A Phase II Study Testing the Feasibility and Efficacy of Coronary Sinus Narrowing in Patients With Coronary Microvascular Dysfunction
Phase: NA
Conditions: Coronary Microvascular Dysfunction
Sponsor: Amir Lerman

 
A PHASE II STUDY TESTING THE 
FEASABILITY AND EFFICACY OF 
CORONARY SINUS NARROWING 
IN PATIENTS WITH CORONARY 
MICROVASCULAR DYSFUNCTION 
 
NCT# 04523168 
 
September 8, 2022 

Coronary Sinus Reducer and CMD 
 
Version 4.0 9/8/2022 
 
A PHASE II STUDY TESTING THE FEASABILITY AND EFFICACY 
OF CORONARY SINUS NARROWING IN PATIENTS WITH 
CORONARY MICROVASCULAR DYSFUNCTION 
Amir Lerman, MD and Michel T. Corban, MD  
Department of Cardiovascular Disease, Mayo Clinic, Rochester MN, USA 
 
 
Sponsor-Investigator: 
Amir Lerman, M.D. 
Cardiovascular Diseases 
200 First Street SW 
Rochester, MN 55905 
 507-255-6670 
   
Study Device: 
 
Principal Investigator:  
 
Co-Principal Investigator: 
 
Co-Investigators:  
 
 
Study Coordinator: 
The Reducer (Neovasc Inc., Richmond, B.C., Canada) 
 
Amir Lerman, MD 
 
Michel T. Corban, MD 
 
Mohamad Adnan Alkhouli, MD; Rajiv Gulati, MD, PhD; 
Abhiram Prasad, MD 
 
Diana Albers 
 
Protocol Number: (IRBe) 
20-006386  
IDE Number: 
G200153  
 
 
 
Initial version; Version (1.0):                             May 4, 2020  
Revised version; Version (1.1): 
 
     September 24, 2020  
Revised version; Version (1.2): 
 
     January 6, 2021 
Revised version; Version (1.3): 
 
     March 5, 2021 
Revised version; Version (1.4);                         August 31, 2021 
 Revised version; Version (2.0)                         October 12, 2021 
Revised version: Version (3.0)    
                  April 1,2022 
 Revised version: Version (4.0)  
 
     September 8, 2022 
 
 

Coronary Sinus Reducer and CMD 
 
Version 4.0 9/8/2022 
 
STUDY SYNOPSIS............................................................................... ERROR! BOOKMARK NOT DEFINED. 
STUDY SUMMARY/ABSTRACT ....................................................................................................................... 7 
1 
INTRODUCTION ......................................................................................................................................... 9 
2 
BACKGROUND ............................................................................................................................................ 9 
     2.1 
Coronary microvascular dysfunction: Magnitude of the problem ..................................................... 8 
     2.2 
Coronary microvascular dysfunction: Symptoms and adverse outcomes .......................................... 8 
     2.3 
Coronary microvascular dysfunction: Pathophysiology of ischemia and angina .............................. 8 
     2.4 
Coronary microvascular dysfunction: Diagnosis ............................................................................. 11 
     2.5 
Coronary microvascular dysfunction: Current limited treatment options and unmet clinical need . 13 
     2.6 
Coronary Sinus Narrowing: A potential treatment for patients with microvascular dysfunction .... 14 
3 
THE CORONARY SINUS REDUCER ..................................................................................................... 15 
4 
STUDY HYPOTHESIS ................................................................................................................................ 9 
5 
STUDY AIMS .............................................................................................................................................. 20 
5.1 
AIM I: ....................................................................................................................................................... 20     
5.2 
AIM II: ...................................................................................................................................................... 20 
5.3 
AIM III: ..................................................................................................................................................... 20 
5.4 
AIM IV: ..................................................................................................................................................... 20 
5.5 
AIM V: ...................................................................................................................................................... 20 
6 
STUDY DESIGN ......................................................................................................................................... 20 
     6.1 
GENERAL DESIGN ..................................................................................................................................... 20 
6.2 
PRIMARY STUDY ENDPOINTS ................................................................................................................... 22 
6.3 
SECONDARY STUDY ENDPOINTS............................................................................................................... 22 
7 
STUDY POPULATION .............................................................................................................................. 22 
     7.1 
INCLUSION CRITERIA ................................................................................................................................ 23 
7.2 
EXCLUSION CRITERIA ............................................................................................................................... 23 
7.3 
SUBJECT RECRUITMENT, ENROLLMENT AND SCREENING ......................................................................... 24 
     7.4    WHEN AND HOW TO WITHDRAW SUBJECTS ................................................................................ 25 
     7.5    DATA COLLECTION AND FOLLOW-UP FOR WITHDRAWN SUBJECTS .................................... 25 
8 
STUDY DEVICE, IMPLANTATION PROCEDURE, SUBJECT COMPLIANCE MONITORING 26 
8.1 
STUDY DEVICE ......................................................................................................................................... 26 
8.2 
IMPLANTATION PROCEDURE .................................................................................................................... 28 
8.3 
SUBJECT COMPLIANCE MONITORING ......................................................................................................... 29  
9 
CORONARY REACTIVITY TESTING .................................................................................................. 29 
10 
PRIOR AND CONCOMITANT THERAPY ............................................................................................ 30 
11 
STUDY PROCEDURES ............................................................................................................................. 30 
11.1 VISIT 1: SCREENING VISIT ........................................................................................................................ 30 
11.2 PRE-IMPLANT DAY 1-5 ............................................................................................................................. 31 
11.3 IMPLANT DAY 0 ........................................................................................................................................ 32 
11.4 POST-IMPLANT DAY 30 ............................................................................................................................. 32 
11.5 POST-IMPLANT DAY 60 ............................................................................................................................. 33 
11.6 POST-IMPLANT DAY 90 ............................................................................................................................. 33 
11.7 POST-IMPLANT DAY 120 ........................................................................................................................... 33 
11.8 SCHEDULE OF STUDY PROCEDURES AND ASSESSMENTS ............................................................................ 34 
12 
STATISTICAL PLAN ................................................................................................................................ 35 
13 
SAFETY AND ADVERSE EVENTS ......................................................................................................... 36 
13.1 DEFINITIONS ............................................................................................................................................. 36 

