ankola DD, Bhardwaj V, Sahana DK, Kumar MN. Role of antioxidants in prophylaxis and therapy: a pharmaceutical perspective. J Control Release. 2006;113:189-207.
FULL TEXT
|
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Additional articles abstracted in ACP Journal Club
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Antioxidant Supplements and Mortality
Albanes
JAMA 2007;298:400-400.
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Antioxidant Supplements and Mortality
Hemila
JAMA 2007;298:401-401.
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Antioxidant Supplements and Mortality
Huang et al.
JAMA 2007;298:400-401.
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Taylor and Dawsey
JAMA 2007;298:401-402.
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From the Library
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Antioxidant Supplements and All-Cause Mortality
JWatch General 2007;2007:3-3.
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