MICROPROTECT: Impact of PCSK9 Inhibitors on Coronary Microvascular Dysfunction in Patients With Atherosclerotic Cardiovascular Disease Proved by Myocardial Ischemia and Needing Coronarography

Sponsor

University Hospital, Grenoble (Other)

Overall Status

Recruiting

CT.gov ID

NCT04338165

Collaborator

(none)

Enrollment

Location

Arms

21.7

Anticipated Duration (Months)

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

Proprotein convertase subtilisin/kexin type 9 inhibitor monoclonal antibodies (anti-PCSK9) significantly reduce the serum LDL-C level, leading to a regression of the coronary epicardial plaque demonstrated by intracoronary ultrasonography (IVUS), as well as cardiovascular events (CV) in patients with atherosclerotic CV disease treated with statin. The impact of PCSK9 inhibition on coronary microcirculation has never been assessed. However, microvascular coronary dysfunction (CMVD) is a powerful prognostic marker, irrespective of conventional CV risk factors, but also of the severity of the epicardial coronary involvement detected during coronary angiography. The investigators hypothesized that anti-PCSK9 would decrease CMVD, measured by the microcirculatory resistance index (MRI) during coronary angioplasty (Percutaneous coronary intervention, PCI) in patients with myocardial ischemia proved in myocardial scintigraphy.

Condition or Disease	Intervention/Treatment	Phase
Atherosclerotic Cardiovascular Disease	Drug: Evolocumab 140 MG/ML [Repatha]	Phase 2

Study Design

Study Type:

Interventional

Anticipated Enrollment :

66 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

Effect of Impact of PCSK9 Inhibitors on Coronary Microvascular Dysfunction in Patients With Atherosclerotic Cardiovascular Disease Proved by Myocardial Ischemia and Needing Coronarography : a Monocentric, Prospective, Randomized and Open-label Phase II Trial

Actual Study Start Date :

Jan 8, 2021

Anticipated Primary Completion Date :

Nov 1, 2022

Anticipated Study Completion Date :

Nov 1, 2022

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Evolocumab, 420 milligrams Single injection of 420 milligrams of evolocumab (REPATHA®) one month before coronary angiography and coronary microcirculation (IMR) measurement.	Drug: Evolocumab 140 MG/ML [Repatha] 3 injections of evolocumab 140 milligrams performed within 30 minutes and self-administered (subcutaneously in the abdomen, thigh, or upper arm)
No Intervention: Control arm Measurement of coronary microcirculation (IMR) during coronary angiography, without prior evolocumab injection.

Arm

Intervention/Treatment

Experimental: Evolocumab, 420 milligrams

Single injection of 420 milligrams of evolocumab (REPATHA®) one month before coronary angiography and coronary microcirculation (IMR) measurement.

Drug: Evolocumab 140 MG/ML [Repatha]

3 injections of evolocumab 140 milligrams performed within 30 minutes and self-administered (subcutaneously in the abdomen, thigh, or upper arm)

No Intervention: Control arm

Measurement of coronary microcirculation (IMR) during coronary angiography, without prior evolocumab injection.

Outcome Measures

Primary Outcome Measures

Impact of a PCSK9 inhibitor treatment on coronary microvascular dysfunction (CMVD) at 4 weeks in patients with atherosclerotic cardiovascular disease. [4 weeks]
Index of microcirculatory resistance (IMR), measured during invasive coronary angiography and expressed in mmHg.s

Secondary Outcome Measures

Impact of a PCSK9 inhibitor treatment on soluble VE-cadherin rate (sVE). [4 weeks]
Measurement of sVE rate at baseline and four weeks after treatment with evolocumab or without treatment.
Impact of a PCSK9 inhibitor treatment on brachial hyperemia (HB). [4 weeks]
Variation of the luminal diameter of the humeral artery with baseline and four weeks after treatment with evolocumab or without treatment.
Impact of a PCSK9 inhibitor treatment on the rate of peri-procedural myocardial infarction. [4 weeks]
Troponin I level after PCI (peri-procedural myocardial pain will be defined as a post-angioplasty troponin level 10 times higher than the 99th percentile of troponin I).
Correlations between invasive and non-invasive (myocardial scintigraphy - myocardial perfusion entropy (MPE), concentration of sVE, HB) measurements of coronary microvascular dysfunction. [4 weeks]
IMR, MPE, sVE and the variation of the luminal diameter of the humeral artery.
Correlations between the cardiovascular risk and the concentration of sVE and MPE. [4 weeks]
Risk score, sVE rate and MPE.

