Qualitative and Quantitative Changes in Coronary Plaque Associated With Atorvastatin Therapy

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1 ORIGINAL ARTICLE Ischemic Heart Disease Circ J 2009; 73: Qualitative and Quantitative Changes in Coronary Plaque Associated With Atorvastatin Therapy Atsushi Hirayama, MD; Satoshi Saito, MD; Yasunori Ueda, MD; Tadateru Takayama, MD; Junko Honye, MD; Sei Komatsu, MD ; Osamu Yamaguchi, MD ; Yuxin Li, MD; Junji Yajima, MD ; Shinsuke Nanto, MD; Kenji Takazawa, MD ; Kazuhisa Kodama, MD Background: The aim of this study was to elucidate the time course of atorvastatin-induced changes in vulnerable plaque using angioscopy and intravascular ultrasound (IVUS). Methods and Results: Fifty-seven hypercholesterolemic patients with coronary artery disease (CAD) were treated with atorvastatin (10 20 mg/day) for 80 weeks and then coronary plaques were evaluated with angioscopy and IVUS. Angioscopic images were classified into 6 grades (0 5) based on yellow color intensity. A 20-mm segment containing angioscopically-identified yellow plaque was also examined by IVUS to measure atheroma volume. The mean angioscopic grade of 58 yellow plaques significantly decreased from 1.5 (95% confidence interval [CI] 1.2 to 1.8) to 1.1 (95%CI 0.9 to 1.3, P=0.012) at week 28 and 1.2 (95%CI 0.9 to 1.4, P=0.024) at week 80. Mean volume of 30 lesions, including the 58 yellow plaques, significantly reduced 8.3% (95%CI 11.5 to 5.2) at week 28 (P<0.001 for baseline vs week 28) and 17.8% (95%CI 23.9 to 11.8) at week 80 (P<0.001 for baseline vs week 80). Conclusions: In patients with CAD treated with atorvastatin, serial analysis with angioscopy demonstrated early loss of yellow color in plaques, and IVUS volumetric analysis showed subsequent plaque regression. Both changes possibly indicate reduction of plaque vulnerability in an additive manner. (Circ J 2009; 73: ) Key Words: Angioscopy; Coronary disease; IVUS; Plaque; Statins There have been many reports that intensive lowering of low-density lipoprotein-cholesterol (LDL-C) with 3-hydroxy-3-methylglutaryl-coenzyme A (HMG- CoA) reductase inhibitors (statins) is effective in preventing cardiovascular events. 1 3 Although the mechanism by which statins confer cardiovascular benefit is not precisely understood, regression of coronary plaque volume and reduction of plaque vulnerability are presumed to play important roles. Angioscopic observations have shown that the presence of yellow plaque is associated with unstable symptoms, which suggests that as plaques become more yellow in appearance, they also become more prone to rupture. 4 6 Editorial p 628 Angioscopy is used to assess plaque vulnerability on the (Received August 10, 2008; accepted December 2, 2008; released online February 18, 2009) Division of Cardiology, Department of Medicine, Nihon University School of Medicine, Tokyo, Cardiovascular Division, Osaka Police Hospital, Osaka, Cardiovascular Division, Kansai Rosai Hospital, Amagasaki, Department of Cardiovascular Medicine, Osaka University Graduate School of Medicine, Suita, Department of Cardiology, The Cardiovascular Institute Hospital, Tokyo, Department of Cardiology, Tokyo Medical University Hachioji Medical Center, Hachioji and Cardiovascular Division, Amagasaki Chuou Hospital, Amagasaki, Japan Mailing address: Atsushi Hirayama, MD, Division of Cardiology, Department of Medicine, Nihon University School of Medicine, 30-1 Ohyaguchi-kamicho, Itabashi-ku, Tokyo , Japan. ahirayam@med.nihon-u.ac.jp All rights are reserved to the Japanese Circulation Society. For permissions, please cj@j-circ.or.jp basis of its color and the presence of thrombi. 7,8 Angioscopy gives a full-color, 3-dimensional perspective of the intracoronary surface morphology, and reasonably accurate information regarding a specific lesion, if performed by trained technicians. Intravascular ultrasound (IVUS) is an alternative imaging modality that provides real-time tomographic images of blood vessels on a monitor. It generates information on vessel wall structure, atheroma volume, and the echogenicity of plaque, which is amenable to qualitative and quantitative analysis and can be used to evaluate plaque regression. 