Coronary Sinus Reducer and CMD 
 
Version 4.0 9/8/2022 
 
13.2 ADVERSE EVENTS ..................................................................................................................................... 38 
13.3 SERIOUS ADVERSE EVENTS ....................................................................................................................... 38 
13.4 ADVERSE EVENT REPORTING PERIOD ........................................................................................................ 39 
13.5 PREEXISTING CONDITION .......................................................................................................................... 40 
13.6 GENERAL PHYSICAL EXAMINATION FINDINGS .......................................................................................... 40 
13.7 POST-STUDY ADVERSE EVENTS ................................................................................................................. 40 
13.8 PATIENTS ON ANTICOAGULANTS AND ANTIPLATELETS ............................................................................. 40 
13.9 HOSPITALIZATION, PROLONGED HOSPITALIZATION OR SURGERY ............................................................. 41 
13.10 RECORDING OF ADVERSE EVENTS ............................................................................................................ 42 
13.11 REPORTING OF SERIOUS ADVERSE EVENTS AND UNANTICIPATED PROBLEMS ............................................ 42 
13.12 SPONSOR-INVESTIGATOR REPORTING: NOTIFYING THE MAYO IRB ............................................................ 43 
13.13 SPONSOR-INVESTIGATOR REPORTING: NOTIFYING THE FDA .................................................................... 44 
13.14 STOPPING RULES ....................................................................................................................................... 45 
13.15 MEDICAL MONITORING ............................................................................................................................. 45 
14 
DATA HANDLING AND RECORD KEEPING...................................................................................... 45 
14.1 CONFIDENTIALITY .................................................................................................................................... 46 
14.2 SOURCE DOCUMENTS ............................................................................................................................... 47 
14.3 CASE REPORT FORMS ............................................................................................................................... 47 
15 
DATA MANAGEMENT ............................................................................................................................ 48 
15.1 
DATA QUALITY ASSURANCE ............................................................................................................... 48 
15.2 
DATA CLARIFICATION PROCESS .......................................................................................................... 48 
15.3 
RECORDS RETENTION .......................................................................................................................... 48 
16 
STUDY MONITORING, AUDITING, AND INSPECTING .................................................................. 49 
16.1 
STUDY MONITORING PLAN .................................................................................................................. 49 
16.2 
AUDITING AND INSPECTING ................................................................................................................. 50 
17 
ETHICAL CONSIDERATIONS ............................................................................................................... 50 
18 
STUDY FINANCES .................................................................................................................................... 51 
13.1 
FUNDING SOURCE ................................................................................................................................ 51 
13.2 
CONFLICT OF INTEREST ....................................................................................................................... 51 
19 
PUBLICATION PLAN ............................................................................................................................... 51 
20 
REFERENCES ............................................................................................................................................ 53 
 
 

Coronary Sinus Reducer and CMD 
 
Version 4.0 9/8/2022 
 
Page 2 of 65 
 
Confidential 
 
Study synopsis 
Title  
A Phase II Study Testing the Feasibility and Efficacy of 
Coronary Sinus Narrowing in Patients with Coronary 
Microvascular Dysfunction 
Study objective  
To evaluate the impact of the Neovasc Reducer ™ device 
implantation on coronary microvascular function assessed 
invasively by measurement of coronary flow reserve (CFR) 
and the hyperemic myocardial resistance (HMR) in patients 
with angina but no-obstructive coronary artery disease 
(ANOCA) 
and 
documented 
coronary 
microvascular 
dysfunction (CMD) [CFR≤2.5 and/or HMR≥2.5] or coronary 
blood flow (CBF) response to acetylcholine ≤ 50%. 
Study hypothesis  
In patients with ANOCA and documented CMD, narrowing 
of the CS by Reducer implantation will improve 
microvascular function as measured by CFR and HMR, and 
quality of life 
Device  
The Neovasc Reducer™ System (Neovasc Inc., Richmond, 
B.C., Canada)  
Study design 
• Prospective, single center, single arm, clinical trial  
• Patients with chronic refractory angina (Canadian 
Cardiovascular Society (CCS) grade II-IV, no 
obstructive CAD (<50% stenosis in epicardial vessels 
and/or iFR>0.89 or FFR>0.8 in vessels with 50 to 
70% stenosis), and documented CMD (CFR≤2.5 
and/or HMR≥2.5) or coronary blood flow (CBF) 
response to acetylcholine ≤ 50% on clinically 
indicated coronary angiography and invasive coronary 
reactivity testing which uses Adenosine, 
Acetylcholine & Nitroglycerin as standard clinical 
practice will be eligible for enrolment.  

Coronary Sinus Reducer and CMD 
 
Version 4.0 9/8/2022 
 
Page 3 of 65 
 
Confidential 
 
• After a full clinically indicated coronary flow 
evaluation is performed in the left anterior descending 
artery (LAD) as standard of care using an 
intracoronary combined Doppler-flow and pressure 
wire (ComboWire XT, Philips Volcano Corporation, 
Del Mar, California) that provides iFR/FFR, HMR 
and CFR measurements, patients will be determined 
eligible. 
• Baseline clinical evaluations of eligible patients will 
include clinical characteristics, medication profiles 
including antianginals, evaluation of angina severity 
and frequency by CCS angina class and Seattle 
Angina Questionnaire (SAQ), in addition to ischemia, 
exercise capacity, and left ventricular diastolic 
function and filling pressures at peak exercise on an 
exercise bike echocardiographic stress test (EBEST) 
using a supine bike protocol starting at 25 Watts and 
increasing by 25 Watts every 2 minutes. 
• Eligible patients will undergo percutaneous CS 
Reducer implantation for the treatment of CMD.  
• Adverse events will be collected during the 4 months 
study period and monthly follow-up phone calls with 
study participants will be conducted at 1, 2, and 3 
months post CS reducer implant    
• Study participants will undergo full repeat invasive 
evaluation of coronary blood flow and microvascular 
resistance (CFR and HMR) as well as repeat clinical 
evaluation (including CCS class, SAQ, antianginal 
medication use, adverse events, and EBEST) at 4 
months following Reducer implantation. 
Number of subjects  
30 

Coronary Sinus Reducer and CMD 
 
Version 4.0 9/8/2022 
 
Page 4 of 65 
 
Confidential 
 
Population  
Patients with chronic refractory angina (CCS class II-IV), no 
obstructive CAD (<50% stenosis in epicardial vessels and/or 
iFR>0.89 or FFR>0.8 in vessels with 50 to 70% stenosis), 
and documented CMD (CFR≤2.5 and/or HMR≥2.5) & or  
coronary blood flow (CBF) response to acetylcholine ≤ 50% 
on clinically indicated coronary angiography and invasive 
coronary reactivity testing  which uses Adenosine, 
Acetylcholine & Nitroglycerin as standard clinical practice 
Inclusion criteria  
• Age >18  
• Able to provide written informed consent and willing 
to participate in all required study follow-up 
assessments 
• Symptomatic CAD with refractory angina defined as 
CCS class II to IV, despite optimal tolerated medical 
therapy 
• Abnormal coronary microvascular function indices: 
CFR≤2.5 and/or HMR≥2.5 & o or coronary blood 
flow (CBF) response to acetylcholine ≤ 50% 
Exclusion criteria  
• Recent (within 3 months) acute coronary syndrome 
•  
• Patients with prior coronary artery bypass surgery  
• Unstable angina (recent onset angina, crescendo 
angina, or rest angina with ECG changes) during the 
last 30 days 
• Subjects in cardiogenic shock (systolic pressure < 
80mm/Hg, on vasopressors or intraaortic counter 
pulsation) at the time of consenting. Subjects who 
recover from cardiogenic shock by the time of 
consenting are eligible.  
• Obstructive CAD on coronary angiography (>70% 
stenosis or 50-70% stenosis with iFR<0.89 or 
FFR<0.8 in epicardial artery) 

