Effects of Different Intensive Lipid-Lowering Therapies on Stabilization and Regression of Carotid Plaque: A Randomized Open-Label Trial

Effects of Different Intensive Lipid-Lowering Therapies on Stabilization and Regression of Carotid Plaque: A Randomized Open-Label Trial | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Effects of Different Intensive Lipid-Lowering Therapies on Stabilization and Regression of Carotid Plaque: A Randomized Open-Label Trial Sihua Luo, Lili Lin, Pengda Qiu, Kuan Cai, Hao Liang, Yuhui Lin, and 1 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4604642/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background Atherosclerotic plaques in carotid arteries are significant predictors of cardiovascular events such as stroke and myocardial infarction. Lipid-lowering therapies, particularly statins and proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, have shown promising in plaque regression and stabilization, which are crucial for cardiovascular disease (CVD). Methods This randomized open-label trial was conducted at the Third Affiliated Hospital of Guangzhou Medical University from March 2022 to December 2023. The study included patients at high CVD risk with non-calcified carotid plaque. Participants were randomized into four groups: statin alone (Statin), statin plus ezetimibe (Statin_E), statin plus alirocumab (Statin_P), and statin plus ezetimibe and alirocumab (Statin_EP). The primary outcomes were morphological stabilization of carotid plaque at 6 months and regression at 12 months, assessed by contrast-enhanced carotid ultrasonography. Secondary outcomes were changes in blood lipid levels. Results A total of 312 high CVD risk patients were enrolled, among whom 299 completed the study. After six months, patients in the Statin_P and Statin_EP groups showed significantly lower levels of total cholesterol and low-density lipoprotein cholesterol compared to the other groups. These patients also demonstrated a significantly greater proportion of plaques transforming from types I or II to types III or IV and a significant decrease in intraplaque neovascularization (P < 0.05), indicating the plaques in these groups had stabilized. After 12 months, the regression in plaque size was more pronounced in the Statin_P and Statin_EP groups (left: χ 2 = 26.37, p = 1.90e − 04, CI 95% [0.06, 1.00]; right: χ 2 = 19.00, p = 4.16e − 03, CI 95% [0.00, 1.00]). Conclusion Intensive lipid-lowering therapies that combine statins with PCSK9 inhibitors, such as alirocumab, are more effective in regressing carotid plaques and stabilizing plaque morphology compared to other treatments. These findings support the use of PCSK9 inhibitors in combination with statin therapy for managing atherosclerotic disease and reducing cardiovascular events. Trial registration: The trial was registered in the Chinese Clinical Trial Registry (Registration No. ChiCTR2200058389). Intensive Lipid-Lowering Therapy Atherosclerotic Plaque PCSK9 Inhibitor Contrast-Enhanced Carotid Ultrasonography Intraplaque Neovascularization Plaque Regression Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Figure 7 Figure 8 Figure 9 1. Introduction Atherosclerotic plaques, particularly within the carotid arteries, are key predictors of cardiovascular events such as stroke and myocardial infarction. The formation of these plaques is a complex process involving lipid accumulation, inflammatory responses, and endothelial dysfunction within the arterial walls. Plaque regression and stabilization are important goals in the management of carotid artery disease, as they can reduce the risk of complications such as thromboembolism and rupture. Lipid-lowering therapies, particularly statins, have been the cornerstone of preventing atherosclerotic cardiovascular disease for decades. Recently, their role in inducing plaque regression and promoting plaque stabilization under intensive therapies has emerged as a pivotal objective in managing cardiovascular risk. The ASTEROID trial[ 1 ] demonstrated that high-dose rosuvastatin could promote the regression of coronary atheroma, as assessed by intravascular ultrasound (IVUS). The PRECISE-IVUS trial[ 2 ] showed that a combination of statins and ezetimibe achieved greater coronary plaque regression compared to standard statin monotherapy. As a novel class of lipid-lowering agents, proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors can significantly reduce low-density lipoprotein cholesterol (LDL-C) levels. The addition of the PCSK9 inhibitor evolocumab to statin therapy has also been shown to reverse atherosclerotic plaque[ 3 ]. In addition, studies have shown that PCSK9 inhibitors can reduce intraplaque neovascularization (IPN) within plaques, which is an important factor in plaque progression and vulnerability. Ultrasound imaging techniques, such as contrast-enhanced carotid ultrasonography (CEUS), can evaluate intraplaque vessels and the vasa vasorum. Several studies have verified the presence of IPN using CEUS, indicating that it is a suitable modality for detecting plaque stability. Our previous study showed that intensive therapy with a statin and a PCSK9 inhibitor was more effective for lowering lipid levels of patients at high cardiovascular disease (CVD) risk compared to statin alone or statin plus ezetimibe[ 4 ]. However, the effect on regression and stabilization of carotid plaques remains unknown. CEUS has enabled the accurate quantification and characterization of atherosclerotic plaques, providing an opportunity to directly monitor the impact of therapeutic interventions on plaques. Therefore, we present a nonblind, randomized controlled trial to compare the effects of different intensive lipid-lowering therapies on the regression and stabilization of carotid plaques in patients at high CVD risk. 2. Methods 2.1 Study population Patients were enrolled from the Third Affiliated Hospital of Guangzhou Medical University from March 2022 to December 2023. The study protocol was approved by the Institutional Ethics Committee of the hospital, and written informed consent was obtained from all patients before the treatment. The trial was registered in the Chinese Clinical Trial Registry (registration number: ChiCTR2200058389). Study participants with high CVD risk[ 5 ] with non-calcified plaque on the carotid artery were included based on the following criteria: (1) treatment-naive or receiving non-intensive lipid-lowering therapy; (2) LDL-C ≥ 70 mg/dL; (3) uni- or bilateral carotid artery plaque (maximum plaque thickness > 1.5 mm). Individuals with a history of stroke and myocardial infarction; those with a history of carotid endarterectomy; those with an allergy to the contrast agent or lipid-lowering drugs; those with secondary dyslipidemia caused by hypothyroidism, Cushing's syndrome, nephrotic syndrome, or drug use; and those with heart failure or end-stage renal failure were excluded from the study. 2.2 Study design Information on patients’ sex, age, body mass index (BMI), smoking history, hypertension, diabetes, and other related medical history was collected. Baseline laboratory tests and carotid ultrasonography were performed, and patients who met the inclusion criteria were enrolled. The randomization and allocation procedures were carried out as before [ 4 ]. In short, an assistant used random numbers obtained from sealed envelopes. All selected patients were assigned (1:1:1:1) to one of the following groups: 1) atorvastatin 20 mg/d or its equivalent (Statin) group, 2) atorvastatin 10 mg/d or its equivalent + ezetimibe 10 mg/d (Statin_E) group, 3) atorvastatin 10 mg/d or its equivalent + alirocumab 75 mg/2 weeks (Statin_P) group, and 4) atorvastatin 10 mg/d or its equivalent + ezetimibe 10 mg/d + alirocumab 75 mg/2 weeks (Statin_EP) group. Follow-up ultrasonography was performed every six months after baseline, and lipid panel, including total cholesterol (TC), LDL-C, triglycerides (TG), and high-density lipoprotein cholesterol (HDL-C), was measured every three months. All eligible patients received continuous standard treatments for underlying conditions, along with recommendations for dietary modifications and lifestyle management. These recommendations encompassed abstaining from smoking and alcohol consumption, adhering to a low-fat diet, and participating in appropriate physical exercise. The patients were followed up for 12 months. 2.3 Carotid ultrasonography The patient was requested to lie in a supine position with their head slightly extended. The neck was slightly rotated to the opposite side of the carotid artery being examined to allow better visualization of the artery. Standard carotid ultrasound and CEUS examinations were performed for all patients using a Mindray Resona 8T Ultrasound Machine (Mindray Bio-Medical Electronics Co., Ltd., Shenzhen, China) with a 9–11-MHz linear transducer (Mindray L9-3U). The artery and plaque were examined in longitudinal and transverse planes utilizing standard ultrasound techniques. The degree of carotid artery stenosis was assessed based on peak-systolic and end-diastolic velocities, following the consensus criteria established by the Society of Radiologists in Ultrasound [ 6 ]. All plaques were scanned dynamically in grayscale mode to measure maximum plaque thickness and length, location, echogenicity, and mobility. The CEUS was carried out by injecting a 2-mL bolus of microbubble agent SonoVue (Bracco Imaging, Milan, Italy) via the median cubital vein, followed by a 5-mL normal saline flush. The contrast-specific imaging mode was set at a low mechanical index (− 0.12) to prevent the destruction of contrast microbubbles (measuring 1–11 µm). Cine clips were recorded in the longitudinal plane for 10 to 20 seconds at baseline and continued for up to 100 seconds after the microbubbles reached the arteries. The raw clips were stored for further assessment offline. All procedures were performed by a vascular sonographer with more than 10 years of experience, who was blinded to the clinical characteristics of the participants. CEUS was performed on each participant at least twice (baseline and 6 months) during the trial. 2.4 Image analysis Intima-media thickness (IMT) was measured on the common carotid artery, and maximum plaque height was defined as the maximum distance from the intima-lumen interface to the media-adventitia interface. Atherosclerotic plaques were defined as focal structures encroaching into the arterial lumen with a height > 1.5 mm. The degree of carotid artery stenosis was determined based on peak-systolic and end-diastolic velocities according to the consensus criteria of the Society of Radiologists in Ultrasound[ 6 ]. The maximal plaque thickness, calcified area, and hypoechoic area were measured on the thickest cross-section of the plaque. Morphological features of the carotid plaques were graded according to plaque echogenicity as follows: type I: predominantly hypoechoic with a thin echogenic rim; type II: echogenic plaque with > 50% hypoechoic areas; type III: echogenic plaque with < 50% hypoechoic areas; and type IV: uniformly echogenic plaque. Intraplaque contrast enhancement was semi-quantitatively categorized using the following scales: IPN = 0, no visible microbubbles within the plaque; IPN = 1, mild microbubbles confined to the shoulder and/or adventitial side of the plaque; IPN = 2, linear microbubbles extending into the plaque; and IPN = 3, extensive microbubbles throughout the plaque[ 7 ]. The data were analyzed by two experienced sonographers in CEUS, who were blinded to the clinical information of the patients and each other’s results. Any inconsistent results were discussed, and the final report was determined by consensus. 2.5 Sample size calculation One-way ANOVA was used for comparison of multiple groups. Then, a sample size of at least 232 patients (58 in each group) was required to achieve a statistical power of 0.90 (α = 0.05, effect size = 0.25). 2.6 Outcome measures The primary measures of the study were carotid plaque morphological stabilization at 6-month follow-up, based on plaque echogenicity and IPN categories from CEUS, and carotid plaque regression at 12 months, defined as a reduction in plaque size by at least 10% compared with baseline. The secondary measures were changes in blood lipid levels after 6 months. 2.7 Statistical analyses R software (ver. 4.2.1, The R Foundation, Vienna, Austria) was used for statistical analysis. Normally distributed data are presented as the mean ± standard deviation (SD). One-way ANOVA was performed for comparisons of multiple groups, and t -tests were used for comparisons between two groups. Non-normally distributed data are presented as the median [25th percentile, 75th percentile], and Kruskal‒Wallis one-way ANOVA was performed for comparisons between multiple groups. A nonparametric test (Dunn’s test) with P value adjustment (Holm method) was used for pairwise comparisons. Categorical data are presented as frequencies or percentages, and Chi-square tests were applied for comparisons between groups. McNemar’s test was used to assess paired categorical data regarding changes in responses before treatment and after treatment. A p-value of < 0.05 was considered statistically significant. 3. Results 3.1 Study flow and basic characteristics In total, 312 patients (78 in each group) who met the criteria were initially enrolled. Of these, 13 patients were excluded because of insufficient CEUS images, loss to follow-up, and adverse reactions. Ultimately, 299 patients (74 in the Statin group, 75 in the Statin_E group, 74 in the Statin_P group, and 76 in the Statin_EP group) were included in this study (Fig 1). The basic characteristics of the participants in the four groups are summarized in Table 1. No statistically significant differences were found in terms of sex, age, BMI, hypertension, blood glucose, and lipid levels between the groups. 3.2 Lipid profiles after treatment After 6 months of treatment, TC and LDL-C levels significantly differed among the four groups (Fig 2). Pairwise comparisons showed that the levels of TC and LDL-C in the Statin_P group and the Statin_EP group were significantly lower than those in the Statin group and the Statin_E group. However, there were no significant differences in TC and LDL-C levels between the Statin_P group and the Statin_EP group. HDL-C and TG levels were more favorable in the Statin_EP group, but the differences were not statistically significant at six months. 3.3 Baseline plaque characteristics Of the 299 patients, plaques in bilateral carotid arteries were found in 242 (80.9%) patients, while plaques in one unilateral carotid artery were found in 57 (19.1%) patients. There were no significant differences in plaque sizes and IMT between the four groups before treatment. Moreover, the Chi-square test did not show any significant differences in the proportions of plaque echogenicity types and IPN scales (Table 2). 