Evidence now indicates that high-resolution B-mode ultrasonographic measurement of the combined thickness of the carotid arterial intima-media complex is a reliable end point for lipid-lowering interventional trials [1]. Unlike angiographic imaging procedures that focus on changes in the lumen, noninvasive imaging of the arterial wall 1) directly quantifies the response of early atherosclerotic changes to risk-factor modification, 2) can be done as often as necessary in symptomatic or asymptomatic patients of any age, and 3) carries negligible risk [2]. In addition, the measurement of distal common carotid arterial far wall intima-media thickness (carotid arterial intima-media thickness) by automated computerized edge detection varies less than angiographic measurement of the coronary arteries; therefore, a much smaller sample size is needed to show a therapeutic effect [1, 3-5].

The Cholesterol Lowering Atherosclerosis Study (CLAS), a randomized, placebo-controlled, serial arterial imaging clinical trial [6], was designed to comprehensively survey the effects of colestipol-niacin plus dietary therapy on the progression of atherosclerosis in the coronary [7-9], femoral [10], and carotid arterial beds [3, 4]. That study was the first randomized, controlled clinical trial to provide evidence for a drug-induced reduction in carotid arterial intima-media thickness using B-mode ultrasonographic imaging as an outcome measurement of change in early, preintrusive atherosclerosis (the stage at which atherosclerosis is limited to the arterial wall and does not intrude into the arterial lumen) [3, 4]. The serial ultrasonographic results showed the powerful advantage of modeling sequential change over time [4].

The Monitored Atherosclerosis Regression Study (MARS) was a randomized, double-blind, placebocontrolled, serial arterial imaging clinical trial in which carotid arterial intima-media thickness was measured every 6 months with B-mode ultrasonography. Similar in design to CLAS, MARS was an independent clinical trial that showed that lovastatin plus dietary therapy reduced the progression of lesions of the coronary arteries as determined by both visual assessment of coronary artery change and quantitative coronary angiography [11, 12]. The ultrasonographic methods and findings from CLAS were replicated in a subgroup of 30 patients from MARS who, like the CLAS participants, were nonsmoking men who had had coronary arterial bypass grafts [1].

In this paper, we extend the findings of these studies to the complete cohort of patients from MARS with serial carotid arterial ultrasonographic measurements. We report evidence of benefit from lovastatin plus dietary therapy on early, preintrusive atherosclerosis through the measurement of change in the carotid arterial intima-media thickness in 188 patients evaluated every 6 months for as long as 4 years. We also relate these changes in early atherosclerosis to clinical, lipid, lipoprotein, and apolipoprotein risk factors for atherosclerosis.

Methods

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Design of the Monitored Atherosclerosis Regression Study

This study was a randomized, double-blind, placebo-controlled serial coronary angiographic and carotid arterial ultrasonographic imaging clinical trial that has been described previously [12]. Two hundred seventy patients (91% male, smokers and nonsmokers, 37 to 67 years of age) with total serum cholesterol levels between 4.92 and 7.64 mmol/L (190 mg/dL to 295 mg/dL) were randomly assigned to receive either lovastatin, 80 mg/d, or placebo. Two hundred fifteen patients were at the University of Southern California, and 55 were at the University of Wisconsin. The lovastatin group and the placebo group had identical dietary goals: no more than 250 mg of cholesterol per day, 27% of energy as total fat calories, 7% of energy as saturated fat calories, 10% of energy as monounsaturated fat calories, and 10% of energy as polyunsaturated fat calories. All patients had angiographically confirmed coronary artery disease in at least two segments with at least a 50% stenosis. Coronary angiography was done under standardized conditions at baseline and at 2 and 4 years after randomization; the 2-year results have been reported previously [11]. The 215 patients at the University of Southern California also had B-mode carotid ultrasonography, the results of which were used to measure carotid arterial intima-media thickness at baseline and every 6 months throughout the trial. Of these 215 patients, 196 (91%) had angiography at 2 years; 58% of the patients (77 receiving lovastatin and 48 receiving placebo) agreed to participate in an optional, double-blind, 2-year extension of the original randomized trial. An independent External Data and Safety Monitoring Committee recommended discontinuing the 2-year extension because of the observed treatment benefit in the per-patient reduction in stenosis for high-grade lesions as determined by quantitative coronary angiography, and in a panel assessment of overall change in coronary artery lesions [11]. Sixty-nine (32%) of the 215 patients at the University of Southern California had angiography at 4 years. Patients in the lovastatin group who participated in the 2-year extension had on-trial lipid levels, coronary artery end points, and rates of change in carotid arterial intima-media thickness similar to those of the treated patients who chose not to participate in the extension. Patients in the placebo group who chose not to participate in the extension had poorer coronary outcome at 2 years than did the patients who participated (P = 0.02), but both participants and nonparticipants had similar on-trial lipid levels and equivalent rates of change in carotid arterial intima-media thickness (0.02 ± 0.04 mm/y).

