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The primary objective was to evaluate the effect of PCSK9 inhibitors in addition to the background lipid-modifying therapy (LMT), compared with standard LMT in terms of clinical outcomes in patients with coronary CT angiography (CCTA)-detected high-risk plaques.
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 standard 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 standard 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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| PCSK9 inhibitors plus background lipid-modifying therapy | Experimental | Patients will receive PCSK9 inhibitors treatment and background lipid-modifying therapy for the first 12 months after randomization, and then continue background lipid-modifying therapy for the remainder of the trial. | |
| Standard lipid-modifying therapy | Active Comparator | Patients will receive standard LMT commonly used in clinical practice. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| PCSK9 inhibitors and background lipid-modifying therapy | Drug | Patients will receive subcutaneous injections of PCSK9 inhibitors and oral administration of background LMT (including statins and/or cholesterol absorption inhibitors) for the first 12 months after randomization, with PCSK9 inhibitors administered every 2 weeks. After the first 12 months, patients will discontinue the PCSK9 inhibitors but continue background LMT for the remainder of the trial. |
| Measure | Description | Time Frame |
|---|---|---|
| Major adverse cardiac and cerebrovascular events (MACCEs) | A composite of death from any cause, myocardial infarction (MI), coronary revascularization, or stroke. | 24 months after the last patient's randomization |
| Measure | Description | Time Frame |
|---|---|---|
| MACCEs | a composite of death from any cause, MI, coronary revascularization, or stroke. | 60 months after the last patient's randomization |
| Individual component of MACCEs. | Individual component of MACCEs (death from any cause, MI, coronary revascularization, or stroke) |
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Inclusion Criteria:
Subject must be ≥ 18 years.
Patients with at least one target lesion meet CCTA-detected plaque features of the following:
i. Low-attenuation plaque ii. Positive remodeling iii. Napkin-ring sign iv. Spotty calcium
The target lesion is located at the proximal or mid segment of left anterior descending artery, left circumflex artery or right coronary artery.
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:
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| Name | Role | Phone | Extension | |
|---|---|---|---|---|
| Xinyang Hu | Contact | +86 0571 87784808 | hxy0507@126.com | |
| Jian'an Wang | Contact | +86 0571 87784808 | wangjianan111@zju.edu.cn |
| Name | Affiliation | Role |
|---|---|---|
| Xinyang Hu | Second Affiliated Hospital, School of Medicine, Zhejiang University | Principal Investigator |
| Bon-Kwon Koo | Seoul National University Hospital | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Zhejiang Provincial Hospital of Traditional Chinese Medicine | Recruiting | Hangzhou | Zhejiang | China |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 37647074 | Background | 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. | |
| 27846344 | Background | 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. |
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The deidentified data will be shared after publication of first manuscript.
Data will be available within 12 months of study completion.
Data access requests will be reviewed by an external Independent Review Panel. Requestors will be required to sign a Data Access Agreement.
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| Standard lipid-modifying therapy | Drug | Patients will receive standard LMT commonly used in clinical practice. |
|
| 24 and 60 months after the last patient's randomization |
| Major adverse cardiovascular events (MACEs) | Defined as a composite of death from any cause, MI, coronary revascularization. | 24 and 60 months after the last patient's randomization |
| Target vessel failure (TVF) | Defined as a composite of cardiac death, target-vessel MI, or target vessel revascularization | 24 and 60 months after the last patient's randomization |
| Cost-effectiveness analysis | Cost-effectiveness analysis | 24 and 60 months after the last patient's randomization |
| All-cause and cardiac death. | All-cause and cardiac death. | 24 and 60 months after the last patient's randomization |
| Any target-vessel MI. | Any target-vessel MI. | 24 and 60 months after the last patient's randomization |
| Any target vessel revascularization. | Any target vessel revascularization. | 24 and 60 months after the last patient's randomization |
| Any coronary revascularization (ischemia-driven or all). | Any coronary revascularization (ischemia-driven or all). | 24 and 60 months after the last patient's randomization |
| CT coronary angiography findings | Changes in the CT-derived fractional flow reserve, lumen, plaque quantity and quality between baseline. | 36 months after the last patient's randomization |
| Hangzhou Linping First People's Hospital | Recruiting | Hangzhou | China |
|
| The Second Affiliated Hospital, School of Medicine, Zhejiang University | Recruiting | Hangzhou | China |
|
| Zhejiang Hospital | Recruiting | Hangzhou | China |
|
| Jinhua Central Hospital | Recruiting | Jinhua | China |
|
| Seoul National University Hospital | Not yet recruiting | Seoul | South Korea |
|
| 35368058 | Background | 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. |
| 28304224 | Background | 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. |
| 30403574 | Background | 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. |
| 39210710 | Background | 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. |
| 37471501 | Background | 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. |
| 36222756 | Background | 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. |
| 31097161 | Background | 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. |
| 29322167 | Background | 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. |
| 30678759 | Background | 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. |
| 30145934 | Background | 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. |
| 12800406 | Background | 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. |
| 36053504 | Background | 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. |
| ID | Term |
|---|---|
| D003324 | Coronary Artery Disease |
| ID | Term |
|---|---|
| D003327 | Coronary Disease |
| D017202 | Myocardial Ischemia |
| D006331 | Heart Diseases |
| D002318 | Cardiovascular Diseases |
| D001161 | Arteriosclerosis |
| D001157 | Arterial Occlusive Diseases |
| D014652 | Vascular Diseases |
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| ID | Term |
|---|---|
| D000091362 | PCSK9 Inhibitors |
| ID | Term |
|---|---|
| D000924 | Anticholesteremic Agents |
| D000960 | Hypolipidemic Agents |
| D000963 | Antimetabolites |
| D045504 | Molecular Mechanisms of Pharmacological Action |
| D020228 | Pharmacologic Actions |
| D020164 | Chemical Actions and Uses |
| D015842 | Serine Proteinase Inhibitors |
| D011480 | Protease Inhibitors |
| D004791 | Enzyme Inhibitors |
| D057847 | Lipid Regulating Agents |
| D045506 | Therapeutic Uses |
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