3.4 Changes in carotid plaque characteristics The proportions of plaque echogenicity types on the left side significantly differed before and after treatment in the Statin_P and Statin_EP groups (Fig 3). There was a greater proportion of type I or II plaques in the Statin_P (p = 0.040, g Cohen = 0.306, CI 95% [0.137, 0.408]) and Statin_EP (p = 0.039, g Cohen = 0.364, CI 95% [0.167, 0.453]) groups that transformed into a regular plaque morphology, with a prevalence of fibrous atheroma (type III or IV) after treatment. For the right side, although the transformation of type I or II plaques in Statin_P and Statin_EP groups was similar to that on the left side, no significant differences were found before and after treatment between groups (Fig 4). The proportions of IPN scales on the left side significantly differed before and after treatment only in the Statin_EP group (p = 0.008, g Cohen = 0.413, CI 95% [0.232, 0.476]). The degree of IPN significantly decreased in the Statin_EP group after treatment (Fig 5). On the right side, a greater proportion of IPN 2 or 3 scores in the Statin_P (p = 0.012, g Cohen = 0.362, CI 95% [0.194, 0.445]) and Statin_EP (p = 0.047, g Cohen = 0.306, CI95% [0.137, 0.408]) groups transformed into lower scales after treatment, and McNemar’s test showed that these changes in IPN scale proportions were significantly different (Fig 6). 3.5 Changes in carotid plaque sizes Although no statistically significant differences in plaque sizes were found between the groups at the same time, the changes in plaque size before and after treatment significantly differed across the four groups. The regression tendency was particularly prominent in the Statin_P and Statin_EP groups, as indicated by the changes in carotid plaque sizes (Table 3). The increase in left carotid plaque sizes in the Statin_P and Statin_EP groups was significantly lower than that in the other groups (χ 2 = 24.09, p = 2.39e−05, CI 95% [0.04, 1.00]). On the right side, the increase in plaque sizes in the Statin_EP group was significantly lower than that in the Statin and Statin_E groups, and similar significant difference was found between the Statin_P and Statin groups (χ 2 = 16.79, p = 7.82e−04, CI 95% [0.03, 1.00]). Moreover, no significant differences were found between the Statin_P and Statin_EP groups on either side (Fig 7). The plaque regression proportions on both sides significantly differed on either side (left: χ 2 = 26.37, p = 1.90e−04, CI 95% [0.06, 1.00]; right: χ 2 = 19.00, p = 4.16e−03, CI 95% [0.00, 1.00]) among the four groups after treatment (Fig 8). In the Statin_P and Statin_EP groups, the regression proportions exceeded 30%, while the progression proportions were lower than 30%. Intensive lipid-lowering therapies with a PCSK9 inhibitor showed a greater effect on plaque regression. 3.6 Representative patient Right carotid atherosclerotic plaque in a 70-year-old man was recorded using B-mode ultrasound and CEUS (Fig 9). At baseline, the plaque at the 40th second was predominantly hypoechoic on the B-mode image, and neovessels within the plaques were evident (yellow arrows) and classified as grade 3 on CEUS imaging. After three months, the plaque size had decreased, and the plaque was predominantly echogenic. The microbubbles appeared confined only to the adjacent adventitial layer, classified as IPN grade 1. After six months, no moving microbubbles were observed in the echogenic plaque. 4. Discussion This randomized open-label trial investigated the effects of different intensive lipid-lowering therapies on the stabilization and regression of carotid plaques. After treatment, the Statin_P and Statin_EP groups showed significantly lower levels of TC and LDL-C compared to the Statin and Statin_E groups. Intensive lipid-lowering therapies involving PCSK9 inhibitors were more effective in regressing carotid plaques and stabilizing their morphology compared to other treatments. The benefits included: 1) converting more type I or II plaques into more stable type III or IV plaques; 2) effectively inhibiting IPN to stabilize the plaques; and 3) restraining plaque progression and even reducing plaque size. The findings underscore the efficacy of combining statin therapy with PCSK9 inhibitors, such as alirocumab, in promoting plaque stabilization and regression. The efficacy of statins, ezetimibe, and PCSK9 inhibitors (monoclonal antibodies) in reducing serum LDL-C levels and subsequent cardiovascular events is well-documented. A European study revealed that moderate-dose statin monotherapy was the most common lipid-lowering therapy, with only 18% of very high-risk patients achieving their LDL-C goals[ 8 ]. Human monoclonal antibodies, such as evolocumab and alirocumab, promote the removal of PCSK9 from circulation. This intervention decreases LDL-C levels by 60% even in individuals already on statins[ 9 , 10 ]. Despite improvements in implementation and adherence strategies, the quest for new, effective therapies to lower LDL-C continues. The focus of lipid-lowering therapy is shifting from merely reducing lipid levels to promoting atherosclerotic plaque regression. The significant reduction in LDL-C levels observed in the Statin_P and Statin_EP groups of this study is in line with previous research highlighting the role of PCSK9 inhibitors in achieving very low LDL-C levels, which are associated with greater plaque regression[ 3 ]. This study further supports the therapeutic impact of intensive lipid-lowering therapies by showing significant decreases in carotid plaque sizes in the Statin_P and Statin_EP groups. These findings are in agreement with guidelines indicating that PCSK9 inhibitor combinations significantly reduce the progression of CVD risks in patients on statins[ 5 ]. The significant plaque regression observed in the Statin_P and Statin_EP groups after 12 months of treatment is particularly encouraging, as plaque stabilization and regression is a key goal in the management of atherosclerotic disease to reduce cardiovascular events. Advancements in vascular imaging methodologies, including computed tomography angiography (CTA), magnetic resonance angiography (MRA), ultrasonographic imaging, and positron emission tomography/computed tomography (PET/CT), has facilitated the stratification of patient risk factors. This stratification is no longer solely predicated on the extent of carotid artery stenosis but also encompasses an evaluation of the propensity for plaque rupture, causing adverse events such as ischemic stroke. These imaging techniques are driving a paradigm shift that allows for risk stratifications based on specific imaging features, such as intraplaque hemorrhage, plaque ulceration, plaque neovascularity, fibrous cap thickness, and the presence of a lipid-rich necrotic core[ 11 ]. CEUS is an effective and accurate non-invasive imaging method for evaluating carotid IPN through directly visualizing contrast agent microbubbles within plaques[ 12 ]. Carotid IPN is an important feature of plaque vulnerability and plays a crucial role in predicting future vascular events in patients with recent ischemic stroke or heart disease[ 13 ]. Neovascularization in plaques refers to the formation of new blood vessels within the atherosclerotic plaque as part of the body’s natural healing process, which is important for the progression and regression of atherosclerosis. In atherosclerosis, the inner lining of the artery, known as the endothelium, becomes damaged due to factors such as high blood pressure, high cholesterol levels, smoking, and diabetes. This damage triggers the release of chemicals that promote the growth of new blood vessels, as the body needs to supply oxygen and nutrients to the affected area and remove waste products[ 14 ]. However, in the context of atherosclerosis, this process can be detrimental because the newly formed blood vessels are often fragile and prone to rupture, leading to further damage to the artery, potentially causing a thrombus or clot, increasing the risk of stroke or heart attack[ 15 ]. Our findings suggest that therapy combined with a PCSK9 inhibitor significantly reduced IPN and stabilized plaques. This therapeutic effect is likely the main reason for improved outcomes in patients at a high risk of CVD. The mechanism by which PCSK9 inhibitors inhibit IPN warrants further investigation. The mechanisms involved in neovascularization within atherosclerotic plaques are complex and involve multiple biological processes, including inflammation, cell death, degradation of the extracellular matrix, and the activation of endothelial and connective tissue repair responses[ 16 ]. One of the key factors in neovascularization is the presence of inflammatory cells, such as macrophages and T-lymphocytes[ 17 ], which release pro-angiogenic factors that stimulate the formation of new blood vessels. These factors include vascular endothelial growth factor, basic fibroblast growth factor, and interleukin-8[ 18 ]. Another important mechanism in neovascularization is the degradation of the extracellular matrix by proteases, such as matrix metalloproteinases[ 19 , 20 ]. This process creates space for new blood vessels to form and releases pro-angiogenic factors from the extracellular matrix. Plaque echogenicity, assessed by conventional B-mode ultrasound, refers to the brightness of the plaque on the ultrasound image. Echolucent plaques are known to exhibit a higher number of vulnerable pathological features and are associated with a higher risk of cerebrovascular events[ 21 , 22 ]. Previous studies have shown a correlation between IPN detected by CEUS and plaque echogenicity. Echolucent plaques tend to have a higher degree of neovascularization compared to echogenic plaques[ 23 , 24 ]. However, some studies have reported conflicting results. For instance, 1) vulnerable plaques had denser IPN but did not show more pronounced contrast enhancement on CEUS; and 2) the correlation between immunohistochemical analysis and CEUS analysis was significant for both vulnerable and non-vulnerable plaques[ 25 ], indicating no significant correlation between plaque echogenicity and IPN[ 26 , 27 ]. This study has several limitations that should be acknowledged. Firstly, the open-label nature of the trial may introduce bias, as neither the participants nor the researchers were blinded to the treatment allocation. This could potentially influence the reporting and interpretation of results. Secondly, the study population was limited to patients from a single hospital, which may limit the generalizability of the results to broader populations with different ethnicities, comorbidities, and healthcare settings. Thirdly, the follow-up period was 6 months for plaque stabilization and 12 months for regression, which may be insufficient to capture the long-term effects of the lipid-lowering therapies on plaque stabilization and regression. Longer-term studies are needed to assess the persistent effects and potential late adverse effects. Finally, the use of CEUS for plaque assessment, while non-invasive and effective, may have limitations in terms of inter-observer variability and may not capture all aspects of plaque vulnerability. The study may not fully capture the diversity and complexity of atherosclerotic plaques, as the assessment was primarily based on ultrasound imaging, which may not detect all characteristics of plaques, such as calcification or lipid-rich necrotic cores. Therefore, the study may not fully reflect the diversity and complexity of atherosclerotic plaques. Conclusions In conclusion, this study underscores the importance of intensive lipid-lowering strategies, including high-dose statins, statin-ezetimibe combinations, and PCSK9 inhibitors, in the management of carotid artery disease. Therapies combining statins with PCSK9 inhibitors, such as alirocumab, are more effective in regressing carotid plaques and stabilizing plaque morphology compared to other treatments. The findings highlight the potential of PCSK9 inhibitors, in combination with statins, as a promising therapeutic strategy for reducing the burden of cardiovascular events in high-risk patients. Abbreviations BMI: Body mass index; CEUS: contrast-enhanced carotid ultrasonography CVD: cardiovascular disease HDL-C: high-density lipoprotein cholesterol IPN: intraplaque neovascularization IVUS: intravascular ultrasound LDL-C: low-density lipoprotein cholesterol TC: total cholesterol TG: triglycerides Declarations Ethics approval and consent to participate The study protocol was approved by the Institutional Ethics Committee of the Third Affiliated Hospital of Guangzhou Medical University, and written informed consent was obtained from all patients before the treatment. Consent for publication Not applicable Availability of data and materials The datasets generated and/or analysed during the current study are available in the https://doi.org/10.6084/m9.figshare.25997875.v2 Competing interests The authors declare that they have no competing interests Funding This work was supported by the grants of Leading Research Program of Hunan University of Chinese Medicine (No.2022XJJB002), Science and Technology Innovation Program of Hunan Province (No. 2022RC1021), Plan on enhancing scientific research in GMU (No.204), and 2023 Guangzhou School (Institute) Enterprise Joint Funding Project. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Authors' contributions SL and LL contributed to the investigation and methodology and design of the work. PQ and KC contributed to the acquisition and validation of the data. HL performed the data analysis and drafted the manuscript. 