Eligibility Criteria

Criteria

Ages Eligible for Study:

40 Years to 85 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Male or female patient, aged 40 to 85,
More than 50 kilograms
Defined at high cardiovascular risk according to European guidelines
LDL-C level ≥ 0.7 g / L (biological assessment of less than 6 months)
Having benefited from myocardial scintigraphy
For which coronarography is indicated according to European guidelines
Affiliated with social security,
Signed informed consent form

Exclusion Criteria:

Clinical presentation of unstable angina
Patient whose state of physical or psychological health could compromise the obtaining of his informed consent and his compliance with the requirements of the protocol, with the study evaluation, procedures or completion.
End stage disease (estimated survival of less than one year)
Severe renal dysfunction, defined as an estimated creatinine clearance (MDRD) < 30 mL/min at screening
Contra-indication to adenosin : hypersensitivity to active active substance or to any of the excipients, type II or III atrioventricular block or atrial disease (except for pacemaker users), long QT syndrome, severe arterial hypotension, acute heart failure, asthma and severe chronic obstructive pulmonary disease, unstable angina unstabilized by drug therapy, taking dipyridamole, aminophylline, theophylline or other xanthine base within 24 hours prior to adenosine administration
Contra-indication to heparin: hypersensitivity to active substance or to any of the excipients, past heparin induced thrombopenia type II, haemorrhage.
Prior Coronary Artery Bypass Graft Surgery (CABG)
Prior myocardial infarction in the territory of ischemia
New York Heart Association (NYHA) class III or IV, or last known left ventricular ejection fraction < 30%
Known hemorrhagic stroke at any time
Uncontrolled or recurrent ventricular tachycardia
Uncontrolled hypertension defined as sitting systolic blood pressure (SBP) > 180 mmHg or diastolic BP (DBP) > 110 mmHg
Actual use of PCSK9 inhibitor (evolocumab or others)
Untreated or inadequately treated hyperthyroidism or hypothyroidism, controlled by biological assessment if needed, defined by thyroid stimulating hormone (TSH) < lower limit of normal (LLN) or > 1.5 times the upper limit of normal (ULN), respectively, and free thyroxine (T4) levels that are outside normal range at screening
Active liver disease or hepatic dysfunction, defined as aspartate aminotransferase (AST) or alanine aminotransferase (ALT) > 3 times the ULN at screening
Recipient of any major organ transplant (eg, lung, liver, heart, bone marrow, renal)
Personal or family history of hereditary muscular disorders
LDL apheresis within 12 months prior to randomization
Creatinine Phosphokinase (CPK) > 5 ULN at screening
Active infection or others active disease judge by investigator incompatible with the protocol completion
Main known active infection including positive viral serology (Human Immunodeficiency Virus, Hepatitis B Virus and Hepatitis C Virus)
Malignancy (except non-melanoma skin cancers, cervical in-situ carcinoma, breast ductal carcinoma in situ, or stage 1 prostate carcinoma) within the last 10 years
Known sensitivity to evolocumab or their excipients to be administered during dosing or natural rubber / latex
Patient likely to not be available to complete all protocol-required study visits or procedures.
Patient in exclusion period of another study
Woman able to procreate in the absence of highly effective contraception
Persons referred to in Articles L1121-6 to L1121-8 of the French code of public health (this corresponds to all persons protected: pregnant or parturient women, breastfeeding mothers, persons deprived of liberty by judicial or administrative decision, persons subject to a legal protection measure).