Search

Purpose of Review: Oxidative damage to cells and tissues is considered involved in the aging process and in the development of chronic diseases in humans, including cancer and cardiovascular diseases, the leading causes of death in high-income countries. This has stimulated interest in the preventive potential of antioxidant supplements. Today, more than one half of adults in high-income countries ingest antioxidant supplements hoping to improve their health, oppose unhealthy behaviors, and counteract the ravages of aging., Recent Findings: Older observational studies and some randomized clinical trials with high risks of systematic errors ('bias') have suggested that antioxidant supplements may improve health and prolong life. A number of randomized clinical trials with adequate methodologies observed neutral or negative results of antioxidant supplements. Recently completed large randomized clinical trials with low risks of bias and systematic reviews of randomized clinical trials taking systematic errors ('bias') and risks of random errors ('play of chance') into account have shown that antioxidant supplements do not seem to prevent cancer, cardiovascular diseases, or death. Even more, beta-carotene, vitamin A, and vitamin E may increase mortality. Some recent large observational studies now support these findings. According to recent dietary guidelines, there is no evidence to support the use of antioxidant supplements in the primary prevention of chronic diseases or mortality., Summary: Antioxidant supplements do not possess preventive effects and may be harmful with unwanted consequences to our health, especially in well-nourished populations. The optimal source of antioxidants seems to come from our diet, not from antioxidant supplements in pills or tablets.

Clinical Question: Are antioxidant supplements associated with higher or lower all-cause mortality?, Bottom Line: Antioxidant supplements are not associated with lower all-cause mortality. Beta carotene, vitamin E, and higher doses of vitamin A may be associated with higher all-cause mortality.

Background: Our systematic review has demonstrated that antioxidant supplements may increase mortality. We have now updated this review., Objectives: To assess the beneficial and harmful effects of antioxidant supplements for prevention of mortality in adults., Search Methods: We searched The Cochrane Library, MEDLINE, EMBASE, LILACS, the Science Citation Index Expanded, and Conference Proceedings Citation Index-Science to February 2011. We scanned bibliographies of relevant publications and asked pharmaceutical companies for additional trials., Selection Criteria: 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., Data Collection and Analysis: Three authors extracted data. Random-effects and fixed-effect model meta-analyses were conducted. Risk of bias was considered in order to minimise the risk of systematic errors. Trial sequential analyses were conducted to minimise the risk of random errors. Random-effects model meta-regression analyses were performed to assess sources of intertrial heterogeneity., Main Results: Seventy-eight randomised trials with 296,707 participants were included. Fifty-six trials including 244,056 participants had low risk of bias. Twenty-six trials included 215,900 healthy participants. Fifty-two trials included 80,807 participants with various diseases in a stable phase. The mean age was 63 years (range 18 to 103 years). The mean proportion of women was 46%. Of the 78 trials, 46 used the parallel-group design, 30 the factorial design, and 2 the cross-over design. All antioxidants were administered orally, either alone or in combination with vitamins, minerals, or other interventions. The duration of supplementation varied from 28 days to 12 years (mean duration 3 years; median duration 2 years). Overall, the antioxidant supplements had no significant effect on mortality in a random-effects model meta-analysis (21,484 dead/183,749 (11.7%) versus 11,479 dead/112,958 (10.2%); 78 trials, relative risk (RR) 1.02, 95% confidence interval (CI) 0.98 to 1.05) but significantly increased mortality in a fixed-effect model (RR 1.03, 95% CI 1.01 to 1.05). Heterogeneity was low with an I(2)- of 12%. In meta-regression analysis, the risk of bias and type of antioxidant supplement were the only significant predictors of intertrial heterogeneity. Meta-regression analysis did not find a significant difference in the estimated intervention effect in the primary prevention and the secondary prevention trials. In the 56 trials with a low risk of bias, the antioxidant supplements significantly increased mortality (18,833 dead/146,320 (12.9%) versus 10,320 dead/97,736 (10.6%); RR 1.04, 95% CI 1.01 to 1.07). This effect was confirmed by trial sequential analysis. Excluding factorial trials with potential confounding showed that 38 trials with low risk of bias demonstrated a significant increase in mortality (2822 dead/26,903 (10.5%) versus 2473 dead/26,052 (9.5%); RR 1.10, 95% CI 1.05 to 1.15). In trials with low risk of bias, beta-carotene (13,202 dead/96,003 (13.8%) versus 8556 dead/77,003 (11.1%); 26 trials, RR 1.05, 95% CI 1.01 to 1.09) and vitamin E (11,689 dead/97,523 (12.0%) versus 7561 dead/73,721 (10.3%); 46 trials, RR 1.03, 95% CI 1.00 to 1.05) significantly increased mortality, whereas vitamin A (3444 dead/24,596 (14.0%) versus 2249 dead/16,548 (13.6%); 12 trials, RR 1.07, 95% CI 0.97 to 1.18), vitamin C (3637 dead/36,659 (9.9%) versus 2717 dead/29,283 (9.3%); 29 trials, RR 1.02, 95% CI 0.98 to 1.07), and selenium (2670 dead/39,779 (6.7%) versus 1468 dead/22,961 (6.4%); 17 trials, RR 0.97, 95% CI 0.91 to 1.03) did not significantly affect mortality. In univariate meta-regression analysis, the dose of vitamin A was significantly associated with increased mortality (RR 1.0006, 95% CI 1.0002 to 1.001, P = 0.002)., Authors' Conclusions: We found no evidence to support antioxidant supplements for primary or secondary prevention. Beta-carotene and vitamin E seem to increase mortality, and so may higher doses of vitamin A. Antioxidant supplements need to be considered as medicinal products and should undergo sufficient evaluation before marketing.

