Cochrane for Clinicians
Putting Evidence into Practice
Antioxidant Supplements Do Not Improve Mortality and May Cause Harm
Am Fam Physician. 2008 Nov 1;78(9):1079-1080.
A 42-year-old woman with hypertension and hyperlipidemia presents for her annual physical examination. She is taking several over-the-counter antioxidant supplements because she believes that they will increase her longevity.
Are antioxidant supplements safe and effective for preventing mortality?
In randomized controlled trials of primary and secondary prevention, vitamins A and E, and beta-carotene supplementation increased mortality. Vitamin C and selenium supplementation had no significant effect on mortality.1
Background: Animal and physiologic research, as well as observational studies, suggest that antioxidant supplements may Improve survival.
Objectives: To assess the effect of antioxidant supplements on mortality in primary or secondary prevention randomized clinical trials.
Search Strategy: The authors searched The Cochrane Library (Issue 3, 2005), Medline (1966 to October 2005), EMBASE (1985 to October 2005), and the Science Citation Index Expanded (1945 to October 2005). They scanned bibliographies of relevant publications and wrote to pharmaceutical companies for additional trials.
Selection Criteria: The authors included all primary and secondary prevention randomized clinical trials on antioxidant supplements (beta-carotene, vitamins A, C, and E, and selenium) versus placebo or no intervention. Included participants were healthy (primary prevention trials) or had any disease (secondary prevention trials).
Data Collection and Analysis: Three authors extracted data. Trials with adequate randomization, blinding, and follow-up were classified as having a low risk of bias. Random-effects and fixed-effect meta-analyses were performed. Random-effects meta-regression analyses were performed to assess sources of intertrial heterogeneity.
Main Results: Included were 67 randomized trials with 232,550 participants. Forty-seven trials including 180,938 participants had a low risk of bias. Twenty-one trials included 164,439 healthy participants. Forty-six trials included 68,111 participants with various diseases (gastrointestinal, cardiovascular, neurologic, ocular, dermatologic, rheumatoid, renal, endocrinologic, or unspecified). Overall, the antioxidant supplements had no significant effect on mortality in a random-effects meta-analysis (relative risk [RR] = 1.02; 95% confidence interval [CI], 0.99 to 1.06), but significantly increased mortality in a fixed-effect model (RR = 1.04; 95% CI, 1.02 to 1.06).
In meta-regression analysis, the risk of bias and type of antioxidant supplement were the only significant predictors of intertrial heterogeneity. In the trials with a low risk of bias, the antioxidant supplements significantly increased mortality (RR = 1.05; 95% CI, 1.02 to 1.08). When the different antioxidants were assessed separately, analyses including trials with a low risk of bias and excluding selenium trials found significantly increased mortality with vitamin A (RR = 1.16; 95% CI, 1.10 to 1.24), beta-carotene (RR = 1.07; 95% CI, 1.02 to 1.11), and vitamin E (RR = 1.04; 95% CI, 1.01 to 1.07) supplementation, but no significant detrimental effect with vitamin C (RR = 1.06; 95% CI, 0.94 to 1.20). Low-bias risk trials on selenium found no significant effect on mortality (RR = 0.91; 95% CI, 0.76 to 1.09).
Authors' Conclusions: The authors found no evidence to support antioxidant supplements for primary or secondary prevention. Vitamins A and E, and beta-carotene may increase mortality. Future randomized trials could evaluate the potential effects of vitamin C and selenium for primary and secondary prevention. Such trials should be closely monitored for potential harmful effects. Anti-oxidant supplements need to be considered medicinal products and should undergo sufficient evaluation before marketing.
These summaries have been derived from Cochrane reviews published in the Cochrane Database of SystematicReviews in the Cochrane Library. Their content has, as far as possible, been checked with the authors of the originalreviews, but the summaries should not be regarded as an official product of the Cochrane Collaboration; minorediting changes have been made to the text (http://www.cochrane.org).