Coronary Sinus Reducer and CMD 
 
Version 4.0 9/8/2022 
 
Page 5 of 65 
 
Confidential 
 
• Inability to perform invasive coronary flow evaluation 
and/or measure CFR and HMR in the LAD 
• Severe valvular heart disease 
• LVEF<30% 
•  Decompensated congestive heart failure (CHF) or 
hospitalization due to CHF during the last 3 months  
• Patient with a pacemaker electrode in the CS 
• Mean right atrial pressure >15 mmHg 
• Anomalous or abnormal CS anatomy (e.g., tortuosity, 
aberrant branch, persistent left superior vena cava 
(SVC) as demonstrated on angiogram 
• CS diameter at the site of planned implantation 
greater than 13mm or less than 9.5 mm as measured 
by angiogram 
• Severe chronic obstructive pulmonary disease 
(COPD) indicated by a forced expiratory volume in 
one second that is less than 55 percent of the 
predicted value 
• Tricuspid valve replacement or repair (tissue or 
mechanical) 
• Chronic renal failure (serum creatinine >2mg/dL), 
and or on chronic hemodialysis 
• Moribund, or with comorbidities limiting life 
expectancy to less than one year 
• Known severe reaction to required procedural 
medication 
• Known allergy to stainless steel or nickel 
• Magnetic Resonance Imaging (MRI) within 8 weeks 
of Reducer implantation 
• Participation in another ongoing investigational trial 
• Additional factors deemed unsuitable for trial 
enrollment per discretion of principal investigator 
• Inmates 
Primary endpoint  
Change in CFR and HMR measurements at 4 months 
post Reducer implantation compared to baseline  

Coronary Sinus Reducer and CMD 
 
Version 4.0 9/8/2022 
 
Page 6 of 65 
 
Confidential 
 
Secondary endpoints  
• Change in CCS angina class 
• Change in the score of all 5 domains of the Seattle 
Angina Questionnaire for assessing quality of life 
• Change in short acting nitrates (spray or sublingual 
consumption frequency 
• Change in EBEST parameters at 4 months compared 
with baseline (total exercise duration, time to 1 mm 
ST segment depression, evidence of ischemia, peak 
exercise stage, peak exercise diastolic function and 
filling pressures as measured by echocardiographic 
E/e’, and exercise-induced symptoms) 
• Procedural-related Major Adverse Cardiac Events 
defined as: death, myocardial infarction, perforation 
of the CS, CS total occlusion, or need for urgent 
dilatation of the Reducer within 4 months of follow-
up 
Statistical 
considerations  
The effect of the CS Reducer implantation on microvascular 
function will be evaluated by the change in measured CFR 
and HMR at 4 months follow-up compared to baseline pre-
CS Reducer implantation. Statistical analysis of the absolute 
and percent change in CFR and HMR measurements at 
follow-up will be done. Analysis of the delta change in CFR 
and HMR will also be performed. Change in angina intensity 
and frequency, and quality of life, will be evaluated by 
analyzing the change in CCS angina class, SAQ score in all 
five domains, and antianginals need and frequency rom 
baseline to follow-up. Change in functional capacity will be 
evaluated as the change in baseline to follow-up EBEST total 
exercise duration, peak exercise stage, exercise-induced 
symptoms, and ischemic ECG and echocardiographic 
findings. Change in diastolic function and filling pressures 

Coronary Sinus Reducer and CMD 
 
Version 4.0 9/8/2022 
 
Page 7 of 65 
 
Confidential 
 
will be evaluated as baseline to follow-up change in resting 
and peak exercise echocardiographic E/e’ ratio. 
 
 
 

Coronary Sinus Reducer and CMD 
 
Version 4.0 9/8/2022 
 
Page 8 of 65 
 
Confidential 
 
Project Summary/Abstract 
The estimated patient population that suffers from coronary microvascular dysfunction 
(CMD) is high with limited current available therapeutic strategies. At least 40-50% of 
symptomatic patients referred for a clinically indicated coronary angiography have non-
obstructive coronary artery disease (CAD) and among those, more than 60% have CMD by 
invasive diagnostic coronary reactivity testing. Currently there is no established effective 
treatment for symptomatic patients with CMD, and therefore a novel effective CMD treatment 
remains an important unmet clinical need. Previous studies have demonstrated that narrowing 
of the coronary sinus (CS) using The Neovasc Reducer™ System (Neovasc Inc., Richmond, 
B.C., Canada), has demonstrated to be safe with promising therapeutic results in patients with 
severe refractory angina secondary to obstructive CAD with no revascularization options. 
Procedural success of CS Reducer implantation has been shown to be very high in the 
COSIRA randomized controlled trial, in interim analysis of the largest European prospective 
registry with up to 2 years follow-up and in many smaller observational studies. CS narrowing 
leads to increased backwards pressure that causes slight dilatation and a consequent reduction 
in the resistance to flow in the microvasculature (resistance arterioles) of the ischemic sub-
endocardial myocardium. This subsequently causes a redistribution of blood from the less 
ischemic sub-epicardium to the more ischemic sub-endocardium accompanied by 
symptomatic improvement. A small observational study and few case reports have recently 
suggested that CS narrowing may be effective in improving angina, quality of life, functional 
capacity and reduction in myocardial ischemia in patients with angina but no obstructive 
CAD. The potential benefit of an effective therapy which will improve CMD is far-reaching. 
Considering the already established efficacy of the Reducer in improving symptoms of angina 
and reducing ischemic burden, its beneficial effect on ischemia in patients without obstructive 

Coronary Sinus Reducer and CMD 
 
Version 4.0 9/8/2022 
 
Page 9 of 65 
 
Confidential 
 
CAD, the evidence that increased CS pressure improve microvascular function, and bearing in 
mind the presumed mechanism of action of the CS Reducer, it is plausible that this treatment 
can be effective in this patient population. 
 
Approximately, 30 subjects with angina, no obstructive CAD, and CMD invasively diagnosed 
by abnormal coronary flow reserve (CFR) and/or hyperemic microvascular resistance (HMR) 
will be enrolled in this single arm study. The primary objective is to evaluate the effect of CS 
narrowing using the Neovasc Reducer™ System on CFR and HMR at 4 months post Reducer 
implantation. Additional data will be collected on the adverse events and procedural success 
of the Reducer implantation procedure; as well as 4-months post-implant symptomatic and 
quality of life improvement as measured by the Canadian Cardiovascular Society (CCS) 
angina class, Seattle Angina Questionnaire short acting nitrates consumption frequency, 
functional capacity, intracardiac filling pressures, and ischemia as measured by exercise 
bicycle echocardiogram stress testing. 
  