Lipid, Lipoprotein, and Apolipoprotein Levels

Total serum cholesterol and total serum triglyceride levels were measured using an enzymatic method under the Standardization Program of the National Centers for Disease Control and Prevention; patients fasted 8 hours before samples for analysis were collected. High-density lipoprotein (HDL) cholesterol levels were measured after apolipoprotein B-containing lipoproteins were precipitated in whole plasma with heparin manganese chloride. Low-density lipoprotein (LDL) cholesterol levels were estimated using the Friedewald equation [12, 13].

Plasma apolipoprotein A-I, B, C-III, and E levels [14-17] were measured using electroimmunoassay at the Oklahoma Medical Research Foundation. Apolipoprotein C-III levels were measured in whole plasma as well as in heparin manganese supernatants (apolipoprotein C-III-HS) and heparin manganese precipitates (apolipoprotein C-III-HP) as previously described [18]. Apolipoprotein C-III-HS approximates apolipoprotein C-III in HDL, and apolipoprotein C-III-HP approximates apolipoprotein C-III contained in very-low-density lipoprotein (VLDL) plus LDL. Lipid, lipoprotein, and apolipoprotein levels were measured at baseline, and then lipid levels were measured every 2 months and lipoprotein and apolipoprotein levels were measured every 4 months throughout the study.

Ultrasonography and Image Analysis

The methods for ultrasonography and image analysis for carotid arterial intima-media thickness and their reproducibility have been previously described [3, 5]. B-mode scanning was done with a Diasonics CV400 ultrasound system with a 7.5-MHz probe (Diasonics, Milpitas, California). Longitudinal views of the near wall and the far wall of the right distal common carotid artery were recorded with the minimum gain needed to clearly visualize structures.

An image analyst, blinded to treatment assignment, measured the distal common carotid arterial far wall intima-media thickness by automated computerized edge detection using a 386/33 PC computer equipped with a Data Translation DT 2862 image-processing board (Data Translation, Marboro, Massachusetts). The automated computerized edge-finding algorithm results in closely spaced measurements of intima-media thickness, approximately 100 to 120 points/cm, from which the average intima-media thickness is determined. The distance between the echoes arising from the blood-intima interface and from the media-adventitia interface was taken as the measure of the intima-media thickness complex [19]. The computerized edge-detection method has been described previously [5].

Statistical Analysis

We compared the clinical measures and lipid, lipoprotein, and apolipoprotein levels at baseline for patients with and those without carotid arterial ultrasonographic end point data. For patients with carotid arterial ultrasonographic end point data, we compared carotid arterial intima-media thickness at baseline, and clinical measures and lipid, lipoprotein, and apolipoprotein levels at baseline and on-trial in the treatment group with those in the placebo group. On-trial levels of these variables were computed as averages of all measurements made during the trial, weighted by the time interval between measurements. Significance testing was done using the Student t-test for independent samples, with the two-sided significance level set at 0.05.

