RESCUE: PCSK9 Inhibitors for Carotid Vulnerable Plaque Remodeling

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.

Study Design Overview

RESCUE is a single-center, prospective, randomized, open-label, blinded endpoint evaluation (PROBE) trial designed to test these hypotheses. A total of 120 eligible participants with carotid vulnerable plaques will be randomly assigned in a 1:1 ratio to either the experimental group (statin plus PCSK9 inhibitor) or the control group (statin monotherapy). The study employs a PROBE design to balance operational feasibility with objectivity in endpoint assessment: while treatment allocation is open-label, all HR-MRI analyses and clinical endpoint adjudications will be performed by independent, blinded readers.

Key Methodological Considerations

HR-MRI Protocol and Analysis: A standardized multi-sequence HR-MRI protocol (including T1-weighted, T2-weighted, and contrast-enhanced sequences) will be applied at baseline, 6, 12, and 24 months. Quantitative measurements of plaque components will follow predefined, reproducible criteria. Image analysis will be conducted by two experienced radiologists blinded to treatment allocation and clinical data, with inter-reader reliability assessed.

Temporal Profiling: Serial imaging at 5 time points (baseline, 3, 6, 12, and 24 months) allows for the characterization of the temporal sequence of plaque compositional changes and their correlation with serial LDL-C levels, enabling the exploration of a dose-response relationship between lipid lowering and plaque remodeling.

Early Prediction: By leveraging machine learning or multivariate statistical approaches on early-phase HR-MRI data, the study aims to identify imaging signatures that predict long-term plaque stabilization, addressing a critical unmet need in personalized management of carotid atherosclerosis.

Significance

RESCUE will provide high-level evidence on the efficacy of PCSK9 inhibitors in reshaping carotid vulnerable plaques and establish an HR-MRI-based framework for early prediction of treatment response. The findings are expected to inform future clinical guidelines and support the development of imaging-guided therapeutic strategies for stroke prevention.

Inclusion criteria

• . 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.

Exclusion criteria

• 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.