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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
Annals of Internal Medicine
4 January 2005 | Volume 142 Issue 1
Background: 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.
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 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).
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 meta-analyses. No language restrictions were applied.
Data Extraction: 3 investigators independently abstracted study reports. The investigators of the original publications were contacted if required information was not available.
Data Synthesis: 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.
Limitations: 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.
Conclusion: High-dosage (>=400 IU/d) vitamin E supplements may increase all-cause mortality and should be avoided.

What is the problem and what is known about it so far?
Vitamin E (sometimes called alpha-tocopherol) is in many foods, including nuts, oils, and vegetables. People in western countries usually consume small but adequate amounts of this vitamin in their diets. People also can buy multivitamins and supplements that contain vitamin E. Each multivitamin often contains about 30 international units (IU) of vitamin E. Many experts recommend this daily amount for adults. Supplements often contain much larger amounts, such as 200, 400, or 1000 IU. Some research suggests that taking vitamin E supplements may boost immune systems and prevent heart disease and some types of cancer. Other research suggests that taking large amounts of vitamin E as supplements may increase risks for bleeding problems and death. Because of these risks, some experts set 1500 IU daily as the upper tolerable intake level for vitamin E. To make good decisions about taking or not taking vitamin E, people need information about its safety.
Why did the researchers do this particular study?
To summarize data about the safety of different amounts of vitamin E taken as supplements by adults.
Who was studied?
135,967 adults who had participated in 19 studies. Many were older than 60 years of age. About 60% had heart disease or a risk factor for heart disease, such as tobacco use and high blood pressure.
How was the study done?
The researchers looked at deaths reported in 19 randomized trials that compared vitamin E with either a dummy pill (placebo) or no treatment. They searched medical literature up to August 2004 to find these trials. Each trial lasted longer than 1 year. Amounts of vitamin E tested in the trials ranged from 16.5 IU daily to 2000 IU daily. The researchers combined data from the trials to examine mortality among people taking different amounts of vitamin E.
What did the researchers find?
Compared with placebo or no treatment, intake of vitamin E in amounts of 400 IU or more daily for longer than 1 year increased the risk for death. Whether lower amounts of vitamin E increased or decreased the risk for death was unclear.
What were the limitations of the study?
Trials that tested high amounts of vitamin E often involved older adults with chronic diseases. Findings from these trials may not apply to younger, healthy adults. Some trials assessed multivitamin combinations rather than vitamin E alone. The review did not find the exact lowest amount of vitamin E that was associated with increased risk for death.
What are the implications of the study?
Adults should avoid taking vitamin E preparations in amounts of 400 IU or more. Experts should reconsider the stated upper tolerable intake level of vitamin E. Sellers should consider removing vitamin preparations that contain 400 IU or more per dose from stores.
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