Coronary Sinus Reducer Implantation in Patients With Ischaemia and Non-obstructed Coronary Arteries and Coronary Microvascular Dysfunction.

Study Overview
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Brief Summary
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To demonstrate the feasibility and efficacy of the CS Reducer for the treatment of patients with ischaemia and non-obstructed coronary arteries (INOCA) and coronary microvascular dysfunction (CMD) and through a nested mechanistic substudy investigate the physiological responses in the coronary microcirculation responsible for changes in myocardial perfusion.

Detailed Description
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Symptomatic angina in patients with ischaemia and non-obstructed coronary arteries (INOCA) is common and associated with increased morbidity and adverse outcomes. Myocardial ischaemia often arises from coronary microvascular dysfunction (CMD). Current treatments are limited, and novel evidence-based therapies are needed to address this large unmet clinical need. The Coronary Sinus Reducer (CS Reducer) is a new treatment for refractory angina, which creates a focal narrowing in the coronary sinus that increases back pressure and redistributes blood into ischaemic myocardium at the level of the microcirculation. However the precise mechanism remains unknown. This study will be a randomised double-blinded sham-controlled pilot study (REMEDY-PILOT) to confirm acceptability of CS Reducer implantation, demonstrate feasibility to recruit and quantify its effect on myocardial perfusion. A nested mechanistic substudy within REMEDY-PILOT will test the hypothesis that CS Reducer implantation alters measures of invasive coronary microcirculatory physiology as the mechanistic basis for observed changes in quantitative CMR stress perfusion, symptoms and quality of life.

Official Title
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REducing Microvascular Dysfunction in Patients With Angina, Ischaemia and unobstructED coronarY Arteries - a PILOT Study

Conditions
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Refractory Angina, Microvascular Angina, Microvascular Coronary Artery Disease, Coronary Disease, Angina Pectoris

Intervention / Treatment
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* Device: Coronary sinus reducer
* Other: Sham-procedure
* Diagnostic Test: Invasive coronary physiology


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age >18 years Ongoing symptomatic angina, CCS Class II-IV, for ≥3 months despite background treatment with at least two anti-anginal drug at the maximal tolerated dose. Patients willing to consider no change in anti-anginal drug treatment for the duration of their participation in the trial. Unobstructed coronary arteries with ≤30% epicardial stenoses demonstrated on coronary angiography. Circumferential subendocardial stress-induced hypoperfusion on CMR (global MPR < 2.5). Willingness to comply with the specified follow-up evaluation and to be contactable during the period of the trial. Understands the nature of the trial procedures and provides written informed consent. Exclusion Criteria: Epicardial CAD (stenoses > 30%), previous percutaneous coronary intervention (PCI), coronary artery bypass grafting, or myocardial infarction (MI). Abnormal coronary sinus anatomy (tortuosity, aberrant branch, persistent left superior vena cava) Coronary sinus diameter at site of implant <9.5mm or >13mm Mean right atrial pressure <15mmHg at time of implantation Any structural heart disease including left ventricular hypertrophy; cardiomyopathy; severe valvular heart disease; previous valve replacement; myocardial bridge on angiography; LVEF<45% by CMR. Clinically or angiographically diagnosed coronary vasospasm Previous hospitalisation for decompensated heart failure Pacemaker or defibrillator electrode in the right atrium, right ventricle or coronary sinus Documented arrhythmia requiring planned implantation of a permanent pacemaker or defibrillator Chronic kidney disease (creatinine >200 μmol/L; established on renal replacement therapy; functioning renal transplant) Haemoglobin <80g/L Contraindications to receiving dual anti-platelet therapy Severe chronic obstructive pulmonary disease (FEV1 <55% predicted) Moribund patients with life expectancy < 1year Known allergy to nickel or steel Current enrolment in another investigational device or drug trial Contraindications to CMR or receiving intravenous adenosine Pregnancy

Ages Eligible for Study
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Minimum Age: 18 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: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Randomised, double-blinded, sham-controlled pilot study with parallel arms of participants randomised to CS Reducer or sham procedure
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: CS Reducer implantation<br> | Device: Coronary sinus reducer<br>* The Neovasc coronary sinus reducer is an hourglass-shaped stainless steel device inserted percutaneously into the coronary sinus and currently indicated for the treatment of refractory angina.<br>Diagnostic Test: Invasive coronary physiology<br>* Invasive coronary physiology assessment as part of REMEDY-MECH mechanistic substudy<br>|
| Sham Comparator: Sham procedure<br> | Other: Sham-procedure<br>* Implantation procedure with no device implanted<br>Diagnostic Test: Invasive coronary physiology<br>* Invasive coronary physiology assessment as part of REMEDY-MECH mechanistic substudy<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| number of patients consenting to participate in the study. | Consent rate | 6 months | 
| Premature withdrawal rate including reasons for withdrawal | Registry of patients either failing screening or unwilling to consent to full trial | 6 months | 
| Change in myocardial perfusion | Change at 6 months post randomisation, compared to baseline, in quantitative myocardial perfusion (global myocardial perfusion reserve [MPR]) assessed by cardiac MRI. | 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Canadian Cardiovascular Society (CCS) Angina Score | Change in CCS class from baseline to 6 months post-randomisation. The CCS grading system for angina is a clinical tool used by doctors to assess the degree of severity of a patient's angina. Possible scores range from Class 0 (asymptomatic angina) to Class IV (angina at rest). | 6 months | 
| Seattle Angina Questionnaire (SAQ) score | Change in SAQ score from baseline to 6 months. The Seattle Angina Questionnaire (SAQ) is a disease-specific questionnaire used to quantify patients' symptoms of angina and the extent to which their angina affects their functioning and quality of life. Possible scores range from 0 (daily angina) to 100 (no angina). Lower scores indicate worse angina symptoms. | 6 months | 
| Short-form 36 (SF-36) | Change in SF-36 scores from baseline to 6 months. Validated questionnaire to assess quality of life. 36 items each scored from 0-100 with higher scores indicating a more favourable health state. | 6 months | 
| Hospital Anxiety and Depression Scale (HADS) | Change in HADS score from baseline to 6 months. Scores range from 0 to 21. Normal results are indicated by lower scores. Validated questionnaire to assess psychological wellbeing. | 6 months | 
| 6-minute walk test (6MWT) | Change in exercise capacity from baseline to 6 months. Distance in metres walked in 6 minutes. | 6 months | 
| BORG scale of perceived exertion | Change in BORG scale from baseline to 6 months. Scores range from 0 to 20 (BORG scale) or 0 to 10 (Modified BORG scale). The higher the self-reported score, the greater perceived exertion. | 6 months | 
| Safety events - rate of major adverse events | The rate of occurrence of a composite of death, myocardial infarction (MI), pericardial effusion requiring surgical or percutaneous intervention, device embolisation, or BARC 3 or 5 bleeding evaluation in the CS Reducer arm compared to the sham-procedure arm. | 6 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Angina pectoris, Refractory angina, Microvascular angina, Coronary microvascular dysfunction, Coronary sinus reducer, Chest pain, Coronary disease, Myocardial ischaemia