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Zhang Y, Cao J, Zhou J, Zhang C, Li Q, Chen S, Feinstein S, Grayburn PA, Huang P: Plaque Elasticity and Intraplaque Neovascularisation on Carotid Artery Ultrasound: A Comparative Histological Study . Eur J Vasc Endovasc Surg 2021, 62 (3):358-366. Zhou Y, Xing Y, Li Y, Bai Y, Chen Y, Sun X, Zhu Y, Wu J: An assessment of the vulnerability of carotid plaques: a comparative study between intraplaque neovascularization and plaque echogenicity . BMC Med Imaging 2013, 13 (1):13. D'Oria M, Chiarandini S, Pipitone MD, Fisicaro M, Calvagna C, Bussani R, Rotelli A, Ziani B: Contrast Enhanced Ultrasound (CEUS) Is Not Able to Identify Vulnerable Plaques in Asymptomatic Carotid Atherosclerotic Disease . Eur J Vasc Endovasc Surg 2018, 56 (5):632-642. Cattaneo M, Staub D, Porretta AP, Gallino JM, Santini P, Limoni C, Wyttenbach R, Gallino A: Contrast-enhanced ultrasound imaging of intraplaque neovascularization and its correlation to plaque echogenicity in human carotid arteries atherosclerosis . Int J Cardiol 2016, 223 :917-922. Cattaneo M, Staub D, Porretta AP, Gallino JM, Santini P, Limoni C, Wyttenbach R, Gallino A: Data on consistency among different methods to assess atherosclerotic plaque echogenicity on standard ultrasound and intraplaque neovascularization on contrast-enhanced ultrasound imaging in human carotid artery . Data in Brief 2016, 9 :563-567. Tables Table 1. Basic characteristics of the participants Variable N Statin , N = 74 1 Statin_E , N = 75 1 Statin_P , N = 74 1 Statin_EP , N = 76 1 p-value 2 Sex 299 0.41 Female 42/57% 40/53% 38/51% 33/43% Male 32/43% 35/47% 36/49% 43/57% Age (y) 299 73± 9 71± 9 71± 10 70± 10 0.28 BMI (kg/m 2 ) 299 23.3± 3.1 23.7± 3.6 23.8± 3.5 23.9± 2.9 0.77 HT (mmHg) 299 66/89% 66/88% 61/82% 58/76% 0.12 Smoking 299 19/26% 21/28% 22/30% 29/38% 0.37 T2DM 299 33/45% 31/41% 36/49% 33/43% 0.84 FPG (mmol/L) 299 6.3 [5.4, 9.1] 6.1 [5.2, 8.5] 6.5 [5.5, 9.3] 6.3 [5.3, 8.6] 0.82 HbA1c (%) 299 6.25 [5.90, 6.80] 6.20 [5.90, 6.75] 6.40 [5.80, 7.20] 6.25 [5.90, 6.80] 0.95 TC (mmol/L) 299 3.86 [3.46, 4.57] 4.13 [3.43, 5.08] 3.87 [3.56, 4.50] 4.22 [3.25, 5.03] 0.31 TG (mmol/L) 299 1.37 [0.98, 1.80] 1.49 [0.96, 2.08] 1.46 [1.05, 2.15] 1.27 [0.99, 1.71] 0.41 LDL-C (mmol/L) 299 2.35 [1.87, 2.95] 2.67 [1.96, 3.61] 2.37 [2.02, 2.79] 2.56 [1.88, 3.46] 0.23 HDL-C (mmol/L) 299 1.16 [0.90, 1.52] 1.11 [0.91, 1.46] 1.12 [0.93, 1.32] 1.21 [1.04, 1.48] 0.11 Scr (μmol/L) 299 91 [72, 115] 81 [68, 99] 82 [70, 104] 81 [68, 101] 0.15 UA (μmol/L) 299 359 [307, 474] 381 [321, 458] 393 [335, 467] 384 [315, 431] 0.35 1 n/%; Mean ± SD; Median (IQR) 2 Pearson’s Chi-squared test; One-way ANOVA; Kruskal–Wallis rank sum test BMI = Body Mass Index, FPG = Fasting Plasma Glucose, HbA1c = Glycated Hemoglobin, HDL-C = High-Density Lipoprotein Cholesterol, LDL-C = Low-Density Lipoprotein Cholesterol, Scr = Serum Creatinine, TC = Total Cholesterol, TG = Triglycerides, UA = Uric Acid. Table 2. Plaque characteristics of ultrasound imaging before treatment Variable N Statin, N = 74 1 Statin_E, N = 75 1 Statin_P, N = 74 1 Statin_EP, N = 76 1 p-value 2 LIMT (mm) 299 0.92 ± 0.15 0.97 ± 0.17 0.96 ± 0.20 0.97 ± 0.21 0.28 RIMT (mm) 299 0.91 ± 0.16 0.95 ± 0.18 0.93 ± 0.18 0.95 ± 0.20 0.44 L-size (mm 2 ) 299 14 [5, 25] 13 [7, 30] 19 [11, 33] 14 [7, 28] 0.11 R-size (mm 2 ) 299 14 [7, 27] 14 [8, 25] 17 [9, 29] 17 [10, 32] 0.54 L-type 275 0.92 I 6/72 [8.3%] 11/70 [16%] 10/68 [15%] 6/65 [9.2%] II 30/72 [42%] 25/70 [36%] 29/68 [43%] 26/65 [40%] III 29/72 [40%] 29/70 [41%] 23/68 [34%] 27/65 [42%] IV 7/72 [9.7%] 5/70 [7.1%] 6/68 [8.8%] 6/65 [9.2%] R-type 263 0.98 I 9/64 [14%] 7/68 [10%] 8/65 [12%] 8/66 [12%] II 21/64 [33%] 20/68 [29%] 22/65 [34%] 25/66 [38%] III 28/64 [44%] 31/68 [46%] 29/65 [45%] 26/66 [39%] IV 6/64 [9.4%] 10/68 [15%] 6/65 [9.2%] 7/66 [11%] L-neo 275 0.98 L0 33/72 [46%] 29/70 [41%] 34/68 [50%] 33/65 [51%] L1 19/72 [26%] 22/70 [31%] 16/68 [24%] 15/65 [23%] L2 14/72 [19%] 13/70 [19%] 11/68 [16%] 11/65 [17%] L3 6/72 [8.3%] 6/70 [8.6%] 7/68 [10%] 6/65 [9.2%] R-neo 263 0.97 R0 32/64 [50%] 35/68 [51%] 31/65 [48%] 36/66 [55%] R1 14/64 [22%] 13/68 [19%] 10/65 [15%] 12/66 [18%] R2 12/64 [19%] 12/68 [18%] 14/65 [22%] 10/66 [15%] R3 6/64 [9.4%] 8/68 [12%] 10/65 [15%] 8/66 [12%] 1 Mean ± SD; Median (IQR); n/N (%) 2 One-way ANOVA; Kruskal–Wallis rank sum test; Pearson’s Chi-squared test LIMT = Left Intima-Media Thickness, L-neo = Left Intraplaque Neovascularization, L-size = Left Plaque Size, L-type = Left Plaque Echogenic Type, RIMT = Right Intima-Media Thickness, R-neo = Right Intraplaque Neovascularization, R-size = Right Plaque Size, R-type = Right Plaque Echogenic Type. Table 3. Changes in pre-treatment and post-treatment carotid plaque sizes Variable N Statin , N = 74 1 Statin_E , N = 75 1 Statin_P , N = 74 1 Statin_EP , N = 76 1 p-value 2 L-size 299 14 [5, 25] 13 [7, 30] 19 [11, 33] 14 [7, 28] 0.11 L-size-post 299 19 [9, 35] 18 [11, 36] 17 [10, 34] 16 [8, 27] 0.20 L-change 299 −2 [−8, 0] −3 [−9, 0] 0 [−3, 4] 0 [−3, 3] <0.001 R-size 299 14 [7, 27] 14 [8, 25] 17 [9, 29] 17 [10, 32] 0.54 R-size-post 299 17 [10, 33] 17 [9, 27] 17 [6, 32] 17 [9, 24] 0.94 R-change 299 −2 [−8, 0] 0 [−7, 2] 0 [−2, 3] 0 [0, 4] <0.001 1 Median (IQR) 2 Kruskal–Wallis rank sum test L-change = Left Change of Pre- and Post-Treatment Plaque Size, L-size = Left Plaque Size, L-size-post = Left Post-Treatment Plaque Size, R-change = Right Change of Pre- and Post-Treatment Plaque Size, R-size = Right Plaque Size, R-size-post = Right Post-Treatment Plaque Size. Additional Declarations No competing interests reported. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-4604642","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":323503168,"identity":"a3835c08-0053-4aeb-8192-dc1cbfe60c82","order_by":0,"name":"Sihua Luo","email":"","orcid":"","institution":"The Third Affiliated Hospital of Guangzhou Medical University","correspondingAuthor":false,"prefix":"","firstName":"Sihua","middleName":"","lastName":"Luo","suffix":""},{"id":323503169,"identity":"d5cd35e6-27ab-4e0a-87a9-b867ceeb4cf8","order_by":1,"name":"Lili Lin","email":"","orcid":"","institution":"The Third Affiliated Hospital of Guangzhou 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study\u003c/p\u003e","description":"","filename":"Fig1.png","url":"https://assets-eu.researchsquare.com/files/rs-4604642/v1/78f72ab4dedc32c3acbe22c8.png"},{"id":60600352,"identity":"e66a4d0e-1554-43df-907f-67a6cc1fb110","added_by":"auto","created_at":"2024-07-18 16:01:34","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":240045,"visible":true,"origin":"","legend":"\u003cp\u003eLipid profiles of the groups after six months of treatment\u003c/p\u003e","description":"","filename":"Fig2.png","url":"https://assets-eu.researchsquare.com/files/rs-4604642/v1/ccf92be5bbe7a1498942fb40.png"},{"id":60598298,"identity":"d4f4de56-829e-4226-aff6-0b5a9a5f69af","added_by":"auto","created_at":"2024-07-18 15:53:34","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":107452,"visible":true,"origin":"","legend":"\u003cp\u003eProportions of pre- and post-treatment plaque echogenicity types on the left side\u003c/p\u003e","description":"","filename":"Fig3.png","url":"https://assets-eu.researchsquare.com/files/rs-4604642/v1/758230fd14614aad72219ab3.png"},{"id":60598294,"identity":"9ece0004-9028-4f05-9bca-7daf5d7b1b11","added_by":"auto","created_at":"2024-07-18 15:53:33","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":109703,"visible":true,"origin":"","legend":"\u003cp\u003eProportions of pre- and post-treatment plaque echogenicity types on the right side\u003c/p\u003e","description":"","filename":"Fig4.png","url":"https://assets-eu.researchsquare.com/files/rs-4604642/v1/14332f76c8149bf398358032.png"},{"id":60598296,"identity":"5c5a7376-9214-4145-8968-f14fc2fb50a9","added_by":"auto","created_at":"2024-07-18 15:53:34","extension":"png","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":110063,"visible":true,"origin":"","legend":"\u003cp\u003eProportions of pre- and post-treatment intraplaque neovascularization scales on the left side\u003c/p\u003e","description":"","filename":"Fig5.png","url":"https://assets-eu.researchsquare.com/files/rs-4604642/v1/298730a59cff63f64f7e798d.png"},{"id":60600353,"identity":"f0d7921a-ce62-4b0a-a739-4a518fb00cb9","added_by":"auto","created_at":"2024-07-18 16:01:34","extension":"png","order_by":6,"title":"Figure 6","display":"","copyAsset":false,"role":"figure","size":106375,"visible":true,"origin":"","legend":"\u003cp\u003eProportions of pre- and post-treatment intraplaque neovascularization scales on the right side\u003c/p\u003e","description":"","filename":"Fig6.png","url":"https://assets-eu.researchsquare.com/files/rs-4604642/v1/c414fb3e4003f4a2264e77a6.png"},{"id":60600351,"identity":"f0de86a5-8d13-4c51-be0e-d98bb5ece2ef","added_by":"auto","created_at":"2024-07-18 16:01:33","extension":"png","order_by":7,"title":"Figure 7","display":"","copyAsset":false,"role":"figure","size":141147,"visible":true,"origin":"","legend":"\u003cp\u003eChanges in plaque sizes before and after treatment\u003c/p\u003e","description":"","filename":"Fig7.png","url":"https://assets-eu.researchsquare.com/files/rs-4604642/v1/98c9cb0874821a3494faadd1.png"},{"id":60598297,"identity":"5488890d-9760-4bfd-9977-8a0e20b7b093","added_by":"auto","created_at":"2024-07-18 15:53:34","extension":"png","order_by":8,"title":"Figure 8","display":"","copyAsset":false,"role":"figure","size":83637,"visible":true,"origin":"","legend":"\u003cp\u003ePlaque regression proportions in the four groups after treatment\u003c/p\u003e","description":"","filename":"Fig8.png","url":"https://assets-eu.researchsquare.com/files/rs-4604642/v1/4ea3366f3528e15b5c966f29.png"},{"id":60598300,"identity":"542b984a-d4bd-43b1-88b2-7d964097480e","added_by":"auto","created_at":"2024-07-18 15:53:34","extension":"png","order_by":9,"title":"Figure 9","display":"","copyAsset":false,"role":"figure","size":2561058,"visible":true,"origin":"","legend":"\u003cp\u003eCarotid atherosclerotic plaque in a 70-year-old man at baseline, three months, and six months\u003c/p\u003e","description":"","filename":"Fig9.png","url":"https://assets-eu.researchsquare.com/files/rs-4604642/v1/f8a0b317ca77b4367408843c.png"},{"id":71983284,"identity":"118e0a63-16f6-4d35-9386-db1b9f8a05d5","added_by":"auto","created_at":"2024-12-20 10:17:15","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":7478892,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4604642/v1/c5086a79-ad6c-4256-a0c8-2cb477bc9db0.pdf"},{"id":60598292,"identity":"fe69a1d9-dc54-4280-8e30-01985d942b86","added_by":"auto","created_at":"2024-07-18 15:53:33","extension":"doc","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":225280,"visible":true,"origin":"","legend":"","description":"","filename":"CONSORT2010Checklist.doc","url":"https://assets-eu.researchsquare.com/files/rs-4604642/v1/e21713daa3c36c9321840f05.doc"},{"id":60598293,"identity":"abacf288-1e6a-4ca3-9941-10525c088401","added_by":"auto","created_at":"2024-07-18 15:53:33","extension":"png","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":220718,"visible":true,"origin":"","legend":"","description":"","filename":"GraphicalAbstarct.png","url":"https://assets-eu.researchsquare.com/files/rs-4604642/v1/fdc9509d776d40a30113cb7d.png"}],"financialInterests":"No competing interests reported.","formattedTitle":"Effects of Different Intensive Lipid-Lowering Therapies on Stabilization and Regression of Carotid Plaque: A Randomized Open-Label Trial","fulltext":[{"header":"1. Introduction","content":"\u003cp\u003eAtherosclerotic plaques, particularly within the carotid arteries, are key predictors of cardiovascular events such as stroke and myocardial infarction. The formation of these plaques is a complex process involving lipid accumulation, inflammatory responses, and endothelial dysfunction within the arterial walls. Plaque regression and stabilization are important goals in the management of carotid artery disease, as they can reduce the risk of complications such as thromboembolism and rupture.\u003c/p\u003e \u003cp\u003eLipid-lowering therapies, particularly statins, have been the cornerstone of preventing atherosclerotic cardiovascular disease for decades. Recently, their role in inducing plaque regression and promoting plaque stabilization under intensive therapies has emerged as a pivotal objective in managing cardiovascular risk. The ASTEROID trial[\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e] demonstrated that high-dose rosuvastatin could promote the regression of coronary atheroma, as assessed by intravascular ultrasound (IVUS). The PRECISE-IVUS trial[\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e] showed that a combination of statins and ezetimibe achieved greater coronary plaque regression compared to standard statin monotherapy.\u003c/p\u003e \u003cp\u003eAs a novel class of lipid-lowering agents, proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors can significantly reduce low-density lipoprotein cholesterol (LDL-C) levels. The addition of the PCSK9 inhibitor evolocumab to statin therapy has also been shown to reverse atherosclerotic plaque[\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. In addition, studies have shown that PCSK9 inhibitors can reduce intraplaque neovascularization (IPN) within plaques, which is an important factor in plaque progression and vulnerability. Ultrasound imaging techniques, such as contrast-enhanced carotid ultrasonography (CEUS), can evaluate intraplaque vessels and the vasa vasorum. Several studies have verified the presence of IPN using CEUS, indicating that it is a suitable modality for detecting plaque stability.\u003c/p\u003e \u003cp\u003eOur previous study showed that intensive therapy with a statin and a PCSK9 inhibitor was more effective for lowering lipid levels of patients at high cardiovascular disease (CVD) risk compared to statin alone or statin plus ezetimibe[\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. However, the effect on regression and stabilization of carotid plaques remains unknown. CEUS has enabled the accurate quantification and characterization of atherosclerotic plaques, providing an opportunity to directly monitor the impact of therapeutic interventions on plaques. Therefore, we present a nonblind, randomized controlled trial to compare the effects of different intensive lipid-lowering therapies on the regression and stabilization of carotid plaques in patients at high CVD risk.\u003c/p\u003e"},{"header":"2. Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003e2.1 Study population\u003c/h2\u003e \u003cp\u003ePatients were enrolled from the Third Affiliated Hospital of Guangzhou Medical University from March 2022 to December 2023. The study protocol was approved by the Institutional Ethics Committee of the hospital, and written informed consent was obtained from all patients before the treatment. The trial was registered in the Chinese Clinical Trial Registry (registration number: ChiCTR2200058389).\u003c/p\u003e \u003cp\u003eStudy participants with high CVD risk[\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e] with non-calcified plaque on the carotid artery were included based on the following criteria: (1) treatment-naive or receiving non-intensive lipid-lowering therapy; (2) LDL-C\u0026thinsp;\u0026ge;\u0026thinsp;70 mg/dL; (3) uni- or bilateral carotid artery plaque (maximum plaque thickness\u0026thinsp;\u0026gt;\u0026thinsp;1.5 mm). Individuals with a history of stroke and myocardial infarction; those with a history of carotid endarterectomy; those with an allergy to the contrast agent or lipid-lowering drugs; those with secondary dyslipidemia caused by hypothyroidism, Cushing's syndrome, nephrotic syndrome, or drug use; and those with heart failure or end-stage renal failure were excluded from the study.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003e2.2 Study design\u003c/h2\u003e \u003cp\u003eInformation on patients\u0026rsquo; sex, age, body mass index (BMI), smoking history, hypertension, diabetes, and other related medical history was collected. Baseline laboratory tests and carotid ultrasonography were performed, and patients who met the inclusion criteria were enrolled. The randomization and allocation procedures were carried out as before [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. In short, an assistant used random numbers obtained from sealed envelopes. All selected patients were assigned (1:1:1:1) to one of the following groups: 1) atorvastatin 20 mg/d or its equivalent (Statin) group, 2) atorvastatin 10 mg/d or its equivalent\u0026thinsp;+\u0026thinsp;ezetimibe 10 mg/d (Statin_E) group, 3) atorvastatin 10 mg/d or its equivalent\u0026thinsp;+\u0026thinsp;alirocumab 75 mg/2 weeks (Statin_P) group, and 4) atorvastatin 10 mg/d or its equivalent\u0026thinsp;+\u0026thinsp;ezetimibe 10 mg/d\u0026thinsp;+\u0026thinsp;alirocumab 75 mg/2 weeks (Statin_EP) group. Follow-up ultrasonography was performed every six months after baseline, and lipid panel, including total cholesterol (TC), LDL-C, triglycerides (TG), and high-density lipoprotein cholesterol (HDL-C), was measured every three months. All eligible patients received continuous standard treatments for underlying conditions, along with recommendations for dietary modifications and lifestyle management. These recommendations encompassed abstaining from smoking and alcohol consumption, adhering to a low-fat diet, and participating in appropriate physical exercise. The patients were followed up for 12 months.