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A High-Throughput Luciferase Assay to Evaluate Proteolysis of the Single-Turnover Protease PCSK9
Published on: August 28, 2018
Functional and morphological improvement of significant non-culprit coronary artery stenosis by LDL-C reduction with
Frans B Mensink1, Jonathan Los1, Rohit M Oemrawsingh2
1Department of Cardiology, Radboud University Medical Center, Nijmegen, the Netherlands.
Insights
The FITTER trial investigates if evolocumab, a PCSK9 inhibitor, improves non-culprit lesions in acute coronary syndrome patients. This study assesses its impact on hemodynamics and plaque composition, potentially reducing the need for further stenting.
Area of Science:
- Cardiology
- Interventional Cardiology
- Pharmacology
Background:
- Non-culprit coronary lesions are common in acute coronary syndrome (ACS) patients.
- Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors can reduce plaque size and alter composition in non-culprit lesions.
Purpose of the Study:
- To evaluate if intensive low-density lipoprotein cholesterol (LDL-C) reduction with evolocumab improves non-culprit vessel hemodynamics.
- To assess the effect of evolocumab on reducing plaque rupture risk and potentially obviating the need for additional stenting in non-culprit lesions.
- To investigate changes in plaque size and composition of non-culprit lesions using intravascular imaging.
Main Methods:
- The FITTER trial is a multi-center, randomized, double-blind, placebo-controlled study.
- Patients with ACS and multivessel disease undergo culprit lesion treatment, followed by fractional flow reserve (FFR) assessment of non-culprit lesions.
- Eligible patients receive evolocumab or placebo for 12 weeks alongside high-intensity statins, with follow-up imaging and FFR at 12 weeks.
Main Results:
- All patients have been included as of August 2023, and data analysis is currently ongoing.
- The study is the first to evaluate maximal LDL-C reduction by evolocumab on invasively measured FFR, plaque size, and composition in non-culprit lesions within 12 weeks post-ACS.
Conclusions:
- The study aims to determine if PCSK9 inhibition can non-invasively improve non-culprit lesions, potentially altering treatment strategies for ACS patients with multivessel disease.
- Findings will elucidate the role of intensive LDL-C lowering in managing non-culprit lesions and preventing secondary cardiovascular events.
Abstract:
Non-culprit coronary artery lesions are commonly present in patients presenting with an acute coronary syndrome (ACS). Additional stenting of non-culprit lesions in addition to the culprit lesion intends to prevent secondary events caused by these lesions. At the same time, multiple trials have demonstrated the potential of proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors in reducing plaque size and changing plaque composition of non-culprit lesions. Whether intensive low-density lipoprotein cholesterol (LDL-C) reduction with PCSK9 inhibitor evolocumab improves non-culprit vessel hemodynamics, reduces the risk of plaque rupture of important non-culprit lesions, and might obviate the need for additional stenting has not been investigated. The "Functional Improvement of non-infarcT related coronary artery stenosis by Extensive LDL-C Reduction with a PCSK9 Antibody" (FITTER) trial is a multi-center, randomized, double-blind, placebo-controlled clinical trial for patients presenting with ACS and multivessel disease (MVD). After treatment of the culprit lesion, fractional flow reserve (FFR) is performed in non-culprit vessels amenable for percutaneous coronary intervention (PCI). Coronary intervention in patients with hemodynamically important non-critical lesions (FFR: 0.67-0.85) is staged after baseline imaging using near-infrared spectroscopy (NIRS) and intravascular ultrasound (IVUS). Eligible patients are randomized and treated for 12 weeks with either evolocumab or placebo, in addition to high-intensity statin therapy. Follow-up angiography with repeat FFR and IVUS-NIRS is scheduled at 12 weeks. Staged PCI is performed at the operator's discretion.The FITTER trial is the first study to evaluate the effect of maximal LDL-C reduction by the PCSK9 inhibitor evolocumab on invasively measured FFR, plaque size, and plaque composition in hemodynamically important non-culprit lesions, during a treatment period of just 12 weeks after an ACS. Currently, all patients have been included (August 2023) and data analysis is ongoing.
Trial Registration Number:
clinicaltrials.gov NCT04141579.
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