For each patient, we fit a least-squares regression line relating carotid arterial intima-media thickness to the time since baseline ultrasonography to estimate the annual rate of progression of carotid arterial intima-media thickness. Thus, the unit of analysis was a patient-specific annualized progression rate of intima-media thickness; mean progression rates were then compared between treatment groups. Because carotid arterial intima-media thickness differed significantly at baseline between the treatment groups, we used analysis of covariance, with baseline values as the model covariate, to compare progression rates of carotid arterial intima-media thickness between groups. In addition, absolute changes from the baseline measurement of carotid arterial intima-media thickness by study period (every 6 months) were compared between treatment groups by using analysis of covariance with adjustment for baseline intima-media thickness. Progression rates were also compared between treatment groups within strata defined by the median carotid arterial intima-media thickness at baseline, sex, and smoking status at time of randomization. Interaction terms (treatment by stratification variables) were used to test for the equivalence of treatment effects across strata.

Analysis of these longitudinal data was corroborated by generalized estimating equations [4], which provide for the analysis of general linear models with extension to dependent data (that is, patients contributing repeated measurements of carotid arterial intima-media thickness to the analysis). Carotid arterial intima-media thickness was the dependent variable, and months since baseline ultrasonographic examination was the independent variable, to estimate the linear progression rate of carotid arterial intima-media thickness over time. To test whether the groups differed as to rate of progression, a treatment-by-months covariate was tested. Additional quadratic terms were used to test whether progression rates of carotid arterial intima-media thickness were nonlinear.

On-trial clinical measures and lipid, lipoprotein, and apolipoprotein levels were correlated with the 2-year progression of carotid arterial intima-media thickness. Pearson correlation coefficients were computed over the entire sample, both unadjusted and adjusted for treatment group, as well as within treatment groups. Stepwise linear regression was used to determine independent significant correlates of progression of carotid arterial intima-media thickness.

The authors were responsible for collecting and managing the data, doing the statistical analyses, and interpreting the results.

Results

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Characteristics at Baseline and On-Trial

Of the 215 patients, 188 (99 receiving lovastatin and 89 receiving placebo) had B-mode carotid arterial ultrasonography at baseline and at 2 years. Nineteen patients withdrew from the study, and 8 had baseline ultrasonograms with poor image quality. The 27 patients who did not have complete ultrasonographic data had greater baseline apolipoprotein B levels and systolic blood pressure than the 188 patients with complete carotid arterial intima-media thickness data, but no other significant differences were seen in lipid, lipoprotein, and apolipoprotein levels or in clinical variables between these patients.

The average age of the 188 patients in this study was 58 years. Ninety-two percent were men, and 16% were current smokers; during the trial, 8 of the 158 nonsmokers began smoking, but none of the current smokers quit smoking. Table 1 summarizes the characteristics of the study cohort at baseline and on-trial. The groups did not differ significantly at baseline in clinical variables or lipid, lipoprotein, or apolipoprotein levels; diastolic blood pressure, systolic blood pressure, and pulse rate did not differ significantly on-trial between treatment groups. Except for HDL cholesterol, apolipoprotein A-I, and apolipoprotein C-III-HS, all on-trial lipid, lipoprotein, and apolipoprotein levels differed significantly between the groups.

