Antioxidant vitamins may not always as good as intended, according to some researchers.   A new meta-analysis of 68 randomized trials with 232 606 participants suggests that treatment with beta carotene, vitamin A, and vitamin E may increase risk of death whereas the effect of vitamin c and selenium on the death risk remains unclear.

The study published in the Feb. 28, 2007 issue of the Journal of the American Medical Association has drawn immediate criticism from the Council of Responsible Nutrition which issued a statement suggesting that the analysis is inadequate because the studies used in the analysis differ greatly in terms of their designs, size and quality.

The trade organization representing vitamin supplements manufacturers says in its press release that the researchers “misuse meta-analysis methods to create generalized conclusions that may inappropriately confuse and alarm consumers who can benefit from supplementing with antioxidants."

The antioxidant vitamins of concern are often times marketed as dietary supplements and used by consumers in hopes to maintain their health or protect against diseases such as cancer and heart disease as these compounds can presumably help eliminate free radials (at least in a theoretical sense) that would otherwise injure cells, leading to cancer, premature   aging and other illnesses.   But early studies are inconsistent in terms of the effects of these noted antioxidant vitamins.

In the current study, Dr Goran Bjelakovic, from Copenhagen University Hospital, Denmark and colleagues conducted a comprehensive review on more than 300 trial articles published by October 2005 and meta-analyzed data derived form these publications to examine if these vitamins indeed have any effect on mortality resulting from all causes.

For the study, the researchers selected certain publications/trials based on certain criteria with regard to its quality and reliability.   When 68 were selected from 815 trials, they came to find that the results were inconclusive.   And use of the vitamins was not associated with elevated risk of death. A further reduction of trials by 21 led to results indicating that vitamins were linked with an elevated risk of death.

The researchers found that taking vitamin A was linked to a 16% increased risk of death compared to 7% for beta carotene and 4% for vitamin E.   However, the results for vitamin C were not as clear.   When the researchers looked at data from what they thought the most reliable trials, the death risk was apparently raised by 6%.

There was a bright side on the study.   Based on the best quality trials, selenium was found linked to a 10 percent reduced risk of death when used alone or in combination with other vitamins, but the link was not statistically significant.

Overall, the researchers came to the conclusion that beta carotene, vitamin A, and vitamin E may increase risk of mortality while it was less clear whether vitamin C and selenium increase risk of death from all causes.

Andrew Shao, Ph.D., vice president of CRN, scientific and regulatory affairs said "This meta-analysis combined studies that differ vastly from each other in a number of important ways that compromise the results.”

The pointed out that "the meta-analysis included clinical trials that varied widely in terms of dosage, duration, study population and nutrients tested—such as data from a one-day study with a vitamin A dose of 200,000 IU mixed with data from other studies lasting years."

"In addition, many of the clinical trials included in the meta-analysis tested nutrients beyond those that were the focus of the article (vitamins A, C, and E; beta-carotene; selenium), including lutein and zinc, making it difficult to appropriately evaluate the contribution of those trials to the overall meta-analysis."

“It’s like comparing apples and oranges,” said Dr. Shao.

Dr. Shao also said "the overwhelming majority of the clinical trials included in the meta-analysis tested for secondary prevention, looking at how a nutrient works in those who already are diseased, instead of primary prevention studies in healthy populations."

“Combining secondary prevention and primary prevention trials and then making conclusions for the entire population is an unsound scientific approach,” said Dr. Shao.

“Additionally, many of the treatment trials had limitations, including the expectation that a simple antioxidant vitamin could be expected to overturn serious illness, such as cancer or heart disease. These trials likely statistically skewed the results.”

Dr. Shao further pointed out, “The study authors concluded that overall there was no effect of antioxidant supplements on all-cause mortality.   It was only after the researchers divided the chosen clinical trials into ‘high risk bias’ and ‘low risk bias’ groups, using their own criteria, that they observed a statistically significant effect on mortality.   This meta-analysis appears to be a predetermined conclusion in search of a method to support it.”

A scientist affiliated with foodconsumer.org comments that when a study was proposed to investigate the effect of antioxidant vitamins on the mortality risk, the researchers might have already have some expectation as to what they are going to find, which could lead to biases.

He suggests that the results of this analysis are not the final verdict on the antioxidant vitamins.   Vitamins including vitamin A, E and beta carotene are useful although consumers should not solely rely on them for their health needs.

Mortality in Randomized Trials of Antioxidant Supplements for Primary and Secondary Prevention: Systematic Review and Meta-analysis
Goran Bjelakovic, MD, DrMedSci; Dimitrinka Nikolova, MA; Lise Lotte Gluud, MD, DrMedSci; Rosa G. Simonetti, MD; Christian Gluud, MD, DrMedSci
JAMA. 2007;297:842-857.