High-dosage vitamin E supplementation and all-cause mortality.

The work of Miller et al(1) highlights the danger of assuming the safety of high dose vitamin E in the absence of definitive long-term safety data. Its impact, however, may be mitigated, by methodological concerns. The first issue is the restrictive inclusion criteria stipulating that a trial have at least 10 deaths to be included in the meta-analysis, apparently because the authors "anticipated that many small trials did not collect mortality data". This exclusion contradicts the raison d'e tre of meta-analysis, which involves the statistical pooling of multiple trials that individually have inadequate statistical power. The exclusion of at least 3 reasonably large well-conducted trials(2-4) of high dose vitamin E in which fewer than 10 deaths occurred, while including only trials meeting this arbitrary cut-off, would spuriously increase the power of the meta-analysis. We would also be interested in the funnel plot analysis to determine whether publication bias affected the study results. Although the authors attempted to adjust for average follow-up in their analysis, a more robust statistical treatment of the variance in follow-up periods across included trials would be to express the summary statistic of pooled death risk as the number of deaths per 10, 000 person- year (as opposed to per 10, 000 persons). Heterogeneity in the study populations may not have been fully accounted for despite the use of the random effects model and dosage differentiation. In particular, cardiovascular disease (CVD) may constitute a select group at distinct risk from the effects of high dose vitamin E. Seven of the eight high-dosage trials showing harmful effects of vitamin E involve subjects with vascular risk factors or who had established CVD. In contrast, the DATATOP and ADCS studies utilised mega- doses of vitamin E (2000 IU/day) in individuals with neurodegenerative disorders, rather than CVD, but did not reveal safety concerns with vitamin E. A separate meta-analysis looking solely at the group of neurodegenerative diseases (including a recent study employing 5000 mg/day of vitamin E(5)) may be warranted. Although the focus of the Miller et al study may be on safety, the data ultimately challenges the advocates of high dose vitamin E to re- examine the evidence for its benefit. Efficacy from controlled trials ranges from minimal to modest, in contrast to the more positive results of observational studies. It is time clinicians return to the drawing board and review both the safety and efficacy data for vitamin E supplementation to determine their practice. References: 1. Miller ER 3rd, Pastor-Barriuso R, Dalal D, Riemersma RA, Appel LA, Guallar E. Meta-analysis: High-dosage vitamin E supplementation may increase all-cause mortality. Ann Intern Med. 2005 ; 142:37-46. 2. Berson EL, Rosner B, Sandberg MA, Hayes KC, Nicholson BW, Weigel- DiFranco C, et al. A randomized trial of vitamin A and vitamin E supplementation for retinitis pigmentosa. Arch Ophthalmol. 1993 ; 111:761- 72. 3. de Waart FG, Kok FJ, Smilde TJ, Hijmans A, Wollersheim H, Stalenhoef AF. Effect of gluthathione S-transferase M1 genotype on progression of atherosclerosis in lifelong male smokers. Atherosclerosis. 2001 ; 158:227- 31. 4. Wluka AE, Stuckey S, Brand C, Cicuttini FM. Supplementary vitamin E does not affect the loss cartilage volume in knee osteoarthritis: a 2 year double blind randomized placebo controlled study. J Rheumatol. 2002 ; 29:2585-91. 5. Graf M, Ecker D, Horowski R, Kramer B, Riederer P, Gerlach M, et al. High dose vitamin E therapy in amyotrophic lateral sclerosis as add-on therapy to riluzole: results of a placebo-controlled double-blind study. The German vitamin E/ALS Study Group. J Neural Transm 2004 ; Oct 27 (Epub ahead of print).