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(Circulation. 1996;94:2369-2372.)
© 1996 American Heart Association, Inc.

Articles

Effect of Supplementary Antioxidant Vitamin Intake on Carotid Arterial Wall Intima-Media Thickness in a Controlled Clinical Trial of Cholesterol Lowering

Stanley P. Azen, PhD; Dajun Qian, MS; Wendy J. Mack, PhD; Alex Sevanian, PhD; Robert H. Selzer, MS; Chao-Ran Liu, MD; Ci-Hua Liu, MD; Howard N. Hodis, MD

the Statistical Consultation and Research Center and Department of Preventive Medicine (S.P.A., D.Q., W.J.M., H.N.H.), the Atherosclerosis Research Unit and Department of Medicine (C.-R.L., C.-H.L., H.N.H.), and the Department of Molecular Pharmacology and Toxicology (A.S., H.N.H.), University of Southern California, Los Angeles, and the Jet Propulsion Laboratory, California Institute of Technology, Pasadena, Calif (R.H.S.).

Correspondence to Howard N. Hodis, MD, Atherosclerosis Research Unit, Division of Cardiology, University of Southern California School of Medicine, 2250 Alcazar St, CSC 132, Los Angeles CA 90033.

	Abstract

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Background There is accumulating experimental, epidemiological, and clinical evidence of an association between antioxidant vitamin intake and reduced risk of coronary heart disease. Using data from the Cholesterol Lowering Atherosclerosis Study (CLAS), we explored the association of self-selected supplementary antioxidant vitamin intake on the rate of progression of early preintrusive atherosclerosis.

Methods and Results CLAS was an arterial imaging trial in which nonsmoking 40- to 59-year-old men with previous coronary artery bypass graft surgery were randomized to colestipol/niacin plus diet or placebo plus diet. The rate of progression of early preintrusive atherosclerosis was determined in 146 subjects using high-resolution B-mode ultrasound quantification of the distal common carotid artery far wall intima-media thickness (IMT). From the nutritional supplement database, 22 subjects had an on-trial average supplementary vitamin E intake of 100 IU per day (high users) and 29 subjects had an average on-trial supplementary vitamin C intake of 250 mg per day (high users). Within the placebo group, less carotid IMT progression was found for high supplementary vitamin E users when compared with low vitamin E users (0.008 versus 0.023 mm/y, P=.03). No effect of vitamin E within the drug group was found. No effect of vitamin C within the drug or placebo group was found.

Conclusions Supplementary vitamin E intake appears to be effective in reducing the progression of atherosclerosis in subjects not treated with lipid-lowering drugs while the process is still confined to the arterial wall (early preintrusive atherosclerosis).

Key Words: antioxidants • atherosclerosis • carotid arteries

	Introduction

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A large body of experimental and epidemiological data indicates that antioxidant vitamins may be able to reduce atherosclerosis.^{1 2 3 4 5 6} Observational evidence from case-control, cohort, and cross-cultural studies suggests an association between antioxidant vitamin intake and reduced risk of coronary heart disease (CHD).^{5 6 7 8 9}

High-resolution B-mode ultrasound measurement of carotid arterial wall intima-media thickness (IMT) has been used as a reliable end point for atherosclerosis intervention trials and epidemiological cohort studies.¹⁰ Noninvasive arterial wall imaging has advantages over angiographic imaging procedures that focus on lumen changes since it directly quantifies the response of early atherosclerosis to risk factor modification, can be performed at any frequency in symptomatic or asymptomatic individuals of any age, and carries negligible risk.¹¹

The Cholesterol Lowering Atherosclerosis Study (CLAS), a randomized, placebo-controlled, serial arterial imaging trial¹² designed to provide a comprehensive survey of the effects of colestipol-niacin plus dietary therapy on the progression of atherosclerosis in the coronary,^{13 14 15} femoral,¹⁶ and carotid arterial beds,^{17 18} provided evidence for a drug-induced reduction in carotid IMT through the use of B-mode ultrasound imaging as an outcome measurement of change in early preintrusive atherosclerosis.^{17 18} In a subgroup analysis with the use of the nutritional supplement database collected in CLAS, we have reported on the beneficial effect of supplementary vitamin E intake on the progression of coronary artery atherosclerosis determined by serial quantitative coronary angiography.¹⁹ We now explore the association of antioxidant vitamin intake with the progression of early preintrusive atherosclerosis assessed by serial common carotid artery IMT measurements.