Background: Several liver diseases have been associated with oxidative stress. Accordingly, antioxidants have been suggested as potential therapeutics for various liver diseases. The evidence supporting these suggestions is equivocal., Objectives: To assess the benefits and harms of antioxidant supplements for patients with liver diseases., Search Strategy: We searched The Cochrane Library, MEDLINE, EMBASE, LILACS, the Science Citation Index Expanded, and Conference Proceedings Citation Index-Science to January 2011. We scanned bibliographies of relevant publications and asked experts and pharmaceutical companies for additional trials., Selection Criteria: We considered for inclusion randomised trials that compared antioxidant supplements (beta-carotene, vitamin A, C, E, and selenium) versus placebo or no intervention for autoimmune liver diseases, viral hepatitis, alcoholic liver disease, and cirrhosis (any aetiology)., Data Collection and Analysis: Four authors independently selected trials for inclusion and extracted data. Outcome measures were all-cause mortality, liver-related mortality, liver-related morbidity, biochemical indices at maximum follow-up in the individual trials as well as adverse events, quality-of-life measures, and cost-effectiveness. For patients with hepatitis B or C we also considered end of treatment and sustained virological response. We conducted random-effects and fixed-effect meta-analyses. Results were presented as relative risks (RR) or mean differences (MD), both with 95% confidence intervals (CI)., Main Results: Twenty randomised trials with 1225 participants were included. The trials assessed beta-carotene (3 trials), vitamin A (2 trials), vitamin C (9 trials), vitamin E (15 trials), and selenium (8 trials). The majority of the trials had high risk of bias and showed heterogeneity. Overall, the assessed antioxidant supplements had no significant effect on all-cause mortality (relative risk [RR] 0.84, 95% confidence interval [CI] 0.60 to 1.19, I(2) = 0%), or liver-related mortality (RR 0.89, 95% CI 0.39 to 2.05, I(2) = 37%). Stratification according to the type of liver disease did not affect noticeably the results. Antioxidant supplements significantly increased activity of gamma glutamyl transpeptidase (MD 24.21 IU/l, 95% CI 6.67 to 41.75, I(2) = 0%)., Authors' Conclusions: We found no evidence to support or refute antioxidant supplements in patients with liver disease. Antioxidant supplements may increase liver enzyme activity.

