Remodeling Evaluation and Stabilization of Carotid Vulnerable Plaques by PCSK9 Inhibitors Using HR-MRI for Early Prediction
试验速览
- 阶段
- 4 期
- 状态
- 尚未招募
- 发起方
- 入组人数
- 120
- 主要终点
- Change in lipid-rich necrotic core (LRNC) volume
研究概览
简要总结
Carotid artery stenosis is a major cause of ischemic stroke. However, many strokes occur in patients with only mild-to-moderate stenosis. Evidence shows that it is not the degree of narrowing, but the "vulnerability" of the plaque-its internal composition-that determines rupture risk.
High-risk (vulnerable) plaques have a large lipid-rich necrotic core, a thin fibrous cap, and intraplaque hemorrhage. Statins can lower cholesterol and stabilize plaques, but some patients still experience progression or recurrent events.
PCSK9 inhibitors (such as evolocumab and alirocumab) are a new class of lipid-lowering drugs that reduce LDL cholesterol more strongly than statins alone. They may also have direct effects on the artery wall, improving plaque stability. Whether they can remodel vulnerable carotid plaques and how early this can be detected remains unclear.
This study uses high-resolution magnetic resonance imaging (HR-MRI), a non-invasive technique that visualizes plaque internal structure-including the lipid core, fibrous cap, and hemorrhage-to track changes over time.
Purpose: The RESCUE study aims to determine whether adding a PCSK9 inhibitor to standard statin therapy can remodel and stabilize vulnerable carotid plaques, and to detect these changes early using HR-MRI.
Design: This is a single-center, prospective, randomized, controlled, open-label trial with blinded endpoint evaluation (PROBE design). 120 adults with carotid vulnerable plaques will be enrolled at Beijing Tsinghua Chang Gung Hospital and randomly assigned 1:1 to: (1) Experimental group (n=60): statin PLUS PCSK9 inhibitor (subcutaneous injection); (2) Control group (n=60): statin alone. Follow-up is 24 months. HR-MRI is performed at baseline, 6, 12, and 24 months. Blood samples are collected for lipid and inflammatory markers. HR-MRI analysis is performed by blinded radiologists.
Primary Outcome: Change in lipid-rich necrotic core volume by HR-MRI at 12 and 24 months.
Secondary Outcomes: Fibrous cap thickness, intraplaque hemorrhage, remodeling index, LDL-C levels, inflammatory markers, and clinical events (stroke, TIA, cardiovascular death) over 24 months.
Status: Not yet recruiting. Planned start: January 2027. Conducted at Beijing Tsinghua Chang Gung Hospital, Beijing, China.
详细描述
Background and Rationale
Carotid atherosclerotic plaque vulnerability, rather than the degree of luminal stenosis, is the primary determinant of ischemic stroke risk. High-resolution magnetic resonance imaging (HR-MRI) has emerged as a powerful non-invasive tool capable of characterizing plaque components in vivo, including the lipid-rich necrotic core (LRNC), fibrous cap integrity, intraplaque hemorrhage (IPH), and neovascularization. These imaging biomarkers provide critical insights into plaque phenotype and natural history.
Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, as a class of potent lipid-lowering agents, have demonstrated substantial efficacy in reducing low-density lipoprotein cholesterol (LDL-C) levels and improving cardiovascular outcomes. Beyond their established lipid-lowering effects, emerging evidence suggests that PCSK9 inhibitors may exert direct pleiotropic effects on plaque stabilization, including promoting fibrous cap thickening, reducing intraplaque inflammation, and facilitating lipid regression. However, the temporal dynamics of PCSK9 inhibitor-induced plaque remodeling and their quantitative relationship with LDL-C reduction remain incompletely understood, particularly in the carotid territory.
Study Hypothesis
The RESCUE study hypothesizes that, compared with standard statin monotherapy, the addition of a PCSK9 inhibitor to statin therapy will result in more favorable remodeling of carotid vulnerable plaques, characterized by a significant reduction in LRNC volume, fibrous cap thickening, regression of neovascularization, and decreased incidence of IPH, as quantitatively assessed by HR-MRI. Furthermore, we hypothesize that specific HR-MRI-derived imaging biomarkers at early time points (e.g., 3 or 6 months) can predict long-term plaque stabilization.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Single (Outcomes Assessor)
盲法说明
This study uses a PROBE (Prospective, Randomized, Open-label, Blinded Endpoint) design. Participants and care providers are unmasked to treatment allocation. Outcome assessors (radiologists interpreting HR-MRI images) and data analysts are masked to group assignment. All HR-MRI analyses and clinical endpoint adjudications are performed by independent readers who are blinded to treatment allocation and clinical data.