	Methods

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Study Design
A detailed description of the CLAS trial design and methodology has been published.¹² Between September 1980 and October 1984, 188 nonsmoking 40- to 59-year-old men with previous coronary artery bypass grafting underwent baseline coronary angiography and were randomized to colestipol-niacin plus cholesterol-lowering diet versus placebo plus diet. Of the 188 CLAS subjects, 146 (78%) underwent B-mode carotid ultrasound examinations from which IMT measurements were made at baseline and every 6 months on trial. Of the remaining 42 subjects, 17 were lost to follow-up, 12 had inevaluable IMT readings, and 13 had insufficient data on supplementary vitamin intake. Analysis of IMT progression rates demonstrated significant therapeutic benefit from the lipid-lowering therapy.^{17 18}

Ultrasound Imaging and Image Analysis
Ultrasound imaging and IMT image analysis methods and reproducibility have been previously described.^{17 20} B-mode scanning was performed with a Diasonics CV400 ultrasound system with a 7.5-MHz probe. Longitudinal views of both near and far walls of the right distal common carotid artery were recorded with minimal gain necessary for clear visualization of structures. With treatment assignment masked, an image analyst measured distal common carotid far wall IMT by automated computerized edge detection using a 386/33 PC computer equipped with a Data Translation DT 2862 image processing board. Our automated computerized edge-finding algorithm results in closely spaced measurements of IMT, approximately 100 to 120 points per centimeter, from which average IMT is determined.²⁰ The distance between the echoes arising from the blood-intima interface and the media-adventitia interface was taken as the measure of the IMT complex.²¹

Evaluation of Supplementary Antioxidant Vitamin Intake
Before randomization and every 6 months on trial, an assessment of all supplementary vitamins currently used (including multivitamins and specific vitamin supplements), dose levels of vitamin supplements, and frequency of use were determined.²² Typical doses were assigned for multivitamins (30 IU for vitamin E and 60 mg for vitamin C). Average on-trial daily intakes of supplementary vitamins E and C were then computed. For each supplementary antioxidant vitamin, subjects were categorized into high- and low-intake groups, stratifying the average on-trial daily intake at 100 IU per day for vitamin E and 250 mg per day for vitamin C, the typical quantities in specific vitamin E and vitamin C supplements.

Statistical Analysis
To establish equivalency of each of the supplementary vitamin intake groups with regard to cardiovascular risk factors for progression, we compared each group at baseline on age, blood pressure, smoking status, lipid levels, IMT, and treatment group assignment, as well as on-trial lipid levels and blood pressure. Tests for group equivalency were performed using either a Fisher's exact test (for discrete variables) or a two-sample Student's t test (for continuous variables). A least-squares regression line relating IMT measurements from baseline to 2 years was determined for each subject to provide an estimate of the annual carotid IMT progression rate. Comparison of annual IMT progression rates between each supplementary vitamin intake category was performed overall and within each treatment group with the use of the two-sample Student's t test. Because vitamin E users had a slightly less favorable cardiovascular risk profile (see below), ANCOVAs were also performed to adjust for these differences. For all analyses, the two-sided significance level was set at .05.

	Results

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In the cohort of 146 subjects with repeat carotid IMT measurements at 2 years, 73 subjects had been randomly assigned to drug therapy (colestipol-niacin) and 73 had been assigned to placebo. Twenty-two subjects (15%) had an on-trial average supplementary vitamin E intake of 100 IU per day (high users), while 124 subjects (85%) had an intake <100 IU per day (low users). Twenty-nine subjects (20%) had an average on-trial supplementary vitamin C intake of 250 mg per day (high users), while 117 subjects (80%) had an intake <250 mg per day (low users). The joint distribution of supplementary antioxidant vitamin intake by treatment group assignment was (1) high vitamin E and high vitamin C (8%; 6 drug and 5 placebo); (2) high vitamin E and low vitamin C (8%; 5 drug and 6 placebo); (3) low vitamin E and high vitamin C (12%; 12 drug and 6 placebo); and (4) low vitamin E and low vitamin C (73%; 50 drug and 56 placebo).

Table 1 summarizes the baseline and on-trial characteristics for the study groups stratified by supplementary vitamin E and C usages, respectively. Compared with low supplementary vitamin E users, high supplementary vitamin E users had at baseline greater cholesterol levels (P=.01), LDL cholesterol levels (P=.07), and diastolic blood pressure (P=.05). Compared with low supplementary vitamin C users, high supplementary vitamin C users had on average lower baseline diastolic blood pressure (P=.08) and higher on-trial HDL cholesterol (P=.07). For either of the antioxidant vitamins there was no difference in the proportions of subjects randomized to colestipol-niacin between the high and low groups (50% in both the high and low vitamin E groups; 62% versus 47% in the high and low vitamin C groups).

View this table: [in this window] [in a new window]   Table 1. Baseline and On-Trial Characteristics by Supplementary Vitamin Intake Groups

Table 2 summarizes the average change of early preintrusive common carotid artery atherosclerosis as measured by annual IMT progression rate between high and low supplementary vitamin E users and high and low supplementary vitamin C users overall and within each treatment group. No significant effect in IMT progression was found overall or within the drug group for either supplementary vitamin E intake of 100 IU per day or supplementary vitamin C intake of 250 mg per day. However, within the placebo group, significantly less progression was found for high vitamin E users when compared with low vitamin E users (0.008 versus 0.023 mm/y, P=.02). Furthermore, significantly less progression was found for high vitamin E users after adjusting for baseline differences in total cholesterol, LDL cholesterol, and diastolic blood pressure (P=.03). No significant difference was found within the placebo group for vitamin C.