Changes in Early, Preintrusive Carotid Arterial Atherosclerosis

Patients with at least 2 years (n = 188) of B-mode carotid arterial ultrasonographic data had a mean (±SD) of 5.3 ± 1.3 measurements of carotid arterial intima-media thickness. Patients who remained in the study for 4 years (n = 74) had a mean of 8.7 ± 1.4 such measurements. Table 2 summarizes the within-group and between-group differences in absolute change and annualized progression rates of carotid arterial intima-media thickness. Because significant differences between the treatment groups were noted for baseline values of carotid arterial intima-media thickness (P < 0.001), all between-group analyses of follow-up measurements of carotid arterial intima-media thickness were adjusted for baseline values. The annual rates of change in carotid arterial intima-media thickness (mean ± SE) differed significantly between the lovastatin group and the placebo group at 2 years (–0.038 ± 0.004 mm/y compared with 0.019 ± 0.004 mm/y; P < 0.001) and at 4 years (–0.028 ± 0.003 mm/y compared with 0.015 ± 0.005 mm/y; P < 0.001). The mean difference in the absolute change in carotid arterial intima-media thickness between groups was significant (P < 0.001) at 1 year and at each successive biannual measurement during the trial. The lovastatin group showed a consistent reduction and the placebo group a consistent increase in carotid arterial intima-media thickness relative to baseline values (P < 0.001). A significant reduction in carotid arterial intima-media thickness was detected as early as 12 months in the lovastatin group (P < 0.001).

Longitudinal analyses done by generalized estimating equations supported these results. Figure 1 shows the fitted serial change in carotid arterial intima-media thickness over the 4-year trial, with intima-media thickness regressed on the time since the baseline ultrasonographic examination. If the trend in carotid arterial intima-media thickness is assumed to be linear over the study, the 2-year estimate (mean ± SE) of change in carotid arterial intima-media thickness is 0.021 ± 0.004 mm/y in the placebo group and –0.040 ± 0.004 mm/y in the lovastatin group (P < 0.0001). The 4-year change is 0.018 ± 0.004 mm/y in the placebo group and –0.031 ± 0.004 mm/y in the lovastatin group (P < 0.0001). Although the progression rate of carotid arterial intima-media thickness was linear in the placebo group, the lovastatin group showed a slight quadratic trend such that the treatment effect for the regression of carotid arterial intima-media thickness abated near the end of the study period (Figure 1). The minimal quadratic effect in the lovastatin group is evident in the predicted 4-year carotid arterial intima-media thickness with the linear model (0.632 mm) compared with the model incorporating a quadratic term (0.648 mm). For the first 2 years of the study, the rate of change of intima-media thickness was linear in both groups.

View larger version (14K): [in this window] [in a new window]   Figure 1. Change in the combined thickness of the distal common carotid arterial far wall intima–media complex (IMT) stratified by randomized treatment. Curves represent carotid arterial intima–media thickness regressed on time (months) since the baseline ultrasonographic examination in the placebo group (+) and the lovastatin group (·).

Effects of Baseline Carotid Arterial Intima-Media Thickness, Smoking, and Sex on Change in Early, Preintrusive Carotid Arterial Atherosclerosis

Table 3 shows the baseline carotid arterial intima-media thickness and the treatment effects of lipid-lowering at 2 and 4 years on the rate of change of carotid arterial intima-media thickness, stratified by the baseline median intima-media thickness (0.717 mm). The interactive effect between treatment and baseline intima-media thickness was significant at both 2 and 4 years (P = 0.001). Within each stratum, the annual rate of change differed significantly between the lovastatin group and the placebo group at 2 and 4 years (P < 0.001). In the lovastatin group, carotid arterial intima-media thickness decreased approximately twice as fast in patients with a baseline intima-media thickness of at least 0.717 mm as in patients with a baseline intima-media thickness less than 0.717 mm (P < 0.001 at 2 years; P = 0.04 at 4 years). The carotid arterial intima-media thickness in the placebo group increased at the same rate whether the baseline value was less than 0.717 mm (0.022 mm/y at 2 years; 0.016 mm/y at 4 years) or 0.717 mm or more (0.021 mm/y at 2 years; 0.016 mm/y at 4 years). In the lovastatin group, a negative correlation was seen between baseline carotid arterial intima-media thickness and the annual rate of change in carotid arterial intima-media thickness (r equals – 0.51; P < 0.001). In the placebo group, no such correlation was seen between the intima-media thickness at baseline and rate of change (r equals – 0.06; P > 0.2).