9 The effects of statins on coronary plaque have been evaluated by angioscopy, as well as IVUS, in patients with hypercholesterolemia. Using angioscopy, Takano et al demonstrated that the grade of yellow color decreased during statin therapy, 10 and Nissen et al 11 and Okazaki et al 12 used IVUS to investigate the effects of statins on atheroma volume. However, because no study has serially monitored the coronary plaques of patients receiving statin therapy using both angioscopy and IVUS, the relationship between changes in plaque color and changes in atheroma volume has not been elucidated. Therefore, we used both imaging modalities concurrently to investigate the qualitative and quantitative changes over time in coronary plaques in patients receiving atorvastatin therapy to reduce LDL-C levels to 100 mg/dl. Methods Study Population Patients with coronary artery disease (CAD) complicated by hypercholesterolemia, with a fasting LDL-C level

2 Changes in Plaque Characteristics With Atorvastatin 719 Figure 1. Standard yellow-color grading. The plaques were graded on a 6-point scale: 0, not yellow at all; 1, pale yellow; 2, yellow; 3, deep yellow; 4, bright yellow; and 5, ruptured plaque. 120 mg/dl within 8 weeks of study initiation, were enrolled. Exclusion criteria were acute myocardial infarction, familial hypercholesterolemia homozygote, undergoing apheresis within 8 weeks prior to the enrollment, change in medical treatment for hypercholesterolemia within 12 weeks prior to the enrollment, presence of malignancies or mental disorder within 5 years prior to the enrollment, progressive hepatic disorder, treatment with dialysis, serum creatinine 2 mg/dl or creatine kinase 500 IU/L, and uncontrolled diabetes with hemoglobin A1c 8.0%. All eligible patients received a daily dose of oral atorvastatin 10 mg/day for 80 weeks. If the LDL-C level was 100 mg/dl at week 2, the daily dose was increased to 20 mg/day for the subsequent 78 weeks. Coronary angiography was performed at weeks 0 (baseline), 28 and 80. The study protocol was approved by the Institutional Review Boards of Osaka Police Hospital and Nihon University Itabashi Hospital. All participants provided written informed consent before participation. Angioscopic Examination Immediately after coronary angiography, baseline angioscopy images were obtained with a Fiber Imaging System FT-201 (FiberTech Co Ltd, Tokyo, Japan), using a previously described technique. 7 From these images, lesions located in major coronary arteries were selected for the main angioscopic examination. Percent stenosis was not used for selection of the lesion for angioscopic analysis because plaque color is not necessarily related to it. The positions of the plaques were confirmed with fluoroscopy by determining the location of the fiberscope tip, and plaque maps were prepared. Images were recorded on a digital videotape and graded using a 6-point scale: 0, not yellow at all; 1, pale yellow; 2, yellow; 3, deep yellow; 4, bright yellow; and 5, ruptured plaque (Figure 1). At weeks 28 and 80, the same positions as at baseline were observed with angioscopy, in reference to the positions of side branches used as landmarks at baseline. To determine the color grade, all angioscopic images were reviewed by 2 independent investigators who were unaware of the patients identity and the time of image acquisition. In this study, the interobserver reproducibility for the interpretation of plaque color was 58.0% at the end of the first evaluation. The discordant plaques were intensively reevaluated by the reviewers, but if there was still discordance between them after the second evaluation, they further evaluated the images individually until they reached consensus. During this process, the images were completely blinded to the investigators in terms of patient identity and time of acquisition. IVUS Image Acquisition IVUS measurements were performed with a 2.6F 40- MHz Atlantis Pro IVUS catheter (Boston Scientific Corporation, Natick, MA, USA). The IVUS probe was advanced to a side branch located distal to the target lesion and images were obtained during automatic pullback at a rate of 0.5 mm/s and recorded on s-vhs videotape. Based on the plaque map, the IVUS volumetric analyses of the target lesions were conducted using a 20-mm segment (IVUS analysis segment) at lesion sites as the unit of analysis. Lesions close to culprit plaques treated by percutaneous coronary intervention (PCI), that is, within 5 mm, were excluded. The boundary of the lumen and external elastic membrane (EEM) was traced semi-automatically on digitized cross-sections of the IVUS analysis segment every 0.1 mm (Netra IVUS, Ver.2.04, 00C, ScImage, Inc, Los Angels, CA, USA). At the baseline examination, the IVUS analysis segment was determined to include a yellowcolored position, based on the plaque map and the position of a side branch. At the examinations performed in weeks 28 and 80, the IVUS analysis segment was set using a side branch as a landmark to ensure that at the 3 time points the same position was imaged by IVUS. IVUS volumetric analysis was performed at a core laboratory in the Nihon University School of Medicine by an operator who was not involved in the medical care of the patients. The correlation coefficients for the relationship between 2 independent observers for the IVUS measurement were , as previously described. 13 Two inves-

