With Comments from Russell H. Greenfield, MD
Vitamin E and Increased Mortality
Source: Miller ER, et al. Meta-analysis: High-dose vitamin E supplementation may increase all-cause mortality. Ann Intern Med 2005;142:in press.
Goal: To evaluate a potential dose-dependent effect of vitamin E on total mortality via meta-analysis.
Study design: Meta-analysis of randomized, controlled trials with follow-up longer than one year and occurrence of at least 10 deaths in the trial.
Subjects: A total of 19 clinical trials published between 1993 and 2004 met inclusion criteria (nine using vitamin E alone, 10 using vitamin E combined with other vitamins or minerals) and included data on 135,967 people.
Methods: Studies identified in PubMed and the Cochrane Clinical Trials Database were independently abstracted by three investigators. Authors of the original publications were contacted if required data were not available.
Results: Nine of the 11 trials utilizing high-dose vitamin E (> 400 IU/d) showed an increase in all-cause mortality compared to control. Dose-response analysis showed a statistically significant increase in total mortality with vitamin E doses > 150 IU/d.
Conclusion: High-dose (> 400 IU/d) vitamin E supplementation should be counseled against and avoided.
Study strengths: Focus on all-cause mortality to avoid issues with miscoding; influence of each individual trial was proportional to number of deaths; number of studies included in analysis; two-way factorial design to try to address use of other agents together with vitamin E.
Study weaknesses: Difficult to extrapolate results to healthy adults or children; high-dose trials often were small and performed in people with chronic illness, especially cardiovascular disease (CVD); heterogeneity of trials (e.g., age and number of subjects, chronic illness vs. healthy, vitamin E dosage, use of other supplements, differences in nutritional status, length of follow-up).
Of note: Of the 36 trials initially identified, 12 were excluded because fewer than 10 deaths were reported; mean age of participants: 47-84 years; all but three trials were placebo-controlled and double-blind; vitamin E dosage range: 16.5-2,000 IU/d (median dose: 400 IU/d); overall use of vitamin E supplementation did not affect all-cause mortality (risk ratio 1.01), but pooled risk analysis showed a slight increased risk with high- vs. low-dose vitamin E; in the dose-response analysis, total mortality progressively increased as vitamin E dosage increased above 150 IU/d; all-cause mortality decreased slightly in subjects using less than 150 IU/d; the largest studies included showed minimal effects from vitamin E.
We knew that: Three recently published meta-analyses that did not evaluate dose-response relationships reported no overall effect of vitamin E on survival; vitamin E may have pro-oxidant effects at high doses, and may inhibit glutathione S-transferases, which help detoxify both drugs and endogenous toxins; the ATBC study showed an increased risk of hemorrhagic stroke among participants using vitamin E; average dietary intake of vitamin E is approximately 14 IU/d; the few primary prevention trials examining vitamin E in healthy populations suggest benefit.
Comments: Reviews of meta-analyses do not typically appear in Alternative Medicine Alert, but this particular article was presented at a recent American Heart Association meeting and has generated widespread interest and concern. A number of published trials have called into question the wisdom of vitamin E supplementation, as did a recent review of use of vitamin E for people with CVD. The results of this meta-analysis suggest that doses of vitamin E commonly found in many multivitamins may be harmful to patients, and also that doses of 150 IU/d may offer benefits. However, if indeed there is risk associated with high-dose vitamin E supplementation, the threshold at which risk increases is far from firmly established. This paper raises serious concern about the use of high-dose vitamin E, but by itself presents insufficient evidence to recommend against any kind of vitamin E supplementation. While the lack of utility of vitamin E for people with established CVD seems clear, more studies are required to evaluate the use of vitamin E in preventing illness. Until further data become available, limit vitamin E intake to < 400 IU/d, less for those with significant illness.
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Dr. Greenfield, Medical Director, Carolinas Integrative Health Carolinas HealthCare System Charlotte, NC, Clinical Assistant Professor, School of Medicine, University of North Carolina, Chapel Hill, NC, is Executive Editor of Alternative Medicine Alert.