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Re: Vitamin E may increase and decrease mortality
- Dov Lichtenberg, Yedidya Dotan, Ilya Pinchuk, and Moshe Leshno (2 November 2009)
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Vitamin E may increase and decrease mortality
- Harri Hemilä (15 October 2009)
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Dov Lichtenberg, Professor Tel Aviv University, Yedidya Dotan, Ilya Pinchuk, and Moshe Leshno
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physidov{at}yahoo.com.au Dov Lichtenberg, et al.
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Dr Hemila’s comment relates to the weakest point of our study [1], which is that we had to base our analysis on published data rather than on “raw”, individual level data, which was unavailable to us. Moreover, if the raw data had been available to us, we too may have been able to identify groups of subjects that can be expected to gain from vitamin E supplementation. In spite of this shortcoming, and its possible outcome of ‘ecological fallacy’, we trust the results of our analysis because no reasonable alteration of the assumptions on which it is based yield a positive change in the QALY value. As stated by Dr Hemila, his published data are in line with our assumption that many people may benefit from vitamin E supplementation. The list of such groups is growing. First it included dialysis patients [2], and then came Levy’s diabetes patients [3]. Now we know that middle age smokers who take vitamin C are also likely to benefit from vitamin E. We also know that a large number of AD patients are ‘vitamin E responders’ that benefit from vitamin E supplementation, but we also know that it is harmful to non-responders [4]. As noted by Dr. Hemila, he agrees on what we consider the most important conclusion of our study (“taking supplements of vitamin E should be discouraged until we have better understanding” of who is likely to benefit from it). We agree with Dr. Hemila that his group is working in the right direction, namely collecting individual level data in one reasonable direction of supplementing moderate doses of both vitamins C and E to older (smoking?) men. The only disagreement between our views is that given the heterogeneity of the effect of vitamin E, he views our single estimate of 0.30 QALY decrease misleading. As is clear from his letter, it did not mislead us. What it did is to add support to the conclusion that indiscriminate supplementation of vitamin E “should be discouraged”, which is far from being a consensus. The real challenge is to gain sufficient data to be able to define criteria on which selective supplementation can be based. Our view on this issue is expressed in a communication in BioFactors [5]. References. 1. Dotan, Y., Pinchuk, I., Lichtenberg, D. and Leshno, M. (2009) Decision analysis supports the paradigm that indiscriminate supplementation of vitamin E does more harm than good. Arterioscler. Thromb. Vasc. Biol., 29, 1304-1309. 2. Boaz, M., Smetana, S., Weinstein, T., Matas, Z., Gafter, U., Iaina, A., Knecht, A., Weissgarten, Y., Brunner, D., Fainaru, M. and Green, M.S. (2000) Secondary prevention with antioxidants of cardiovascular disease in endstage renal disease (SPACE): randomised placebo-controlled trial. The Lancet 356, 1213-1218. 3. Milman, U., Blum, S., Shapira, C., Aronson, D., Miller-Lotan, R., Anbinder, Y., Alshiek, J., Bennett, L., Kostenko, M., Landau, M., Keidar, S., Levy, Y., Khemlin, A., Radan, A. and Levy, A.P. (2008) Vitamin E supplementation reduces cardiovascular events in a subgroup of middle-aged individuals with both Type 2 Diabetes Mellitus and the haptoglobin 2-2 genotype: A prospective double-blinded clinical trial. Arterioscler. Thromb. Vasc. Biol. 28, 341-347. 4. Lloret, A., Badia, M.C., Mora, N.J., Pallardo, F.V., Alonso, M.D. and Vina, J. (2009) Vitamin E paradox in Alzheimer's Disease: It does not prevent loss of cognition and may even be detrimental. Journal of Alzheimers Disease, 17, 143-149. 5. Dotan, Y., Lichtenberg, D. and Pinchuk, I. No evidence supports vitamin E indiscriminate supplementation. BioFactors, in press. |
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Harri Hemilä, Associate professor Department of Public Health, University of Helsinki, Helsinki, Finland
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harri.hemila{at}helsinki.fi Harri Hemilä
