Edgar R. Miller III, MD, PhD; Roberto Pastor-Barriuso, PhD; Darshan Dalal, MD, MPH; Rudolph A. Riemersma, PhD, FRCPE; Lawrence J. Appel, MD, MPH; Eliseo Guallar, MD, DrPH
Note: J.A. Baron provided unpublished mortality data from the Polyp Prevention Study.
Grant Support: Dr. Pastor-Barriuso was supported in part by a grant from the Instituto de Salud Carlos III (EPY 1261/02).
Potential Financial Conflicts of Interest:Grants received: R.A. Riemersma (Roche).
Requests for Single Reprints: Edgar R. Miller III, MD, PhD, Welch Center for Prevention, Epidemiology and Clinical Research, The Johns Hopkins Medical Institutions, 2024 East Monument Street, Suite 2-624, Baltimore, MD 21205-2223; e-mail, email@example.com.
Current Author Addresses: Dr. Miller: Welch Center for Prevention, Epidemiology and Clinical Research, The Johns Hopkins Medical Institutions, 2024 East Monument Street, Suite 2-624, Baltimore, MD 21205-2223.
Dr. Pastor-Barriuso: Division of Biostatistics, National Center for Epidemiology, Instituto de Salud Carlos III, 28029 Madrid, Spain.
Dr. Dalal: Division of Cardiology, Department of Medicine, The Johns Hopkins Medical Institutions, BRADY 604, Baltimore, MD 21205.
Dr. Riemersma: Cardiovascular Research Unit, University of Edinburgh, Hugh Robson Building, George Square, Edinburgh EH8 9XF, Scotland, United Kingdom.
Dr. Appel: Welch Center for Prevention, Epidemiology and Clinical Research, The Johns Hopkins Medical Institutions, 2024 East Monument Street, Suite 2-618, Baltimore, MD 21205-2223.
Dr. Guallar: Welch Center for Prevention, Epidemiology and Clinical Research, Department of Epidemiology, The Johns Hopkins Bloomberg School of Public Health, 2024 East Monument Street, Suite 2-639, Baltimore, MD 21205-2223.
Author Contributions: Conception and design: E.R. Miller, E. Guallar.
Analysis and interpretation of the data: E.R. Miller, R. Pastor-Barriuso, D. Dalal, R.A. Riemersma, L.J. Appel, E. Guallar.
Drafting of the article: E.R. Miller, R. Pastor-Barriuso, E. Guallar.
Critical revision of the article for important intellectual content: E.R. Miller, R. Pastor-Barriuso, D. Dalal, R.A. Riemersma, L.J. Appel, E. Guallar.
Final approval of the article: E.R. Miller, R. Pastor-Barriuso, D. Dalal, R.A. Riemersma, L.J. Appel, E. Guallar.
Statistical expertise: R. Pastor-Barriuso, E. Guallar.
Administrative, technical, or logistic support: D. Dalal, E. Guallar.
Collection and assembly of data: E.R. Miller, D. Dalal, R.A. Riemersma, E. Guallar.
Experimental models and observational studies suggest that vitamin E supplementation may prevent cardiovascular disease and cancer. However, several trials of high-dosage vitamin E supplementation showed non–statistically significant increases in total mortality.
To perform a meta-analysis of the dose–response relationship between vitamin E supplementation and total mortality by using data from randomized, controlled trials.
135 967 participants in 19 clinical trials. Of these trials, 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).
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 meta-analyses. No language restrictions were applied.
3 investigators independently abstracted study reports. The investigators of the original publications were contacted if required information was not available.
9 of 11 trials testing high-dosage vitamin E (≥400 IU/d) showed increased risk (risk difference > 0) for all-cause 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 10 000 persons (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.
High-dosage (≥400 IU/d) trials were often small and were performed in patients with chronic diseases. The generalizability of the findings to healthy adults is uncertain. Precise estimation of the threshold at which risk increases is difficult.
High-dosage (≥400 IU/d) vitamin E supplements may increase all-cause mortality and should be avoided.
Does vitamin E supplementation increase mortality in adults?
This meta-analysis of 19 randomized, controlled trials involving more than 135 000 participants found that high-dosage vitamin E supplementation (≥400 IU/d for at least 1 year) increased all-cause mortality. Benefits or harms of lower-dosage supplementation were unclear.
Trials that tested high dosages involved adults with chronic diseases, and these findings may not be generalizable to healthy adults. Some trials evaluated multivitamin combinations. The findings don't clearly establish that the lowest dosage of supplementation is associated with increased mortality risk.
Avoid high-dosage vitamin E supplementation.
Flow diagram of the trial selection process.
Table 1. Clinical Trials of Vitamin E Supplementation and Risk for All-Cause Mortality, Ordered by Dosage of Vitamin E
Risk difference in all-cause mortality for randomized, controlled trials of vitamin E supplementation and pooled results for low-dosage (<400 IU/d) and high-dosage (≥400 IU/d) vitamin E trials.
Dose–response relationship between vitamin E supplementation and all-cause mortality in randomized, controlled trials.solid curveshaded region
Table 2. Pooled All-Cause Mortality Risk Differences and Risk Ratios for Selected Vitamin E Dosages
Risk difference in all-cause mortality for randomized, controlled trials of vitamin E supplementation and pooled results for low-dosage (<400 IU/d) and high-dosage (≥400 IU/d) vitamin E trials based on 4-way analyses of trials that used a factorial design.HOPEMRC/BHF HPS
Table 3. Pooled All-Cause Mortality Risk Differences (per 10 000 persons) and Risk Ratios for Low-Dosage (<400 IU/d) and High-Dosage (≥400 IU/d) Vitamin E Trials Adjusted for Study-Specific Variables
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Miller ER, Pastor-Barriuso R, Dalal D, et al. Meta-Analysis: High-Dosage Vitamin E Supplementation May Increase All-Cause Mortality. Ann Intern Med. 2005;142:37–46. doi: https://doi.org/10.7326/0003-4819-142-1-200501040-00110
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Published: Ann Intern Med. 2005;142(1):37-46.
Cardiology, Coronary Heart Disease, Coronary Risk Factors, Hematology/Oncology, Prevention/Screening.
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