3 720 HIRAYAMA A et al. Intervention 57 patients enrolled 39 patients at week patients excluded from the study 7 Consent withdrawal 7 Study protocol deviation 3 Adverse events 1 Others (lost to follow up) 8 patients excluded from the study 4 Adverse events 3 Consent withdrawal 31 patients at week 80 1 Study protocol l deviation Data analysis 2 pts 29 patients evaluable for angioscopic analysis (162 yellow plaques) partial missing data data set for sub-analysis 2 pts 28 patients evaluable for IVUS analysis (57 IVUS analysis segment) 20 patients with matching data 58 yellow plaques 30 IVUS analysis segments matched data set for primary analysis Figure 2. Overview of study protocol. IVUS, intravascular ultrasound. Table 1. Patients Characteristics N 20 Age, mean ± SD, years 57.5±7.6 Gender Male 17 (85) Female 3 (15) Body mass index, mean ± SD, kg/m ±3.8 Type of dyslipidemia IIa 12 (60) IIb 3 (15) Other 5 (25) Familial hypercholesterolemia 0 (0) Predisposition to hypersensitivity 8 (40) Comorbidity Diabetes mellitus 4 (20) Heart disease (not variant angina) 19 (95) Hypertension 10 (50) Previous medications Antihypercholesterolemic agents 2 (10) HMG-CoA reductase inhibitors 2 (10) Concomitant use of antihypercholesterolemic agents 1 (5) Diet 7 (35) Exercise 0 (0) Daily alcohol consumption (ml) 80 1 (5) (0) <40 9 (45) 0 10 (50) Smoking status Current smoker 4 (20) Former smoker 14 (70) Passive smoker 0 (0) Nonsmoker 2 (10) Concomitant drugs Aspirin 19 (95) Antiplatelet agents other than aspirin 17 (85) ACEI 7 (35) ARB 4 (20) β-blockers 4 (20) Data are n (%), unless otherwise noted. β-blockers include α/β-blockers. HMG-CoA, 3-hydroxy-3-methylglutaryl-coenzyme A; ACEI, angiotensinconverting enzyme inhibitors; ARB, angiotensin II receptor blocker. tigators independent of the core laboratory and blinded to the patients identity and time of image acquisition individually evaluated the images, including the accuracy of target lesion analysis at baseline, and at weeks 28 and 80. The proportion of inappropriately analyzed lesions was 27.0% and these lesions were re-examined at the core laboratory. Data Matching in the Primary Analysis Data for a plaque that had undergone angioscopic colorimetric analyses and IVUS volumetric analyses at baseline, and at weeks 28 and 80 were treated as matched data. When multiple yellow plaques were included in a single 20-mm IVUS analysis segment, the mean value of the color grades was used. For this reason, if any yellow plaques observed at baseline in an IVUS analysis segment were unable to be evaluated angioscopically at either week 28 or 80 because of procedural difficulties, the set of plaques and the IVUS analysis segment in question were excluded from the analysis. For example, if there were 3 yellow plaques within a 20-mm IVUS analysis segment, all 3 plaques needed to have data from all 3 time points of evaluation (ie, 3 3=9 observations) in order to be included in the primary analysis, otherwise they and the IVUS analysis segment were excluded from the primary analysis. Unmatched data of the plaques and IVUS analysis segments that had all 3 time points were separately used for subanalysis, as described later in the Results. Statistical Analysis Because this study was designed as preliminary exploratory research to investigate the relationship between quantitative and qualitative changes of coronary atherosclerotic plaques, the number of patients to be enrolled was planned as 50. The Wilcoxon signed-rank test was used for comparison of plaque color grade between the values before and after treatment. With respect to the IVUS variables, the paired t-test was used to compare the values between time points. The paired t-test was performed to compare LDL-C and HDL-C levels before and after treatment. In all tests, P-values of 0.05 were considered statistically significant.

