Functional Improvement of Coronary Artery Narrowing by Cholesterol Reduction With a PCSK9 Antibody

NCT ID: NCT04141579

Last Updated: 2024-07-18

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: NA
• Total Enrollment: 150 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2020-11-10
• Study Completion Date: 2023-11-09

Brief Summary

In a large number of patients who experienced an acute coronary syndrome, multiple narrowings of the coronary arteries are identified. Mechanical treatment of the infarct related artery is indisputable, yet mechanical treatment of other bystander lesions in non-infarct related arteries is controversial.

Low-density lipoprotein cholesterol can speed up the formation of these coronary artery narrowings, and can increase the risk of a second event.

The investigators want to investigate if treating patients with the new cholesterol-lowering drug evolocumab in addition to statin therapy ameliorates blood flow and reduces atherosclerotic plaque size compared with placebo. Improved blood flow and a reduction of plaque size could prevent the need for additional stenting or surgery.

Detailed Description

In a large number of patients presenting with acute coronary syndrome (ACS) multivessel disease is identified. Mechanical treatment of the infarct related artery (IRA) is indisputable, yet mechanical treatment of other bystander lesions in non-infarct related arteries (non-IRAs) is controversial. Some randomized studies have favored preventive complete revascularization during invasive coronary angiography (ICA) over conservative medical treatment with deferred percutaneous intervention (PCI). Yet patient selection and medical treatment in the conservative medical treatment groups were suboptimal.

Revascularization of lesions in the non-IRA can be guided by fractional flow reserve (FFR). In current practice, a value of 0.80 or lower is often used to mark a functionally significant stenosis at a stabilized moment after initial hyperemic response. However, recent evidence suggests that hyperemic response to adenosine is impaired in patients with ACS, which could underestimate how flow-limiting a non-culprit lesion is as measured by FFR. A large patient-level meta-analysis of multiple FFR trials showed that FFR values below 0.67 most evidently identify those at risk of MI or death. Thus, in patients with values above 0.67, mechanical revascularization has less apparent benefit as compared to patients with values below 0.67. The threshold of 0.67 could be a lower safety margin applied for non-IRA lesions, with percutaneous intervention (PCI) as treatment. For values between 0.67 and 0.85, medical treatment could be optimized using the latest generation LDL-C lowering agents on top of current high-intensity statin therapy (HIST) before directly stenting the lesion.

Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors have shown to induce regression of coronary atherosclerotic plaque volume (PV) in patients with coronary artery disease (CAD). As high-risk lesions with large plaque burden (PB) and lipid content are frequently present in ACS, a rapid response on PB and PV can be expected when starting PCSK9-inhibitors on top of HIST. In addition to plaque size, plaque morphology is important in determining residual risk. Lipid-rich plaques have recently again shown to increase the risk of major adverse cardiac events. Lipid rich plaque can be identified using Near-InfraRed Spectroscopy (NIRS). The amount of lipid is represented in the lipid core burden index (LCBI) and is an independent risk factor for future coronary events. A recent study demonstrated the effect on plaque composition in 52 weeks. In this study, an effect in 12 weeks will be evaluated as a potential independent explanation of reduced events in long-term clinical follow-up studies.The change in plaque volume might be closely related to a change in FFR.

Furthermore, it is now well-appreciated that an ACS, a result of atherosclerotic plaque destabilization, initiates a temporary acceleration of atherogenesis in itself. An ACS induces rapid activation of the bone marrow hematopoietic stem- and progenitor cells resulting in monocytosis and activation of innate immune cells, which subsequently accelerate atherosclerosis progression throughout the body. Hypercholesterolemia also activates the innate immune system bone marrow progenitors resulting in long-term activation of the innate immune system. In patients with familial hypercholesterolemia (FH), PCSK9 treatment reduced monocyte CCR2 expression and ex-vivo migratory capacity. Therefore, in the first weeks after an ACS occurred, there is an optimal time window for preventing atherosclerosis progression by powerful lowering of plasma cholesterol.

This pharmaco-invasive strategy with a combination of HIST and a PCSK9-inhibitor could possibly prevent mechanical revascularization (PCI or CABG) in a large cohort of patients. Evolocumab was the first PCSK9-inhibitor approved for clinical use in 2015 for lowering of LDL-C as an adjunct to diet in patients with FH, primary hypercholesterolemia and in patients with homozygous familial hypercholesterolemia (HoFH). Evolocumab has been evaluated in several large scale studies as GLAGOV (N = 968) and FOURIER (N= 27564) on surrogate and clinical endpoints with important benefits and established safety and tolerability.

In this study we want to investigate the effect of maximal LDL-C reduction by evolocumab in addition to HIST compared to placebo on functional impairment of non-IRA lesions, measured by FFR, and the change in NIRS derived lipid core burden index at the 4mm maximal segment (MaxLCBI4mm) from baseline to follow-up in the non-IRA. Secondly, we want to evaluate the change in multiple plaque characteristics, measured by intravascular ultrasound (IVUS). Finally, we will investigate the change in microvascular function, change in pro-inflammatory monocyte phenotype and explore correlations between on treatment LDL-C, LCBI, plaque characteristics and FFR.