Background: Several liver diseases have been associated with oxidative stress. Accordingly, antioxidants have been suggested as potential therapeutics for various liver diseases. The evidence supporting these suggestions is equivocal., Aim: To assess the benefits and harms of antioxidant supplements for patients with liver diseases., Methods: We identified trials through electronic and manual searches until August 2009. We included randomized trials comparing antioxidant supplements (beta-carotene, vitamin A, C, E and selenium) vs. placebo or no intervention for autoimmune liver diseases, viral hepatitis, alcoholic liver disease and cirrhosis (any aetiology). Random-effects and fixed-effect meta-analyses were conducted. Results were presented as relative risks (RR), or mean difference (MD), both with 95% confidence intervals (CI)., Results: Twenty randomized trials with 1225 participants were included. The trials assessed beta-carotene (3 trials), vitamin A (2 trials), vitamin C (9 trials), vitamin E (15 trials) and selenium (8 trials). The majority of the trials had high risk of bias and showed heterogeneity. Overall, the assessed antioxidant supplements had no significant effect on all-cause mortality [relative risk (RR) 0.84, 95% confidence interval (CI) 0.60-1.19, I(2) = 0%] or liver-related mortality (RR 0.89, 95% CI 0.39-2.05, I(2) = 37%). Stratification according to the type of liver disease assessed did not affect the conclusions. Antioxidant supplements significantly increased the activity of gamma glutamyl transpeptidase (MD 24.21 IU/L, 95% CI 6.67-41.75, I(2) = 0%)., Conclusions: We found no evidence to support or refute antioxidant supplements in patients with liver disease. Antioxidant supplements may increase liver enzymes.

Background: The evidence on whether antioxidant supplements prevent gastrointestinal cancers is contradictory., Aim: To assess the beneficial and harmful effects of antioxidant supplements in preventing gastrointestinal cancers., Methods: Using the Cochrane Collaboration methodology, we reviewed the randomized trials comparing antioxidant supplements with placebo or no intervention on the occurrence of gastrointestinal cancers. We searched electronic databases and reference lists until October, 2007. Our outcome measures were gastrointestinal cancers, overall mortality and adverse events. Outcomes were reported as relative risks (RR) with 95% confidence intervals (CI) based on random-effects and fixed-effect models meta-analyses., Results: We identified 20 randomized trials (211,818 participants) assessing beta-carotene, vitamin A, vitamin C, vitamin E, and selenium. The trial quality was generally high. The antioxidant supplements were without a significant effect on the occurrence of gastrointestinal cancers (RR 0.94, 95% CI 0.83-1.06, I(2) = 54.0%). The heterogeneity seemed to be explained by bias risk (low-bias risk trials RR 1.04, 95% CI 0.96-1.13 compared to high-bias risk trials RR 0.59, 95% CI 0.43-0.80, test of interaction P < 0.0005) and type of antioxidant supplement (beta-carotene potentially increasing and selenium potentially decreasing cancer risk). Antioxidant supplements had no significant effect on mortality in a random-effects model meta-analysis (RR 1.02, 95% CI 0.97-1.07, I(2) = 53.5%) but significantly increased mortality in a fixed-effect model meta-analysis (RR 1.04, 95% CI 1.02-1.07)., Conclusions: We could not find evidence that the studied antioxidant supplements prevented gastrointestinal cancers. On the contrary, they seem to increase overall mortality.