4 Changes in Plaque Characteristics With Atorvastatin 721 Table 2. Changes in Lipid Levels Baseline (n=20) 28 weeks (n=20) 80 weeks (n=20) Percent Percent Mean (SD) Mean (SD) 95%CI Mean (SD) change change LDL-C (mg/dl) (29.6) 86.4 (13.0) ~ (13.3) ~ 42.6 TC (mg/dl) (33.2) (19.1) ~ (22.6) ~ 31.1 HDL-C (mg/dl) 36.7 (7.6) 42.6 (7.9) ~ (9.5) ~ 10.0 Phospholipids (mg/dl) (29.6) (19.9) ~ (25.4) ~ 17.0 Apolipoprotein A-1 (mg/dl) (18.8) (16.4) ~ (18.6) ~ 10.7 Apolipoprotein B (mg/dl) (16.2) 75.7 (10.9) ~ (13.4) ~ 34.4 TG (mg/dl) 124 (92 ~ 141) 98 (83 ~ 147) 108 (78 ~ 147) RLP-C (mg/dl) 5.1 (4.2 ~ 6.8) 4.6 (3.4 ~ 5.9) 6.4 (5.3 ~ 8.1) Lipoprotein(a) (mg/dl) 14.9 (7.5 ~ 28.3) 13.2 (5.8 ~ 24.1) 17.7 (8.3 ~ 24.3) hs-crp (mg/dl) (0.030 ~ 0.119) (0.019 ~ 0.072) (0.018 ~ 0.087) Median (interquartile range) is provided because of the lack of normality of the distribution. Significantly different from baseline by paired t-test (P<0.001). Significantly different from baseline by paired t-test (P=0.001). Average of the individual change from a baseline value. CI, confidence interval; LDL-C, low-density lipoprotein-cholesterol; TC, total cholesterol; HDL-C, high-density lipoprotein-cholesterol; TG, triglycerides; RLP-C, remnant-like particle-cholesterol; hs-crp, high-sensitivity C-reactive protein. 95%CI Figure 3. Representative angioscopic and intravascular ultrasound (IVUS) images of a yellow plaque and a 20-mm IVUS analysis segment at the 3 time points (baseline, week 28 and week 80). Results Patient Population From July 2003 through March 2004, 71 patients gave informed consent to participate in the study. After exclusion of 14 patients who did not meet the inclusion criteria, 57 eligible patients were enrolled. At week 2, 15 patients had their dose of atorvastatin increased to 20 mg daily while 42 continued on 10 mg daily. The safety evaluation included the 57 patients who received at least 1 dose of the study drug. Among the 57 patients, 31 had been followed for 80 weeks and of these 31 patients, 20 had matched angioscopy and IVUS data for all 3 time points: baseline, week 28 and week 80 (Figure 2). The mean age of the 20 patients was 57.5±7.6 years (17 (85%) men; Table 1), 10 (50%) had hypertension, and 4 (20%) had diabetes mellitus. Prior to study initiation, 2 patients had received a statin other than atorvastatin and switched to atorvastatin after enrollment in

5 722 HIRAYAMA A et al. e plaqu llow of ye rade Mean g e plaqu ellow e of y Grad weeks P=0.003 P<0.001 P<0.001 baseline 28 weeks P=0.024 P= Mean percent change (%) P < P < Baseline 28 weeks 80 weeks P=0.012 Figure 4. Changes in the mean grade of yellow of plaques (n=58) and percent change in mean atheroma volume of the intravascular ultrasound analysis segments (n=30) of matched plaques at baseline, and weeks 28 and 80. P values estimated with the Wilcoxon signedrank test; P values estimated with the paired t-test for absolute values between baseline and week 28 or 80; P values estimated with paired t-test for absolute values between weeks 28 and 80. Median Mean Figure 5. Changes in the grade of yellow of plaques. The mean and median grades of yellow of 162 plaques from 29 patients serially observed with angioscopy at 3 time points: baseline, weeks 28 and 80. The box extends from the 1 st to the 3 rd quartile. P values were estimated with the Wilcoxon signed-rank test. the study. At the end of the study, 13 patients were being treated with atorvastatin 10 mg/day and 7 were taking atorvastatin 20 mg/day. One patient was being concomitantly treated with non-statin antihypercholesterolemic therapy after study commencement. Change in Laboratory Values During the study, LDL-C levels decreased from 144.4± 29.6 mg/dl at baseline to 86.4±13.0 mg/dl at week 28 and 89.4±13.3 mg/dl at week 80 (Table 2). HDL-C levels increased from 36.7±7.6 mg/dl to 42.6±7.9 mg/dl at week 28 and 43.4±9.5 mg/dl at week 80. The median (interquartile range) of high-sensitivity C-reactive protein level decreased from mg/dl ( ) at baseline to mg/dl ( ) at week 28, and mg/dl ( ) at week 80. A 10 e(%) hang nt C perce Mean B e (mm 3 ) Volum % Change at week 28 from baseline % Change at week 80 from baseline EEM Lumen Atheroma EEM Lumen Atheroma Matched Data A complete set of angioscopy and IVUS images matched at all 3 time points