入排标准
- 年龄范围
- 40 Years 至 80 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •. Carotid stenosis ≥30% detected by carotid ultrasound, not meeting criteria for surgical intervention, and confirmed presence of vulnerable plaque by HR-MRI (meeting any of the following: incomplete or thin fibrous cap <0.5 mm; lipid-rich necrotic core [LRNC] volume ≥40% of plaque volume; intraplaque hemorrhage [IPH]; or neovascularization).
- •Receiving standard statin therapy (moderate intensity or higher) for ≥3 months, with LDL-C still ≥1.8 mmol/L (70 mg/dL).
- •Willing to adhere to follow-up and provide signed informed consent.
排除标准
- •Allergy or contraindication to PCSK9 inhibitors.
- •Active liver disease, myopathy, or creatine kinase (CK) elevation >5 times the upper limit of normal.
- •History of carotid revascularization (carotid endarterectomy [CEA] or carotid artery stenting [CAS]).
- •Renal insufficiency (estimated glomerular filtration rate [eGFR] <30 ml/min).
- •MRI contraindications such as metallic implants or claustrophobia.
- •Life expectancy <3 years.
研究组 & 干预措施
Experimental: Statin + PCSK9 Inhibitor
Participants will receive standard statin therapy (either atorvastatin 20 mg or rosuvastatin 10 mg orally once daily, dose-adjusted to achieve target LDL-C) plus a PCSK9 inhibitor (either evolocumab 140 mg subcutaneously every 2 weeks or alirocumab 75 mg subcutaneously every 2 weeks, dose-adjusted per protocol). Treatment duration is 24 months. HR-MRI assessments will be performed at baseline, 3, 6, 12, and 24 months.
干预措施: Intervention 1 (Drug)
Experimental: Statin + PCSK9 Inhibitor
Participants will receive standard statin therapy (either atorvastatin 20 mg or rosuvastatin 10 mg orally once daily, dose-adjusted to achieve target LDL-C) plus a PCSK9 inhibitor (either evolocumab 140 mg subcutaneously every 2 weeks or alirocumab 75 mg subcutaneously every 2 weeks, dose-adjusted per protocol). Treatment duration is 24 months. HR-MRI assessments will be performed at baseline, 3, 6, 12, and 24 months.
干预措施: Intervention 2 (Drug)
Active Comparator: Statin Monotherapy
Participants will receive standard statin monotherapy (either atorvastatin 20 mg or rosuvastatin 10 mg orally once daily, dose-adjusted to achieve target LDL-C) without PCSK9 inhibitor. Treatment duration is 24 months. HR-MRI assessments will be performed at baseline, 3, 6, 12, and 24 months.
干预措施: Intervention 3 (Drug)
Active Comparator: Statin Monotherapy
Participants will receive standard statin monotherapy (either atorvastatin 20 mg or rosuvastatin 10 mg orally once daily, dose-adjusted to achieve target LDL-C) without PCSK9 inhibitor. Treatment duration is 24 months. HR-MRI assessments will be performed at baseline, 3, 6, 12, and 24 months.
干预措施: Intervention 4 (Drug)
结局指标
主要结局
Change in lipid-rich necrotic core (LRNC) volume
时间窗: Baseline, 6 months, and 12 months
Change from baseline in the volume of the lipid-rich necrotic core (LRNC) of the carotid plaque, measured by high-resolution magnetic resonance imaging (HR-MRI) at baseline, 6, and 12 months. LRNC volume is quantified using 3D multi-contrast HR-MRI sequences (including contrast-enhanced T1-weighted imaging) with semi-automated segmentation. The percentage change from baseline will also be reported.
Change in fibrous cap thickness
时间窗: Baseline, 6 months, and 12 months
Change from baseline in the thickness of the fibrous cap of the carotid plaque, measured by high-resolution magnetic resonance imaging (HR-MRI) at baseline, 6, and 12 months. Fibrous cap thickness is quantified at the thinnest point of the plaque using 3D multi-contrast HR-MRI sequences with semi-automated segmentation and same-plaque longitudinal co-registration. The percentage change from baseline will also be reported.
Change in intraplaque hemorrhage
时间窗: Baseline, 6 months, and 12 months
Change in intraplaque hemorrhage (volume or signal characteristics) of the carotid plaque, as measured by high-resolution magnetic resonance imaging (HR-MRI) at 6 months, and 12 months
次要结局
- Change from baseline in low-density lipoprotein cholesterol (LDL-C) levels(Baseline, 6 months, and 12 months)
- Serum concentrations of inflammatory markers (hs-CRP, IL-6) at baseline, 6, and 12 months(Baseline, 6 months, and 12 months)
- Number of participants with clinical events (ischemic stroke, transient ischemic attack [TIA], or cardiovascular death)(6 months, and 12 、24months)
研究者
Keqiang Zhao
Deputy Chief Physician, Department of Vascular Surgery, Beijing Tsinghua Chang Gung Hospital
Beijing Tsinghua Chang Gung Hospital