We hope that this study, the first of its kind in the USA using the CS Reducer as potential 
therapy for angina with no obstructive CAD (ANOCA) will address the therapeutic potential 
of CS narrowing for the treatment of CMD, an important unmet clinical need, and generate 
preliminary data for larger randomized phase 2 and 3 trials.  
 
 

Coronary Sinus Reducer and CMD 
 
Version 4.0 9/8/2022 
 
Page 10 of 65 
 
Confidential 
 
Study protocol 
1- Introduction 
This document is a human research study protocol. This study will be carried out in 
accordance with the applicable United States government regulations and Mayo Clinic 
research policies and procedures.  
 
2- Background  
2.1 Coronary microvascular dysfunction: Magnitude of the problem 
Coronary microvascular dysfunction is not uncommon. The prevalence of non-obstructive 
coronary artery disease (CAD) in patients suffering from angina pectoris undergoing 
clinically indicated coronary angiography is 30-50% 1, 2. Of those patients with angina and 
non-obstructive coronary artery disease (ANOCA), 90% have identifiable abnormal coronary 
physiology 3 and 50-60% have coronary microvascular dysfunction (CMD) 3, 4. 
  
2.2 Coronary microvascular dysfunction: Symptoms and adverse outcomes 
Coronary microvascular dysfunction contributes to myocardial perfusion abnormalities and 
ischemia 5 and leads to poor outcomes. In addition to disabling angina and severely limited 
quality of life 3, CMD has been associated with a 6-fold increase in adjusted mortality and 
higher risk of major adverse cardiovascular events (MACE), including diastolic heart failure, 
acute coronary syndrome, myocardial infarction, and sudden cardiac death 5-10.   
 
2.3 Coronary microvascular dysfunction: Pathophysiology of ischemia and angina 
Coronary microvascular dysfunction (CMD) refers to the subset of disorders affecting the 
structure and function of the coronary microcirculation. It is prevalent in patients across a 
broad spectrum of cardiovascular conditions such as left ventricular diastolic dysfunction, 
cardiomyopathies, coronary atherosclerosis, hypertensive heart disease, and diabetes mellitus. 

Coronary Sinus Reducer and CMD 
 
Version 4.0 9/8/2022 
 
Page 11 of 65 
 
Confidential 
 
The coronary arterial system represents a continuous network of functionally distinct vessel 
segments of decreasing size and diameter. The epicardial arteries (>400 µm) have a primary 
conductance function and exhibit minimal resistance to coronary flow under normal 
conditions, with their diameters regulated by shear stress and endothelial function. In contrast, 
the pre-arterioles (100 to 400 µm) and arterioles (<100 µm) make up most of the resistance 
circuit of the heart and are responsible for regulation and distribution of blood flow to match 
the dynamic needs of local tissue metabolism via the coronary capillaries bed (<10 µm) 5. In 
healthy arteries, coronary blood flow and myocardial perfusion are regulated by coronary 
arteriolar tone. Coronary blood flow remains constant over a wide range of coronary 
perfusion pressures through dynamic changes in resistance vessel tone. These dynamic 
changes result from a series of mechanisms, including adrenergic stimuli, changes in local 
oxygen tension, and the response to changes in transmural pressure 5. Such control of 
coronary blood flow helps to mitigate myocardial ischemia during the development and 
progression of epicardial atherosclerosis. In the heart, oxygen extraction is near-maximal at 
rest; therefore, myocardial oxygen delivery is almost completely dependent on coronary blood 
flow 11. Consequently, an increase in myocardial oxygen demand must be matched by a 
proportional increase in coronary blood flow to prevent myocardial ischemia. CMD attenuates 
coronary flow augmentation in response to stress, and, if severe enough to lead to demand-
supply mismatch, may lead to myocardial ischemia and to angina 12.  
A number of structural and functional changes have been linked to CMD. Structural changes 
include microvascular obstruction with intramural arteriolar luminal narrowing/obliteration 
and capillary rarefaction 13, and is known to be magnified by the presence of atherosclerosis, 
particularly in patients with CV risk factors including diabetes, hypertension, and renal 
impairment, or evidence of diffuse epicardial atherosclerosis.  

Coronary Sinus Reducer and CMD 
 
Version 4.0 9/8/2022 
 
Page 12 of 65 
 
Confidential 
 
Functional abnormalities of the microcirculation regulating arteriolar tone are present in the 
majority of patients with CMD. Attenuated vasodilator responses to papaverine, adenosine, or 
dipyridamole, which are largely mediated by vascular smooth muscle relaxation of resistive 
vessels, have been documented in patients with diabetes, metabolic syndrome and other 
cardiovascular risk factors 12. Thus, assessing microvascular function is essential for the 
diagnosis and risk stratification of patients with angina or myocardial ischemia and non-
obstructive CAD 14, 15.   
 
2.4  Coronary microvascular dysfunction: Diagnosis  
Visualization of the coronary microcirculation is beyond the resolution of both invasive 
angiography and noninvasive coronary imaging modalities. Therefore, direct interrogation of 
coronary microvascular function is necessary to establish the diagnosis of CMD. Coronary 
flow reserve (CFR), calculated as the ratio of hyperemic to rest coronary blood flow, is a 
measure of coronary vasomotor function that integrates the hemodynamic effects of not only 
focal and/or diffuse epicardial disease but also small vessel disease on coronary blood flow in 
response to hyperemic pharmacologic (such as adenosine) or physiologic (exercise) stimuli. 
Therefore, in the absence of the obstructive epicardial disease, abnormal CFR is diagnostic of 
CMD. CFR can be measured by invasive coronary reactivity testing 11 and non-invasive 
imaging modalities such as positron emission tomography (PET), cardiac magnetic resonance 
imaging and transthoracic echocardiography 12. However, while these non-invasive imaging 
modalities are able to identify impaired CFR, they are not able to reliably evaluate the 
hemodynamic significance of a moderate or severe epicardial lesion and thus rule out the 
presence of concomitant obstructive CAD. On the hand, invasive angiography by combining 
the ability to exclude obstructive epicardial CAD, with complementary catheter-based 

Coronary Sinus Reducer and CMD 
 
Version 4.0 9/8/2022 
 
Page 13 of 65 
 
Confidential 
 
techniques to probe epicardial [by fractional flow reserve (FFR) or instantaneous flow reserve 
(iFR)] and microvascular coronary physiology [by CFR and hyperemic microvascular 
resistance (HMR)], is an accurate, comprehensive, and reproducible approach to evaluate 
patients with CMD. Accordingly (Figure 1): 
• FFR (the ratio between coronary pressure distal to a stenosis and aortic pressure 
during maximal hyperemia, normal > 0.8) and iFR (the ratio between coronary 
pressure distal to a stenosis and aortic pressure during diastolic wave-free phase of the 
cardiac cycle, normal >0.89) are used to rule out flow limiting lesions in epicardial 
arteries 16-19. Both FFR and iFR are assessed using a pressure guidewire. 
• CFR (the ratio of hyperemic over rest coronary blood flow) ≤2.5 is diagnostic of CMD 
in the absence of obstructive epicardial disease 11. It is most commonly assessed using 
an intracoronary Doppler-tipped guidewire or thermodilution techniques.  
3 HMR (the ratio of distal coronary pressure divided by coronary blood flow at maximal 
hyperemia using a combined pressure-flow intracoronary guidewire), similar to the index 
of microvascular resistance (IMR) [ratio of distal coronary pressure divided by the inverse 
of the mean transit time during maximal hyperemia using a pressure-thermodilution 
intracoronary guidewire and commercially available software], is a direct measure of 
microcirculatory resistance and is independent of epicardial vascular function. Using a 
combined pressure-flow wire, HMR ≥2.5 mHg/cm/s  is diagnostic of CMD in the absence 
of obstructive epicardial disease and significant collateral coronary flow 12, 20, 21.  
 