Conditions

Coronary Artery Disease; Atherosclerosis of Coronary Artery

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: TRIPLE

Study Groups

Treatment arm

Evolocumab (140mg) will be administered subcutaneously every two weeks (Q2W) on day 1 through week 12 with personal injectors, containing 1 mL deliverable volume of 140 mg/mL Evolocumab.

Group Type: EXPERIMENTAL

Evolocumab 140 MG/ML [Repatha]

Intervention Type: DRUG

Evolocumab (also known as Repatha, formerly referred to as AMG 145) is a human monoclonal immunoglobulin G2 (IgG2) that specifically binds to proprotein convertase subtilisin/kexin type 9 (PCSK9) preventing its interaction with the low-density lipoprotein receptor (LDLR). The inhibition of PCSK9 by evolocumab leads to increased LDLR expression and subsequent decreased circulating concentrations of low-density lipoprotein cholesterol (LDL-C).

Comparator arm

Placebo will be administered subcutaneously every two weeks (Q2W) on day 1 through week 12 with personal injectors, containing 1 mL deliverable volume of placebo.

Group Type: PLACEBO_COMPARATOR

Placebo

Intervention Type: DRUG

Matching placebo

Interventions

Evolocumab 140 MG/ML [Repatha]

Evolocumab (also known as Repatha, formerly referred to as AMG 145) is a human monoclonal immunoglobulin G2 (IgG2) that specifically binds to proprotein convertase subtilisin/kexin type 9 (PCSK9) preventing its interaction with the low-density lipoprotein receptor (LDLR). The inhibition of PCSK9 by evolocumab leads to increased LDLR expression and subsequent decreased circulating concentrations of low-density lipoprotein cholesterol (LDL-C).

Intervention Type: DRUG

Placebo

Matching placebo

Intervention Type: DRUG

Other Intervention Names

AMG145; Repatha; Placebo injection

Eligibility Criteria

Inclusion Criteria

• ACS with PCI of infarct related artery
• MVD
• FFR of non-IRA lesion 0.67 - 0.85
• 18 years old at screening

Exclusion Criteria

Refusal or inability to provide informed consent

• Prior coronary artery bypass graft
• Known left ventricular ejection fraction (LVEF) < 30%
• Untreated functional left main stem stenosis (FFR ≤ 0.80)
• Contra-indication for antithrombotic therapy according to ESC guidelines
• Non-IRA stenosis not amenable for PCI treatment (operator's decision)
• Complicated IRA treatment, with one or more of the following:
• Extravasation
• Permanent no re-flow after IRA treatment (TIMI flow 0-1)
• Inability to implant a stent
• Known severe cardiac valve dysfunction that will require surgery in the follow-up period.
• Severe kidney disease defined as an eGFR < 30 ml/min.
• Known severe liver disease defined as Child-Pugh score of 10-15.
• Female subject is pregnant, breastfeeding or planning to become pregnant or planning to breastfeed during treatment and for an additional 15 weeks after the last dose of investigational product. Females of childbearing potential should only be included in the study after a confirmed menstrual period and a negative highly sensitive serum pregnancy test.
• Female subjects of childbearing potential unwilling to use 1 acceptable method of effective contraception during treatment and for an additional 15 weeks after the last dose of investigational product.
• Female subject who has not used an acceptable method(s) of birth control for at least 1 month prior to screening, unless the female subject is sterilized or postmenopausal.

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Amgen

INDUSTRY

Sponsor Role: collaborator

Radboud University Medical Center

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Robert Jan van Geuns, MD, PhD

Role: PRINCIPAL_INVESTIGATOR

robertjan.vangeuns@radboudumc.nl

Locations

Radboud University Medical Center

Nijmegen, Gelderland, Netherlands

Countries

Netherlands

References

Mensink FB, Los J, Reda Morsy MM, Oemrawsingh RM, von Birgelen C, Ijsselmuiden AJJ, Meuwissen M, Cheng JM, van Wijk DF, Smits PC, Paradies V, van Wijk DJ, Rai H, Ten Cate TJF, Camaro C, Damman P, van Nunen LX, Dimitriu-Leen AC, van Wely MH, Cetinyurek-Yavuz A, Byrne RA, van Royen N, van Geuns RM. Changes in non-culprit coronary lesions with PCSK9 inhibitors: the randomised, placebo-controlled FITTER trial. EuroIntervention. 2025 Aug 18;21(16):910-920. doi: 10.4244/EIJ-D-24-01065.

Reference Type: DERIVED

PMID: 40828313 (View on PubMed)

Mensink FB, Los J, Oemrawsingh RM, von Birgelen C, Ijsselmuiden A, Meuwissen M, Cheng JM, van Wijk DF, Smits PC, Paradies V, van der Heijden DJ, Rai H, Ten Cate TJ, Camaro C, Damman P, van Nunen LX, Dimitriu-Leen AC, van Wely MH, Cetinyurek-Yavuz A, Byrne RA, van Royen N, van Geuns RM. Functional and morphological improvement of significant non-culprit coronary artery stenosis by LDL-C reduction with a PCSK9 antibody: Rationale and design of the randomized FITTER trial. Heliyon. 2024 Sep 18;10(19):e38077. doi: 10.1016/j.heliyon.2024.e38077. eCollection 2024 Oct 15.

Reference Type: DERIVED

PMID: 39430462 (View on PubMed)

Other Identifiers

NL71538.091.19

Identifier Type: -

Identifier Source: org_study_id