Approximately one third of Americans have used antioxidant supplements.2 Oxidation of low-density lipoprotein cholesterol plays a role in the formation of atherogenic plaques.2 Oxidative stress may also contribute to the formation of some cancers, such as lung and prostate cancers.3 Vitamins A, C, and E, beta-carotene, and selenium supplements have been studied extensively to assess the effects on disease states such as cancer and cardiovascular disease.1,4 Despite promising in-vitro antioxidant properties, the outcomes of clinical trials measuring patient-oriented outcomes such as mortality have been mixed. The American Heart Association (AHA) does not recommend antioxidants for risk reduction of cardiovascular disease.2 The U.S. Preventive Services Task Force (USPSTF) found the evidence for cancer and cardiovascular disease prevention inconclusive (Rating: I) regarding vitamins A, C, and E, and multivitamins with folic acid. They recommended against the use of beta-carotene (D recommendation) because of a higher incidence of lung cancer and all-cause mortality in two trials restricted to heavy smokers.4
In this Cochrane review, the authors found trials comparing beta-carotene, vitamins A, C, and E, and selenium supplements (alone or in combination) with placebo or no intervention. The trials did not evaluate patients with specific vitamin deficiencies, malnutrition, or pregnancy.
A meta-analysis of all the included trials using a random effects model showed no significant effect on mortality. The random effects meta-analysis is used to compare heterogeneous studies and assumes that the effect of the antioxidant use may vary between studies, but follows a general distribution. A fixed-effect meta-analysis of the same data showed an increase in mortality in patients taking antioxidants. A fixed-effect meta-analysis assumes that antioxidant use has a fixed or similar effect in each of the clinical trials.
The investigators also evaluated each supplement separately and divided the trials based on their risk of bias. Trials with a low risk of bias (i.e., adequate randomization, blinding, and follow-up) showed that vitamins A and E, and beta-carotene, increased mortality. There was no detrimental effect found with vitamin C or selenium. Selenium showed a benefit in mortality in all combined trials, but showed no significant effect when low-bias trials were evaluated alone. These results were consistent in trials examining primary and secondary prevention. Based on these results, the authors recommended further randomized, controlled studies with vitamin C and selenium with a specific focus on harms and benefits. They did not recommend further study of supplementation with vitamins A and E, or beta-carotene, because of the potential for adverse effects.
The authors were careful to point out that these trials only evaluated antioxidant supplementation, not dietary intake of anti-oxidants from fruits and vegetables. The AHA and USPSTF recommend a diet high in fruits and vegetables as a natural source of antioxidants.2,4
1. Bjelakovic G, Nikolova D, Gluud LL, Simonetti RG, Gluud C. Antioxidant supplements for prevention of mortality in healthy participants and patients with various diseases. Cochrane Database Syst Rev. 2008;2:CD007176.
2. Kris-Etherton PM, Lichtenstein AH, Howard BV, Steinberg D, Witztum JL, for the Nutrition Committee of the American Heart Association Council on Nutrition, Physical Activity, and Metabolism. Antioxidant vitamin supplements and cardiovascular disease. Circulation. 2004;110(5):637–641.
3. Abeloff MD. Clinical Oncology. 4th ed. Philadelphia, Pa.: Elsevier Churchill Livingstone; 2008:546–547.
4. U.S. Preventive Services Task Force. Routine vitamin supplementation to prevent cancer and cardiovascular disease: recommendations and rationale. Ann Intern Med. 2003;139(1):51–55. http://www.guideline.gov/summary/summary.aspx?ss=15&doc_id=3698. Accessed August 1, 2008.
The Cochrane Abstract is a summary of a review from the Cochrane Library. It is accompanied by an interpretation that will help clinicians put evidence into practice. Dr. Walker presents a clinical scenario and question based on the Cochrane Abstract, followed by an evidence-based answer and a critique of the review. The practice recommendations in this activity are available at http://www.cochrane.org/reviews/en/ab007176.html.
The series coordinator for AFP is Clarissa Kripke, MD, Department of Family and Community Medicine, University of California, San Francisco.
Copyright © 2008 by the American Academy of Family Physicians.
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