Coronary Sinus Reducer and CMD 
 
Version 4.0 9/8/2022 
 
Page 14 of 65 
 
Confidential 
 
 
Figure 1: CFR: Coronary flow reserve; FFR: Fractional flow reserve; IMR: Index 
of microvascular resistance  
 
2.5 Coronary microvascular dysfunction: Current limited treatment options and unmet 
clinical need 
Small, short-term studies of symptomatic patients with ischemia but no obstructive CAD 
using anti-atherosclerotic and/or anti-ischemic agents have produced limited symptomatic, 
ischemic, or functional improvement. Accordingly, in the absence of large randomized 
controlled trials demonstrating effective therapies for CMD, existing guidelines focus on 
reassurance and symptom management 22, 23 with current standard therapy mostly extrapolated 
from obstructive epicardial coronary artery disease and consisting of cardiovascular risk 
factors control, statins and traditional antianginal therapies, such as beta-blockers, calcium 
channel blockers, and long-acting nitroglycerine 24, 25. Angiotensin converting enzyme 
inhibitors, L-arginine and aspirin may also sometimes be used for treatment of CMD 24-26. 
CORMICA, a randomized controlled blinded clinical trial of stratified medical therapy versus 
standard care in patients with angina and non-obstructive angiographic CAD, showed that 
invasive assessment of the microvascular function at the time of the coronary angiogram as a 

Coronary Sinus Reducer and CMD 
 
Version 4.0 9/8/2022 
 
Page 15 of 65 
 
Confidential 
 
mechanism of ischemia, and stratified medical treatment of CMD improves symptoms and 
quality of life in this patient population 14. However, current traditional antianginal drugs were 
shown to be effective in only about half of patients with CMD. This is suboptimal and hence 
the growing need for more research to investigate novel therapies addressing this unmet 
clinical need. A personalized approach is therefore needed with follow-up of individual 
patients to tailor therapy according to symptom relief and side-effects 24. 
 
2.6 Coronary Sinus Narrowing: A potential treatment for microvascular dysfunction in 
patients with ANOCA 
Augmentation of coronary sinus (CS) pressure for the treatment of chronic angina is a long-
standing concept. In the 1950’s and 1960’s, surgical narrowing of the CS by Claude Beck for 
treatment of angina by redistribution of myocardial blood flow into ischemic myocardial 
territories showed remarkable success 27, 28. In the 1980’s,  Mohl and colleagues used a closed 
loop CS balloon system to automatically occlude and release the CS to elevate CS pressure 29, 
30. In 2015, Verheye and colleagues showed, in the COSIRA double-blind, sham-controlled, 
multicenter trial, that CS Reducer (Neovasc Inc) improves Canadian Cardiovascular Society 
(CCS) angina class and quality of life with a trend to reduction in ischemic burden in patients 
with refractory angina and obstructive CAD with no revascularization options 31. More recently, 
a small observational study (n= 8) by Giannini and colleagues showed that CS Reducer also 
improved CCS class, myocardial ischemia by perfusion cardiac MRI, all domains of the Seattle 
Angina Questionnaire (SAQ), and 6-minute walk test (6MWT) in patients with angina and no 
obstructive CAD 32. Most recently, De Maria and colleagues demonstrated that CS pressure 
elevation using the pressure-controlled intermittent CS occlusion (PICSO) system in patients 
presenting with first anterior STEMI, not only improves microvascular function evaluated by 

Coronary Sinus Reducer and CMD 
 
Version 4.0 9/8/2022 
 
Page 16 of 65 
 
Confidential 
 
IMR, but also reduces infarct size (OxAMI-PISCO study) 33. It has been suggested that CS 
narrowing leads to increased backwards pressure that causes slight dilatation and a consequent 
reduction in the resistance to flow in the arterioles of the ischemic sub-endocardial myocardium. 
This subsequently causes a redistribution of blood from the less ischemic subepicardium to the 
more ischemic subendocardium 34. The enhancement of blood flow within the ischemic 
subendocardial layers of the myocardium reduces ischemia and leads to symptoms relief and 
improved quality of life.   
 
3- The Coronary Sinus  Reducer 
The Neovasc Reducer™ System (Neovasc Inc., Richmond, B.C., Canada), hereby referred to 
as the CS Reducer in this protocol, is a CE marked, balloon-mounted, hourglass-shaped 
stainless steel mesh for percutaneous transvenous implantation into the coronary sinus. The 
CE Mark indication for use is in patients with refractory angina pectoris and objective 
evidence of reversible myocardial ischemia, who have limited treatment options and are thus 
referred to as ‘no-option’ patients. These patients are either not amenable to, or are high risk 
for, revascularization by coronary artery bypass grafting (CABG) or by percutaneous 
coronary intervention (PCI). The Reducer System is intended to create a permanent and 
controlled narrowing of the coronary sinus (CS), to improve perfusion to ischemic 
myocardium. As discussed above, CS Reducer is emerging as a potentially effective therapy 
for disabling angina in patients (n=104) with obstructive CAD and no revascularization 
options 31 with objective evidence to support reduction in myocardial ischemia on MRI, 
SPECT and dobutamine stress echocardiography 35-37 and improvement in diastolic left 
ventricular function 38. However, the role of the CS Reducer in patients with microvascular 
angina and no obstructive CAD remains unclear. Observational data from a first-in-human 

Coronary Sinus Reducer and CMD 
 
Version 4.0 9/8/2022 
 
Page 17 of 65 
 
Confidential 
 
(n=8) preliminary study of compassionate CS Reducer implantation for presumed refractory 
microvascular angina post at least one PCI procedure and no residual epicardial obstructive 
disease demonstrated improvement in CCS class, SAQ score, and 6MWT at 4 months post 
implant 32, with improved myocardial perfusion reserve index in a subgroup of patients (n=3) 
suggestive of improved microvascular function (Figure 2). Yet, CS Reducer has not yet been 
specifically tested in ANOCA patients with invasively documented microvascular 
dysfunction.  
 
