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

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

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.

Study Overview

• Status: Recruiting
• Conditions: Coronary Disease; Angina Pectoris; Refractory Angina; Microvascular Angina; Microvascular Coronary Artery Disease
• Intervention / Treatment: Device: Coronary sinus reducer; Diagnostic test: Invasive coronary physiology; Other: Sham-procedure

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Estimated): 54
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Ranil de Silva, FRCP, PhD; Phone Number: +44 2073518626; Email: r.desilva@imperial.ac.uk
• Study Contact Backup: Name: Kevin Cheng, BM BCh, MRCP; Phone Number: +44 2073518626; Email: kevin.cheng@imperial.ac.uk

Study Locations

• United Kingdom
  • London, United Kingdom, SW36NP
    • Recruiting
    • National Heart and Lung Institute (Brompton Campus), Imperial College London
    • Contact: Ranil de Silva, FRCP, PhD; Email: r.desilva@imperial.ac.uk
    • Contact: Kevin Cheng, BM BCh, MRCP; Email: kevin.cheng@imperial.ac.uk

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Age >18 years
2. 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.
3. Patients willing to consider no change in anti-anginal drug treatment for the duration of their participation in the trial.
4. Unobstructed coronary arteries with ≤30% epicardial stenoses demonstrated on coronary angiography.
5. Circumferential subendocardial stress-induced hypoperfusion on CMR (global MPR < 2.5).
6. Willingness to comply with the specified follow-up evaluation and to be contactable during the period of the trial.
7. Understands the nature of the trial procedures and provides written informed consent.

Exclusion Criteria:

1. Epicardial CAD (stenoses > 30%), previous percutaneous coronary intervention (PCI), coronary artery bypass grafting, or myocardial infarction (MI).
2. Abnormal coronary sinus anatomy (tortuosity, aberrant branch, persistent left superior vena cava)
3. Coronary sinus diameter at site of implant <9.5mm or >13mm
4. Mean right atrial pressure <15mmHg at time of implantation
5. Any structural heart disease including left ventricular hypertrophy; cardiomyopathy; severe valvular heart disease; previous valve replacement; myocardial bridge on angiography; LVEF<45% by CMR.
6. Clinically or angiographically diagnosed coronary vasospasm
7. Previous hospitalisation for decompensated heart failure
8. Pacemaker or defibrillator electrode in the right atrium, right ventricle or coronary sinus
9. Documented arrhythmia requiring planned implantation of a permanent pacemaker or defibrillator
10. Chronic kidney disease (creatinine >200 μmol/L; established on renal replacement therapy; functioning renal transplant)
11. Haemoglobin <80g/L
12. Contraindications to receiving dual anti-platelet therapy
13. Severe chronic obstructive pulmonary disease (FEV1 <55% predicted)
14. Moribund patients with life expectancy < 1year
15. Known allergy to nickel or steel
16. Current enrolment in another investigational device or drug trial
17. Contraindications to CMR or receiving intravenous adenosine
18. Pregnancy

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: CS Reducer implantation	Device: Coronary sinus reducer; 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.; Diagnostic test: Invasive coronary physiology; Invasive coronary physiology assessment as part of REMEDY-MECH mechanistic substudy
Sham Comparator: Sham procedure	Diagnostic test: Invasive coronary physiology; Invasive coronary physiology assessment as part of REMEDY-MECH mechanistic substudy; Other: Sham-procedure; Implantation procedure with no device implanted

What is the study measuring?

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

Other Outcome Measures

Outcome Measure	Time Frame
Change in absolute global myocardial perfusion (ml/min/g) at rest and during adenosine stress (transmural, endocardial, epicardial) from baseline to 6 months post-randomisation	6 months
Change in absolute myocardial perfusion (ml/min/g) at rest and during adenosine stress (transmural, endocardial, epicardial) from baseline to 6 months post-randomisation in the distribution territory of the left coronary circulation.	6 months
Change in global endocardial:epicardial perfusion ratio at rest and after adenosine stress from baseline to 6 months post-randomisation	6 months
Change in endocardial:epicardial perfusion ratio at rest and after adenosine stress from baseline to 6 months post-randomisation in the distribution territory of the left coronary circulation.	6 months

Collaborators and Investigators

• Sponsor: Imperial College London
• Collaborators: Guy's and St Thomas' NHS Foundation Trust; Liverpool University Hospitals NHS Foundation Trust; Royal Brompton & Harefield NHS Foundation Trust; East and North Hertfordshire NHS Trust; Oxford University Hospitals NHS Trust; Imperial College Healthcare NHS Trust; St George's University Hospitals NHS Foundation Trust; London North West Healthcare NHS Trust; Epsom and St Helier University Hospitals NHS Trust; Bradford Teaching Hospitals NHS Foundation Trust; Kingston Hospital NHS Trust
• Investigators: Principal Investigator: Ranil E de Silva, FRCP, PhD, Imperial College London

Study record dates

Study Major Dates

• Study Start (Actual): April 17, 2023
• Primary Completion (Estimated): April 6, 2025
• Study Completion (Estimated): August 7, 2025

Study Registration Dates

• First Submitted: August 4, 2022
• First Submitted That Met QC Criteria: August 5, 2022
• First Posted (Actual): August 8, 2022

Study Record Updates

• Last Update Posted (Actual): July 20, 2023
• Last Update Submitted That Met QC Criteria: July 18, 2023
• Last Verified: July 1, 2023

More Information

Terms related to this study

• Keywords: Chest pain; Angina pectoris; Myocardial ischaemia; Coronary disease; Refractory angina; Microvascular angina; Coronary microvascular dysfunction; Coronary sinus reducer
• Additional Relevant MeSH Terms: Pathologic Processes; Myocardial Ischemia; Heart Diseases; Cardiovascular Diseases; Vascular Diseases; Arteriosclerosis; Arterial Occlusive Diseases; Pain; Neurologic Manifestations; Chest Pain; Coronary Artery Disease; Coronary Disease; Ischemia; Angina Pectoris; Microvascular Angina
• Other Study ID Numbers: 21IC7301

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No