CRD summary

This review assessed the dose-response relationship between vitamin E supplementation and mortality, and found that doses greater than or equal to 400 IU per day may have increased all-cause mortality. The lack of a quality assessment and the clinical differences across the included studies weaken the evidence presented.

Authors' objectives

To determine the dose-response relationship between vitamin E supplementation and total mortality.

Searching

MEDLINE (from inception to August 2004) and the Cochrane Controlled Trials Register were searched; the search terms were given. In additional, the reference lists of retrieved articles and reviews and meta-analyses were checked and the investigators' files were searched. No language restrictions were imposed.

Study selection

Assessment of study quality

The authors did not state that they assessed validity.

Data extraction

Three reviewers independently extracted the data and any disagreements were resolved by consensus.

Methods of synthesis

Results of the review

Nineteen RCTs (n=135,967) were included in the review.

When all of the trial results were analysed together, vitamin E supplementation did not affect all-cause mortality. However, in 9 of the 11 trials testing high-dosage vitamin E (greater than 400 IU/day), a significantly increased risk for all-cause mortality in comparisons of vitamin E versus control was observed. The pooled all-cause mortality risk difference in the high-dosage vitamin E trials was 39 additional deaths per 10,000 persons. For the low-dosage trials, there were no statistically significant risk differences between the participants receiving vitamin E and those receiving placebo. Overall, the meta-analysis showed a statistically significant relationship between vitamin E dosage and all-cause mortality, with increased risk at dosages greater than 150 IU/day.

Authors' conclusions

High-dose (greater than or equal to 400 IU/day) vitamin E supplements may increase all-cause mortality and should be avoided.

CRD commentary

The review addressed a clear research question and the inclusion criteria appeared appropriate. Two relevant databases were searched and attempts were made to identify unpublished studies. The methods used to select studies for inclusion were not reported, although the authors stated that trial investigators were contacted to confirm eligibility if needed. Methods were used to reduce reviewer error and bias in the data extraction process and, where necessary, further details were obtained from the trial investigators. It was unclear whether the quality of the included studies was assessed, thus it is difficult for the reader to establish the validity of the included studies on which the conclusions are based.

Available details of the included studies indicated that there were clinical differences across these studies. Most of the studies were performed in patients with chronic disease and more than half of the included studies evaluated vitamin E combined with other vitamins and minerals. The authors acknowledged that the generalisability of the findings to healthy adults is uncertain. In addition, they highlighted that the high-dosage trials had small sample sizes and a precise estimation of the threshold at which the risk increases was difficult. The apparent absence of a quality assessment and clinical differences across the studies weaken the evidence presented.

Implications of the review for practice and research

Practice: The authors stated that high-dose vitamin E supplementation should be discouraged until evidence of efficacy is demonstrated from well-conducted trials.

Research: The authors stated that further research is needed to determine the effects of low-dosage vitamin E supplementation in western populations.

Bibliographic details

Miller E R, Pastor-Barriuso R, Dalal D, Riemersma R A, Appel L J, Guallar E. Meta-analysis: high-dosage vitamin E supplementation may increase all-cause mortality. Annals of Internal Medicine 2005; 142(1): 37-46. [PubMed: 15537682]

Original Paper URL

http://www.annals.org/cgi/content/full/142/1/37

Other publications of related interest

Lundin Yale S. The vitamin E meta-analysis. Cause for concern? Altern Complement Ther 2005;11:7-11.

These additional published commentaries may also be of interest. Simon JA. Review: high-dose vitamin E supplementation is associated with increased all-cause mortality. ACP J Club 2005;143:1. Mariano C. Review: high dose vitamin E supplementation is associated with increased all cause mortality. Evid Based Nurs 2005;8:82.

Indexing Status

Subject indexing assigned by NLM

MeSH

Adult; Dietary Supplements /adverse effects; Dose-Response Relationship, Drug; Humans; Mortality; Randomized Controlled Trials as Topic; Sensitivity and Specificity; Vitamin E /administration & dosage /adverse effects

AccessionNumber

12005008131

Database entry date

30/09/2005

Record Status

This is a critical abstract of a systematic review that meets the criteria for inclusion on DARE. Each critical abstract contains a brief summary of the review methods, results and conclusions followed by a detailed critical assessment on the reliability of the review and the conclusions drawn.