Negative JAMA Meta-Analysis of Antioxidants is Critiqued.

A meta-analysis conducted at Copenhagen University Hospital Copenhagen, Denmark and published in the Journal of the American Medical Association (297, 8:842-57, 2007) found that the antioxidant supplements beta-carotene, vitamin A and vitamin E may increase all-cause mortality. Vitamin C and selenium were also studied but no significant results were found.

Researchers reviewed 68 randomized trials that analyzed the antioxidants individually or in combination as compared placebo or no intervention. These trails included a total of 232,606 subjects. When all 68 trials were pooled, no significant associations were seen. When researchers segregated what they concluded were “low-bias” (high quality) from “high-bias” (low quality) studies, they found that antioxidant supplements were associated with a 5% increased risk of mortality (beta-carotene 7%, vitamin A 16% and vitamin E 4%). The “low-bias” trials included 180,938 participants.

In their conclusion researchers noted a number of limitations of their analysis including an inability to determine the cause of increased mortality, an inclusion of both secondary prevention and primary prevention trials in their analysis, and a wide variability in nutrients, doses, durations and populations in analyzed studies. They proposed a possible explanation for a link between antioxidants and increased mortality: “Although oxidative stress has a hypothesized role in the pathogenesis of many chronic diseases, it may be the consequence of pathological conditions. By eliminating free radicals from our organism, we interfere with some essential defense mechanisms.” They also suggested that, “antioxidant supplements are synthetic and not subjected to the same rigorous toxicity studies as other pharmaceutical agents.”

Industry representatives put the study’s findings in context. Andrew Shao, Ph.D., vice president of scientific and regulatory affairs at the Council for Responsible Nutrition (CRN), said, “While meta-analyses can be useful when the included studies are very similar in design and study population, this meta-analysis combined studies that differ vastly from each other in a number of important ways that compromise the results.” He added that the combination of secondary and primary prevention trials is an “unsound” approach, and only by dividing the trials into low- or high-quality trials, with researchers using their own criteria, was there a statistically significant effect on mortality. Dr. Shao concluded, “This meta-analysis appears to be a predetermined conclusion in search of a method to support it.”

Daniel Fabricant, Ph.D., vice president of scientific affairs for the Natural products Association, agreed with Dr. Shao’s assessment, “In some cases, meta-analysis works and works well, but not in the biased way it was used here. It’s the scientific equivalent of using a screw driver to hammer a nail. Looking at people in clinical trials to draw mortality conclusions is a fundamental mistake because most of them are not healthy to begin with, and thus already at greater risk of mortality. To call into question vitamins that have a well-documented history of providing health benefits is irresponsible and may cause those individuals most in need of supplementation to avoid it.”