Dimitrinka Nikolova

Antioxidant supplements for prevention of gastrointestinal cancers: a systematic review and meta-analysis

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.

Assessment of risk of bias in randomized clinical trials in surgery.

Meta‐analysis of randomized clinical trials (RCTs) with low risk of bias is considered the highest level of evidence available for evaluating an intervention. Bias in RCTs may overestimate or underestimate the true effectiveness of an intervention.

Antioxidant supplements and mortality.

Purpose of reviewOxidative 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 findingsOlder 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. SummaryAntioxidant 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.

Systematic review: primary and secondary prevention of gastrointestinal cancers with antioxidant supplements

Background  The evidence on whether antioxidant supplements prevent gastrointestinal cancers is contradictory.

Meta-Regression Analyses, Meta-Analyses, and Trial Sequential Analyses of the Effects of Supplementation with Beta-Carotene, Vitamin A, and Vitamin E Singly or in Different Combinations on All-Cause Mortality: Do We Have Evidence for Lack of Harm?

Background and Aims Evidence shows that antioxidant supplements may increase mortality. Our aims were to assess whether different doses of beta-carotene, vitamin A, and vitamin E affect mortality in primary and secondary prevention randomized clinical trials with low risk of bias. Methods The present study is based on our 2012 Cochrane systematic review analyzing beneficial and harmful effects of antioxidant supplements in adults. Using random-effects meta-analyses, meta-regression analyses, and trial sequential analyses, we examined the association between beta-carotene, vitamin A, and vitamin E, and mortality according to their daily doses and doses below and above the recommended daily allowances (RDA). Results We included 53 randomized trials with low risk of bias (241,883 participants, aged 18 to 103 years, 44.6% women) assessing beta-carotene, vitamin A, and vitamin E. Meta-regression analysis showed that the dose of vitamin A was significantly positively associated with all-cause mortality. Beta-carotene in a dose above 9.6 mg significantly increased mortality (relative risk (RR) 1.06, 95% confidence interval (CI) 1.02 to 1.09, I2 = 13%). Vitamin A in a dose above the RDA (> 800 µg) did not significantly influence mortality (RR 1.08, 95% CI 0.98 to 1.19, I2 = 53%). Vitamin E in a dose above the RDA (> 15 mg) significantly increased mortality (RR 1.03, 95% CI 1.00 to 1.05, I2 = 0%). Doses below the RDAs did not affect mortality, but data were sparse. Conclusions Beta-carotene and vitamin E in doses higher than the RDA seem to significantly increase mortality, whereas we lack information on vitamin A. Dose of vitamin A was significantly associated with increased mortality in meta-regression. We lack information on doses below the RDA. Background All essential compounds to stay healthy cannot be synthesized in our body. Therefore, these compounds must be taken through our diet or obtained in other ways [1]. Oxidative stress has been suggested to cause a variety of diseases [2]. Therefore, it is speculated that antioxidant supplements could have a potential role in preventing diseases and death. Despite the fact that a normal diet in high-income countries may provide sufficient amounts of antioxidants [3,4], more than one third of adults regularly take antioxidant supplements [5,6].

Meta-analysis: antioxidant supplements for primary and secondary prevention of colorectal adenoma

Colorectal cancer may be prevented by reducing the development of adenomatous polyps.

Antioxidant Supplements to Prevent Mortality

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.

Quality assessment of reports on clinical trials in the Journal of Hepatology

BACKGROUND/AIMS Electronic searches on databases for randomised clinical trials and controlled clinical trials do not identify as many trials as handsearches, and trial reporting may be flawed. The aims were to identify all fully reported randomised clinical trials in the Journal of Hepatology and to make a qualitative assessment of the reporting. METHODS The publications were identified by systematically handsearching the full text of the journal and searching MEDLINE. Central dimensions of trial quality were used to assess the reporting quality of the trials. RESULTS Randomised clinical trials represented 8.4% of the original articles (171/2028). Ten original articles (0.5%) could not be classified. A search on MEDLINE identified 81.3% of the randomised clinical trials, i.e., 139 out of the 171 identified by the handsearch. A total of 166 randomised clinical trials could be quality assessed. Forty-seven (28.3%) of them reported adequate generation of allocation sequence; 22 (13.3%) adequate allocation concealment; 95 (57.2%) allowed intention-to-treat analysis with only a few losses to follow-up; 50 (30.1%) were double-blind; 33 (19.9%) reported sample-size calculations; 13 trials (7.8%) employed the crossover design; and the median number of subjects per intervention arm in parallel group trials was 19 subjects (interquartile range: 11-31; range: 5-519). The quality of reporting was significantly better in regular issue articles than in supplement articles. CONCLUSIONS Many important randomised clinical trials are published in the Journal of Hepatology, but there seems to be ample room for improvement of quality of reporting.

Meta-analysis: antioxidant supplements for liver diseases - the Cochrane Hepato-Biliary Group.

Aliment Pharmacol Ther 2010; 32: 356–367

Likely country of origin in publications on randomised controlled trials and controlled clinical trials during the last 60 years

BackgroundThe number of publications on clinical trials is unknown as well as the countries publishing most trial reports. To try to examine these questions we performed an ecological study.MethodsWe searched the 454,449 records on publications in The Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library, Issue 3, 2005 (CD-ROM version) for possible country of origin. We inspected a random sample of 906 records for information on country and type of trial.ResultsThere was an exponential growth of publications on randomised controlled trials and controlled clinical trials since 1946, but the growth seems to have seized since 2000. We identified the possible country of origin of 210,974 publications (46.4%). The USA is leading with about 46,789 publications followed by UK, Germany, Italy, the Netherlands, Canada, and France. Sweden becomes the leader with 891 publications per million inhabitants during the last 60 years followed by Denmark (n = 864), New Zealand (n = 791), Finland (n = 781), the Netherlands (n = 570), Switzerland (n = 547), and Norway (n = 543). In depth assessment of the random sample backed these findings.ConclusionMany records lacked country of origin, even after the additional scrutiny. The number of publications on clinical trials increased exponentially until the turn of the century. Rather small, democratic, and wealthy countries take the lead when the number of publications on clinical trials is calculated based on million inhabitants. If all countries produced the same number of trials as these countries, this could mean thousands of new effective treatments during the next 60 years.