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003e2.3 Carotid ultrasonography\u003c/h2\u003e \u003cp\u003eThe patient was requested to lie in a supine position with their head slightly extended. The neck was slightly rotated to the opposite side of the carotid artery being examined to allow better visualization of the artery. Standard carotid ultrasound and CEUS examinations were performed for all patients using a Mindray Resona 8T Ultrasound Machine (Mindray Bio-Medical Electronics Co., Ltd., Shenzhen, China) with a 9\u0026ndash;11-MHz linear transducer (Mindray L9-3U). The artery and plaque were examined in longitudinal and transverse planes utilizing standard ultrasound techniques. The degree of carotid artery stenosis was assessed based on peak-systolic and end-diastolic velocities, following the consensus criteria established by the Society of Radiologists in Ultrasound [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. All plaques were scanned dynamically in grayscale mode to measure maximum plaque thickness and length, location, echogenicity, and mobility.\u003c/p\u003e \u003cp\u003eThe CEUS was carried out by injecting a 2-mL bolus of microbubble agent SonoVue (Bracco Imaging, Milan, Italy) via the median cubital vein, followed by a 5-mL normal saline flush. The contrast-specific imaging mode was set at a low mechanical index (\u0026minus;\u0026thinsp;0.12) to prevent the destruction of contrast microbubbles (measuring 1\u0026ndash;11 \u0026micro;m). Cine clips were recorded in the longitudinal plane for 10 to 20 seconds at baseline and continued for up to 100 seconds after the microbubbles reached the arteries. The raw clips were stored for further assessment offline. All procedures were performed by a vascular sonographer with more than 10 years of experience, who was blinded to the clinical characteristics of the participants. CEUS was performed on each participant at least twice (baseline and 6 months) during the trial.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003e2.4 Image analysis\u003c/h2\u003e \u003cp\u003eIntima-media thickness (IMT) was measured on the common carotid artery, and maximum plaque height was defined as the maximum distance from the intima-lumen interface to the media-adventitia interface. Atherosclerotic plaques were defined as focal structures encroaching into the arterial lumen with a height\u0026thinsp;\u0026gt;\u0026thinsp;1.5 mm. The degree of carotid artery stenosis was determined based on peak-systolic and end-diastolic velocities according to the consensus criteria of the Society of Radiologists in Ultrasound[\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. The maximal plaque thickness, calcified area, and hypoechoic area were measured on the thickest cross-section of the plaque. Morphological features of the carotid plaques were graded according to plaque echogenicity as follows: type I: predominantly hypoechoic with a thin echogenic rim; type II: echogenic plaque with \u0026gt;\u0026thinsp;50% hypoechoic areas; type III: echogenic plaque with \u0026lt;\u0026thinsp;50% hypoechoic areas; and type IV: uniformly echogenic plaque.\u003c/p\u003e \u003cp\u003eIntraplaque contrast enhancement was semi-quantitatively categorized using the following scales: IPN\u0026thinsp;=\u0026thinsp;0, no visible microbubbles within the plaque; IPN\u0026thinsp;=\u0026thinsp;1, mild microbubbles confined to the shoulder and/or adventitial side of the plaque; IPN\u0026thinsp;=\u0026thinsp;2, linear microbubbles extending into the plaque; and IPN\u0026thinsp;=\u0026thinsp;3, extensive microbubbles throughout the plaque[\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. The data were analyzed by two experienced sonographers in CEUS, who were blinded to the clinical information of the patients and each other\u0026rsquo;s results. Any inconsistent results were discussed, and the final report was determined by consensus.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec7\" class=\"Section2\"\u003e \u003ch2\u003e2.5 Sample size calculation\u003c/h2\u003e \u003cp\u003eOne-way ANOVA was used for comparison of multiple groups. Then, a sample size of at least 232 patients (58 in each group) was required to achieve a statistical power of 0.90 (α\u0026thinsp;=\u0026thinsp;0.05, effect size\u0026thinsp;=\u0026thinsp;0.25).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003e2.6 Outcome measures\u003c/h2\u003e \u003cp\u003eThe primary measures of the study were carotid plaque morphological stabilization at 6-month follow-up, based on plaque echogenicity and IPN categories from CEUS, and carotid plaque regression at 12 months, defined as a reduction in plaque size by at least 10% compared with baseline. The secondary measures were changes in blood lipid levels after 6 months.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec9\" class=\"Section2\"\u003e \u003ch2\u003e2.7 Statistical analyses\u003c/h2\u003e \u003cp\u003eR software (ver. 4.2.1, The R Foundation, Vienna, Austria) was used for statistical analysis. Normally distributed data are presented as the mean\u0026thinsp;\u0026plusmn;\u0026thinsp;standard deviation (SD). One-way ANOVA was performed for comparisons of multiple groups, and \u003cem\u003et\u003c/em\u003e-tests were used for comparisons between two groups. Non-normally distributed data are presented as the median [25th percentile, 75th percentile], and Kruskal‒Wallis one-way ANOVA was performed for comparisons between multiple groups. A nonparametric test (Dunn\u0026rsquo;s test) with P value adjustment (Holm method) was used for pairwise comparisons. Categorical data are presented as frequencies or percentages, and Chi-square tests were applied for comparisons between groups. McNemar\u0026rsquo;s test was used to assess paired categorical data regarding changes in responses before treatment and after treatment. A p-value of \u0026lt;\u0026thinsp;0.05 was considered statistically significant.\u003c/p\u003e \u003c/div\u003e"},{"header":"3. Results","content":"\u003cp\u003e\u003cstrong\u003e\u003cem\u003e3.1 Study flow and basic characteristics\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eIn total, 312 patients (78 in each group) who met the criteria were initially enrolled. Of these, 13 patients were excluded because of insufficient\u0026nbsp;CEUS images, loss to follow-up, and\u0026nbsp;adverse reactions. Ultimately, 299 patients (74 in the Statin group, 75 in the Statin_E group, 74 in the Statin_P group, and 76 in the Statin_EP group) were included in this study (Fig 1). The basic characteristics of the participants in the four groups are summarized in\u0026nbsp;Table 1. No statistically significant differences were found in terms of sex, age, BMI, hypertension, blood glucose, and lipid levels between the groups.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e3.2 \u003cem\u003eLipid profiles after treatment\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAfter 6 months of treatment, TC and LDL-C levels significantly differed among the four groups (Fig 2). Pairwise comparisons showed that the levels of TC and LDL-C in the Statin_P group and the Statin_EP group were significantly lower than those in the Statin group and the Statin_E group. However, there were no significant differences in TC and LDL-C levels between the Statin_P group and the Statin_EP group. HDL-C and TG levels were more favorable in the Statin_EP group, but the differences were not statistically significant at six months.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e3.3 \u003cem\u003eBaseline plaque characteristics\u0026nbsp;\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eOf the 299 patients, plaques in bilateral carotid arteries were found in 242 (80.9%) patients, while plaques in one unilateral carotid artery were found in 57 (19.1%) patients. There were no significant differences in plaque sizes and IMT between the four groups before treatment. Moreover, the Chi-square test did not show any significant differences in the proportions of plaque echogenicity types and IPN scales (Table 2).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e3.4\u0026nbsp;\u003cem\u003eChanges in carotid plaque characteristics\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe proportions of plaque echogenicity types on the left side significantly differed before and after treatment in the Statin_P and Statin_EP groups (Fig 3). There was a greater proportion of type I or II plaques in the Statin_P (p = 0.040,\u0026nbsp;g\u003csub\u003eCohen\u003c/sub\u003e = 0.306, CI 95% [0.137, 0.408]) and Statin_EP (p = 0.039, g\u003csub\u003eCohen\u003c/sub\u003e = 0.364, CI 95% [0.167, 0.453]) groups that transformed into a regular plaque morphology, with a prevalence of fibrous atheroma (type III or IV) after treatment. For the right side, although the transformation of type I or II plaques in Statin_P and Statin_EP groups was similar to that on the left side, no significant differences were found before and after treatment between groups (Fig 4).\u003c/p\u003e\n\u003cp\u003eThe proportions of IPN scales on the left side significantly differed before and after treatment only in the Statin_EP group (p = 0.008,\u0026nbsp;g\u003csub\u003eCohen\u003c/sub\u003e = 0.413, CI 95% [0.232, 0.476]). The degree of IPN significantly decreased in the Statin_EP group after treatment (Fig 5). On the right side, a greater proportion of IPN 2 or 3 scores in the Statin_P (p = 0.012, g\u003csub\u003eCohen\u003c/sub\u003e = 0.362, CI 95% [0.194, 0.445]) and Statin_EP (p = 0.047, g\u003csub\u003eCohen\u003c/sub\u003e = 0.306, CI95% [0.137, 0.408]) groups transformed into lower scales after treatment, and McNemar\u0026rsquo;s test showed that these changes in IPN scale proportions were significantly different (Fig 6).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003e3.5 Changes in carotid plaque sizes\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAlthough no statistically significant differences in plaque sizes were found between the groups at the same time, the changes in plaque size before and after treatment significantly differed across the four groups. The regression tendency was particularly prominent in the Statin_P and Statin_EP groups, as indicated by the changes in carotid plaque sizes (Table 3).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe increase in left carotid plaque sizes in the\u0026nbsp;Statin_P\u0026nbsp;and\u0026nbsp;Statin_EP\u0026nbsp;groups was significantly lower than that in the other groups (\u0026chi;\u003csup\u003e2\u0026nbsp;\u003c/sup\u003e= 24.09, p = 2.39e\u0026minus;05, CI 95% [0.04, 1.00]). On the right side, the increase in plaque sizes in the\u0026nbsp;Statin_EP group was\u0026nbsp;significantly lower than that in the\u0026nbsp;Statin\u0026nbsp;and\u0026nbsp;Statin_E groups, and similar significant difference was found between the Statin_P and Statin groups (\u0026chi;\u003csup\u003e2\u0026nbsp;\u003c/sup\u003e= 16.79, p = 7.82e\u0026minus;04, CI 95% [0.03, 1.00]). Moreover, no significant differences were found between the Statin_P\u0026nbsp;and\u0026nbsp;Statin_EP\u0026nbsp;groups on either side (Fig 7).\u003c/p\u003e\n\u003cp\u003eThe plaque regression proportions on both sides significantly differed on either side (left: \u0026chi;\u003csup\u003e2\u0026nbsp;\u003c/sup\u003e = 26.37, p = 1.90e\u0026minus;04, CI 95% [0.06, 1.00]; right: \u0026chi;\u003csup\u003e2\u0026nbsp;\u003c/sup\u003e = 19.00, p = 4.16e\u0026minus;03, CI 95% [0.00, 1.00]) among the four groups after treatment (Fig 8). In the Statin_P and Statin_EP groups, the regression proportions exceeded 30%, while the progression proportions were lower than 30%. Intensive lipid-lowering therapies with a PCSK9 inhibitor showed a greater effect on plaque regression.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e3.6 \u003cem\u003eRepresentative patient\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eRight carotid atherosclerotic plaque in a 70-year-old man was recorded using B-mode ultrasound and CEUS (Fig 9). At baseline, the plaque at the 40th second was predominantly hypoechoic on the B-mode image, and neovessels within the plaques were evident (yellow arrows) and classified as grade 3 on CEUS imaging. After three months, the plaque size had decreased, and the plaque was predominantly echogenic. The microbubbles appeared confined only to the adjacent adventitial layer, classified as IPN grade 1. After six months, no moving microbubbles were observed in the echogenic plaque.\u003c/p\u003e"},{"header":"4. Discussion","content":"\u003cp\u003eThis randomized open-label trial investigated the effects of different intensive lipid-lowering therapies on the stabilization and regression of carotid plaques. After treatment, the Statin_P and Statin_EP groups showed significantly lower levels of TC and LDL-C compared to the Statin and Statin_E groups. Intensive lipid-lowering therapies involving PCSK9 inhibitors were more effective in regressing carotid plaques and stabilizing their morphology compared to other treatments. The benefits included: 1) converting more type I or II plaques into more stable type III or IV plaques; 2) effectively inhibiting IPN to stabilize the plaques; and 3) restraining plaque progression and even reducing plaque size. The findings underscore the efficacy of combining statin therapy with PCSK9 inhibitors, such as alirocumab, in promoting plaque stabilization and regression.\u003c/p\u003e \u003cp\u003eThe efficacy of statins, ezetimibe, and PCSK9 inhibitors (monoclonal antibodies) in reducing serum LDL-C levels and subsequent cardiovascular events is well-documented. A European study revealed that moderate-dose statin monotherapy was the most common lipid-lowering therapy, with only 18% of very high-risk patients achieving their LDL-C goals[\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. Human monoclonal antibodies, such as evolocumab and alirocumab, promote the removal of PCSK9 from circulation. This intervention decreases LDL-C levels by 60% even in individuals already on statins[\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. Despite improvements in implementation and adherence strategies, the quest for new, effective therapies to lower LDL-C continues. The focus of lipid-lowering therapy is shifting from merely reducing lipid levels to promoting atherosclerotic plaque regression. The significant reduction in LDL-C levels observed in the Statin_P and Statin_EP groups of this study is in line with previous research highlighting the role of PCSK9 inhibitors in achieving very low LDL-C levels, which are associated with greater plaque regression[\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. This study further supports the therapeutic impact of intensive lipid-lowering therapies by showing significant decreases in carotid plaque sizes in the Statin_P and Statin_EP groups. These findings are in agreement with guidelines indicating that PCSK9 inhibitor combinations significantly reduce the progression of CVD risks in patients on statins[\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. The significant plaque regression observed in the Statin_P and Statin_EP groups after 12 months of treatment is particularly encouraging, as plaque stabilization and regression is a key goal in the management of atherosclerotic disease to reduce cardiovascular events.