Clinical trial NCT06863545: Further Lipid-Lowering With PCSK9 Inhibitors for Cardiovascular Outcomes in High-Risk Coronary Plaques Assessed by CT Angiography
Official title: Further Lipid-Lowering With PCSK9 Inhibitors for Cardiovascular Outcomes in High-Risk Coronary Plaques Assessed by CT Angiography
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: NA
Conditions: Coronary Artery Disease
CT Angiography
PCSK9
Cardiovascular Events
Keywords: PCSK9 inhibitors
Lipid-lowering therapy
High-Risk Coronary Plaques
Coronary CT angiography
Lead sponsor: Second Affiliated Hospital, School of Medicine, Zhejiang University
Sponsor class: OTHER
First posted: 2025-03-07
Enrollment: 3596
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The primary objective was to evaluate the effect of PCSK9 inhibitors in addition to the background lipid-modifying therapy (LMT), compared with placebo plus background LMT in terms of clinical outcomes in patients with coronary CT angiography (CCTA)-detected high-risk plaques.

Detailed description: CCTA is an accurate, noninvasive alternative to invasive coronary angiography. CCTA can provide detailed information about the characteristics of coronary artery plaques, such as their composition, morphology, and distribution. Various CCTA-detected plaque characteristics indicative of plaque quantity and quality have been identified as high-risk features independently predicting clinical events, including the presence of positive remodeling, low attenuation plaque, spotty calcification, and napkin ring sign. Currently, the treatment for CCTA-detected high-risk plaque has been receiving increasing interest. The current study aimed to prove the efficacy of PCSK9 inhibitors in addition to the background LMT, as compared with placebo plus background LMT in patients with CCTA-detected high-risk plaques.

Hypothesis: PCSK9 inhibitors in addition to background LMT will show a superior event rate, compared with placebo plus background LMT, in terms of major adverse cardiac and cerebrovascular events (MACCEs) at 24 months after the last patient's randomization in patients with high-risk coronary plaques assessed by CT Angiography.

Eligibility criteria: Inclusion Criteria:

1. Subject must be ≥ 18 years.
2. Patients with at least one target lesion meet CCTA-detected plaque features of the following:

   1. Degree of stenosis ≥ 50%
   2. At least 2 of the following high-risk plaque features:

   i. Low-attenuation plaque ii. Positive remodeling iii. Napkin-ring sign iv. Spotty calcium
3. The target lesion is located at the proximal or mid segment of left anterior descending artery, left circumflex artery or right coronary artery.
4. Subject is able to confirm his/her understanding of the risks, benefits, and treatment alternatives of receiving study-related treatment. He/she or his/her legally authorized representative provides written informed consent prior to any study-related procedure.

Exclusion Criteria:

1. Target lesions underwent or planned to revascularization.
2. Patients with acute coronary syndrome.
3. New York Heart Association class III or IV, or last known left ventricular ejection fraction \< 30%.
4. Uncontrolled or recurrent ventricular tachycardia.
5. Homozygous familial hypercholesterolemia.
6. Active liver disease or hepatic dysfunction.
7. Failed CCTA plaque analysis.
8. Non-cardiac co-morbid conditions with life expectancy \< 2 years.
9. Pregnant and/or lactating women.
10. Known hypersensitivity or contraindication to statin or PCSK9 inhibitors.

