Study Claims Antioxidant Danger—A Repeat of Flawed Conclusions A Healthnotes Newswire Opinion By Alan R. Gaby, MD Healthnotes Newswire (April 17, 2008)—A new study published by the Cochrane Database of Systematic Reviews reports that taking antioxidant supplements does not prolong life, and that using certain specific antioxidants may slightly increase the risk of death. But vitamin users shouldn’t take this report as seriously as its widespread publicity would suggest. The new study is essentially a rewritten version of a study published a year ago in the Journal of the American Medical Association that received heavy media coverage. The new study presents the same data that has already been reported and subsequently discredited. Exclusion of certain trials skewed results As before, the researchers looked at 67 clinical trials involving antioxidants and categorized them as either a high or low risk for error. The 20 clinical trials considered “high-bias risk” were excluded from the study—but just why the researchers felt the need to exclude these trials isn’t clear and, unfortunately, excluding them significantly changed the results. After excluding these trials, when the data from the remaining 47 trials (involving a total of 180,939 people) were pooled, taking any antioxidant increased the risk of death by 5%. For individual supplements, the risk was increased by 4% with vitamin E, 7% with synthetic beta-carotene, and 16% with vitamin A. All of these increases were statistically significant. Vitamin C and selenium had no significant effect on mortality. Also as before, the reasons for the exclusion don’t make scientific sense. Criteria the researchers used to decide whether a clinical trial should be considered reliable included the way in which participants were assigned to receive antioxidants or placebo, and whether the trial was double-blind. While these methods are usually the standard to which we agree most studies should be held, a study of this type doesn’t require that kind of strict research design because a subtle imperfection in randomization method or a researcher’s awareness of treatment assignments is unlikely to influence a result as objective as death. In other words, a researcher assigning a participant to a particular treatment or knowing which treatment someone is getting probably won’t affect whether that person dies. In the case of the current study, the so-called “high-bias risk” studies probably did not endanger the reliability of study results and there was, therefore, no compelling reason to exclude them. Had the researchers included those trials, there would have been no significant effect of antioxidant use in general, or of any specific antioxidant, on mortality. Combining divergent studies not appropriate Another weakness in this study was the pooling of the results of trials that had crucial differences, which led to inappropriate conclusions about the overall effects of antioxidants. Even though this study was published in a reputable and well-known medical journal, the Cochrane Database is not a publication that specializes in nutrition, and neither the authors nor the reviewers who read the material prior to publication appear to have been aware of how failing to adjust for the differences between these trials may have affected the study conclusions. (For specific examples of how these oversights might impact interpretation, see “Study details” at the end of this article.) Previous research can’t be ignored Antioxidant supplements are used by tens of millions of people, with many uses supported by a wide body of research developed over many years and published in reputable medical journals that are dedicated more specifically to managing health through nutrition. Studies have shown, for example, that vitamin C may prevent or help treat heart disease, diabetes, high blood pressure, asthma, and more. Vitamin E is beneficial for intermittent claudication (difficulty walking caused by hardened arteries) and rheumatoid arthritis. Selenium may help prevent heart disease and certain types of cancer. Only rarely could a single study negate an entire body of research; rather, each new study adds to the medical “conversation” and helps determine the direction of future investigation. Even within this study, despite its negative overall conclusions, some of the “low-bias risk” trials that were included showed a clear benefit from antioxidant supplementation. For example, in a study that lasted 7.5 years and included more than 13,000 people, modest doses of a combination of vitamin C, vitamin E, beta-carotene, selenium, and zinc reduced the death rate in men by 37%, although no effect was seen in women. Results like these should encourage further research to determine what doses and combinations of nutrients are safest and most effective for people of different ages and different genders and with different health concerns and lifestyles. Even the most enthusiastic nutritional supplement supporters recognize the importance of a broad-spectrum approach to managing wellness and preventing disease that includes eating well, exercising, limiting exposure to toxins, and supplementing with nutrients that may not be obtained from the typical diet. Despite the concern that is likely to result from the republishing of this old research, it’s important to put its findings into context and remember that there is well-demonstrated evidence that antioxidants may improve or prevent certain medical conditions and improve overall quality of life. (Cochrane Database of Systematic Reviews 2008: CD007176. DOI:10.1002/14651858.CD007176.) Study details: As described in the above article, the pooling of the results of trials that had crucial differences, which led to inappropriate conclusions about the overall effects of antioxidants. For example: • Beta-carotene—It is well established that synthetic beta-carotene increases the risk of lung cancer and death in smokers, possibly because of a toxic interaction with cigarette smoke. In nonsmokers, however, synthetic beta-carotene has no effect on mortality (natural beta-carotene, which has a different chemical structure, has not been well studied). Pooling all of the beta-carotene trials was therefore inappropriate, and led to the erroneous conclusion that synthetic beta-carotene supplements are bad for everyone, not just for smokers. • Vitamin A—Researchers concluded that vitamin A increases risk of death by pooling five vitamin A trials, the largest of which studied smokers given a combination of vitamin A and synthetic beta-carotene. The increased mortality seen in the supplement group compared with the placebo group may have been due entirely to the beta-carotene and unrelated to the vitamin A. In another of the vitamin A trials, patients with a previous skin cancer received 25,000 IU of vitamin A per day or a placebo for up to five years. During the entire trial, which included a follow-up period after vitamin A was discontinued, the death rate was slightly higher in the vitamin A group than in the placebo group (5.4% versus 4.6%). However, during the time that people were actually taking vitamin A, the death rate was slightly lower in the vitamin A group than in the placebo group (2.07% versus 2.11%). The bottom line: there is no way of knowing whether vitamin A was responsible for the small increase in mortality that occurred after supplementation was stopped. In a third vitamin A trial, elderly nursing home residents were given a single dose of 200,000 IU of vitamin A or a placebo, and were then observed for signs of infection. During the follow-up period, the death rate was higher in the vitamin A group than in the placebo group (11.3% versus 7.1%); however, people receiving vitamin A were on average 4.8 years older than those receiving placebo. The higher death rate may have been entirely due to that age difference. • Vitamin E—The issues surrounding vitamin E are complicated and some of the concern about adverse effects may be justified. In one large trial, the combination of vitamin E and beta-carotene was given to cigarette smokers. The increased mortality observed in that trial may have been entirely due to the beta-carotene and unrelated to vitamin E. In other trials, however, the adverse effect of vitamin E is difficult to dismiss. It is important to note, however, that while vitamin E occurs in food in four different forms—alpha-, beta-, gamma-, and delta-tocopherol—virtually all of the research on vitamin E has used pure alpha-tocopherol. Alpha-tocopherol has a number of positive effects on cardiovascular function. But taking large amounts of it can deplete gamma-tocopherol, a component of the “vitamin E complex” that may be even more important for the heart than alpha-tocopherol is. Therefore, “mixed tocopherols,” which contains all four naturally occurring forms of vitamin E, may be preferable to pure alpha-tocopherol, both in terms of safety and effectiveness. • Selenium—It is curious that the study’s authors paid such little attention to evidence of a beneficial effect. When all of the trials were pooled, selenium supplementation reduced mortality by 9%. When the “high-bias risk” trials were excluded, selenium’s beneficial effect was even more pronounced (10% reduction) but, because of the smaller number of participants, that improvement was no longer statistically significant.