\u003c/p\u003e \u003cp\u003eAdvancements in vascular imaging methodologies, including computed tomography angiography (CTA), magnetic resonance angiography (MRA), ultrasonographic imaging, and positron emission tomography/computed tomography (PET/CT), has facilitated the stratification of patient risk factors. This stratification is no longer solely predicated on the extent of carotid artery stenosis but also encompasses an evaluation of the propensity for plaque rupture, causing adverse events such as ischemic stroke. These imaging techniques are driving a paradigm shift that allows for risk stratifications based on specific imaging features, such as intraplaque hemorrhage, plaque ulceration, plaque neovascularity, fibrous cap thickness, and the presence of a lipid-rich necrotic core[\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. CEUS is an effective and accurate non-invasive imaging method for evaluating carotid IPN through directly visualizing contrast agent microbubbles within plaques[\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. Carotid IPN is an important feature of plaque vulnerability and plays a crucial role in predicting future vascular events in patients with recent ischemic stroke or heart disease[\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. Neovascularization in plaques refers to the formation of new blood vessels within the atherosclerotic plaque as part of the body’s natural healing process, which is important for the progression and regression of atherosclerosis.\u003c/p\u003e \u003cp\u003eIn atherosclerosis, the inner lining of the artery, known as the endothelium, becomes damaged due to factors such as high blood pressure, high cholesterol levels, smoking, and diabetes. This damage triggers the release of chemicals that promote the growth of new blood vessels, as the body needs to supply oxygen and nutrients to the affected area and remove waste products[\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. However, in the context of atherosclerosis, this process can be detrimental because the newly formed blood vessels are often fragile and prone to rupture, leading to further damage to the artery, potentially causing a thrombus or clot, increasing the risk of stroke or heart attack[\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. Our findings suggest that therapy combined with a PCSK9 inhibitor significantly reduced IPN and stabilized plaques. This therapeutic effect is likely the main reason for improved outcomes in patients at a high risk of CVD. The mechanism by which PCSK9 inhibitors inhibit IPN warrants further investigation.\u003c/p\u003e \u003cp\u003eThe mechanisms involved in neovascularization within atherosclerotic plaques are complex and involve multiple biological processes, including inflammation, cell death, degradation of the extracellular matrix, and the activation of endothelial and connective tissue repair responses[\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. One of the key factors in neovascularization is the presence of inflammatory cells, such as macrophages and T-lymphocytes[\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e], which release pro-angiogenic factors that stimulate the formation of new blood vessels. These factors include vascular endothelial growth factor, basic fibroblast growth factor, and interleukin-8[\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. Another important mechanism in neovascularization is the degradation of the extracellular matrix by proteases, such as matrix metalloproteinases[\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e, \u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. This process creates space for new blood vessels to form and releases pro-angiogenic factors from the extracellular matrix.\u003c/p\u003e \u003cp\u003ePlaque echogenicity, assessed by conventional B-mode ultrasound, refers to the brightness of the plaque on the ultrasound image. Echolucent plaques are known to exhibit a higher number of vulnerable pathological features and are associated with a higher risk of cerebrovascular events[\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e, \u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]. Previous studies have shown a correlation between IPN detected by CEUS and plaque echogenicity. Echolucent plaques tend to have a higher degree of neovascularization compared to echogenic plaques[\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e, \u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e]. However, some studies have reported conflicting results. For instance, 1) vulnerable plaques had denser IPN but did not show more pronounced contrast enhancement on CEUS; and 2) the correlation between immunohistochemical analysis and CEUS analysis was significant for both vulnerable and non-vulnerable plaques[\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e], indicating no significant correlation between plaque echogenicity and IPN[\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e, \u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThis study has several limitations that should be acknowledged. Firstly, the open-label nature of the trial may introduce bias, as neither the participants nor the researchers were blinded to the treatment allocation. This could potentially influence the reporting and interpretation of results. Secondly, the study population was limited to patients from a single hospital, which may limit the generalizability of the results to broader populations with different ethnicities, comorbidities, and healthcare settings. Thirdly, the follow-up period was 6 months for plaque stabilization and 12 months for regression, which may be insufficient to capture the long-term effects of the lipid-lowering therapies on plaque stabilization and regression. Longer-term studies are needed to assess the persistent effects and potential late adverse effects. Finally, the use of CEUS for plaque assessment, while non-invasive and effective, may have limitations in terms of inter-observer variability and may not capture all aspects of plaque vulnerability. The study may not fully capture the diversity and complexity of atherosclerotic plaques, as the assessment was primarily based on ultrasound imaging, which may not detect all characteristics of plaques, such as calcification or lipid-rich necrotic cores. Therefore, the study may not fully reflect the diversity and complexity of atherosclerotic plaques.\u003c/p\u003e "},{"header":"Conclusions","content":"\u003cp\u003eIn conclusion, this study underscores the importance of intensive lipid-lowering strategies, including high-dose statins, statin-ezetimibe combinations, and PCSK9 inhibitors, in the management of carotid artery disease. Therapies combining statins with PCSK9 inhibitors, such as alirocumab, are more effective in regressing carotid plaques and stabilizing plaque morphology compared to other treatments. The findings highlight the potential of PCSK9 inhibitors, in combination with statins, as a promising therapeutic strategy for reducing the burden of cardiovascular events in high-risk patients.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eBMI: Body mass index;\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eCEUS: contrast-enhanced carotid ultrasonography\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eCVD: cardiovascular disease\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eHDL-C: high-density lipoprotein cholesterol\u003c/p\u003e\n\u003cp\u003eIPN: intraplaque neovascularization\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eIVUS: intravascular ultrasound\u003c/p\u003e\n\u003cp\u003eLDL-C: low-density lipoprotein cholesterol\u003c/p\u003e\n\u003cp\u003eTC: total cholesterol\u003c/p\u003e\n\u003cp\u003eTG: triglycerides\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003e\u003cem\u003eEthics approval and consent to participate\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe study protocol was approved by the Institutional Ethics Committee of the\u0026nbsp;Third Affiliated Hospital of Guangzhou Medical University, and written informed consent was obtained from all patients before the treatment.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eConsent for publication\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eAvailability of data and materials\u0026nbsp;\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe datasets generated and/or analysed during the current study are available in the https://doi.org/10.6084/m9.figshare.25997875.v2\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eCompeting interests\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that they have no competing interests\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eFunding\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis work was supported by the grants of Leading Research Program of Hunan University of Chinese Medicine (No.2022XJJB002), Science and Technology Innovation Program of Hunan Province (No. 2022RC1021), Plan on enhancing scientific research in GMU (No.204), and 2023 Guangzhou School (Institute) Enterprise Joint Funding Project. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eAuthors\u0026apos; contributions\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eSL and LL contributed to the investigation and methodology and design of the work. PQ and KC contributed to the acquisition and validation of the data. HL performed the data analysis and drafted the manuscript. YL contributed to the supervision, conception and manuscript revision. YX performed project administration and substantively revised and validated the work. All authors read and approved the final manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eAcknowledgements\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eChhatriwalla AK, Nicholls SJ, Nissen SE: \u003cstrong\u003eThe ASTEROID trial: coronary plaque regression with high-dose statin therapy\u003c/strong\u003e. \u003cem\u003eFuture Cardiol \u003c/em\u003e2006, \u003cstrong\u003e2\u003c/strong\u003e(6):651-654.\u003c/li\u003e\n\u003cli\u003eTsujita K, Sugiyama S, Sumida H, Shimomura H, Yamashita T, Yamanaga K, Komura N, Sakamoto K, Oka H, Nakao K\u003cem\u003e et al\u003c/em\u003e: \u003cstrong\u003eImpact of Dual Lipid-Lowering Strategy With Ezetimibe and Atorvastatin on Coronary Plaque Regression in Patients With Percutaneous Coronary Intervention\u003c/strong\u003e. \u003cem\u003eJ Am Coll Cardiol \u003c/em\u003e2015, 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\u003cstrong\u003eGeneral principles and overview of vascular contrast-enhanced ultrasonography\u003c/strong\u003e. \u003cem\u003eUltrasonography \u003c/em\u003e2020, \u003cstrong\u003e39\u003c/strong\u003e(1):22.\u003c/li\u003e\n\u003cli\u003eCui L, Xing Y, Zhou Y, Wang L, Liu K, Zhang D, Chen Y: \u003cstrong\u003eCarotid intraplaque neovascularisation as a predictive factor for future vascular events in patients with mild and moderate carotid stenosis: an observational prospective study\u003c/strong\u003e. \u003cem\u003eTher Adv Neurol Disord \u003c/em\u003e2021, \u003cstrong\u003e14\u003c/strong\u003e:17562864211023992.\u003c/li\u003e\n\u003cli\u003eTarbell J, Mahmoud M, Corti A, Cardoso L, Caro C: \u003cstrong\u003eThe role of oxygen transport in atherosclerosis and vascular disease\u003c/strong\u003e. \u003cem\u003eJournal of The Royal Society Interface \u003c/em\u003e2020, \u003cstrong\u003e17\u003c/strong\u003e(165):20190732.\u003c/li\u003e\n\u003cli\u003eGoncalves I, Sun J, Tengryd C, Nitulescu M, Persson AF, Nilsson J, Edsfeldt A: \u003cstrong\u003ePlaque Vulnerability Index Predicts Cardiovascular Events: A Histological Study of an Endarterectomy Cohort\u003c/strong\u003e. \u003cem\u003eJournal of the American Heart Association \u003c/em\u003e2021, \u003cstrong\u003e10\u003c/strong\u003e(15):e021038.\u003c/li\u003e\n\u003cli\u003eLyu Q, Tian X, Ding Y, Yan Y, Huang Y, Zhou P, Hui P: \u003cstrong\u003eEvaluation of Carotid Plaque Rupture and Neovascularization by Contrast-Enhanced Ultrasound Imaging: an Exploratory Study Based on Histopathology\u003c/strong\u003e. \u003cem\u003eTranslational Stroke Research \u003c/em\u003e2021, \u003cstrong\u003e12\u003c/strong\u003e(1):49-56.\u003c/li\u003e\n\u003cli\u003eYurdagul A: \u003cstrong\u003eCrosstalk Between Macrophages and Vascular Smooth Muscle Cells in Atherosclerotic Plaque Stability\u003c/strong\u003e. \u003cem\u003eArterioscler Thromb Vasc Biol \u003c/em\u003e2022, 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outcome\u003c/strong\u003e. \u003cem\u003eJ Intern Med \u003c/em\u003e2020, \u003cstrong\u003e287\u003c/strong\u003e(5):493-513.\u003c/li\u003e\n\u003cli\u003eBrinjikji W, Huston J, Rabinstein AA, Kim G-M, Lerman A, Lanzino G: \u003cstrong\u003eContemporary carotid imaging: from degree of stenosis to plaque vulnerability\u003c/strong\u003e. \u003cem\u003eJournal of Neurosurgery JNS \u003c/em\u003e2016, \u003cstrong\u003e124\u003c/strong\u003e(1):27-42.\u003c/li\u003e\n\u003cli\u003eDoonan RJ, Gorgui J, Veinot JP, Lai C, Kyriacou E, Corriveau MM, Steinmetz OK, Daskalopoulou SS: \u003cstrong\u003ePlaque echodensity and textural features are associated with histologic carotid plaque instability\u003c/strong\u003e. \u003cem\u003eJ Vasc Surg \u003c/em\u003e2016, \u003cstrong\u003e64\u003c/strong\u003e(3):671-677.e678.\u003c/li\u003e\n\u003cli\u003eZhang Y, Cao J, Zhou J, Zhang C, Li Q, Chen S, Feinstein S, Grayburn PA, Huang P: \u003cstrong\u003ePlaque Elasticity and Intraplaque Neovascularisation on Carotid Artery Ultrasound: A Comparative Histological Study\u003c/strong\u003e. \u003cem\u003eEur J Vasc Endovasc Surg \u003c/em\u003e2021, \u003cstrong\u003e62\u003c/strong\u003e(3):358-366.\u003c/li\u003e\n\u003cli\u003eZhou Y, Xing Y, Li Y, Bai Y, Chen Y, Sun X, Zhu Y, Wu J: \u003cstrong\u003eAn assessment of the vulnerability of carotid plaques: a comparative study between intraplaque neovascularization and plaque echogenicity\u003c/strong\u003e. \u003cem\u003eBMC Med Imaging \u003c/em\u003e2013, \u003cstrong\u003e13\u003c/strong\u003e(1):13.\u003c/li\u003e\n\u003cli\u003eD\u0026apos;Oria M, Chiarandini S, Pipitone MD, Fisicaro M, Calvagna C, Bussani R, Rotelli A, Ziani B: \u003cstrong\u003eContrast Enhanced Ultrasound (CEUS) Is Not Able to Identify Vulnerable Plaques in Asymptomatic Carotid Atherosclerotic Disease\u003c/strong\u003e. \u003cem\u003eEur J Vasc Endovasc Surg \u003c/em\u003e2018, \u003cstrong\u003e56\u003c/strong\u003e(5):632-642.\u003c/li\u003e\n\u003cli\u003eCattaneo M, Staub D, Porretta AP, Gallino JM, Santini P, Limoni C, Wyttenbach R, Gallino A: \u003cstrong\u003eContrast-enhanced ultrasound imaging of intraplaque neovascularization and its correlation to plaque echogenicity in human carotid arteries atherosclerosis\u003c/strong\u003e. \u003cem\u003eInt J Cardiol \u003c/em\u003e2016, \u003cstrong\u003e223\u003c/strong\u003e:917-922.