Further Lipid-Lowering With PCSK9 Inhibitors for Cardiovascular Outcomes in High-Risk Coronary Plaques Assessed by CT Angiography

Overview

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.

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 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.

Interventions

• Drug PCSK9 inhibitors and background lipid-modifying therapy
  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.
• Drug Standard lipid-modifying therapy
  Patients will receive standard LMT commonly used in clinical practice.

Primary outcome measures

• Major adverse cardiac and cerebrovascular events (MACCEs) [Time frame: 24 months after the last patient's randomization]

Secondary outcome measures (10)

• MACCEs [Time frame: 60 months after the last patient's randomization]
• Individual component of MACCEs. [Time frame: 24 and 60 months after the last patient's randomization]
• Major adverse cardiovascular events (MACEs) [Time frame: 24 and 60 months after the last patient's randomization]
• Target vessel failure (TVF) [Time frame: 24 and 60 months after the last patient's randomization]
• Cost-effectiveness analysis [Time frame: 24 and 60 months after the last patient's randomization]
• All-cause and cardiac death. [Time frame: 24 and 60 months after the last patient's randomization]
• Any target-vessel MI. [Time frame: 24 and 60 months after the last patient's randomization]
• Any target vessel revascularization. [Time frame: 24 and 60 months after the last patient's randomization]
• Any coronary revascularization (ischemia-driven or all). [Time frame: 24 and 60 months after the last patient's randomization]
• CT coronary angiography findings [Time frame: 36 months after the last patient's randomization]

Eligibility criteria

Inclusion criteria

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

• Degree of stenosis ≥ 50% or plaque burden ≥ 70%
• At least 2 of the following high-risk plaque features:

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

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

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Single blind

Primary purpose

Treatment

Study locations

China · 5 centers

• Zhejiang Provincial Hospital of Traditional Chinese Medicine — Hangzhou
• Hangzhou Linping First People's Hospital — Hangzhou
• The Second Affiliated Hospital, School of Medicine, Zhejiang University — Hangzhou
• Zhejiang Hospital — Hangzhou
• Jinhua Central Hospital — Jinhua

South Korea · 1 center

• Seoul National University Hospital — Seoul

Publications

• 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. PMID 37647074
• 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. PMID 27846344
• 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 Ac PMID 35368058
• 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. PMID 28304224
• 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):2097-2 PMID 30403574
• 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 mana PMID 39210710
• 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 W PMID 37471501
• 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. PMID 36222756

Identifiers

NCT: NCT06863545 · 2025-0052

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