CRD summary

This review assessed the effects of antioxidant vitamins on long-term cardiovascular outcomes. The authors concluded that the routine use of vitamin E cannot be recommended, and that the use of vitamin supplements containing beta-carotene should be actively discouraged. The authors' conclusions appear to be reliable, but the limited search means that some relevant studies might have been missed.

Authors' objectives

To assess the effects of antioxidant vitamins on long-term all-cause mortality and cardiovascular death.

Searching

MEDLINE was searched; the search terms were given. In addition, reviews and bibliographies of identified studies were screened.

Study selection

Assessment of study quality

Study inclusion was based on the quality of the study methods, i.e. sample size, method of randomisation and use of intention-to-treat (ITT) analysis. However, it was unclear how methods of randomisation or use of ITT was assessed. Two reviewers independently assessed validity.

Data extraction

Two reviewers independently extracted the data on an ITT basis. For each study, the number of events per treatment group was extracted and the absolute events rates and odds ratios (ORs) were calculated, along with 95% confidence intervals (CIs). Authors of reports with missing data were contacted for additional information.

Methods of synthesis

Results of the review

Twelve RCTs were included. Seven RCTs (n=81,788) examined vitamin E and 8 RCTs (n=138,113) examined beta-carotene.

Vitamin E.

Over all studies, there was no statistically significant difference between vitamin E and control for all-cause mortality (OR 1.02, 95% CI: 0.98, 1.06, P=0.42), cardiovascular mortality (OR 1.0, 95% CI: 0.94, 1.06, P=0.94), or cerebrovascular accident (OR 1.02, 95% CI: 0.92, 1.12, P=0.71). No statistically significant heterogeneity was detected.

A subgroup analysis found no statistically significant difference between vitamin E and control for all-cause mortality among secondary or primary prevention studies. The results were similar after including 2 RCTs that did not meet the inclusion criterion for size.

No statistically significant difference was found between vitamin E and control for the combined outcome of cardiovascular death or nonfatal MI, but statistical heterogeneity was found (P=0.053).

Beta-carotene.

Beta-carotene was associated with a slight statistically significantly increase in all-cause mortality (OR 1.07, 95% CI: 1.02, 1.11, P=0.003) and cardiovascular death (OR 1.1, 95% CI: 1.03, 1.17, P=0.003) when compared with control. Based on 3 RCTs, there was no statistically significant difference between treatments for all-cause cerebrovascular accident (OR 1.0, 95% CI: 0.91, 1.09, P=0.92). No statistically significant heterogeneity was detected.

Authors' conclusions

The studies consistently showed no reduction in cardiovascular disease among diverse populations with vitamin E, thus the routine use of vitamin E cannot be recommended. The use of vitamin supplements containing beta-carotene should be actively discouraged.

CRD commentary

The review question was clear in terms of the study design, intervention, participants and outcomes. Only one database was searched, which might have resulted in the omission of other relevant studies. The search strategy was not reported in full and it was unclear whether any language limitations were applied. Some limited attempts to minimise small study bias were made. Two reviewers independently selected the studies and extracted the data, which reduces the potential for bias and errors. The validity of the included studies was assessed systematically and used to select studies for inclusion.

Adequate details of each included study were given. The studies were combined in a meta-analysis and statistical heterogeneity was assessed. However, limitations in the reporting of validity means it is not possible to assess whether it was appropriate. Potential causes of the significant heterogeneity found in the meta-analysis of vitamin E using the combined outcome were not explored. The evidence presented appears to support the authors' conclusions, although the limited search means it is likely that some relevant studies might have been overlooked.

Implications of the review for practice and research

Practice: The authors stated that the use of vitamin supplements containing beta-carotene and vitamin A should be actively discouraged, and that vitamin E should not be included in future studies of primary or secondary prevention in patients at high risk of coronary artery disease.

Research: The authors stated that further research, to determine the reason for the increased risk of death with beta-carotene and the lack of improvement in cardiovascular outcomes with vitamin E, is required.

Bibliographic details

Vivekananthan D P, Penn M S, Sapp S K, Hsu A, Topol E J. Use of antioxidant vitamins for the prevention of cardiovascular disease: meta-analysis of randomised trials. Lancet 2003; 361: 2017-2023. [PubMed: 12814711]

Other publications of related interest

This additional published commentary may also be of interest. Gundling K. Use of antioxidant vitamins for the prevention of cardiovascular disease: meta-analysis of randomised trials. FACT 2004;9:27-8.

Indexing Status

Subject indexing assigned by NLM

MeSH

Antioxidants /adverse effects /therapeutic use; Cardiovascular Diseases /mortality /prevention & control; Cause of Death; Humans; Odds Ratio; Randomized Controlled Trials as Topic; Risk Factors; alpha-Tocopherol /therapeutic use; beta Carotene /adverse effects /therapeutic use

AccessionNumber

12003009690

Database entry date

30/04/2005

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.