\u003c/li\u003e\n\u003cli\u003eCattaneo M, Staub D, Porretta AP, Gallino JM, Santini P, Limoni C, Wyttenbach R, Gallino A: \u003cstrong\u003eData on consistency among different methods to assess atherosclerotic plaque echogenicity on standard ultrasound and intraplaque neovascularization on contrast-enhanced ultrasound imaging in human carotid artery\u003c/strong\u003e. \u003cem\u003eData in Brief \u003c/em\u003e2016, \u003cstrong\u003e9\u003c/strong\u003e:563-567.\u003c/li\u003e\n\n\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003eTable\u0026nbsp;1. Basic characteristics of the participants\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003ctd width=\"20.549927641099856%\"\u003e\n \u003cp\u003e\u003cstrong\u003eVariable\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.24891461649783%\"\u003e\n \u003cp\u003e\u003cstrong\u003eN\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.748191027496382%\"\u003e\n \u003cp\u003e\u003cstrong\u003eStatin\u003c/strong\u003e, N = 74\u003cem\u003e\u003csup\u003e1\u003c/sup\u003e\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.050651230101302%\"\u003e\n \u003cp\u003e\u003cstrong\u003eStatin_E\u003c/strong\u003e, N = 75\u003cem\u003e\u003csup\u003e1\u003c/sup\u003e\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.050651230101302%\"\u003e\n \u003cp\u003e\u003cstrong\u003eStatin_P\u003c/strong\u003e, N = 74\u003cem\u003e\u003csup\u003e1\u003c/sup\u003e\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.35311143270622%\"\u003e\n \u003cp\u003e\u003cstrong\u003eStatin_EP\u003c/strong\u003e, N = 76\u003cem\u003e\u003csup\u003e1\u003c/sup\u003e\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.998552821997105%\"\u003e\n \u003cp\u003e\u003cstrong\u003ep-value\u003c/strong\u003e\u003cem\u003e\u003csup\u003e2\u003c/sup\u003e\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd width=\"20.549927641099856%\"\u003e\n \u003cp\u003e\u003cstrong\u003eSex\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.24891461649783%\"\u003e\n \u003cp\u003e299\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.748191027496382%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.050651230101302%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.050651230101302%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.35311143270622%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.998552821997105%\"\u003e\n \u003cp\u003e0.41\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"20.549927641099856%\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; Female\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.24891461649783%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.748191027496382%\"\u003e\n \u003cp\u003e42/57%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.050651230101302%\"\u003e\n \u003cp\u003e40/53%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.050651230101302%\"\u003e\n \u003cp\u003e38/51%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.35311143270622%\"\u003e\n \u003cp\u003e33/43%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.998552821997105%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"20.549927641099856%\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; Male\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.24891461649783%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.748191027496382%\"\u003e\n \u003cp\u003e32/43%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.050651230101302%\"\u003e\n \u003cp\u003e35/47%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.050651230101302%\"\u003e\n \u003cp\u003e36/49%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.35311143270622%\"\u003e\n \u003cp\u003e43/57%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.998552821997105%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"20.549927641099856%\"\u003e\n \u003cp\u003e\u003cstrong\u003eAge (y)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.24891461649783%\"\u003e\n \u003cp\u003e299\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.748191027496382%\"\u003e\n \u003cp\u003e73\u0026plusmn; 9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.050651230101302%\"\u003e\n \u003cp\u003e71\u0026plusmn; 9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.050651230101302%\"\u003e\n \u003cp\u003e71\u0026plusmn; 10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.35311143270622%\"\u003e\n \u003cp\u003e70\u0026plusmn; 10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.998552821997105%\"\u003e\n \u003cp\u003e0.28\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"20.549927641099856%\"\u003e\n \u003cp\u003e\u003cstrong\u003eBMI (kg/m\u003csup\u003e2\u003c/sup\u003e)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.24891461649783%\"\u003e\n \u003cp\u003e299\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.748191027496382%\"\u003e\n \u003cp\u003e23.3\u0026plusmn; 3.1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.050651230101302%\"\u003e\n \u003cp\u003e23.7\u0026plusmn; 3.6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.050651230101302%\"\u003e\n \u003cp\u003e23.8\u0026plusmn; 3.5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.35311143270622%\"\u003e\n \u003cp\u003e23.9\u0026plusmn; 2.9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.998552821997105%\"\u003e\n \u003cp\u003e0.77\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"20.549927641099856%\"\u003e\n \u003cp\u003e\u003cstrong\u003eHT (mmHg)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.24891461649783%\"\u003e\n \u003cp\u003e299\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.748191027496382%\"\u003e\n \u003cp\u003e66/89%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.050651230101302%\"\u003e\n \u003cp\u003e66/88%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.050651230101302%\"\u003e\n \u003cp\u003e61/82%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.35311143270622%\"\u003e\n \u003cp\u003e58/76%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.998552821997105%\"\u003e\n \u003cp\u003e0.12\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"20.549927641099856%\"\u003e\n \u003cp\u003e\u003cstrong\u003eSmoking\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.24891461649783%\"\u003e\n \u003cp\u003e299\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.748191027496382%\"\u003e\n \u003cp\u003e19/26%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.050651230101302%\"\u003e\n \u003cp\u003e21/28%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.050651230101302%\"\u003e\n \u003cp\u003e22/30%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.35311143270622%\"\u003e\n \u003cp\u003e29/38%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.998552821997105%\"\u003e\n \u003cp\u003e0.37\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"20.549927641099856%\"\u003e\n \u003cp\u003e\u003cstrong\u003eT2DM\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.24891461649783%\"\u003e\n \u003cp\u003e299\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.748191027496382%\"\u003e\n \u003cp\u003e33/45%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.050651230101302%\"\u003e\n \u003cp\u003e31/41%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.050651230101302%\"\u003e\n \u003cp\u003e36/49%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.35311143270622%\"\u003e\n \u003cp\u003e33/43%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.998552821997105%\"\u003e\n \u003cp\u003e0.84\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"20.549927641099856%\"\u003e\n \u003cp\u003e\u003cstrong\u003eFPG (mmol/L)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.24891461649783%\"\u003e\n \u003cp\u003e299\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.748191027496382%\"\u003e\n \u003cp\u003e6.3 [5.4, 9.1]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.050651230101302%\"\u003e\n \u003cp\u003e6.1 [5.2, 8.5]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.050651230101302%\"\u003e\n \u003cp\u003e6.5 [5.5, 9.3]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.35311143270622%\"\u003e\n \u003cp\u003e6.3 [5.3, 8.6]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.998552821997105%\"\u003e\n \u003cp\u003e0.82\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"20.549927641099856%\"\u003e\n \u003cp\u003e\u003cstrong\u003eHbA1c (%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.24891461649783%\"\u003e\n \u003cp\u003e299\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.748191027496382%\"\u003e\n \u003cp\u003e6.25 [5.90, 6.80]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.050651230101302%\"\u003e\n \u003cp\u003e6.20 [5.90, 6.75]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.050651230101302%\"\u003e\n \u003cp\u003e6.40 [5.80, 7.20]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.35311143270622%\"\u003e\n \u003cp\u003e6.25 [5.90, 6.80]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.998552821997105%\"\u003e\n \u003cp\u003e0.95\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"20.549927641099856%\"\u003e\n \u003cp\u003e\u003cstrong\u003eTC (mmol/L)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.24891461649783%\"\u003e\n \u003cp\u003e299\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.748191027496382%\"\u003e\n \u003cp\u003e3.86 [3.46, 4.57]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.050651230101302%\"\u003e\n \u003cp\u003e4.13 [3.43, 5.08]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.050651230101302%\"\u003e\n \u003cp\u003e3.87 [3.56, 4.50]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.35311143270622%\"\u003e\n \u003cp\u003e4.22 [3.25, 5.03]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.998552821997105%\"\u003e\n \u003cp\u003e0.31\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"20.549927641099856%\"\u003e\n \u003cp\u003e\u003cstrong\u003eTG (mmol/L)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.24891461649783%\"\u003e\n \u003cp\u003e299\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.748191027496382%\"\u003e\n \u003cp\u003e1.37 [0.98, 1.80]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.050651230101302%\"\u003e\n \u003cp\u003e1.49 [0.96, 2.08]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.050651230101302%\"\u003e\n \u003cp\u003e1.46 [1.05, 2.15]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.35311143270622%\"\u003e\n \u003cp\u003e1.27 [0.99, 1.71]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.998552821997105%\"\u003e\n \u003cp\u003e0.41\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"20.549927641099856%\"\u003e\n \u003cp\u003e\u003cstrong\u003eLDL-C (mmol/L)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.24891461649783%\"\u003e\n \u003cp\u003e299\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.748191027496382%\"\u003e\n \u003cp\u003e2.35 [1.87, 2.95]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.050651230101302%\"\u003e\n \u003cp\u003e2.67 [1.96, 3.61]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.050651230101302%\"\u003e\n \u003cp\u003e2.37 [2.02, 2.79]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.35311143270622%\"\u003e\n \u003cp\u003e2.56 [1.88, 3.46]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.998552821997105%\"\u003e\n \u003cp\u003e0.23\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"20.549927641099856%\"\u003e\n \u003cp\u003e\u003cstrong\u003eHDL-C (mmol/L)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.24891461649783%\"\u003e\n \u003cp\u003e299\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.748191027496382%\"\u003e\n \u003cp\u003e1.16 [0.90, 1.52]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.050651230101302%\"\u003e\n \u003cp\u003e1.11 [0.91, 1.46]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.050651230101302%\"\u003e\n \u003cp\u003e1.12 [0.93, 1.32]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.35311143270622%\"\u003e\n \u003cp\u003e1.21 [1.04, 1.48]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.998552821997105%\"\u003e\n \u003cp\u003e0.11\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"20.549927641099856%\"\u003e\n \u003cp\u003e\u003cstrong\u003eScr (\u0026mu;mol/L)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.24891461649783%\"\u003e\n \u003cp\u003e299\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.748191027496382%\"\u003e\n \u003cp\u003e91 [72, 115]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.050651230101302%\"\u003e\n \u003cp\u003e81 [68, 99]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.050651230101302%\"\u003e\n \u003cp\u003e82 [70, 104]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.35311143270622%\"\u003e\n \u003cp\u003e81 [68, 101]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.998552821997105%\"\u003e\n \u003cp\u003e0.15\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"20.549927641099856%\"\u003e\n \u003cp\u003e\u003cstrong\u003eUA (\u0026mu;mol/L)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.24891461649783%\"\u003e\n \u003cp\u003e299\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.748191027496382%\"\u003e\n \u003cp\u003e359 [307, 474]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.050651230101302%\"\u003e\n \u003cp\u003e381 [321, 458]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.050651230101302%\"\u003e\n \u003cp\u003e393 [335, 467]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.35311143270622%\"\u003e\n \u003cp\u003e384 [315, 431]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.998552821997105%\"\u003e\n \u003cp\u003e0.35\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"100%\" colspan=\"7\"\u003e\n \u003cp\u003e\u003cem\u003e\u003csup\u003e1\u003c/sup\u003e\u003c/em\u003en/%; Mean \u0026plusmn; SD; Median (IQR)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"100%\" colspan=\"7\"\u003e\n \u003cp\u003e\u003cem\u003e\u003csup\u003e2\u003c/sup\u003e\u003c/em\u003ePearson\u0026rsquo;s Chi-squared test; One-way ANOVA; Kruskal\u0026ndash;Wallis rank sum test\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"100%\" colspan=\"7\"\u003e\n \u003cp\u003eBMI =\u0026nbsp;Body Mass Index, FPG = Fasting Plasma Glucose, HbA1c = Glycated Hemoglobin, HDL-C = High-Density Lipoprotein Cholesterol, LDL-C = Low-Density Lipoprotein Cholesterol, Scr = Serum Creatinine, TC = Total Cholesterol, TG = Triglycerides, UA = Uric Acid.