for all plaques observed at baseline were obtained for 20 patients; 30 segments observed by IVUS and 58 yellow plaques observed by angioscopy (representative images are shown in Figure 3). Because in some cases multiple yellow plaques were included in the segment used for IVUS measurement, the total number of yellow plaques was more than the total number of IVUS analysis segments. In the matched data, the mean grade of yellow plaques was 1.5±0.8 (95%CI 1.2 to 1.8), 1.1±0.5 (95%CI 0.9 to 1.3), and 1.2±0.7 (95%CI 0.9 to 1.4) at baseline, week 28, and week 80, respectively (Figure 4). The grade of yellow was significantly lower at weeks 28 (P=0.012) and 80 (P= 0.024) than at baseline, with no significant difference between weeks 28 and 80 (P=0.508). Atheroma volume decreased significantly ( 8.3±8.5% [95%CI 11.5 to 5.2]) at week 28 (P<0.001 for baseline vs week 28) and by 17.8±16.2% (95%CI 23.9 to 11.8) at week 80 (P<0.001 for baseline vs week 80). The decrease in atheroma volume Baseline 28 weeks 80 weeks Figure 6. Changes in atheroma volume of intravascular ultrasound (IVUS) analysis segments. (A) Percent change in external elastic membrane (EEM), lumen and atheroma volume at each time point from baseline. Bars indicate 95% confidence intervals. Asterisks denote a significant change from baseline (P<0.001 by paired t-test). (B) Mean values for EEM, lumen and atheroma volume of 57 lesions serially evaluated by IVUS from 28 patients. Bars indicate 95% confidence intervals. Asterisks denote a significant change from baseline (P<0.001 by paired t-test).

6 Changes in Plaque Characteristics With Atorvastatin from weeks 28 to 80 was also significant (P=0.003 for week 28 vs week 80). These changes were observed simultaneously with the decrease in LDL-C concentration. Because the criteria for selecting the plaques to be used in the primary analysis were set strictly (see Methods section), complete matched data sets were obtained from 20 patients only. Although the main conclusion should be drawn from the matched data of these 20 patients, we conducted subanalyses with the angioscopy or IVUS data from when they were successfully evaluated at all 3 time points, even if the data were not matched, in order to see if we obtained similar results to those achieved with the matched data. Subanalysis for Changes in Angioscopic Findings There were 162 yellow plaques collected from 29 patients who had successful angioscopy at all 3 time points, though not all of the plaques were accompanied by corresponding IVUS images. For these plaques, the mean grade was significantly reduced from 1.5±0.8 (95%CI 1.3 to 1.6) at baseline to 1.1±0.7 (95%CI 1.0 to 1.2, P<0.001) at week 28, and 1.2±0.8 (95%CI 1.0 to 1.3, P<0.001) at week 80 (Figure 5). Thus, a significant color grade reduction in yellow plaques at week 28 was maintained until week 80, similar to the analysis of matched data. Subanalysis for Changes in IVUS Findings Fifty-seven IVUS analysis segments that contained yellow plaques were collected from 28 patients at all 3 time points, regardless of the existence of corresponding angioscopy data. The mean percent change in EEM volume was 5.0±8.4% (95%CI 7.3 to 2.8, P<0.001 for baseline vs week 28) at week 28 and 7.4±10.0% (95%CI 10.0 to 4.7, P<0.001 for baseline vs week 80) at week 80 (Figures 6A,B). Atheroma volume also decreased significantly ( 9.4±10.3% [95%CI 12.1 to 6.6], P<0.001 for baseline vs week 28) at week 28 and by 18.9±14.1% (95%CI 22.7 to 15.2, P<0.001 for baseline vs week 80) at week 80. In contrast, lumen volume showed no appreciable change ( 0.7±16.0% [95%CI 4.9 to 3.6] at week 28, and 2.2± 17.6% [95%CI 2.5 to 6.8] at week 80). Discussion This is the first study to use angioscopy and IVUS concurrently to prospectively investigate the qualitative and quantitative changes in coronary plaques in hypercholesterolemic patients with CAD receiving atorvastatin titrated to achieve LDL-C levels 100 mg/dl. We demonstrated that qualitative changes in plaque occur relatively early after the beginning of atorvastatin therapy (by week 28), quantitative changes in atheroma volume occurred continuously, even after week 28, up to week 80, and those changes were not correlated. These results suggest that there may be 2 different, probably independent, mechanisms involved in the reduction of vulnerability, improvement in characteristics, and reduction of the volume of yellow plaques. In addition, the different time courses of these changes suggest that the improvement in plaque characteristics occurs early, whereas atheroma volume reduction occurs over a prolonged period of time. Early and Late Benefit of Statin Therapy Several studies have demonstrated that the intensity of the yellow color of a plaque is positively associated with its vulnerability to disruption. 