Table 3 also shows the effect of lipid-lowering therapy at 2 years and 4 years on the rate of change of carotid arterial intima-media thickness stratified by smoking status at baseline (current smoker and nonsmoker). The interactive effect between treatment and smoking status was not significant at 2 years but was significant at 4 years (P = 0.04). When compared with their respective placebo-treated patients, lipid lowering significantly reduced carotid arterial intima-media thickness in lovastatin-treated smokers (P < 0.001 at 2 years; P = 0.006 at 4 years) and in lovastatin-treated nonsmokers (P < 0.001 at both 2 and 4 years). No significant differences were found in progression rates between smokers and nonsmokers within each treatment group.

Table 3 also shows the effect of lipid-lowering therapy at 2 years and 4 years on the rate of change of carotid arterial intima-media thickness stratified by sex. The interactive effect between treatment and sex was not significant at 2 or 4 years. Compared with men receiving placebo, men receiving lovastatin had significantly reduced carotid arterial intima-media thickness (P < 0.001 at both 2 and 4 years). Compared with women receiving placebo, women receiving lovastatin had similar (although nonsignificant) treatment effects. Furthermore, although there were only eight women in the placebo group and seven women in the lovastatin group, the magnitude of the rate of change of the carotid arterial intima-media thickness in these women was similar to that of the men within each group. The mean difference in progression rate between groups at 2 years was – 0.025 (95% CI, – 0.069 to 0.019) for women and – 0.058 (CI, – 0.069 to – 0.047) for men. At 4 years, these differences were – 0.064 (CI, – 0.134 to 0.006) for women and – 0.042 (CI, – 0.053 to – 0.031) for men.

Correlates to Change Rate in Early, Preintrusive Carotid Arterial Atherosclerosis

Table 4 summarizes the univariate correlations between rate of change in carotid arterial intima-media thickness (estimated over 2 years) and on-trial clinical parameters and levels of lipids, lipoproteins, and apolipoproteins in the combined groups, unadjusted for treatment group. Rate of change of carotid arterial intima-media thickness was significantly associated with on-trial total cholesterol, LDL cholesterol, total triglycerides, and apolipoproteins B, E, C-III-HP, C-III-HS, and C-III in whole serum (P < 0.05 for all). In multivariate stepwise regression, on-trial total cholesterol was the single independent correlate of the rate of change of carotid arterial intima-media thickness (R² equals 0.35). If on-trial total cholesterol is excluded from the multivariate stepwise regression model, on-trial LDL cholesterol (P < 0.001) and apolipoprotein E (P < 0.01) are independently correlated with the rate of change of carotid arterial intima-media thickness, accounting for the same degree of variability (R² equals 0.39) detected for the total cholesterol level alone. The correlation of the rate of change of carotid arterial intima-media thickness with total cholesterol was reduced to 0.005 (nonsignificant) after adjustment for LDL cholesterol and apolipoprotein E. After controlling for treatment group, only apolipoprotein B remained significantly correlated (r = 0.14; P = 0.05) with the rate of change of carotid arterial intima-media thickness. Within the placebo group, apolipoprotein B was the only risk factor significantly associated with the rate of change of carotid arterial intima-media thickness (r = 0.23; P < 0.05). No significant correlations were seen between the rate of change of carotid arterial intima-media thickness and on-trial risk factors in the lovastatin group.

Discussion

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Our results show that lipid-lowering therapy significantly reduces the progression of early, preintrusive atherosclerosis. A trend for reduction in carotid arterial intima-media thickness was shown after only 6 months of therapy. Significant differences in the absolute change of carotid arterial intima-media thickness between the lovastatin group and the placebo group were first detected at 1 year and persisted through the remaining 3 years of the trial (P < 0.001; Table 2).

Patients treated with lovastatin who had carotid arterial intima-media thickness greater than the median at baseline (0.717 mm) had an approximately two-fold greater decrease in carotid arterial intima-media thickness than did patients treated with lovastatin who had baseline values below the median (Table 3). Progression of carotid arterial intima-media thickness was unrelated to intima-media thickness at baseline in placebo recipients. The significant interactive effect between treatment and carotid arterial intima-media thickness at baseline has been seen previously [20].

