The Impact of Pcsk-9 Inhibition on PET CFR in Patients at High CV Risk

Study Overview
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Brief Summary
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The study protocol is a single-arm, open label pilot study designed to evaluate the impact of PCSK-9 inhibition on coronary blood flow in patients with stable coronary artery disease. Patients with stable coronary artery disease will be recruited from the BWH Cardiovascular Medicine clinic and/or from the BWH Nuclear Cardiology Laboratory. A target sample size of 50 participants will undergo imaging with N-13 ammonia or Rubidium-82 positron emission tomography (PET) and coronary computed tomography angiography (CCTA) before and after 12 months of PCSK-9 inhibition with Evolocumab to assess changes in myocardial blood flow, and plaque volume. To help account for physiological changes that may occur in myocardial blood flow and inflammatory biomarkers during the study period, we will also recruit a parallel control group of stable CAD patients who will undergo similar baseline and 12-month imaging and biomarker assessment. We plan to recruit 15 patients in the parallel control group.

Detailed Description
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The investigators propose an open-label investigator-initiated trial to directly test whether PCSK-9 inhibition with Evolocumab in patients with stable CAD improves PET CFR and stress MBF. To further elucidate the possible mechanisms by which myocardial blood flow improves with PCSK-9 inhibition, the investigators will assess changes in inflammatory biomarkers. The findings of this translational study will provide a physiological read-out of the comprehensive effects of Evolocumab on tissue perfusion and microvascular function in a high-risk population. As such, these data would serve to provide a mechanistic explanation for why Evolocumab may reduce cardiovascular events beyond a reduction in plaque burden and composition. The central hypothesis of this study is that PCSK-9 inhibition will quantitatively improve myocardial blood flow as measured by positron emission tomography (PET) in patients with stable coronary artery disease. The investigators postulate that the improvement in myocardial blood flow will correlate with a reduction in inflammatory biomarkers, and not simply an improvement in coronary epicardial plaque burden.

Official Title
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The Impact of Pcsk-9 Inhibition on PET Coronary Flow Reserve in Patients at High Cardiovascular Risk (EMPOWER Study)

Conditions
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Stable Coronary Disease

Intervention / Treatment
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* Drug: Evolocumab


Participation Criteria
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Eligibility Criteria
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Intervention Group: Inclusion Criteria: Age: ≥ 50 (men) or ≥ 55 (women) Low-density lipoprotein cholesterol (LDL-C) ≥ 70 mg/dL Stable coronary artery disease (without plan to undergo revascularization before randomization) defined as one or more of the following: Abnormal nuclear perfusion imaging At least moderate ischemia involving >10% of the LV myocardium or Global coronary flow reserve (CFR) <1.8 or Stress myocardial blood flow (MBF) <1.8 Abnormal coronary angiography (invasive coronary angiography or coronary computed tomography) ≥ 50% stenosis in ≥ 2 coronary vessels or Diffuse atherosclerosis in a 3-vessel distribution Elevated coronary calcium score CAC >100 + >1 ASCVD risk factor CAC >300 If the patient is on a statin they must be on a stable dose for at least 3 months prior to enrollment. Exclusion Criteria: History of myocardial infarction or stroke CABG < 3 months prior to screening Homozygous familial hypercholesterolemia History of cardiac transplantation LV ejection fraction < 40% or New York Heart Failure Association (NYHA) class III-IV for angina and/or dyspnea. History of infiltrative or hypertrophic cardiomyopathy Severe valvular disease Uncontrolled or recurrent ventricular tachycardia Fasting triglycerides > 500 mg/dL GFR ˂ 30 mL/min/1.73 m² Current use of a PCSK-9 inhibitor Currently pregnant or breastfeeding Contraindication to receive vasodilator agent Latex allergy Parallel Control Group: Patients will be invited to participate in the parallel control group if they meet study criteria, but 1) have a latex allergy and cannot use the Evolocumab autoinjector 2) LDL-C is just below the enrollment criteria (LDL 60-69), or 3) meet study criteria but prefer to not take an injectable medication at this time.

Ages Eligible for Study
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Minimum Age: 50 Years
Maximum Age: 90 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Other
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: The study protocol is an open label pilot study with a parallel control group.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Evolocumab<br>Informed consent will be obtained from study participants willing to participate in EMPOWER. Study participants will then undergo the baseline rest/stress cardiac PET scan along with CCTA. The final PET scan and CCTA will occur at 12 months after the intervention. | Drug: Evolocumab<br>* Evolocumab is a human monoclonal antibody that inhibits proprotein convertase subtilisin-kexin type 9 (PCSK9). Evolocumab was FDA approved in 2015 for the treatment of hyperlipidemia and subsequently approved in 2017 for the prevention of stroke and heart attack. 140mg single use SureClick autoinjector that is administered subcutaneously once every 2 weeks.<br>* Other names: Repatha;|
| No Intervention: Control<br>Informed consent will be obtained from study participants willing to participate in EMPOWER. Study participants will then undergo the baseline rest/stress cardiac PET scan along with CCTA. The final PET scan and CCTA will occur at 12 months after the baseline. | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Coronary Flow Reserve | Change in global coronary flow reserve (CFR) after 12 months of therapy with Evolocumab | Change (from baseline) in global CFR, as measured by PET imaging at 52 weeks after initiation of Evolocumab therapy. | 
| Stress Myocardial Blood Flow (MBF) | Change in stress Myocardial Blood Flow (MBF) after 12 months of therapy with Evolocumab | Change (from baseline) in stress MBF, as measured by PET imaging at 52 weeks after initiation of Evolocumab therapy. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Total Perfusion Deficit (TPD) | Change in Total Perfusion Deficit (TPD) after 12 months of therapy with Evolocumab | Change (from baseline) in TPD, as measured by PET imaging at 52 weeks after initiation of Evolocumab therapy. |