Primary outcomes:
measure: Major adverse cardiac and cerebrovascular events (MACCEs)
timeFrame: 24 months after the last patient's randomization
Secondary outcomes:
measure: MACCEs
timeFrame: 60 months after the last patient's randomization
measure: Individual component of MACCEs.
timeFrame: 24 and 60 months after the last patient's randomization
measure: Major adverse cardiovascular events (MACEs)
timeFrame: 24 and 60 months after the last patient's randomization
measure: Target vessel failure (TVF)
timeFrame: 24 and 60 months after the last patient's randomization
measure: Cost-effectiveness analysis
timeFrame: 24 and 60 months after the last patient's randomization
measure: All-cause and cardiac death.
timeFrame: 24 and 60 months after the last patient's randomization
measure: Any target-vessel MI.
timeFrame: 24 and 60 months after the last patient's randomization
measure: Any target vessel revascularization.
timeFrame: 24 and 60 months after the last patient's randomization
measure: Any coronary revascularization (ischemia-driven or all).
timeFrame: 24 and 60 months after the last patient's randomization
measure: CT coronary angiography findings
timeFrame: 36 months after the last patient's randomization
Other outcomes:
Locations:
city: Hangzhou
country: China
facility: The Second Affiliated Hospital, School of Medicine, Zhejiang University
city: Seoul
country: Korea, Republic of
facility: Seoul National University Hospital
Study officials:
affiliation: Second Affiliated Hospital, School of Medicine, Zhejiang University
name: Xinyang Hu
role: PRINCIPAL_INVESTIGATOR
affiliation: Seoul National University Hospital
name: Bon-Kwon Koo
role: PRINCIPAL_INVESTIGATOR
References:
citation: Iatan I, Guan M, Humphries KH, Yeoh E, Mancini GBJ. Atherosclerotic Coronary Plaque Regression and Risk of Adverse Cardiovascular Events: A Systematic Review and Updated Meta-Regression Analysis. JAMA Cardiol. 2023 Oct 1;8(10):937-945. doi: 10.1001/jamacardio.2023.2731.
citation: Nicholls SJ, Puri R, Anderson T, Ballantyne CM, Cho L, Kastelein JJ, Koenig W, Somaratne R, Kassahun H, Yang J, Wasserman SM, Scott R, Ungi I, Podolec J, Ophuis AO, Cornel JH, Borgman M, Brennan DM, Nissen SE. Effect of Evolocumab on Progression of Coronary Disease in Statin-Treated Patients: The GLAGOV Randomized Clinical Trial. JAMA. 2016 Dec 13;316(22):2373-2384. doi: 10.1001/jama.2016.16951.
citation: Raber L, Ueki Y, Otsuka T, Losdat S, Haner JD, Lonborg J, Fahrni G, Iglesias JF, van Geuns RJ, Ondracek AS, Radu Juul Jensen MD, Zanchin C, Stortecky S, Spirk D, Siontis GCM, Saleh L, Matter CM, Daemen J, Mach F, Heg D, Windecker S, Engstrom T, Lang IM, Koskinas KC; PACMAN-AMI collaborators. Effect of Alirocumab Added to High-Intensity Statin Therapy on Coronary Atherosclerosis in Patients With Acute Myocardial Infarction: The PACMAN-AMI Randomized Clinical Trial. JAMA. 2022 May 10;327(18):1771-1781. doi: 10.1001/jama.2022.5218.
citation: Sabatine MS, Giugliano RP, Keech AC, Honarpour N, Wiviott SD, Murphy SA, Kuder JF, Wang H, Liu T, Wasserman SM, Sever PS, Pedersen TR; FOURIER Steering Committee and Investigators. Evolocumab and Clinical Outcomes in Patients with Cardiovascular Disease. N Engl J Med. 2017 May 4;376(18):1713-1722. doi: 10.1056/NEJMoa1615664. Epub 2017 Mar 17.
citation: Schwartz GG, Steg PG, Szarek M, Bhatt DL, Bittner VA, Diaz R, Edelberg JM, Goodman SG, Hanotin C, Harrington RA, Jukema JW, Lecorps G, Mahaffey KW, Moryusef A, Pordy R, Quintero K, Roe MT, Sasiela WJ, Tamby JF, Tricoci P, White HD, Zeiher AM; ODYSSEY OUTCOMES Committees and Investigators. Alirocumab and Cardiovascular Outcomes after Acute Coronary Syndrome. N Engl J Med. 2018 Nov 29;379(22):2097-2107. doi: 10.1056/NEJMoa1801174. Epub 2018 Nov 7.