The reduction in the progression of carotid arterial intima-media thickness was greater, although nonsignificant, in smokers receiving lovastatin than in nonsmokers receiving lovastatin (P = 0.11; Table 3). Similar findings have been reported from the Kuopio Atherosclerosis Prevention Study [21]. Consistent with the results of a previous report [20], the lipid-lowering treatment effect on the progression of carotid arterial intima-media thickness was similar in both sexes.

The reduction of the progression of carotid arterial intima-media thickness with lipid-lowering mono-therapy in MARS confirms, with the same methods, the CLAS findings of the significant therapeutic effects of colestipol-niacin on early, preintrusive atherosclerosis [3, 4]. The rate of progression of carotid arterial intima-media thickness in the patients receiving lipid-lowering therapy was similar in both studies: – 0.028 mm/y in MARS and – 0.026 mm/y in CLAS. The rate of progression of the placebo groups in both studies was also similar: 0.015 mm/y in MARS and 0.018 mm/y in CLAS. In these studies, the reduced rate of progression of carotid arterial intima-media thickness in the treated groups relative to the placebo groups parallel the changes in coronary artery lesions as determined by quantitative coronary angiographic end points [9, 11]. These findings indicate that treatment response and natural history of progression are similar in early, preintrusive carotid arterial atherosclerosis and in intrusive coronary arterial atherosclerosis.

Although these and other data indicate that the carotid arterial intima-media thickness is an excellent surrogate end point for clinical trials of coronary arterial atherosclerosis [1-3, 22-24], these results are generalizable only to patients with established coronary artery disease. Carotid arterial intima-media thickness has not been studied in relation to coronary arterial atherosclerosis in asymptomatic persons.

In lovastatin recipients, the reduction of carotid arterial intima-media thickness was associated with reductions during the trial of 32% in total cholesterol, 45% in LDL cholesterol, 21% in total triglyceride, 26% in apolipoprotein B, 8% in apolipoprotein E, 11% in apolipoprotein C-III-HP, and 8% in apolipoprotein C-III-WS, and with an increase of 9% in HDL cholesterol. These effects on the lipid, lipoprotein, and apolipoprotein levels contributed to the reversal of coronary arterial atherosclerosis in the same patients, an effect shown at 2 years by coronary angiography [11, 25]. Furthermore, on-trial lipid, lipoprotein, and apolipoprotein findings, which correlated with reduction in progression of carotid and coronary atherosclerosis, were similar in both MARS (Table 4) and CLAS [3, 26].

On-trial total cholesterol accounted for 35% of the variation in the rate of change of carotid arterial intima-media thickness, all of which was accounted for by LDL cholesterol and apolipoprotein E. In the placebo group, apolipoprotein B was the only variable significantly correlated with the progression of carotid arterial intima-media thickness. With a 26% reduction in apolipoprotein B in the lovastatin group, no lipid, lipoprotein, or apolipoprotein remained significantly correlated with progression of carotid arterial intima-media thickness. These findings and the multivariate analysis controlling for treatment group indicate that apolipoprotein B was a predominant risk factor associated with the progression of early, preintrusive carotid atherosclerosis. In CLAS, HDL cholesterol increased 38%, apolipoprotein A-I increased 19%, and apolipoprotein C-III-HS increased 24%. All of these increases differed significantly between groups, and were associated with a reduction in the progression of carotid arterial intima-media thickness [3]. In MARS, HDL cholesterol increased 9%, apolipoprotein A-I increased 2%, and apolipoprotein C-III-HS increased 2%. These percentage changes were much lower than those in CLAS, did not differ significantly between treatment groups, and were not associated with a reduced progression of carotid arterial intima-media thickness. These results suggest that drug-induced elevation of HDL cholesterol may also be important in reducing the progression of early, preintrusive atherosclerosis. Because entrance criteria in MARS limited the risk from hypertension, on-trial blood pressure was not significantly correlated with the progression of carotid arterial intima-media thickness.

