Is Antioxidant Therapy Indicated for Ischemic Heart Disease?

ABSTRACT & COMMENTARY

Synopsis: The frequency of major coronary events in men with previous myocardial infarction who smoked cigarettes was not decreased with either alpha-tocopherol or beta-carotene.

Source: Rapola JM, et al. Lancet 1997;3498:1715-1720.

It has been reported that oxidative modification of low density lipoprotein may be an important event in the initiation and progression of atherosclerosis. Prospective studies have suggested that dietary intakes of vitamin E and beta-carotene, which apparently act to protect low-density lipoprotein cholesterol from oxidation in vitro, are inversely associated with the development of symptomatic coronary artery disease;1-4 however, published controlled clinical trials have not thus far supported these findings.

Rapola et al from the National Public Health Institute in Helsinki, Finland, reported the results of a study of 862 men who were cigarette smokers between the ages of 50 and 69 who had suffered a previous myocardial infarction. In this randomized, double-blind, placebo-controlled study, men received dietary supplements of alpha-tocopherol (50 mg/d), beta-carotene (20 mg/d), both drugs, or placebo and were followed for a median of 5.3 years. There are no significant differences in the number of major coronary events that occurred when comparing any of the dietary supplement groups and the placebo group except that there were significantly more deaths from fatal coronary heart disease in the beta-carotene and alpha-tocopherol/beta-carotene groups than there were in the placebo group. The authors conclude that the frequency of major coronary events in men with previous myocardial infarction who smoked cigarettes was not decreased with either alpha-tocopherol or beta-carotene; therefore, they did not recommend the use of these supplements in this group of patients.

COMMENT BY HAROLD L. KARPMAN, MD

Low-density lipoprotein cholesterol is a benign non-pathogenic moiety until it becomes oxidized, at which time it starts to interact with macrophage scavenger receptors, thus promoting inflammation in coronary arterial walls and the growth of atheromatous plaques. In theory, if one can prevent this oxidation, atherosclerosis formation will be retarded; therefore, the clinical frequency of plaque rupture and myocardial infarctions should be lessened.

Two excellent studies5,6 have revealed that the administration of beta-carotene had no significant effects upon the reduction of cardiovascular disease end points. The study reported by Rapola et al confirms the conclusion that there is no virtue in the use of beta-carotene in the primary and probably in the secondary prevention of cardiovascular disease end points, and, in fact, the results suggest that the use of beta-carotene may actually increase the frequency of deaths from fatal coronary artery disease when compared to the control group.

The value or lack thereof of vitamin E (alpha-tocopherol) is not as clear-cut as the reported results on the frequency of symptomatic coronary disease in patients who are given beta-carotene. Rapola et al’s study found that major coronary events were not decreased when vitamin E in a dose of 50 mg/d was given to patients who smoke cigarettes; however, other studies have suggested that higher doses of vitamin E (i.e., 400-800 IU/d) reduced risk of non-fatal myocardial infarction in patients with proven coronary artery disease.7 Also, there has been some evidence to suggest that the potency of the antioxidant effect may differ between natural source and synthetic vitamin E. Rapola et al concluded that the balance of evidence was in favor of using vitamin E in patients with proven coronary artery disease.

Fortunately, several large-scale randomized trials studying the effects of antioxidant vitamins on cardiovascular disease are in progress and will almost certainly provide the necessary epidemiological answers to the question of whether or not large doses of vitamin E are effective in reducing the incidence of symptomatic coronary artery disease. For the time being, there continues to be adequate information available to suggest that high doses of vitamin E may prevent myocardial infarctions in patients who have coronary artery disease, but there seems to be little indication for continued use of beta-carotene in either primary or secondary coronary disease prevention.

References

1. Rimm EB, et al. Vitamin E consumption and the risk of coronary heart disease in men. N Engl J Med 1993;328:1450-1456.

2. Stampfer MJ, et al. Vitamin E consumption and the risk of coronary disease in women. N Engl J Med 1993;328:1444-1449.

3. Knekt P, et al. Antioxidant vitamin intake and coronary mortality in a longitudinal population study. Am J Epidemiol 1994;139:1180-1189.

4. Pandey DK, et al. Dietary vitamin C and beta-carotene and risk of death in middle-aged men: The Western Electric study. Am J Epidemiol 1995;142:1269-1278.

5. Omenn GS, et al. Effects of a combination of beta carotene and retinol on lung cancer and cardiovascular disease. N Engl J Med 1996;334:1150-1155.

6. Hennekens CH, et al. Lack of effect of long term supplementation with beta carotene on the incidence of malignant neoplasms and cardiovascular disease. N Engl J Med 1996;334:1145-1149.

7. Stephens NG, et al. A randomized controlled trial of vitamin E in patients with coronary disease: the Cambridge Heart Antioxidant Study (CHAOS). Lancet 1996;347:781-786.