citation: Vrints C, Andreotti F, Koskinas KC, Rossello X, Adamo M, Ainslie J, Banning AP, Budaj A, Buechel RR, Chiariello GA, Chieffo A, Christodorescu RM, Deaton C, Doenst T, Jones HW, Kunadian V, Mehilli J, Milojevic M, Piek JJ, Pugliese F, Rubboli A, Semb AG, Senior R, Ten Berg JM, Van Belle E, Van Craenenbroeck EM, Vidal-Perez R, Winther S; ESC Scientific Document Group. 2024 ESC Guidelines for the management of chronic coronary syndromes. Eur Heart J. 2024 Sep 29;45(36):3415-3537. doi: 10.1093/eurheartj/ehae177. No abstract available.
citation: Virani SS, Newby LK, Arnold SV, Bittner V, Brewer LC, Demeter SH, Dixon DL, Fearon WF, Hess B, Johnson HM, Kazi DS, Kolte D, Kumbhani DJ, LoFaso J, Mahtta D, Mark DB, Minissian M, Navar AM, Patel AR, Piano MR, Rodriguez F, Talbot AW, Taqueti VR, Thomas RJ, van Diepen S, Wiggins B, Williams MS; Peer Review Committee Members. 2023 AHA/ACC/ACCP/ASPC/NLA/PCNA Guideline for the Management of Patients With Chronic Coronary Disease: A Report of the American Heart Association/American College of Cardiology Joint Committee on Clinical Practice Guidelines. Circulation. 2023 Aug 29;148(9):e9-e119. doi: 10.1161/CIR.0000000000001168. Epub 2023 Jul 20.
citation: Yang S, Hoshino M, Yonetsu T, Zhang J, Hwang D, Shin ES, Doh JH, Nam CW, Wang J, Chen S, Tanaka N, Matsuo H, Kubo T, Chang HJ, Kakuta T, Koo BK. Outcomes of non-ischaemic coronary lesions with high-risk plaque characteristics on coronary CT angiography. EuroIntervention. 2023 Jan 23;18(12):1011-1021. doi: 10.4244/EIJ-D-22-00562.
citation: Lee JM, Choi KH, Koo BK, Park J, Kim J, Hwang D, Rhee TM, Kim HY, Jung HW, Kim KJ, Yoshiaki K, Shin ES, Doh JH, Chang HJ, Cho YK, Yoon HJ, Nam CW, Hur SH, Wang J, Chen S, Kuramitsu S, Tanaka N, Matsuo H, Akasaka T. Prognostic Implications of Plaque Characteristics and Stenosis Severity in Patients With Coronary Artery Disease. J Am Coll Cardiol. 2019 May 21;73(19):2413-2424. doi: 10.1016/j.jacc.2019.02.060.
citation: Ferencik M, Mayrhofer T, Bittner DO, Emami H, Puchner SB, Lu MT, Meyersohn NM, Ivanov AV, Adami EC, Patel MR, Mark DB, Udelson JE, Lee KL, Douglas PS, Hoffmann U. Use of High-Risk Coronary Atherosclerotic Plaque Detection for Risk Stratification of Patients With Stable Chest Pain: A Secondary Analysis of the PROMISE Randomized Clinical Trial. JAMA Cardiol. 2018 Feb 1;3(2):144-152. doi: 10.1001/jamacardio.2017.4973.
citation: Williams MC, Moss AJ, Dweck M, Adamson PD, Alam S, Hunter A, Shah ASV, Pawade T, Weir-McCall JR, Roditi G, van Beek EJR, Newby DE, Nicol ED. Coronary Artery Plaque Characteristics Associated With Adverse Outcomes in the SCOT-HEART Study. J Am Coll Cardiol. 2019 Jan 29;73(3):291-301. doi: 10.1016/j.jacc.2018.10.066.
citation: SCOT-HEART Investigators; Newby DE, Adamson PD, Berry C, Boon NA, Dweck MR, Flather M, Forbes J, Hunter A, Lewis S, MacLean S, Mills NL, Norrie J, Roditi G, Shah ASV, Timmis AD, van Beek EJR, Williams MC. Coronary CT Angiography and 5-Year Risk of Myocardial Infarction. N Engl J Med. 2018 Sep 6;379(10):924-933. doi: 10.1056/NEJMoa1805971. Epub 2018 Aug 25.
citation: Virmani R, Burke AP, Kolodgie FD, Farb A. Pathology of the thin-cap fibroatheroma: a type of vulnerable plaque. J Interv Cardiol. 2003 Jun;16(3):267-72. doi: 10.1034/j.1600-0854.2003.8042.x.
citation: Koo BK, Hu X, Kang J, Zhang J, Jiang J, Hahn JY, Nam CW, Doh JH, Lee BK, Kim W, Huang J, Jiang F, Zhou H, Chen P, Tang L, Jiang W, Chen X, He W, Ahn SG, Yoon MH, Kim U, Lee JM, Hwang D, Ki YJ, Shin ES, Kim HS, Tahk SJ, Wang J; FLAVOUR Investigators. Fractional Flow Reserve or Intravascular Ultrasonography to Guide PCI. N Engl J Med. 2022 Sep 1;387(9):779-789. doi: 10.1056/NEJMoa2201546.