Methods

This trial assessing the effect of lipid-lowering therapy on coronary lipid-rich plaque (LRP) was an open-label, single-blinded, single-center (The Second Affiliated Hospital of Harbin Medical Hospital, Harbin, China) study using OCT and IVUS to compare the impact of intensive versus moderate statin therapy on the FCT and plaque volume in coronary plaques. OCT and IVUS were performed in patients who underwent successful percutaneous coronary intervention with at least one untreated moderate lesion in a nonculprit site. The patients who met the study criteria were assigned randomly to receive AT 60 mg, AT 20 mg, or rosuvastatin 10 mg for 12 months. Patients and study staff were blinded to treatment assignment. The rosuvastatin 10-mg group was initially included to test the hypothesis that the degree of LDL-C reduction rather than specific statin was important on vascular response. However, this group was excluded in the final analysis because it created more confusion rather than proving our hypothesis.

Eligible participants were men or women aged 18 to 75 years with coronary artery disease. The inclusion criteria were (1) de novo lesion with luminal diameter stenosis between 20% and 70% (visual estimation) on coronary angiogram, (2) LRP by OCT (FCT ≤120 μm and lipid arc ≥100°), and (3) LDL-C range between 70 mg/dl and 160 mg/dl. The exclusion criteria included: (1) life expectancy <12 months, (2) contraindication to atorvastatin and rosuvastatin, (3) creatinine level >2.0 mg/dl or end-stage renal disease, (4) severe hepatic dysfunction (AST and/or ALT >3 times the upper limit of normal), and (5) congestive heart failure or left ventricle ejection fraction ≤35%. At 6 months and 12 months, OCT and IVUS examinations were repeated in the same segments as those imaged at baseline. All images were analyzed at the independent core laboratory at Massachusetts General Hospital. This protocol was approved by the institutional review board of Harbin Medical University. All patients provided informed consent before participation.

All OCT procedures were performed after an intracoronary administration of 100 to 200 μg of nitroglycerin. OCT imaging was performed using a time-domain (M3 Cardiology Imaging System; LightLab Imaging, Inc., Westford, Massachusetts) or frequency domain OCT system (C7-XR OCT Intravascular Imaging System, St. Jude Medical, St. Paul, Minnesota).

OCT image analysis was performed by 2 experienced investigators who were blinded to clinical information using proprietary software (LightLab Imaging, Inc.). The paired baseline and follow-up images were analyzed by the person who was blinded to the sequence and group information. Stent edge, calcification, and side branches were used as landmarks to confirm the target plaque. All OCT images were analyzed at 1-mm interval. If any portion of the image was out of the screen, a side branch occupied >45° of the cross-section, or the image had poor quality caused by residual blood, sew-up artifact, or reverberation, the image was excluded from analysis. When there was discordance between the readers, a consensus reading was obtained from a third independent investigator.

All OCT images were analyzed using the previously validated criteria for plaque characterization. LRP was defined as the plaque with lipid arc >100° and fibrous cap <120 μm on OCT image. Although a pathology study showed FCT of ≤65 μm for 95% of ruptured plaques, the study by Yonetsu et al reported that the median representative cap thickness in vivo was 116 μm. Because the aim of our study was to follow the evolution of LRP, we adopted the definition of Dr. Yonetsu and rounded the number to 120 μm. At baseline, FCT of lipid plaque was measured at its thinnest part 3 times, and the average value was calculated. At follow-up, FCT was measured at the same site as it was measured at baseline using the same method. Lipid arc was measured on the cross-section with largest lipid pool. Thin-cap fibroatheroma (TCFA) was defined as a lipid plaque occupying ≥2 quadrants and FCT ≤65 μm on a cross-sectional image. Macrophage infiltration was defined as signal-rich, distinct, or confluent punctuated regions that exceeded the intensity of background speckle noise. Microchannel was defined as a small black hole within a plaque with a diameter of 50 to 100 μm that was present on at least 3 consecutive frames. Thrombus was defined as a mass >250 μm, which was attached to luminal surface or floating within the lumen. Calcification was also recorded when an area with low backscatter and a sharp border was visualized.

IVUS images were obtained using a commercially available system (iLab1. 3; Boston Scientific, Fremont, California) and a 40 MHz, 2.6Fr catheter. After intracoronary administration of nitroglycerin 100 to 200 μg, automatic pullback was performed at 0.5 mm/s from at least 10 mm distal to the target lesion. Off-line analysis was performed using a software program (EchoPlaque; Indec Systems, Mountain View, California). All qualitative and quantitative analysis was performed in accordance with the standards of the American College of Cardiology and the European Society of Cardiology. For each 1 mm of axial length, the lumen cross-sectional area (CSA) and external elastic membrane (EEM) CSA were measured. Plaque plus media CSA was calculated as EEM CSA minus lumen CSA. Plaque burden was calculated as plaque plus media CSA, divided by EEM CSA. Total atheroma volumes (TAVs) were calculated as the sum of the differences between EEM and lumen areas across all evaluable slices using Simpson’s rule : TAV = ∑ (EEM _CSA − LUMEN _CSA ), where EEM _CSA = EEM CSA and LUMEN _CSA = luminal CSA. The percentage change in TAV was computed as: [TAV(follow−up)−(baseline)TAV(baseline)×100]
[ TAV ( follow − up ) − ( baseline ) TAV ( baseline ) × 100 ]
. Considering that the length of pullback for serial evaluations was determined by the anatomic location of the arterial side branches, there was heterogeneity in segment length between the patients. The TAV for each patient was normalized as the average area of atheroma multiplied by the median number of cross-sections in the pullbacks for all patients in the study. Change in normalized TAV was calculated as TAV _follow-up − TAV _baseline . PAV was calculated using the following formula: [∑(EEMCSA–LUMENCSA)∑EEMCSA×100]
[ ∑ ( EEMCSA – LUMENCSA ) ∑ EEMCSA × 100 ]
. Change in PAV was calculated as PAV _follow-up − PAV _baseline .

Categorical data were presented as counts and proportions and were compared using either a chi-square test or Fisher’s exact test, depending on the data. Continuous measurements were presented as mean ± SD or median (25th to 75th percentile). The data with normal distribution was analyzed with the analysis of variance and Bonferroni correction for multiple comparisons, otherwise nonparametric analysis was used. For comparisons between the AT 60 mg and AT 20 mg groups, analysis was performed by means of the generalized estimating equations approach to take into account the within-subject correlation attributable to multiple plaques analyzed within a single subject. Comparisons of continuous measurements between baseline and follow-up were performed by paired t -test. All analyses were performed using SPSS 22.0. A 2-sided p value <0.05 was considered statistically significant.