Elsevier

The Lancet

Volume 361, Issue 9374, 14 June 2003, Pages 2017-2023
The Lancet

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Use of antioxidant vitamins for the prevention of cardiovascular disease: meta-analysis of randomised trials

https://doi.org/10.1016/S0140-6736(03)13637-9Get rights and content

Summary

Introduction

Oxidised LDL is thought to play an important part in the pathogenesis of atherosclerosis. Observational studies have associated α tocopherol (vitamin E), β carotene, or both, with reductions in cardiovascular events, but not clinical trials. We did a meta-analysis to assess the effect of these compounds on long-term cardiovascular mortality and morbidity.

Methods

We analysed seven randomised trials of vitamin E treatment and, separately, eight of β carotene treatment; all trials included 1000 or more patients. The dose range for vitamin E was 50–800 IU, and for β carotene was 15–50 mg. Follow-up ranged from 1·4 to 12·0 years.

Findings

The vitamin E trials involved a total of 81 788 patients and the p carotene trials 138 113 in the all-cause mortality analyses. Vitamin E did not provide benefit in mortality compared with control treatment (11·3 vs 11·1%, odds ratio 1·02 [95% Cl 0·98–1·06] p=0·42) or significantly decrease risk of cardiovascular death (6·0 vs 6·0%, p=0·86) or cerebrovascular accident (3·6 vs 3·5%, p=0·31). β carotene led to a small but significant increase in all-cause mortality (7·4 vs 7·0%, 1·07 [1·02–1·11] p=0·003) and with a slight increase in cardiovascular death (3·4 vs 3·1%, 1·1 [1·03-1·17] p=0·003). No significant heterogeneity was noted for any analysis.

Interpretation

The lack of a salutary effect was seen consistently for various doses of vitamins in diverse populations. Our results, combined with the lack of mechanistic data for efficacy of vitamin E, do not support the routine use of vitamin E.

Introduction

The oxidative-modification hypothesis of atherosclerosis1, 2, 3, 4 has prompted the study of antioxidant vitamins in the prevention of the initiation and progression of cardiovascular disease. Preclinical studies suggested that supplementation of the diet with various compounds that have antioxidant properties before the development of vascular disease inhibited the atherogenic process.5, 6, 7, 8, 9 These findings led to several large, prospective, cohort studies in human beings, in which significant reductions in mortality10 and cardiovascular events11, 12 were identified in men and women taking antioxidant vitamins. However, sizeable randomised trials of antioxidant vitamins13, 14, 15, 16, 17 have shown no such mortality reduction, although in one study non-fatal myocardial infarction (MI) was significantly reduced.18 More importantly, in two randomised trials of β carotene16, 19 no benefit, and possibly an increased risk of cardiovascular events, was seen. Findings from small randomised studies of antioxidant vitamins have also suggested a potential harmful effect of antioxidant vitamins in patients with known or suspected coronary disease.20, 21

Despite the absence of efficacy of antioxidant vitamins reported in larger randomised trials, two important opinion articles have favoured the universal use of multivitamins by consumers.22'23 The multivitamins recommended, however, contain β carotene and α tocopherol (vitamin E), two compounds that have not been proven to reduce cardiovascular morbidity or mortality, and may adversely affect lipid concentrations when used at higher doses.13'20 Since the use of antioxidant vitamins continues to grow, partly encouraged by physicians advocating their use,24 we did a meta-analysis of randomised trials to find out what effect antioxidant vitamins have on all-cause mortality and cardiovascular death.

Section snippets

Study population

We did a MEDLINE search to identify all randomised controlled trials of antioxidant vitamins in primary and secondary prevention. We used the search terms: “randomized controlled trials”, “vitamin E”, and “beta carotene”. We did additional searches for known trial acronyms cited in review articles, and searched by hand the bibliographies of primary studies identified through the initial search. To limit the effects of publication bias of smaller trials we included only studies of 1000 or more

Discussion

The small harmful effect we noted for β carotene was driven by the increased risk reported in the CARET and ATBC studies, in which the patients were at high risk of lung cancer, and represented 34% of our total sample of patients. With the exception of the NSCP trial,27 the tendency towards a harmful effect on death was strikingly consistent across all major trials, including diverse populations. Our findings are especially concerning given that the relevant β carotene doses are commonly used

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