Background: Oxidative stress may cause gastrointestinal cancers. The evidence on whether antioxidant supplements are effective in preventing gastrointestinal cancers is contradictory., Objectives: To assess the beneficial and harmful effects of antioxidant supplements in preventing gastrointestinal cancers., Search Strategy: We identified trials through the trials registers of the four Cochrane Review Groups on gastrointestinal diseases, The Cochrane Central Register of Controlled Trials in The Cochrane Library (Issue 2, 2007), MEDLINE, EMBASE, LILACS, SCI-EXPANDED, and The Chinese Biomedical Database from inception to October 2007. We scanned reference lists and contacted pharmaceutical companies., Selection Criteria: Randomised trials comparing antioxidant supplements to placebo/no intervention examining occurrence of gastrointestinal cancers., Data Collection and Analysis: Two authors (GB and DN) independently selected trials for inclusion and extracted data. Outcome measures were gastrointestinal cancers, overall mortality, and adverse effects. Outcomes were reported as relative risks (RR) with 95% confidence interval (CI) based on random-effects and fixed-effect model meta-analysis. Meta-regression assessed the effect of covariates across the trials., Main Results: We identified 20 randomised trials (211,818 participants), assessing beta-carotene (12 trials), vitamin A (4 trials), vitamin C (8 trials), vitamin E (10 trials), and selenium (9 trials). Trials quality was generally high. Heterogeneity was low to moderate. Antioxidant supplements were without significant effects on gastrointestinal cancers (RR 0.94, 95% CI 0.83 to 1.06). However, there was significant heterogeneity (I(2) = 54.0%, P = 0.003). The heterogeneity may have been explained by bias risk (low-bias risk trials RR 1.04, 95% CI 0.96 to 1.13 compared to high-bias risk trials RR 0.59, 95% CI 0.43 to 0.80; test of interaction P < 0.0005), and type of antioxidant supplement (beta-carotene potentially increasing and selenium potentially decreasing cancer risk). The antioxidant supplements had no significant effects on mortality in a random-effects model meta-analysis (RR 1.02, 95% CI 0.97 to 1.07, I(2) = 53.5%), but significantly increased mortality in a fixed-effect model meta-analysis (RR 1.04, 95% CI 1.02 to 1.07). Beta-carotene in combination with vitamin A (RR 1.16, 95% CI 1.09 to 1.23) and vitamin E (RR 1.06, 95% CI 1.02 to 1.11) significantly increased mortality. Increased yellowing of the skin and belching were non-serious adverse effects of beta-carotene. In five trials (four with high risk of bias), selenium seemed to show significant beneficial effect on gastrointestinal cancer occurrence (RR 0.59, 95% CI 0.46 to 0.75, I(2) = 0%)., Authors' Conclusions: We could not find convincing evidence that antioxidant supplements prevent gastrointestinal cancers. On the contrary, antioxidant supplements seem to increase overall mortality. The potential cancer preventive effect of selenium should be tested in adequately conducted randomised trials.

Background: Animal and physiological research as well as observational studies suggest that antioxidant supplements may improve survival., Objectives: To assess the effect of antioxidant supplements on mortality in primary or secondary prevention randomised clinical trials., Search Strategy: 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., Selection Criteria: 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)., Data Collection and Analysis: 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., Main 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)., Authors' 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.

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, 1.04[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.

Background: Colorectal cancer may be prevented by reducing the development of adenomatous polyps., Aim: To assess the benefits and harms of antioxidant supplements in preventing colorectal adenoma., Methods: Using the Cochrane Collaboration methodology we reviewed all randomized clinical trials comparing antioxidant supplements with placebo or no intervention. We searched electronic databases and the reference lists until October 2005. Outcome measures were development of colorectal adenoma adverse events. We analysed dichotomous outcomes with fixed- and random-effects model meta-analyses and calculated the relative risk with 95% confidence interval., Results: We identified eight randomized trials (17 620 participants). Neither fixed-effect (relative risk: 0.93, 95% CI: 0.81-1.1) nor random-effect model meta-analyses (0.82, 0.60-1.1) showed statistically significant effects of supplementation with beta-carotene, vitamins A, C, E and selenium alone or in combination. Antioxidant supplements seemed to increase the development of colorectal adenoma in three low-bias risk trials (1.2, 0.99-1.4) and significantly decrease its development in five high-bias risk trials (0.59, 0.47-0.74). The estimates difference is significant (P < 0.0001). There was no significant difference between the intervention groups regarding adverse events, including mortality (0.82, 0.47-1.4)., Conclusion: We found no convincing evidence that antioxidant supplements have significant beneficial effect on primary or secondary prevention of colorectal adenoma.

