Cochrane Review Questions Value of Antioxidant Supplements

COPENHAGEN, Denmark—Antioxidant supplements do not prevent disease, and some may even increase mortality, according to a meta-analysis published in The Cochrane Database of Systematic Reviews (April 2008;2:CD007176). Researchers from Copenhagen University Hospital, led by Goran Bjelakovic, M.D., included 67 randomized clinical trials in which participants (n=232,550) received antioxidant supplements (beta-carotene, vitamin A, vitamin C, vitamin E and/or selenium) versus placebo. Trials were stratified by risk as “low-bias” (high quality) or “high-bias” (low quality), and studies were excluded from inclusion if there were no deaths reported during the trial. In addition, the researchers said there were no significant differences seen between the data in trials using healthy individuals (primary prevention) versus those including participants with various diseases (secondary prevention).

In their random-effects meta-analysis, antioxidant supplements had no significant effect on mortality; however, using a fixed-effect model, intervention significantly increased mortality (relative risk [RR] 1.04). Among studies with “low-bias”, after analysis by individual antioxidant, the researchers found a significant increase in all-cause mortality for vitamin A (RR 1.16), beta-carotene (RR 1.07) and vitamin E (RR 1.04). Low-bias trials on selenium found no significant effect on all-cause mortality (RR 0.91). The focus on “all-cause” mortality means deaths that may have been unrelated to the use of the supplements (i.e., accident, unrelated medical condition) were included, with no further explanation.

Additionally, the researchers concluded antioxidant supplements “need to be considered medical products and should undergo sufficient evaluation before marketing.” This conclusion was challenged in the press by industry and researchers, among them Jeffrey Blumberg, Ph.D., from Tufts University, who told Health Behavior News Service that the recommendation went too far: “I could find nowhere in this report any review of regulatory practices and effectiveness or the evaluation of public health policies, procedures or perspectives.”

Interestingly, the same authors published a similar meta-analysis in February 2007 in the Journal of the American Medical Association (JAMA), which also came under fire from scientists and industry for, among other items, combining secondary and primary prevention trials to reach data conclusions and excluding studies that showed no deaths. (See INSIDER's take on the 2007 JAMA study online.)

After the release of the Cochrane study, the Council for Responsible Nutrition (CRN) issued an analysis and response. John Hathcock, Ph.D., senior vice president, scientific and international affairs, said: “With nearly 750 studies to choose from, it’s interesting that they chose to include only 67 studies—less than 9 percent of the total clinical trials on antioxidants that are available. Moreover, the possible 750 clinical trials do not even account for other sources of evidence, such as observational studies, which were not considered by the authors at all. It is their exclusions, not the inclusions, where the fault lies.”

CRN’s statement further noted: “Although [the authors] have updated their meta-analysis, by handpicking additional studies and correcting a litany of minor mistakes made in previous versions, it is for all intents and purposes not a new study, nor is it truly new information. In fact, it appears to be a systematic attempt by the authors to publish work that supports their own pre-determined conclusions about antioxidants and the way they should be regulated.”