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Review
Meta-Analysis: High-Dosage Vitamin E Supplementation May Increase
All-Cause Mortality
Edgar R. Miller III, MD, PhD; Roberto Pastor-Barriuso, PhD; Darshan Dalal, MD, MPH; Rudolph A. Riemersma, PhD, FRCPE;
Lawrence J. Appel, MD, MPH; and Eliseo Guallar, MD, DrPH

Background: Experimental models and observational studies
suggest that vitamin E supplementation may prevent cardiovasculardisease and cancer. However, several trials of high-dosage
vitamin E supplementation showed non–statistically significant increases in total mortality.
Purpose: To perform a meta-analysis of the dose–response relationship between vitamin E supplementation and total mortality
by using data from randomized, controlled trials.

Patients: 135 967 participants in 19 clinical trials. Of thesetrials,
9 tested vitamin E alone and 10 tested vitamin E combined with
other vitamins or minerals. The dosages of vitamin E ranged from
16.5 to 2000 IU/d (median, 400 IU/d).
Data Sources: PubMed search from 1966 through August 2004,
complemented by a search of the Cochrane Clinical Trials Database and review of citations of published reviews and metaanalyses. No language restrictions wereapplied.
Data Extraction: 3 investigators independently abstracted
study reports. The investigators of the original publications were
contacted if required information was not available.

O

n the basis of the premise that vitamin E reduces
oxidative stress, many clinical trials have tested vitamin E supplementation as a therapy to prevent various
chronic diseases. The results of these trialshave been
largely disappointing (1–3). Three recent meta-analyses,
which did not consider dose–response relationships, reported no overall effect of vitamin E on survival (4 – 6).
However, several trials of high-dosage vitamin E supplementation have reported non–statistically significant increases in total mortality. Because individual trials typically
tested only 1 dosage of vitamin E andlarge-scale trials with
several dosages are not feasible, we performed this dose–
response meta-analysis to evaluate a potential dose-dependent effect of vitamin E supplementation. We focused on
all-cause mortality because this end point has unambiguous
clinical relevance and, in contrast to cause-specific events
such as cardiovascular morbidity or death, is resistant to
miscoding.

DataSynthesis: 9 of 11 trials testing high-dosage vitamin E
(>400 IU/d) showed increased risk (risk difference > 0) for allcause mortality in comparisons of vitamin E versus control. The
pooled all-cause mortality risk difference in high-dosage vitamin E
trials was 39 per 10 000 persons (95% CI, 3 to 74 per 10 000
persons; P
0.035). For low-dosage vitamin E trials, the risk
difference was 16 per 10 000persons (CI, 41 to 10 per 10 000
persons; P > 0.2). A dose–response analysis showed a statistically
significant relationship between vitamin E dosage and all-cause
mortality, with increased risk of dosages greater than 150 IU/d.
Limitations:

High-dosage (>400 IU/d) trials were often small
and were performed in patients with chronic diseases. The generalizability of the findings to healthyadults is uncertain. Precise
estimation of the threshold at which risk increases is difficult.

Conclusion:

High-dosage (>400 IU/d) vitamin E supplements
may increase all-cause mortality and should be avoided.

Ann Intern Med. 2005;142:37-46.
For author affiliations, see end of text.

www.annals.org

through August 2004. We complemented the MEDLINE
search by searching the Cochranedatabase of randomized,
controlled trials; reviewing the reference lists from original
research, review articles, and previous meta-analyses; and
reviewing the files of the investigators.
Our prespecified inclusion criteria were 1) random allocation of participants, 2) use of vitamin E supplementation alone or combined with other vitamins or minerals, 3)
presence of a control or placebo group,...