Figure 2: A) Improvement in Canadian Cardiovascular Society (CCS) class, Seattle Angina 
Questionnaire (SAQ) score, and 6 minute walk test (6MWT) at 4 months post CS Reducer 
implantation. B) Improved myocardial perfusion reserve index in a subgroup of patients. 
Adapted from Giannini F et al., JACC Cardiovascular Interventions 32.  
 
More supportive data for the concept that increased CS pressure might improve microvascular 
function can be found in a very recent case presented by Tommaso Gori 39 of a 61 year old 
man who presented with severe (CCS class 4) angina, non-obstructive CAD and elevated 
IMR. This patient was treated with Reducer implantation with consequent resolution of 
angina and dramatic reduction in IMR.  Also, CS pressure elevation using pressure-controlled 

Coronary Sinus Reducer and CMD 
 
Version 4.0 9/8/2022 
 
Page 18 of 65 
 
Confidential 
 
intermittent CS occlusion (PICSO) in patients presenting with first anterior STEMI, resulted 
in improves microvascular function (reduction in IMR values) as well as reduction of infarct 
size (OxAMI-PISCO study) 33. 
 
Safety and Procedural Success of CS Reducer System and Implantation Procedure 
The safety and procedural success of CS Reducer implantation has been demonstrated in one 
randomized clinical trial and numerous observational studies done in Europe and Canada 36, 37, 
40, 41. To date, no feasibility and efficacy studies have been done in the United States.  
Potential complications of the procedure include dissection or perforation of the CS and 
device migration. However, as demonstrated in previous studies (COSIRA, n=52 and 
REDUCER-I, n=204) and non-published post-marketing commercial use in more than 1800 
patients worldwide,  no cases of mortality has been recorded and the rates of aforementioned 
complications, including myocardial infarction or permanent damage related to the device or 
procedure such as perforation, are very low (Table 1). Moreover, implantation procedure has 
very high success rates. The largest multicenter Italian registry reports 98.6% (n=139) 
procedural success with 2 patients (1.4%) failing due to unfavorable anatomy of the coronary 
sinus 41. Summary of technical success data of CS Reducer implantation procedure from four 
previous studies is summarized in Table 2. 
 
Table 1: Safety Data of CS Reducer System and Implantation Procedure3 
 
Potential Complications 
(REDIFU-002 Reducer 
IFUCE Mark REV K) 
Pre-Market Event 
Rate 
(COSIRA) 
N=52 
n(%) 
Post-Market Event 
Rate 
(REDUCER-I) 
N=204 
n(%) 
Post-Market Event 
Rate 
(Commercial Use) 
N=1840 
n(%) 
Allergic reaction 
0(0.00) 
0(0.00) 
0(0.00) 

Coronary Sinus Reducer and CMD 
 
Version 4.0 9/8/2022 
 
Page 19 of 65 
 
Confidential 
 
Arrhythmias (e.g. 
ventricular tachycardia 
(VT) or ventricular 
fibrillation (VF)  
1(1.92) 
4(1.96) 
0(0.00) 
Dissection (e.g. coronary 
sinus) 
0(0.00) 
4(1.96) 
2(0.11) 
Embolism (e.g. pulmonary 
or vessel) 
0(0.00) 
0(0.00) 
0(0.00) 
Conduction Disturbances 
0(0.00) 
0(0.00) 
0(0.00) 
Hypotension/hypertension 
0(0.00) 
0(0.00) 
1(0.05) 
Infection 
0(0.00) 
0(0.00) 
0(0.00) 
Access site complications 
1(1.92) 
1(0.49)2 
0(0.00) 
Access site hematoma (not 
SAE) 
Not reported 
8(3.92) 
Not reported 
Access site minor bleed 
(not SAE) 
Not reported 
4(1.96) 
Not reported 
Ischemic events (e.g. 
myocardial infarction (MI) 
or unstable angina) 
1(1.92) 
0(0.00) 
0(0.00) 
Minor or major bleeding 
events (e.g. hemorrhage, 
cardiac tamponade, or 
pericardial effusion) 
1(1.92) 
1(0.49) 
1(0.05) 
Vascular event (e.g. 
pseudoaneurysm or 
thrombus) 
0(0.00) 
0(0.00) 
0(0.00) 
Perforation/rupture of 
coronary sinus, right 
atrium (RA), or internal 
jugular vein 
0(0.00) 
1(0.49) 
3(0.16) 
Pulmonary edema 
0(0.00) 
0(0.00) 
0(0.00) 
Reducer and/or coronary 
sinus occlusion (e.g. 
thrombus) 
0(0.00) 
0(0.00) 
0(0.00) 
Reducer fracture 
0(0.00) 
0(0.00) 
0(0.00) 
Reducer malposition, 
migration or embolization 
2(3.85) 
2(0.98) 
10(0.54) 
Respiratory failure 
0(0.00) 
0(0.00) 
0(0.00) 
Spasm of CS or jugular 
vein 
0(0.00) 
0(0.00) 
0(0.00) 
Cardiac valve injury 
(tricuspid) 
0(0.00) 
0(0.00) 
0(0.00) 
Myocardial damage 
0(0.00) 
0(0.00) 
0(0.00) 
Pyrogenic immunological 
or toxicological reaction 
0(0.00) 
0(0.00) 
0(0.00) 
Angina 
0(0.00) 
3(1.47) 
0(0.00) 
Chest pain1 
1(1.92) 
1(0.49) 
0(0.00) 

Coronary Sinus Reducer and CMD 
 
Version 4.0 9/8/2022 
 
Page 20 of 65 
 
Confidential 
 
Minor neurologic event, 
including dysphagia, 
blurred vision, or TIA 
0(0.00) 
3(1.47) 
0(0.00) 
 
1Chest pain has previously been categorized as angina and is therefore not currently included 
as an independent complication in the IFU 
2Access Site Complications: one (1) access site complication due to device retrieval via the 
femoral vein 
3Source: 022-CLN-012-2019 Rev A 
 
Table 2: Technical Success of CS Reducer Implantation Procedure 
Study 
N 
Technical Success 
% (n) 
COSIRA Treatment 
Arm 
52 
96.2 (50/52)1 
FIM 
15 
93.3 (14/15)2 
REDUCER-I Overall  
211 
96.6 (204/211)3 
REDUCER-I Arm 1 
161 
95.6 (154/161)3 
 
1 Two subjects were not implanted – one due to inability to cannulate the CS and 
one due to inability to advance the guide catheter in the CS to the intended implant 
location 
 
2  One subject experienced a migration post-implantation.  The Reducer was noted 
to have moved during insertion but was inflated.  As a result, the position of the 
deployed Reducer device was more proximal than desired.  The dislodged Reducer 
then migrated and a 2nd Reducer was implanted without complications 
 
3  Seven subjects were not implanted – 2 for CS dissection, 2 for tortuous anatomy, 
1 for CS too small, 1 for inability to advance the guiding catheter, and 1 for 
movement of the Reducer while retracting the guidewire 
 
Accordingly, in this Phase-1 study we aim to evaluate the feasibility of CS Reducer 
implantation and its efficacy on invasively assessed microvascular function in ANOCA 
patients with CMD.      
 