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Dotan et al. estimated that vitamin E supplementation might reduce the mean number of quality-adjusted life years (QALYs) by 0.30 units (1). Nevertheless, they noted that this does not mean that all individuals are harmed by vitamin E; in fact they believed that many individuals may even benefit from vitamin E supplements. This assessment by Dotan et al. was based on study-level data of several controlled trials. However, study-level analyses can lead to different conclusions than do corresponding individual-level analysis, a difference called the “ecological fallacy” (2). For this reason, examination of individual-level data is recommended, whenever feasible, in order to avoid the potential for the ecological fallacy introduced by study-level analyses (2). Recently, we analyzed the heterogeneity of the effect on total mortality of 50 mg/day vitamin E in the large-scale ATBC Study, restricted to male smokers (3). We found strong evidence that the combination of age and dietary vitamin C intake modified the vitamin E effect (P=0.0005). This evidence of heterogeneity refutes the notion that the vitamin E effect might be uniform throughout the study population. Vitamin E supplements had no effect on participants who had vitamin C intake below the median. On the other hand, among participants who had vitamin C intake above the median, vitamin E increased mortality by 19% in men between 50 and 62 years of age, but reduced mortality by 41% in men who were 66 and older. Since the vitamin E effect is heterogeneous, a single estimate such as a 0.30 QALY decrease by vitamin E supplementation is misleading. Our focus on age and dietary vitamin C as potential modifying factors was based on studies in which we explored the heterogeneity of the vitamin E effect on respiratory infections (4-6). Thus, our analysis of mortality was not exploratory; instead, we were testing the hypothesis that the previously identified factors might also modify the effect of vitamin E on mortality (3). Dotan et al. (1) commented that small groups of people for whom vitamin E may be beneficial could be invisible within large trials. Our findings support this notion. The complexity observed in the ATBC study cautions about drawing generalized conclusions and encourages us to have patience until further research results are available. Given the mainly negative findings in the vitamin E trials, I agree with Dotan et al. that taking supplements of vitamin E should be discouraged until we have a better understanding of the population groups that might benefit from it. Yet, Dotan et al.’s analysis of the study- level data does not indicate which path should be explored or in what direction investigation should proceed, whereas our analysis of the individual-level data of the ATBC Study suggests that trials on vitamin E and C effects on older men are warranted. Referencess 1. Dotan Y, Pinchuk I, Lichtenberg D, Leshno M. Decision analysis supports the paradigm that indiscriminate supplementation of vitamin E does more harm than good. Arterioscler Thromb Vasc Biol. 2009;29:1304- 1309. 2. Berlin JA, Santanna J, Schmid CH, Szczech LA, Feldman HI. Individual patient- versus group-level data meta-regressions for the investigation of treatment effect modifiers: ecological bias rears its ugly head. Stat Med. 2002;21:371-387. 3. Hemilä H, Kaprio J. Modification of the effect of vitamin E supplementation on the mortality of male smokers by age and dietary vitamin C. Am J Epidemiol. 2009;169:946-953. http://dx.doi.org/10.1093/aje/kwn413 4. Hemilä H, Virtamo J, Albanes D, Kaprio J. The effect of vitamin E on common cold incidence is modified by age, smoking and residential neighborhood. J Am Coll Nutr. 2006;25:332-339. http://www.jacn.org/cgi/content/abstract/25/4/332 5. Hemilä H, Kaprio J. Vitamin E supplementation and pneumonia risk in males who initiated smoking at an early age: effect modification by body weight and dietary vitamin C. Nutr J. 2008;7:33. http://dx.doi.org/10.1186/1475-2891-7-33 6. Hemilä H, Kaprio J. Vitamin E supplementation may transiently increase tuberculosis risk in males who smoke heavily and have high dietary vitamin C intake. Br J Nutr. 2008;100:896-902. http://dx.doi.org/10.1017/S0007114508923709 |
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