4 6 It has also been reported that 723 the number of yellow plaques is associated with the risk of acute coronary syndrome (ACS). 14 It is inferable that the reduction in yellow color intensity is attributable to a change in the thickness of the fibrous cap, as was reported in an ex vivo comparative study, using integrated backscatter IVUS and angioscopy on tissues isolated from autopsied patients. 15 In that study, angioscopic plaque color was inversely dependent on the thickness of the fibrous cap and did not depend on the size of the lipid core. Angioscopy in combination with optical coherence tomography in humans has revealed that intensive yellow plaques have a thinner fibrous cap, suggesting plaque color is closely related to plaque vulnerability. 16 In the present study, the mean change in angioscopic plaque color grade was not large, 0.4-point decrease from the baseline grade; however, as shown in Figure 5, the 75-percentile point at baseline was 2.0 and it had reduced to less than 1.0, even at week 28, which means that more than 75% of plaques examined had a color grade of less than 1 after a 28-week treatment with atorvastatin and this improvement is thought to be clinically significant. In the context of the previous studies, our finding that the yellow color of plaques fades as early as week 28 after beginning treatment with atorvastatin suggests that the vulnerability of the plaques was reduced early during the course of therapy. Considering this early benefit of statin treatment, large-scale clinical trials, such as the PROVE IT-TIMI 22 trial 17 and the MIRACL study, 18 have reported that intensive lipid-lowering treatment with atorvastatin decreased coronary events occurring in the first 30 days or 16 weeks. 1 The early qualitative changes in coronary plaques as shown here may be involved in the early benefit of atorvastatin therapy. Recent results from the large-scale trials, REVERSAL 11 and ASTEROID, 19 show that intensive lowering of LDL-C with statins for months elicits slower progression, or regression, of plaque, as measured by IVUS. In addition, several studies that used 3-dimensional IVUS to evaluate changes in coronary plaques after long-term statin therapy showed decreases in atheroma volume. 12,20 22 Our present results show a continuous reduction in atheroma volume under statin treatment from baseline to week 80 (Figure 6), which suggests that lipid-lowering treatment with statins may be able to regress atherosclerosis in coronary disease patients over time; in other words, a late benefit of statin therapy. In the present study, the time course of plaque color change and that of volumetric change differed. The color change (ie, qualitative change) of plaque seemed to reach a plateau after week 28, whereas atheroma volume reduction (ie, quantitative change) continued until week 80. These findings also suggest that both these changes reduce plaque vulnerability in an additive manner, because there was not a clear relationship between the percent changes and the absolute differences in plaque color grade and atheroma volume from the baseline values among the study population (data not shown). The possible mechanisms of reducing cardiovascular events with statins may be explained at least in part by a reduction in plaque vulnerability by these 2 different mechanisms of action. The discordance of the qualitative and quantitative changes in plaque was also reported by Schartl et al, 23 who demonstrated that administration of atorvastatin increased echogenicity without plaque regression as evaluated by IVUS. The results of the previous studies, together with ours, suggest that the qualitative and quantitative changes reflect independent processes mediated by different mecha-