Background: Oxidative stress may cause gastrointestinal cancers. The evidence on whether antioxidant supplements are effective in preventing gastrointestinal cancers is contradictory., Objectives: To assess the beneficial and harmful effects of antioxidant supplements in preventing gastrointestinal cancers., Search Strategy: We identified trials through the trials registers of the four Cochrane Review Groups on gastrointestinal diseases, The Cochrane Central Register of Controlled Trials on The Cochrane Library (Issue 1, 2003), MEDLINE, EMBASE, LILACS, and SCI-EXPANDED from inception to February 2003, and The Chinese Biomedical Database (March 2003). We scanned reference lists and contacted pharmaceutical companies., Selection Criteria: Randomised trials comparing antioxidant supplements to placebo/no intervention examining the incidence of gastrointestinal cancers., Data Collection and Analysis: Two reviewers independently selected trials for inclusion and extracted data. The outcome measures were incidence of gastrointestinal cancers, overall mortality, and adverse events. Outcomes were reported as relative risks (RR) with 95% confidence interval (CI) based on fixed and random effects meta-analyses., Main Results: We identified 14 randomised trials (170,525 participants), assessing beta-carotene (9 trials), vitamin A (4 trials), vitamin C (4 trials), vitamin E (5 trials), and selenium (6 trials). Trial quality was generally high. Heterogeneity was low to moderate. Neither the fixed effect (RR 0.96, 95% CI 0.88 to 1.04) nor random effects meta-analyses (RR 0.90, 95% CI 0.77 to 1.05) showed significant effects of supplementation with antioxidants on the incidences of gastrointestinal cancers. Among the seven high-quality trials reporting on mortality (131,727 participants), the fixed effect (RR 1.06, 95% CI 1.02 to 1.10) unlike the random effects meta-analysis (RR 1.06, 95% CI 0.98 to 1.15) showed that antioxidant supplements significantly increased mortality. Two low-quality trials (32,302 participants) found no significant effect of antioxidant supplementation on mortality. The difference between the mortality estimates in high- and low-quality trials was significant by test of interaction (z = 2.10, P = 0.04). Beta-carotene and vitamin A (RR 1.29, 95% CI 1.14 to 1.45) and beta-carotene and vitamin E (RR 1.10, 95% CI 1.01 to 1.20) significantly increased mortality, while beta-carotene alone only tended to do so (RR 1.05, 95% CI 0.99 to 1.11). Increased yellowing of the skin and belching were non-serious adverse effects of beta-carotene. In four trials (three with unclear/inadequate methodology), selenium showed significant beneficial effect on gastrointestinal cancer incidences., Reviewers' Conclusions: We could not find evidence that antioxidant supplements prevent gastrointestinal cancers. On the contrary, they seem to increase overall mortality. The potential cancer preventive effect of selenium should be studied in adequately conducted randomised trials.

Background: Oxidative stress can cause cancer. Our aim was to establish whether antioxidant supplements reduce the incidence of gastrointestinal cancer and mortality., Methods: With the Cochrane Collaboration methodology, we reviewed all randomised trials comparing antioxidant supplements with placebo for prevention of gastrointestinal cancers. We searched electronic databases and reference lists (February, 2003). Outcome measures were incidence of gastrointestinal cancers, overall mortality, and adverse effects. Outcomes were analysed with fixed-effect and random-effects model meta-analyses and were reported as relative risk with 95% CIs., Findings: We identified 14 randomised trials (n=170,525). Trial quality was generally high. Heterogeneity of results was low to moderate. Neither the fixed-effect (relative risk 0.96, 95% CI 0.88-1.04) nor random-effects meta-analyses (0.90, 0.77-1.05) showed significant effects of supplementation with beta-carotene, vitamins A, C, E, and selenium (alone or in combination) versus placebo on oesophageal, gastric, colorectal, pancreatic, and liver cancer incidences. In seven high-quality trials (n=131727), the fixed-effect model showed that antioxidant significantly increased mortality (1.06, 1.02-1.10), unlike the random-effects meta-analysis (1.06, 0.98-1.15). Low-quality trials showed no significant effect of antioxidant supplementation on mortality. The difference between the mortality estimates in high-quality and low-quality trials was significant (Z=2.10, p=0.04 by test of interaction). beta-carotene and vitamin A (1.29, 1.14-1.45) and beta-carotene and vitamin E (1.10, 1.01-1.20) significantly increased mortality, whereas beta-carotene alone only tended to increase mortality (1.05, 0.99-1.11). In four trials (three with unclear or inadequate methodology), selenium showed significant beneficial effect on the incidence of gastrointestinal cancer., Interpretation: We could not find evidence that antioxidant supplements can prevent gastrointestinal cancers; on the contrary, they seem to increase overall mortality. The potential preventive effect of selenium should be studied in adequate randomised trials.

A response by the G. Bjelakovic and colleagues to a letter to the editor on their article "Metaanalysis: antioxidant supplements for liver disease: the Cochrane Hepato-Biliary Group" in the 2010 issue is presented.