Randomised trial of α-tocopherol and β-carotene supplements on incidence of major coronary events in men with previous myocardial infarction

doi:10.1016/S0140-6736(97)01234-8

The Lancet

Volume 349, Issue 9067, 14 June 1997, Pages 1715-1720

https://doi.org/10.1016/S0140-6736(97)01234-8 Get rights and content

Summary

Background

Epidemiological data suggest that the intake of antioxidants such as α-tocopherol (vitamin E) and β-carotene has an inverse correlation with the incidence of coronary heart disease. The results from clinical trials of antioxidant supplementation in people with known coronary heart disease are inconclusive.

Methods

We studied the frequency of major coronary events in 1862 men enrolled in the Alpha-tocopherol Beta-carotene Cancer Prevention Study (smokers aged between 50 and 69 years) who had a previous myocardial infarction. In this randomised, double-blind, placebo-controlled study, men had received dietary supplements of α-tocopherol (50 mg/day), β-carotene (20 mg/day), both, or placebo. The median follow-up was 5·3 years. The endpoint of this substudy was the first major coronary event after randomisation. Analyses were by intention to treat.

Findings

424 major coronary events (non-fatal myocardial infarction and fatal coronary heart disease) occurred during follow-up. There were no significant differences in the number of major coronary events between any supplementation group and the placebo group (α-tocopherol 94/466; β-carotene 113/461; α-tocopherol and β-carotene 123/497; placebo 94/438 [log-rank test, p=0·25]). There were significantly more deaths from fatal coronary heart disease in the β-carotene (74/461, multivariate-adjusted relative risk 1·75 [95% Cl 1·16–2·64], p=0·007) and combined α-tocopherol and β-carotene groups (67/497, relative risk 1·58 [1·05–2·40], p=0·03) than in the placebo group (39/438), but there was no significant increase in the α-tocopherol supplementation group (54/466, relative risk 1·33 [0·86–2·05], p=0·20).

Interpretation

The proportion of major coronary events in men with a previous myocardial infarction who smoke was not decreased with either α-tocopherol or β-carotene supplements. In fact, the risk of fatal coronary heart disease increased in the groups that received either β-carotene or the combination of α-tocopherol and β-carotene; there was a non-significant trend of increased deaths in the α-tocopherol group. We do not recommend the use of α-tocopherol or β-carotene supplements in this group of patients.

Introduction

Oxidative modification of low-density lipoprotein may be a key event in the initiation and progression of atherosclerosis. Dietary α-tocopherol (vitamin E) supplements protect low-density-lipoprotein cholesterol from oxidation in vitro, but β-carotene supplements have not always shown this effect.1, 2, 3 Data from prospective cohort studies suggest that dietary intakes of vitamin E and β-carotene are inversely associated with coronary heart disease.4, 5, 6, 7 However, data from controlled clinical trials do not support these findings.

Large studies of antioxidant supplementation for chronic disease prevention have found either no effect on cardiovascular disease⁸ or a slight increase in cardiovascular mortality.9, 10, 11 Only two studies have investigated the use of antioxidant supplements for secondary prevention of coronary heart disease. The Cambridge Heart Antioxidant Study¹² found that among patients with pre-existing coronary heart disease, supplementation with α-tocopherol decreased the incidence of non-fatal myocardial infarction, but not the risk of cardiovascular death. In the Physicians' Health Study,¹³ a subgroup of men with pre-existing coronary heart disease initially seemed to benefit from β-carotene supplementation, but further analysis showed a non-significant increase in cardiovascular deaths.¹⁴ Thus, the safety and efficacy of antioxidants in these patients is not proven.

The primary aim of the Alpha-tocopherol Beta-carotene Cancer Prevention (ATBC) Study was to investigate the effects of α-tocopherol and β-carotene supplements on the incidence of lung cancer. An evaluation of the effects of the supplements on cardiovascular diseases, however, was also a part of the study protocol. We report here the effects of α-tocopherol and β-carotene supplements on the frequency of major coronary events among men at high risk of a coronary event because of myocardial infarction before entry to the ATBC Study.

Section snippets

Methods

29 133 male smokers aged 50–69 were recruited between 1985 and 1988 by a postal questionnaire from the male population living in southwestern Finland (n=290406) (figure 1). The study design, methods, participants' characteristics, and compliance have been reported in detail.¹⁵

The exclusion criteria were: proven malignant disease, severe angina pectoris (defined as angina on walking on level ground), chronic renal insufficiency, cirrhosis of the liver, alcoholism, other medical problems that

Statistical methods

Supplementation-specific cumulative frequencies for α-tocopherol and β-carotene were calculated by the Kaplan-Meier method, and the log-rank test was used to test for differences between the groups. Age and multivariate-adjusted relative risks and their 95% Cl were estimated by Cox's proportional-hazards regression with the supplementation groups as explanatory variables. The proportional-hazards assumption was evaluated and tested. All analyses were by intention to treat.

Interaction between

Results

The numbers of participants and endpoints are summarised in figure 1. Baseline characteristics are given in table 1. The median age ranged from 59·0 to 60·2 years between the four groups (p=0·005). There were no other significant differences between groups. 17% of all participants stopped smoking while taking part in the study; this percentage did not differ significantly between the supplementation groups. Of the men who had an endpoint event, 76% were active participants in the study at the

Discussion

Dietary supplementation with α-tocopherol, β-carotene, or their combination had little effect on the total number of major coronary events. However, both dietary supplements, especially β-carotene, increased the risk of fatal coronary heart disease. A non-significant decrease in non-fatal myocardial infarction was found with both supplements, and although a protective effect cannot be ruled out, the decrease is probably a reflection of the increased mortality. The excess mortality was greatest

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ArticlesRandomised trial of α-tocopherol and β-carotene supplements on incidence of major coronary events in men with previous myocardial infarction

Summary

Background

Methods

Findings

Interpretation

Introduction

Section snippets

Methods

Statistical methods

Results

Discussion

J Lipid Res

Lancet

J Am Coll Cardiol

J Mol Cell Cardiol

Lancet

J Am Coll Cardiol

Supplementation of vitamin E but not beta-carotene in vivo protects low density lipoprotein from lipid peroxidation in vitro

Arterioscler Thromb Vasc Biol

Effect of dietary antioxidant combinations in humans

Arterioscler Thromb Vasc Biol

Vitamin E consumption and the risk of coronary heart disease in men

N Engl J Med

Vitamin E consumption and the risk of coronary disease in women

N Engl J Med

Antioxidant vitamin intake and coronary mortality in a longitudinal population study

Am J Epidemiol

Dietary vitamin C and beta-carotene and risk of death in middle-aged men: the Western Electric study

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Lack of effect of long-term supplementation with beta carotene on the incidence of malignant neoplasms and cardiovascular disease

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The effect of vitamin E and beta carotene on the incidence of lung cancer and other cancers in male smokers

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Articles
Randomised trial of α-tocopherol and β-carotene supplements on incidence of major coronary events in men with previous myocardial infarction