7 724 HIRAYAMA A et al. nisms, which are yet to be fully elucidated. Pathological findings have demonstrated that statin therapy reduces matrix metalloproteinase activity, apoptosis, and macrophages, with increased collagen content. 24 These changes might explain the qualitative changes in plaque color, which might represent the thickened fibrous cap. 16 On the other hand, animal experiments showed lipid core depletion by statin treatment, 25 and it has been also shown that long-term statin treatment reduces the size of the lipid-rich necrotic core of atherosclerotic lesions. 26 It is likely that statins reduce the size of the lipid core through improvement of the plasma lipid profile, and this is at least 1 of the mechanisms underlying the quantitative changes induced by statin treatment. Size of the Effect Takano et al reported that the score of coronary plaque color decreased from 2.03 to 1.13 in Japanese patients with hypercholesterolemia and CAD treated with atorvastatin for 12 months to achieve LDL-C levels <100 mg/dl. 10 Okazaki et al reported that a 6-month treatment with atorvastatin reduced plaque volume by 13.1% in Japanese patients with ACS. 12 Although minor differences in the evaluation methodology preclude direct comparison with our study, the present results of reductions in plaque score and atheroma plaque volume are similar to those previous studies. On the other hand, the percent reduction in atheroma volume was considerably larger when compared with those previously reported in Caucasian populations. 11,19 The relatively large reduction in atheroma volume among Japanese patients with CAD compared with similar Caucasian subjects might be attributable to different ethnicity, including lifestyle, of Japanese and Westerners, which requires further studies. Study Limitations This study did not include control patients who received placebo or mild lipid-lowering therapy. At the time of planning this study, aggressive lipid-lowering therapy with atorvastatin was reported as effective in lowering the incidence of death or nonfatal ischemic events in patients with CAD, 18,27 and it was deemed inappropriate from an ethical viewpoint to conduct a study that included a control group of patients with CAD. Second, the amount of missing data was larger than we expected when planning this study. Angioscopically-observed yellow plaques were concentrated over short distances, which made it difficult to obtain completely matched data for all plaques with IVUS analysis at all time points. However, the missing data occurred in a random manner, so omitting those data does not introduce systematic error. Third, the number of participating patients was relatively small. To confirm the findings, large, randomized control studies are needed in patients with different degrees of coronary artery stenosis. Conclusions In CAD patients treated with atorvastatin, serial analysis with angioscopy demonstrated early loss of yellow color in plaques, and IVUS volumetric analysis showed subsequent plaque regression. The qualitative and quantitative changes involved in the reduction in plaque vulnerability appear to be additive. Early initiation and long-term continuation of LDL-C lowering therapy with atorvastatin could be useful for reducing plaque vulnerability in patients with CAD. Disclosures This study was funded by Astellas Pharma, Inc, and Pfizer Japan, Inc. There are no conflicts of interest. References 1. Cannon CP, Braunwald E, McCabe CH, Rader DJ, Rouleau JL, Belder R, et al. Intensive versus moderate lipid lowering with statins after acute coronary syndromes. N Engl J Med 2004; 350: LaRosa JC, Grundy SM, Waters DD, Shear C, Barter P, Fruchart JC, et al. Intensive lipid lowering with atorvastatin in patients with stable coronary disease. N Engl J Med 2005; 352: Pedersen TR, Faergeman O, Kastelein JJ, Olsson AG, Tikkanen MJ, Holme I, et al. High-dose atorvastatin versus usual-dose simvastatin for secondary prevention after myocardial infarction: The IDEAL study [a randomized controlled trial]. JAMA 2005; 294: Ueda Y, Ohtani T, Shimizu M, Hirayama A, Kodama K. Assessment of plaque vulnerability by angioscopic classification of plaque color. Am Heart J 2004; 148: Waxman S, Mittleman MA, Zarich SW, Fitzpatrick PJ, Lewis SM, Leeman DE, et al. 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