RESCUE: PCSK9 Inhibitors for Carotid Vulnerable Plaque Remodeling

Summary

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.

Timeline

Start

2027-01-01

Primary completion

2029-01-01

Completion

2029-12-01

Publications

• Background Kini AS, Vengrenyuk Y, Liu J, Yasumura K, Revaiah PC, Mandava A, Shah H, Sweeny JM, Khera S, Kapur V, Melarcode-Krishnamoorthy P, Hooda A, Minatoguchi S, Baruah N, Pineda DA, Chen V, Ellis E, Hahn A, Krishnan P, Baber U, Moreno PR, Mehran R, Sebra R, Boerwinkle E, Zhou X, Narula J, Sharma SK. Intracoronary Imaging and Transcriptomic Characteristics Before and After Maximum Lipid-Lowering Therapy: YELLOW-III Study of Evolocumab and Maximum Statin Therapy in Chronic Coronary Disease. JACC Cardiovasc Imaging. 2026 Apr;19(4):516-534. doi: 10.1016/j.jcmg.2025.12.013. Epub 2026 Feb 27.
• Background Huang J, Liu C, Jiao S, Chen Y, Xu L, Gong T, Zhu C, Song Y. Application of high-resolution MRI in evaluating statin efficacy on symptomatic intracranial atherosclerosis. Eur Radiol. 2025 Jan;35(1):441-452. doi: 10.1007/s00330-024-10968-1. Epub 2024 Jul 19.
• Background Di Giovanni G, Fujino M, Kataoka Y, Butters J, Hucko T, Puri R, Nissen SE, Nelson AJ, Psaltis PJ, Nicholls SJ. Impact of evolocumab on plaque phenotypic changes in patients with acute coronary syndrome and elevated lipoprotein(a) levels: a HUYGENS secondary analysis. Eur J Prev Cardiol. 2025 Apr 8:zwaf211. doi: 10.1093/eurjpc/zwaf211. Online ahead of print.
• Background Addeo L, Guarini P, Campana P, Argenziano L, Nardi S, Tedeschi C, Scatteia A, Silvestre M, Rapacciuolo A, Esposito G, Giordano S, Dalla Vecchia LA, Donatelli F. Patient with Vulnerable Coronary Plaque and Treatment with Evolocumab: A Clinical Case. J Clin Med. 2025 Feb 14;14(4):1257. doi: 10.3390/jcm14041257.
• Background Papafaklis MI, Koros R, Tsigkas G, Karanasos A, Moulias A, Davlouros P. Reversal of Atherosclerotic Plaque Growth and Vulnerability: Effects of Lipid-Modifying and Anti-Inflammatory Therapeutic Agents. Biomedicines. 2024 Oct 23;12(11):2435. doi: 10.3390/biomedicines12112435.
• Background Marfella R, Prattichizzo F, Sardu C, Paolisso P, D'Onofrio N, Scisciola L, La Grotta R, Frige C, Ferraraccio F, Panarese I, Fanelli M, Modugno P, Calafiore AM, Melchionna M, Sasso FC, Furbatto F, D'Andrea D, Siniscalchi M, Mauro C, Cesaro A, Calabro P, Santulli G, Balestrieri ML, Barbato E, Ceriello A, Paolisso G. Evidence of an anti-inflammatory effect of PCSK9 inhibitors within the human atherosclerotic plaque. Atherosclerosis. 2023 Aug;378:117180. doi: 10.1016/j.atherosclerosis.2023.06.971. Epub 2023 Jun 29.
• Background Cui E, Kersche G, Grubic N, Hetu MF, Pang SC, Sillesen H, Johri AM. Effect of pharmacologic anti-atherosclerotic therapy on carotid intraplaque neovascularization: A systematic review. J Clin Lipidol. 2023 May-Jun;17(3):315-326. doi: 10.1016/j.jacl.2023.04.009. Epub 2023 Apr 26.
• Background Ota H, Omori H, Kawasaki M, Hirakawa A, Matsuo H. Clinical impact of PCSK9 inhibitor on stabilization and regression of lipid-rich coronary plaques: a near-infrared spectroscopy study. Eur Heart J Cardiovasc Imaging. 2022 Jan 24;23(2):217-228. doi: 10.1093/ehjci/jeab034.
• Background Lepor NE, Sun J, Canton G, Contreras L, Hippe DS, Isquith DA, Balu N, Kedan I, Simonini AA, Yuan C, Hatsukami TS, Zhao XQ. Regression in carotid plaque lipid content and neovasculature with PCSK9 inhibition: A time course study. Atherosclerosis. 2021 Jun;327:31-38. doi: 10.1016/j.atherosclerosis.2021.05.008. Epub 2021 May 19.
• Background Porambo ME, DeMarco JK. MR imaging of vulnerable carotid plaque. Cardiovasc Diagn Ther. 2020 Aug;10(4):1019-1031. doi: 10.21037/cdt.2020.03.12.

Drugs

Indications