Antioxidant Supplements for Coronary Artery Disease?
ABSTRACT & COMMENTARY
Synopsis: Both a-tocopherol and b-carotene increase the risk of fatal coronary artery disease, and smokers with a prior myocardial infarction should not use these agents.
Source: Rapola JM, et al. Lancet 1997;349:1715-1720.
The hypothesis that oxidative modification of LDL cholesterol may have a major adverse effect on the initiation and progression on coronary atherosclerosis has received considerable attention. Little clinical data is available, but observational studies suggest that individuals who consume high amounts of antioxidants in the diet may be protected from coronary artery disease. The CHAOS and Physicians’ Health studies have previously reported conflicting results regarding the use of vitamin E supplements in subjects with existing CAD. The latest data are from the ATBC (a-tocopherol and b-carotene Cancer Prevention Study) that was first reported in 1994. This was an investigation into the possible benefits of two antioxidant supplements on almost 30,000 male smokers from Finland. The results were negative with respect to cancer prevention, and a preliminary assessment did not suggest a reduction in CAD events. The present analysis is a prospective cohort follow-up of 1862 men enrolled in the ATBC study who had a prior myocardial infarction. The trial was of a 2 × 2 factorial design, with random assignment to a-tocopherol 50 mg/d, b-carotene 20 mg/d, both supplements, or placebo in a double-blind fashion. Follow-up averaged 5.3 years. The primary end point was a major coronary event, either fatal or non-fatal myocardial infarction (MI). Data collection was virtually complete, including autopsy reports that were available for most deaths. The four groups had an equivalent proportion of CAD risk factors, all were smokers, and the mean cholesterol level was more than 250 mmHg. Thus, the risk profile and the presence of prior MI indicated a high-risk population, manifest by major CAD event rate of approximately 4% per year. Plasma levels of b-carotene and vitamin E were available at entry and after three years of therapy. The mean age was 60 years. Seventy-six percent of this entire cohort remained active participants of the study, with no significant differences among the groups.
Antioxidant vitamin supplementation did not favorably affect the total number of subsequent MIs, although the risk for non-fatal MI was lower than placebo in the two supplement groups, significant for vitamin E after multivariate adjustment. However, there was a substantial increase in fatal CAD events in the b-carotene supplemented patients, and a small proportional increase in fatal events in the vitamin E cohort (a-tocopherol) compared to placebo. Kaplan-Meier analysis demonstrated no difference in study end point in total events and non-fatal events, but a significant increase in fatal MI for all three supplement groups, with a multivariate adjusted increase in risk of 33% for vitamin E, 75% for b-carotene, and 58% for the combination. These differences were highly significant for b-carotene and the combination. Overall, b-carotene supplementation alone or in combination increased the risk of fatal coronary artery disease by 43%. Total or all-cause mortality was highest in b-carotene and lowest in the placebo group, with similar numbers of non-CAD deaths in all groups. Serum concentrations of a-tocopherol and b-carotene were increased with supplementation, with no differences in the levels between those with and without events. Multivariate adjustment for known CAD risk factors did not change the results. Rapola and colleagues conclude that both a-tocopherol and b-carotene increase the risk of fatal coronary artery disease, and they categorically state that smokers with a prior MI should not use these agents. They discuss the results for vitamin E in the CHAOS trial; that study showed 29% more deaths in the a-tocopherol group vs. placebo (NS), but the study showed a 77% decrease in non-fatal MI. In the Physicians’ Health Study, b-carotene also was associated with a non-significant increase in cardiovascular deaths. While several mechanisms of possible adverse actions of these antioxidants are mentioned, no conclusion is provided.
COMMENT BY JONATHAN ABRAMS, MD
This data is an amplification of the limited results in CAD patients reported in the primary ATBC manuscript (N Engl J Med 1994;330:1029). The present analysis is of rather high-risk individuals and may not reflect benefits of antioxidant supplements for primary prevention or lower degrees of CAD risk; nevertheless, the results are sobering and do not appear to offer much promise for these compounds. Certainly, a role for b-carotene in prevention of vascular disease is untenable. In an accompanying editorial comment, it is pointed out that b-carotene is a weak antioxidant, and it has previously shown to be ineffective or even increase mortality in prior supplement trials. The question of a-tocopherol or vitamin E remains less clear. The CHAOS trial, previously discussed in Clinical Cardiology Alert (1996;15:33-34), suggests benefit from vitamin E supplementation with either 400 or 800 IU in patients who had angiographically documented CAD. Even that trial, however, suggested increased mortality with vitamin E, with the risk reduction confined to non-fatal MI.
Of potential importance in interpreting these conflicting results is the level of supplementation used in the CHAOS and the ATBC trial. Although not discussed by the authors of the ATBC trial, an editorial by Stevens in the same issue of the Lancet states that "the vitamin E dosage used in ATBC was a tenth of that in CHAOS." Furthermore, the ATBC trial used a synthetic vitamin E preparation, whereas CHAOS employed a natural source, which could reflect differences in antioxidant potency. The observational data for dietary vitamin E or supplementation is robust for both men and women, and both the CHAOS and the ATBC trials demonstrated a decreased incidence of non-fatal MI. One may conclude that the jury is still out regarding the efficacy of vitamin E in preventing CAD events. The discrepancy between fatal and non-fatal disease seen in both CHAOS and the ATBC trial with vitamin E supplementation is puzzling, and it may reflect the rather modest number of individuals in both of these trials, allowing for the play of chance and other factors that are not identifiable. As with the argument that the smoking burden in the ATBC patients was so great such that it would be too late for a short duration of antioxidant therapy to benefit lung cancer rates, it is conceivable that the cohort examined in the present report had such advanced CAD that it would be unrealistic for antioxidants to have much favorable impact in a period of five years, given the very high-risk profile of these individuals. In conclusion, the antioxidant hypothesis remains unproven with respect to dietary supplements of vitamin E, whereas b-carotene appears to be hazardous. Several large prospective antioxidant trials are in process that will ultimately provide an answer (HOPE, The Womens’ Health Study, and continued follow-up of the U.S. Physicians’ Health Study).
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