View this table: [in this window] [in a new window]   Table 2. On-Trial Annualized Rate of Intima-Media Thickness Change (mm/y) Between High and Low Vitamin E and Vitamin C Intake Groups

	Discussion

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In the CLAS cohort, placebo-treated subjects who had supplementary vitamin E intake 100 IU per day demonstrated significantly less (P<.03) common carotid IMT progression than those subjects with supplementary vitamin E intake <100 IU per day (Table 2). We have reported previously that CLAS men who had supplementary vitamin E intake 100 IU per day demonstrated significantly less coronary artery lesion progression than did men with supplementary vitamin E intake <100 IU per day.¹⁹ Benefit of supplementary vitamin E intake was demonstrated among all subjects (regardless of randomized assignment) and for subjects randomized to niacin/colestipol (P<.04). Furthermore, the benefit of vitamin E supplementation was demonstrated (P<.02) for mild/moderate lesions (baseline percent diameter stenosis <50%) but not for severe lesions (50% diameter stenosis). A nonsignificant trend for benefit of supplementary vitamin E intake was found within the placebo group.¹⁹

The disparate within-group results of vitamin E supplementation on the progression of coronary artery disease (as determined by coronary angiography) and on the progression of early preintrusive atherosclerosis (as determined by carotid IMT) are not surprising; coronary angiography does not permit the differentiation between treatment effects at the arterial wall level and remodeling of coronary arteries as explanations for improved lumen size. We have previously shown that coronary artery remodeling with lipid-lowering therapy plays a role in improved lumen size.²³ Therefore, the effect of vitamin E supplementation on coronary artery lumen improvement in the drug-treated group may be apparent only with angiography under conditions of lipid lowering. In contrast, the effect of vitamin E supplementation on carotid artery IMT progression found in the placebo group provides evidence for the beneficial effect of vitamin E supplementation directly on the progression of atherosclerosis itself at the arterial wall level. The lack of effect of vitamin E supplementation on the progression of carotid IMT in the drug-treated group probably reflects the overpowering effect of lipid lowering on the progression of atherosclerosis. Furthermore, the effect of vitamin E supplementation on the progression of carotid IMT in the placebo group is consistent with the coronary angiographic effect on mild/moderate lesions as compared with that on severe lesions.

In the Atherosclerosis Risk in Communities (ARIC) study, an inverse relationship was also seen between carotid arterial wall thickness (measured at baseline and represented as an average over 12 carotid artery sites) and combined dietary and supplementary vitamin E intake.²⁴ Among subjects who were not on special diets, this inverse relationship was significant in women (P=.033) but not in men (P=.13). In addition, dietary consumption of vitamin C in ARIC was found to be inversely associated with baseline carotid artery wall thickness in asymptomatic women (P=.019) and men (P=.035) between 55 and 64 years of age.²⁴ In contrast, CLAS men who had supplementary vitamin C intake 250 mg per day did not demonstrate significantly less carotid IMT progression than did men with supplementary vitamin C intake <250 mg per day (Table 2). The disparate associations found in CLAS and ARIC may be attributed to differences in study designs. ARIC was a cross-sectional study in which a single semiquantitative dietary and/or supplementary antioxidant intake estimate was correlated with a single baseline IMT measure. In contrast, CLAS was a longitudinal study in which on-trial supplementary antioxidant intake was correlated to the rate of carotid artery atherosclerosis progression determined from serial IMT measurements.

In the Cambridge Heart Antioxidant Study (CHAOS), a double-blind, placebo-controlled, secondary prevention randomized trial in 2002 patients with coronary atherosclerosis, supplementary vitamin E treatment ranging between 400 and 800 IU per day significantly reduced the risk of nonfatal myocardial infarction (relative risk=.23, P=.005).²⁵ The benefit of supplementary vitamin E intake is additionally strengthened by the finding that atherosclerosis progression in the CLAS cohort was found to be predictive of subsequent CHD events, including coronary death.²⁶

Although epidemiological studies have demonstrated that higher supplementary vitamin E intake is associated with decreased incidence of CHD events in both men and women,^{5 6} it should be pointed out that in CHAOS, total and coronary mortalities were not reduced.²⁵ Furthermore, in the Alpha-Tocopherol, Beta Carotene Cancer Prevention Study, hemorrhagic stroke was slightly increased in the vitamin E group.²⁷ These findings need further investigation in randomized controlled clinical trials in asymptomatic and symptomatic individuals before public health recommendations concerning the use of vitamin E supplementation for CHD prevention can be made.

	Acknowledgments

 
This study was supported by the National Heart, Lung, and Blood Institute (RO1-HL-45005 and RO1-HL-49885) and the National Institute of Aging (RO1-AG-13860).

Received June 27, 1996; revision received September 9, 1996; accepted September 12, 1996.

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