4- Study Hypothesis  

Coronary Sinus Reducer and CMD 
 
Version 4.0 9/8/2022 
 
Page 21 of 65 
 
Confidential 
 
In patients with ANOCA and invasive evidence of CMD, CS Reducer implantation is safe and 
will improve microvascular function as measured by CFR and HMR. 
 
5- Aims 
5.1 To evaluate the potential efficacy of CS Reducer implantation in ANOCA patients 
with CMD on microvascular function using invasive CFR and HMR assessments  
5.2 To evaluate the potential efficacy of CS Reducer implantation in ANOCA patients 
with CMD on angina severity and frequency as assessed by CCS angina class and 
short-acting nitrates use, ischemia and exercise capacity as assessed by exercise bike 
echocardiographic stress test (EBEST), and quality of life as assessed by SAQ score. 
5.3 To evaluate the potential efficacy of CS Reducer on left ventricular diastolic function 
and filling pressures as assessed by transthoracic echocardiographic parameters at 
peak exercise      
5.4 To confirm the safety and feasibility of CS Reducer implantation patients with 
ANOCA and invasively documented CMD.  
5.5 A successful demonstration in the proposed trial that CS Reducer implantation can be 
beneficial to patients with CMD will significantly advance the field of research aimed 
at FDA approval of the CS Reducer for treatment of ANOCA patients with CMD and 
opening the door to commercialization of CS Reducer for treatment of CMD, which is 
a critical unmet clinical need. If successful, the next stage of investigation will be the 
conduct of one or more pivotal registration studies to support FDA approval, and the 
proposed trial will provide information necessary to design these studies.   
 
6- Study design 

Coronary Sinus Reducer and CMD 
 
Version 4.0 9/8/2022 
 
Page 22 of 65 
 
Confidential 
 
6.1 
General Study Design: 
• Prospective, single center, open label, single arm, clinical trial  
• Number of participants: 30 subjects 
• Duration of study: 4 months 
• Patients with chronic refractory angina (CCS class II-IV), no obstructive CAD (<50% 
stenosis in epicardial vessels and/or iFR>0.89 or FFR>0.8 in vessels with 50 to 70% 
stenosis), and documented CMD (CFR≤2.5 and/or HMR≥2.5) & or coronary blood 
flow (CBF) response to acetylcholine ≤ 50%.on clinically indicated coronary 
angiography and invasive coronary reactivity testing  which uses Adenosine, 
Acetylcholine & Nitroglycerin as standard clinical practice will be eligible for 
enrolment.  
• A full clinically indicated coronary flow evaluation will be performed in the left 
anterior descending artery (LAD) as standard of care using an intracoronary combined 
Doppler-flow and pressure wire (ComboWire XT, Philips Volcano Corporation, Del 
Mar, California) that provides iFR/FFR, HMR and CFR measurements. This will 
determine patient eligibility. If patients are deemed eligible, and wish to participate, 
they will go through the informed consent process to enroll in the study after their 
procedure. 
• Baseline clinical evaluations of eligible patients will include clinical characteristics, 
medication profiles including antianginals, evaluation of angina severity and 
frequency by CCS angina class and Seattle Angina Questionnaire (SAQ), in addition 
to ischemia, exercise capacity, and left ventricular diastolic function and filling 
pressures at peak exercise on an exercise bike echocardiographic stress test (EBEST) 

Coronary Sinus Reducer and CMD 
 
Version 4.0 9/8/2022 
 
Page 23 of 65 
 
Confidential 
 
using a supine bike protocol starting at 25 Watts and increasing by 25 Watts every 2 
minutes. 
• Eligible patients will undergo percutaneous implantation of The Neovasc Reducer™ 
System (Neovasc Inc., Richmond, B.C., Canada) for the treatment of CMD.  
• Adverse events will be collected during the 4 months study period and monthly 
follow-up phone calls with study participants will be conducted at 1, 2, and 3 months 
post CS reducer implant    
• Study participants will undergo full repeat invasive evaluation of coronary blood flow 
and microvascular resistance (CFR and HMR) as well as repeat clinical evaluation 
(including CCS class, SAQ, antianginal medication use, adverse events, and EBEST) 
at 4 months following Reducer implantation. 
6.2 
Primary Endpoint 
Change in CFR and HMR measurements at 4 months post CS Reducer implantation 
compared to baseline 
6.3 
Secondary Endpoints 
• Change in CCS angina class 
• Change in the score of all 5 domains of the Seattle Angina Questionnaire for assessing 
quality of life 
• Change in the consumption and frequency of short acting nitrates (spray or sublingual 
tablets) 
• Change in EBEST parameters at 4 months compared with baseline (total exercise 
duration, time to 1 mm ST segment depression, evidence of ischemia, peak exercise 
stage, peak exercise diastolic function and filling pressures as measured by 
echocardiographic E/e’, and exercise-induced symptoms) 

Coronary Sinus Reducer and CMD 
 
Version 4.0 9/8/2022 
 
Page 24 of 65 
 
Confidential 
 
• Procedural-related Major Adverse Cardiac Events (MACE) defined as: death, 
myocardial infarction, perforation of the CS, CS total occlusion, or need for urgent 
dilatation of the Reducer within 4 months of follow-up  
 
7- Study Population: 
Patients with chronic refractory angina (CCS class II-IV), no obstructive CAD (<50% 
stenosis in epicardial vessels and/or iFR>0.89 or FFR>0.8 in vessels with 50 to 70% stenosis), 
and documented CMD (CFR≤2.5 and/or HMR≥2.5) & or coronary blood flow (CBF) 
response to acetylcholine ≤ 50%. on clinically indicated coronary angiography and invasive 
coronary reactivity testing  which uses Adenosine, Acetylcholine & Nitroglycerin as standard 
clinical practice 
7.1 
Inclusion Criteria: 
• Age >18  
• Able to provide written informed consent and willing to participate in all required 
study follow-up assessments 
• Symptomatic CAD with refractory angina defined as CCS class II to IV, despite 
optimal tolerated medical therapy for more than 3 months. 
• Abnormal coronary microvascular function indices: CFR≤2.5 and/or HMR≥2.5 & or 
coronary blood flow (CBF) response to acetylcholine ≤ 50%.   
7.2 
Exclusion Criteria: 
• Recent (within 3 months) acute coronary syndrome 
• Recent (within 6 months) percutaneous coronary intervention revascularization by 
stent  
• Patients with prior coronary artery bypass surgery  