\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u0026nbsp;\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eTable\u0026nbsp;2. Plaque characteristics of ultrasound imaging before treatment\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd width=\"13.95007342143906%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eVariable\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.020558002936857%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eN\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.831130690161528%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eStatin, N = 74\u003cem\u003e\u003csup\u003e1\u003c/sup\u003e\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.061674008810574%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eStatin_E, N = 75\u003cem\u003e\u003csup\u003e1\u003c/sup\u003e\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.061674008810574%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eStatin_P, N = 74\u003cem\u003e\u003csup\u003e1\u003c/sup\u003e\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.383259911894275%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eStatin_EP, N = 76\u003cem\u003e\u003csup\u003e1\u003c/sup\u003e\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.691629955947137%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003ep-value\u003cem\u003e\u003csup\u003e2\u003c/sup\u003e\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"13.95007342143906%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eLIMT (mm)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.020558002936857%\" valign=\"top\"\u003e\n \u003cp\u003e299\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.831130690161528%\" valign=\"top\"\u003e\n \u003cp\u003e0.92 \u0026plusmn; 0.15\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.061674008810574%\" valign=\"top\"\u003e\n \u003cp\u003e0.97 \u0026plusmn; 0.17\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.061674008810574%\" valign=\"top\"\u003e\n \u003cp\u003e0.96 \u0026plusmn; 0.20\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.383259911894275%\" valign=\"top\"\u003e\n \u003cp\u003e0.97 \u0026plusmn; 0.21\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.691629955947137%\" valign=\"top\"\u003e\n \u003cp\u003e0.28\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"13.95007342143906%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eRIMT (mm)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.020558002936857%\" valign=\"top\"\u003e\n \u003cp\u003e299\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.831130690161528%\" valign=\"top\"\u003e\n \u003cp\u003e0.91 \u0026plusmn; 0.16\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.061674008810574%\" valign=\"top\"\u003e\n \u003cp\u003e0.95 \u0026plusmn; 0.18\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.061674008810574%\" valign=\"top\"\u003e\n \u003cp\u003e0.93 \u0026plusmn; 0.18\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.383259911894275%\" valign=\"top\"\u003e\n \u003cp\u003e0.95 \u0026plusmn; 0.20\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.691629955947137%\" valign=\"top\"\u003e\n \u003cp\u003e0.44\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"13.95007342143906%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eL-size (mm\u003csup\u003e2\u003c/sup\u003e)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.020558002936857%\" valign=\"top\"\u003e\n \u003cp\u003e299\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.831130690161528%\" valign=\"top\"\u003e\n \u003cp\u003e14 [5, 25]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.061674008810574%\" valign=\"top\"\u003e\n \u003cp\u003e13 [7, 30]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.061674008810574%\" valign=\"top\"\u003e\n \u003cp\u003e19 [11, 33]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.383259911894275%\" valign=\"top\"\u003e\n \u003cp\u003e14 [7, 28]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.691629955947137%\" valign=\"top\"\u003e\n \u003cp\u003e0.11\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"13.95007342143906%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eR-size (mm\u003csup\u003e2\u003c/sup\u003e)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.020558002936857%\" valign=\"top\"\u003e\n \u003cp\u003e299\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.831130690161528%\" valign=\"top\"\u003e\n \u003cp\u003e14 [7, 27]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.061674008810574%\" valign=\"top\"\u003e\n \u003cp\u003e14 [8, 25]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.061674008810574%\" valign=\"top\"\u003e\n \u003cp\u003e17 [9, 29]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.383259911894275%\" valign=\"top\"\u003e\n \u003cp\u003e17 [10, 32]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.691629955947137%\" valign=\"top\"\u003e\n \u003cp\u003e0.54\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"13.95007342143906%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eL-type\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.020558002936857%\" valign=\"top\"\u003e\n \u003cp\u003e275\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.831130690161528%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.061674008810574%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.061674008810574%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.383259911894275%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.691629955947137%\" valign=\"top\"\u003e\n \u003cp\u003e0.92\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"13.95007342143906%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp; \u0026nbsp; I\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.020558002936857%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.831130690161528%\" valign=\"top\"\u003e\n \u003cp\u003e6/72 [8.3%]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.061674008810574%\" valign=\"top\"\u003e\n \u003cp\u003e11/70 [16%]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.061674008810574%\" valign=\"top\"\u003e\n \u003cp\u003e10/68 [15%]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.383259911894275%\" valign=\"top\"\u003e\n \u003cp\u003e6/65 [9.2%]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.691629955947137%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"13.95007342143906%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp; \u0026nbsp; II\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.020558002936857%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.831130690161528%\" valign=\"top\"\u003e\n \u003cp\u003e30/72 [42%]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.061674008810574%\" valign=\"top\"\u003e\n \u003cp\u003e25/70 [36%]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.061674008810574%\" valign=\"top\"\u003e\n \u003cp\u003e29/68 [43%]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.383259911894275%\" valign=\"top\"\u003e\n \u003cp\u003e26/65 [40%]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.691629955947137%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"13.95007342143906%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp; \u0026nbsp; III\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.020558002936857%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.831130690161528%\" valign=\"top\"\u003e\n \u003cp\u003e29/72 [40%]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.061674008810574%\" valign=\"top\"\u003e\n \u003cp\u003e29/70 [41%]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.061674008810574%\" valign=\"top\"\u003e\n \u003cp\u003e23/68 [34%]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.383259911894275%\" valign=\"top\"\u003e\n \u003cp\u003e27/65 [42%]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.691629955947137%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"13.95007342143906%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp; \u0026nbsp; IV\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.020558002936857%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.831130690161528%\" valign=\"top\"\u003e\n \u003cp\u003e7/72 [9.7%]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.061674008810574%\" valign=\"top\"\u003e\n \u003cp\u003e5/70 [7.1%]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.061674008810574%\" valign=\"top\"\u003e\n \u003cp\u003e6/68 [8.8%]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.383259911894275%\" valign=\"top\"\u003e\n \u003cp\u003e6/65 [9.2%]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.691629955947137%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"13.95007342143906%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eR-type\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.020558002936857%\" valign=\"top\"\u003e\n \u003cp\u003e263\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.831130690161528%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.061674008810574%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.061674008810574%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.383259911894275%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.691629955947137%\" valign=\"top\"\u003e\n \u003cp\u003e0.98\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"13.95007342143906%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp; \u0026nbsp; I\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.020558002936857%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.831130690161528%\" valign=\"top\"\u003e\n \u003cp\u003e9/64 [14%]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.061674008810574%\" valign=\"top\"\u003e\n \u003cp\u003e7/68 [10%]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.061674008810574%\" valign=\"top\"\u003e\n \u003cp\u003e8/65 [12%]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.383259911894275%\" valign=\"top\"\u003e\n \u003cp\u003e8/66 [12%]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.691629955947137%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"13.95007342143906%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp; \u0026nbsp; II\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.020558002936857%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.831130690161528%\" valign=\"top\"\u003e\n \u003cp\u003e21/64 [33%]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.061674008810574%\" valign=\"top\"\u003e\n \u003cp\u003e20/68 [29%]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.061674008810574%\" valign=\"top\"\u003e\n \u003cp\u003e22/65 [34%]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.383259911894275%\" valign=\"top\"\u003e\n \u003cp\u003e25/66 [38%]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.691629955947137%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"13.95007342143906%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp; \u0026nbsp; III\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.020558002936857%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.831130690161528%\" valign=\"top\"\u003e\n \u003cp\u003e28/64 [44%]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.061674008810574%\" valign=\"top\"\u003e\n \u003cp\u003e31/68 [46%]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.061674008810574%\" valign=\"top\"\u003e\n \u003cp\u003e29/65 [45%]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.383259911894275%\" valign=\"top\"\u003e\n \u003cp\u003e26/66 [39%]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.691629955947137%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"13.95007342143906%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp; \u0026nbsp; IV\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.020558002936857%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.831130690161528%\" valign=\"top\"\u003e\n \u003cp\u003e6/64 [9.4%]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.061674008810574%\" valign=\"top\"\u003e\n \u003cp\u003e10/68 [15%]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.061674008810574%\" valign=\"top\"\u003e\n \u003cp\u003e6/65 [9.2%]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.383259911894275%\" valign=\"top\"\u003e\n \u003cp\u003e7/66 [11%]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.691629955947137%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"13.95007342143906%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eL-neo\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.020558002936857%\" valign=\"top\"\u003e\n \u003cp\u003e275\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.831130690161528%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.061674008810574%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.061674008810574%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.383259911894275%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.691629955947137%\" valign=\"top\"\u003e\n \u003cp\u003e0.98\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"13.95007342143906%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp; \u0026nbsp; L0\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.020558002936857%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.831130690161528%\" valign=\"top\"\u003e\n \u003cp\u003e33/72 [46%]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.061674008810574%\" valign=\"top\"\u003e\n \u003cp\u003e29/70 [41%]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.061674008810574%\" valign=\"top\"\u003e\n \u003cp\u003e34/68 [50%]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.383259911894275%\" valign=\"top\"\u003e\n \u003cp\u003e33/65 [51%]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.691629955947137%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"13.95007342143906%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp; \u0026nbsp; L1\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.020558002936857%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.831130690161528%\" valign=\"top\"\u003e\n \u003cp\u003e19/72 [26%]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.061674008810574%\" valign=\"top\"\u003e\n \u003cp\u003e22/70 [31%]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.061674008810574%\" valign=\"top\"\u003e\n \u003cp\u003e16/68 [24%]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.383259911894275%\" valign=\"top\"\u003e\n \u003cp\u003e15/65 [23%]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.691629955947137%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"13.95007342143906%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp; \u0026nbsp; L2\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.020558002936857%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.831130690161528%\" valign=\"top\"\u003e\n \u003cp\u003e14/72 [19%]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.061674008810574%\" valign=\"top\"\u003e\n \u003cp\u003e13/70 [19%]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.061674008810574%\" valign=\"top\"\u003e\n \u003cp\u003e11/68 [16%]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.383259911894275%\" valign=\"top\"\u003e\n \u003cp\u003e11/65 [17%]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.691629955947137%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"13.95007342143906%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp; \u0026nbsp; L3\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.020558002936857%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.831130690161528%\" valign=\"top\"\u003e\n \u003cp\u003e6/72 [8.3%]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.061674008810574%\" valign=\"top\"\u003e\n \u003cp\u003e6/70 [8.6%]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.061674008810574%\" valign=\"top\"\u003e\n \u003cp\u003e7/68 [10%]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.383259911894275%\" valign=\"top\"\u003e\n \u003cp\u003e6/65 [9.2%]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.691629955947137%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"13.95007342143906%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eR-neo\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.020558002936857%\" valign=\"top\"\u003e\n \u003cp\u003e263\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.831130690161528%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.061674008810574%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.061674008810574%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.383259911894275%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.691629955947137%\" valign=\"top\"\u003e\n \u003cp\u003e0.97\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"13.95007342143906%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp; \u0026nbsp; R0\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.020558002936857%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.831130690161528%\" valign=\"top\"\u003e\n \u003cp\u003e32/64 [50%]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.061674008810574%\" valign=\"top\"\u003e\n \u003cp\u003e35/68 [51%]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.061674008810574%\" valign=\"top\"\u003e\n \u003cp\u003e31/65 [48%]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.383259911894275%\" valign=\"top\"\u003e\n \u003cp\u003e36/66 [55%]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.691629955947137%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"13.95007342143906%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp; \u0026nbsp; R1\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.020558002936857%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.831130690161528%\" valign=\"top\"\u003e\n \u003cp\u003e14/64 [22%]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.061674008810574%\" valign=\"top\"\u003e\n \u003cp\u003e13/68 [19%]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.061674008810574%\" valign=\"top\"\u003e\n \u003cp\u003e10/65 [15%]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.383259911894275%\" valign=\"top\"\u003e\n \u003cp\u003e12/66 [18%]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.691629955947137%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"13.95007342143906%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp; \u0026nbsp; R2\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.020558002936857%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.831130690161528%\" valign=\"top\"\u003e\n \u003cp\u003e12/64 [19%]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.061674008810574%\" valign=\"top\"\u003e\n \u003cp\u003e12/68 [18%]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.061674008810574%\" valign=\"top\"\u003e\n \u003cp\u003e14/65 [22%]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.383259911894275%\" valign=\"top\"\u003e\n \u003cp\u003e10/66 [15%]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.691629955947137%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"13.95007342143906%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp; \u0026nbsp; R3\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.020558002936857%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.831130690161528%\" valign=\"top\"\u003e\n \u003cp\u003e6/64 [9.4%]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.061674008810574%\" valign=\"top\"\u003e\n \u003cp\u003e8/68 [12%]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.061674008810574%\" valign=\"top\"\u003e\n \u003cp\u003e10/65 [15%]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.383259911894275%\" valign=\"top\"\u003e\n \u003cp\u003e8/66 [12%]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.691629955947137%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"100%\" colspan=\"7\" valign=\"top\"\u003e\n \u003cp\u003e\u003cem\u003e\u003csup\u003e1\u003c/sup\u003e\u003c/em\u003eMean \u0026plusmn; SD; Median (IQR); n/N (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"100%\" colspan=\"7\" valign=\"top\"\u003e\n \u003cp\u003e\u003cem\u003e\u003csup\u003e2\u003c/sup\u003e\u003c/em\u003eOne-way ANOVA; Kruskal\u0026ndash;Wallis rank sum test; Pearson\u0026rsquo;s Chi-squared test\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"100%\" colspan=\"7\" valign=\"top\"\u003e\n \u003cp\u003eLIMT = Left Intima-Media Thickness, L-neo = Left Intraplaque Neovascularization, L-size = Left Plaque Size, L-type = Left Plaque Echogenic Type, RIMT = Right Intima-Media Thickness, R-neo = Right Intraplaque Neovascularization,\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003eR-size = Right Plaque Size, R-type = Right Plaque Echogenic Type.\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003ch2\u003e\u0026nbsp;\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/h2\u003e\n\u003cp\u003eTable\u0026nbsp;3. Changes in pre-treatment and post-treatment carotid plaque sizes\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003ctd width=\"11.987381703470032%\" valign=\"bottom\"\u003e\n \u003cp\u003e\u003cstrong\u003eVariable\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.413249211356467%\" valign=\"bottom\"\u003e\n \u003cp\u003e\u003cstrong\u003eN\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.299684542586752%\" valign=\"bottom\"\u003e\n \u003cp\u003e\u003cstrong\u003eStatin\u003c/strong\u003e, N = 74\u003cem\u003e\u003csup\u003e1\u003c/sup\u003e\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.50788643533123%\" valign=\"bottom\"\u003e\n \u003cp\u003e\u003cstrong\u003eStatin_E\u003c/strong\u003e, N = 75\u003cem\u003e\u003csup\u003e1\u003c/sup\u003e\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.350157728706623%\" valign=\"bottom\"\u003e\n \u003cp\u003e\u003cstrong\u003eStatin_P\u003c/strong\u003e, N = 74\u003cem\u003e\u003csup\u003e1\u003c/sup\u003e\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.400630914826497%\" valign=\"bottom\"\u003e\n \u003cp\u003e\u003cstrong\u003eStatin_EP\u003c/strong\u003e, N = 76\u003cem\u003e\u003csup\u003e1\u003c/sup\u003e\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.041009463722398%\" valign=\"bottom\"\u003e\n \u003cp\u003e\u003cstrong\u003ep-value\u003c/strong\u003e\u003cem\u003e\u003csup\u003e2\u003c/sup\u003e\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"11.987381703470032%\"\u003e\n \u003cp\u003e\u003cstrong\u003eL-size\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.413249211356467%\"\u003e\n \u003cp\u003e299\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.299684542586752%\"\u003e\n \u003cp\u003e14 [5, 25]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.50788643533123%\"\u003e\n \u003cp\u003e13 [7, 30]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.350157728706623%\"\u003e\n \u003cp\u003e19 [11, 33]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.400630914826497%\"\u003e\n \u003cp\u003e14 [7, 28]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.041009463722398%\"\u003e\n \u003cp\u003e0.11\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"11.987381703470032%\"\u003e\n \u003cp\u003e\u003cstrong\u003eL-size-post\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.413249211356467%\"\u003e\n \u003cp\u003e299\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.299684542586752%\"\u003e\n \u003cp\u003e19 [9, 35]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.50788643533123%\"\u003e\n \u003cp\u003e18 [11, 36]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.350157728706623%\"\u003e\n \u003cp\u003e17 [10, 34]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.400630914826497%\"\u003e\n \u003cp\u003e16 [8, 27]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.041009463722398%\"\u003e\n \u003cp\u003e0.20\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"11.987381703470032%\"\u003e\n \u003cp\u003e\u003cstrong\u003eL-change\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.413249211356467%\"\u003e\n \u003cp\u003e299\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.299684542586752%\"\u003e\n \u003cp\u003e\u0026minus;2 [\u0026minus;8, 0]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.50788643533123%\"\u003e\n \u003cp\u003e\u0026minus;3 [\u0026minus;9, 0]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.350157728706623%\"\u003e\n \u003cp\u003e0 [\u0026minus;3, 4]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.400630914826497%\"\u003e\n \u003cp\u003e0 [\u0026minus;3, 3]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.041009463722398%\"\u003e\n \u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"11.987381703470032%\"\u003e\n \u003cp\u003e\u003cstrong\u003eR-size\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.413249211356467%\"\u003e\n \u003cp\u003e299\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.299684542586752%\"\u003e\n \u003cp\u003e14 [7, 27]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.50788643533123%\"\u003e\n \u003cp\u003e14 [8, 25]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.350157728706623%\"\u003e\n \u003cp\u003e17 [9, 29]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.400630914826497%\"\u003e\n \u003cp\u003e17 [10, 32]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.041009463722398%\"\u003e\n \u003cp\u003e0.54\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"11.987381703470032%\"\u003e\n \u003cp\u003e\u003cstrong\u003eR-size-post\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.413249211356467%\"\u003e\n \u003cp\u003e299\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.299684542586752%\"\u003e\n \u003cp\u003e17 [10, 33]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.50788643533123%\"\u003e\n \u003cp\u003e17 [9, 27]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.350157728706623%\"\u003e\n \u003cp\u003e17 [6, 32]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.400630914826497%\"\u003e\n \u003cp\u003e17 [9, 24]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.041009463722398%\"\u003e\n \u003cp\u003e0.94\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"11.987381703470032%\"\u003e\n \u003cp\u003e\u003cstrong\u003eR-change\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.413249211356467%\"\u003e\n \u003cp\u003e299\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.299684542586752%\"\u003e\n \u003cp\u003e\u0026minus;2 [\u0026minus;8, 0]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.50788643533123%\"\u003e\n \u003cp\u003e0 [\u0026minus;7, 2]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.350157728706623%\"\u003e\n \u003cp\u003e0 [\u0026minus;2, 3]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.400630914826497%\"\u003e\n \u003cp\u003e0 [0, 4]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.041009463722398%\"\u003e\n \u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"100%\" colspan=\"7\"\u003e\n \u003cp\u003e\u003cem\u003e\u003csup\u003e1\u003c/sup\u003e\u003c/em\u003eMedian (IQR)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"100%\" colspan=\"7\"\u003e\n \u003cp\u003e\u003cem\u003e\u003csup\u003e2\u003c/sup\u003e\u003c/em\u003eKruskal\u0026ndash;Wallis rank sum test\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"100%\" colspan=\"7\"\u003e\n \u003cp\u003eL-change = Left Change of Pre- and Post-Treatment Plaque Size, L-size = Left Plaque Size, L-size-post = Left Post-Treatment Plaque Size, R-change = Right Change of Pre- and Post-Treatment Plaque Size, R-size = Right Plaque Size, R-size-post = Right Post-Treatment Plaque Size.\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n\u003c/table\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":true,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Intensive Lipid-Lowering Therapy, Atherosclerotic Plaque, PCSK9 Inhibitor, Contrast-Enhanced Carotid Ultrasonography, Intraplaque Neovascularization, Plaque Regression","lastPublishedDoi":"10.21203/rs.3.rs-4604642/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4604642/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003eAtherosclerotic plaques in carotid arteries are significant predictors of cardiovascular events such as stroke and myocardial infarction. Lipid-lowering therapies, particularly statins and proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, have shown promising in plaque regression and stabilization, which are crucial for cardiovascular disease (CVD).\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eThis randomized open-label trial was conducted at the Third Affiliated Hospital of Guangzhou Medical University from March 2022 to December 2023. The study included patients at high CVD risk with non-calcified carotid plaque. Participants were randomized into four groups: statin alone (Statin), statin plus ezetimibe (Statin_E), statin plus alirocumab (Statin_P), and statin plus ezetimibe and alirocumab (Statin_EP). The primary outcomes were morphological stabilization of carotid plaque at 6 months and regression at 12 months, assessed by contrast-enhanced carotid ultrasonography. Secondary outcomes were changes in blood lipid levels.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eA total of 312 high CVD risk patients were enrolled, among whom 299 completed the study. After six months, patients in the Statin_P and Statin_EP groups showed significantly lower levels of total cholesterol and low-density lipoprotein cholesterol compared to the other groups. These patients also demonstrated a significantly greater proportion of plaques transforming from types I or II to types III or IV and a significant decrease in intraplaque neovascularization (P\u0026thinsp;\u0026lt;\u0026thinsp;0.05), indicating the plaques in these groups had stabilized. After 12 months, the regression in plaque size was more pronounced in the Statin_P and Statin_EP groups (left: χ\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;26.37, p\u0026thinsp;=\u0026thinsp;1.90e\u0026thinsp;\u0026minus;\u0026thinsp;04, CI 95% [0.06, 1.00]; right: χ\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;19.00, p\u0026thinsp;=\u0026thinsp;4.16e\u0026thinsp;\u0026minus;\u0026thinsp;03, CI 95% [0.00, 1.00]).\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e \u003cp\u003eIntensive lipid-lowering therapies that combine statins with PCSK9 inhibitors, such as alirocumab, are more effective in regressing carotid plaques and stabilizing plaque morphology compared to other treatments. These findings support the use of PCSK9 inhibitors in combination with statin therapy for managing atherosclerotic disease and reducing cardiovascular events.\u003c/p\u003e\u003ch2\u003eTrial registration:\u003c/h2\u003e \u003cp\u003eThe trial was registered in the Chinese Clinical Trial Registry (Registration No. ChiCTR2200058389).\u003c/p\u003e","manuscriptTitle":"Effects of Different Intensive Lipid-Lowering Therapies on Stabilization and Regression of Carotid Plaque: A Randomized Open-Label Trial","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-07-18 15:53:27","doi":"10.21203/rs.3.rs-4604642/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"a02c1a8a-0781-477c-ad92-e7c473798fd3","owner":[],"postedDate":"July 18th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2024-12-20T10:08:56+00:00","versionOfRecord":[],"versionCreatedAt":"2024-07-18 15:53:27","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-4604642","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4604642","identity":"rs-4604642","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}