Significant correlation between the progression of carotid arterial intima-media thickness and the LDL-VLDL-apolipoprotein C-III content (apolipoprotein C-III-HP) and apolipoprotein E suggests that triglyceride-rich lipoprotein metabolism is important in the progression of early, preintrusive atherosclerosis (Table 4). The association of apolipoprotein C-III with the progression of carotid arterial intima-media thickness in MARS is consistent with the findings of CLAS [3]. Apolipoprotein C-III has also been found to be an important risk factor for the progression of coronary arterial atherosclerosis in both CLAS [26] and MARS [25]. These findings are also consistent with the reported association between sequence variations in the A-I/C-III/A-IV gene cluster and carotid arterial intima-media thickness [27] and with the association between carotid arterial intima-media thickness and the postprandial triglyceride response [28]. Apolipoprotein C-III inhibits lipoprotein lipase activity [29, 30] and decreases apolipoprotein E-mediated remnant removal [31, 32], thereby reducing the clearance of triglyceride-rich lipoproteins. These findings suggest that increased residence time and prolonged exposure of the arterial wall to triglyceride-rich lipoproteins may contribute to progression of both carotid and coronary atherosclerosis [33].

Results from MARS and CLAS provide strong evidence that the progression of early, preintrusive atherosclerosis can be significantly reduced with single-agent or combined lipid-lowering therapy. These results are consistent with those from the Pravastatin, Lipids, and Atherosclerosis in the Carotid Arteries (PLAC-II) study, a randomized trial comparing pravastatin with placebo in 151 patients with a history of coronary artery disease [20]. In this trial, the primary end point measure of carotid arterial atherosclerosis was the rate of change in the mean of the maximum intima-media thickness measurements from the near and far walls of the common carotid artery, the bifurcation, and the internal carotid arteries of both the left and right carotid arteries (12 walls) over 3 years. Although this primary end point was negative, the progression rate of the maximum intima-media thickness in the distal common carotid artery was significantly reduced. Results from the Asymptomatic Carotid Artery Progression Study (ACAPS) [34] showed that lovastatin therapy reduces carotid arterial atherosclerosis in asymptomatic patients. However, patient selection criteria and end points for arterial wall imaging in both PLAC-II and ACAPS differed from those in MARS and CLAS, which included patients with angiographically defined coronary artery disease regardless of carotid arterial intima-media thickness at baseline. In PLAC-II, patients had to have both coronary artery disease and an ultrasonographically qualifying carotid artery lesion of at least 1.3 mm. In ACAPS, asymptomatic patients were selected on the basis of an ultrasonographically qualifying carotid artery lesion of at least 1.5 mm. This preselection process based on B-mode ultrasonographic criteria excluded as many as 50% of otherwise qualified participants [20, 34]. Nonetheless, the results of these four studies indicate that lipid-lowering therapy reduces progression of carotid arterial atherosclerosis in patients with established coronary artery disease and in asymptomatic patients.

In summary, we report that lovastatin plus lipid-lowering dietary therapy significantly reduces the combined thickness of the distal common carotid arterial far wall intima-media complex. Both cholesterol-rich and triglyceride-rich lipoproteins are associated with the progression of early, preintrusive atherosclerosis. Our results extend those of CLAS and confirm the feasibility of small-scale trials of atherosclerosis risk-factor intervention using automated computerized measurements of distal common carotid arterial intima-media thickness as an arterial imaging end point for anti-atherosclerosis therapies [1, 2].

Drs. Mack and Azen and Ms. LaBree: Department of Preventive Medicine, University of Southern California School of Medicine, 1540 Alcazar Street, CHP 218, Los Angeles, CA 90033.

Mr. Selzer and Ms. Kwong-Fu: Jet Propulsion Laboratory, 4800 Oak Grove Drive, 168-514, Pasadena, CA 91103.

Dr. Alaupovic: Oklahoma Medical Research Foundation, 825 Northeast 13th Street, Oklahoma City, OK 73104.