Coronary Sinus Reducer and CMD 
 
Version 4.0 9/8/2022 
 
Page 25 of 65 
 
Confidential 
 
• Unstable angina (recent onset angina, crescendo angina, or rest angina with ECG 
changes) during the last 30 days 
• Subjects in cardiogenic shock (systolic pressure < 80mm/Hg, on vasopressors or 
intraaortic counter pulsation) at the time of consenting. Subjects who recover from 
cardiogenic shock by the time of consenting are eligible.  
• Obstructive CAD on coronary angiography (>70% stenosis or 50-70% stenosis with 
iFR<0.89 or FFR<0.8 in epicardial artery) 
• Inability to perform invasive coronary flow evaluation and/or measure CFR and HMR 
in the LAD 
• Severe valvular heart disease 
•  LVEF<30%  
•  Decompensated congestive heart failure (CHF) or hospitalization due to CHF during 
the last 3 months  
• Patient with a pacemaker electrode in the CS 
• Mean right atrial pressure >15 mmHg 
• Anomalous or abnormal CS anatomy (e.g., tortuosity, aberrant branch, persistent left 
superior vena cava (SVC) as demonstrated on angiogram 
• CS diameter at the site of planned implantation greater than 13mm or less than 9.5 mm 
as measure by angiogram 
• Severe chronic obstructive pulmonary disease (COPD) indicated by a forced 
expiratory volume in one second that is less than 55 percent of the predicted value 
• Tricuspid valve replacement or repair 
• Chronic renal failure (serum creatinine >2mg/dL), and or on chronic hemodialysis 
• Moribund, or with comorbidities limiting life expectancy to less than one year 

Coronary Sinus Reducer and CMD 
 
Version 4.0 9/8/2022 
 
Page 26 of 65 
 
Confidential 
 
• Known severe reaction to required procedural medication 
• Known allergy to stainless steel or nickel 
• Magnetic Resonance Imaging (MRI) within 8 weeks of Reducer implantation 
• Participation in another ongoing investigational trial 
• Additional factors deemed unsuitable for trial enrollment per discretion of principal 
investigators 
• Inmates 
7.3 
Subject Recruitment, Enrollment and Screening: 
The first six patients will be sequentially enrolled, and subsequent enrollment will be held 
until one-month follow-up. Provided there are no safety concerns at this time, enrollment will 
continue. Staggered enrollment will help ensure that subsequent patients are not enrolled until 
there is adequate follow-up and safety of initial patients. The patients for this study will be 
recruited through the outpatient clinics in the Department of cardiology, including the Chest 
Pain and Coronary Physiology Clinic and the Coronary Artery Disease Clinic at Mayo Clinic. 
There have been over 35,000 patients seen in the Cardiovascular Division at Mayo Clinic 
yearly. There are over 6,000 cardiac catheterizations performed yearly in the cardiac 
catheterization lab. As a part of our clinical practice, patients with angina referred to the 
catheterization laboratory for a clinically indicated coronary angiography and found to have 
non-obstructive CAD are undergoing a comprehensive coronary reactivity testing including 
assessment of microvascular function with CFR and HMR. Typically, 8-10 patients per month 
undergo this comprehensive coronary physiology study. This will be mediated through 
referring physicians. Patients that meet inclusion and exclusion criteria will be considered for 
recruitment in the study. 
 

Coronary Sinus Reducer and CMD 
 
Version 4.0 9/8/2022 
 
Page 27 of 65 
 
Confidential 
 
7.4 
When and How to Withdraw Subjects: 
 Subjects will be withdrawn from the study prior to completion of all study related procedures 
if 1 of 5 consecutive patients have serious adverse safety events.  
 
7.5 
Data Collection and Follow-up for Withdrawn Subjects: 
Even though a subject has withdrawn from the study, it may be important to collect some 
follow-up or survival data on such subjects throughout the protocol defined follow-up period. 
Such data is important to the integrity of the final study analysis since early withdrawal could 
be related to the safety profile of the study device and/or implantation procedure. If a subject 
withdraws consent to participate in the study, for subject safety reasons, we will make 
attempts to obtain permission to collect follow up information whenever possible.
 

Coronary Sinus Reducer and CMD 
 
Version 4.0 9/8/2022 
 
Page 28 of 65 
 
Confidential 
 
Figure 3: Flow chart of the study design. CAD: coronary artery disease; CMD: coronary 
microvascular dysfunction; CRT: coronary reactivity testing; CFR: coronary flow reserve; 
HMR: Hyperemic microvascular resistance; CCS: Canadian cardiovascular society; SAQ: 
Seattle angina questionnaire; EBEST: Exercise bike echocardiographic stress test. 
  
8- Study Device, Implantation Procedure, and Subject Compliance Monitoring 
8.1 
Study Device: 
The Neovasc Reducer™ System (Neovasc Inc., Richmond, B.C., Canada) is a stainless-steel 
mesh pre-mounted on a customized hourglass shaped balloon catheter, is designed to create a 
focal narrowing in the lumen of the CS to generate a pressure gradient across it 42 (Figure 4). 
When inflated, the expanded balloon gives the metal mesh its final hourglass configuration. 
The narrowing within the CS, and the pressure gradient across the device are established 4–6 
weeks after implantation, when the metal mesh should be covered by tissue ingrowth. The 
semi-compliant delivery balloon is available in one single size, and the final expanded 
diameters are dependent on the inflation pressure. The proximal and distal portions of the 
device are configured to different diameters, based on balloon expansion, allowing the device 
to conform to the tapered configuration of the anatomy of the CS, with a central narrowing of 
3 mm in diameter. 
Importantly, since the narrow central part of the device is not in direct contact with the vessel 
wall, and does not cause any vessel wall injury, there is no trigger for tissue growth at this 
point, and therefore, the vessel lumen at the center of the device remains patent. Moreover, 
acceleration of venous blood flow through the narrowed center of the device prevents 
thrombosis at that site. 

Coronary Sinus Reducer and CMD 
 
Version 4.0 9/8/2022 
 
Page 29 of 65 
 
Confidential 
 
 
Figure 4: Neovasc Reducer™ System. A) Coronary sinus Reducer pre-mounted on the 
Reducer Balloon. B) Expanded Reducer over the Reducer Balloon.     
 
8.2 
Implantation Procedure: 
The Reducer is implanted in the CS through a 9F guiding catheter from the right (or left) 
internal jugular vein as was previously described 42. Use instructions of the Neovasc Reducer 
System and implantation procedure steps are detailed in the accompanying confidential 
‘Instructions For Use’ document. In brief, the Reducer system is advanced over a wire inside 
a 9 F guiding catheter and located within the designated implanting location. When proper 
location is confirmed, the guiding catheter is withdrawn, exposing the Reducer, which is held 
in the landing zone previously identified. The balloon is inflated to 4–6 atm to achieve 10–
20% oversize of the vessel . Oversizing is important and helps to achieve two goals: (1) to 

Coronary Sinus Reducer and CMD 
 
Version 4.0 9/8/2022 
 
Page 30 of 65 
 
Confidential 
 
anchor into the elastic vessel wall to help prevent migration and (2) to trigger a process of 
injury-induced tissue proliferation 43-45. 
 
8.3 
Subject Compliance Monitoring: 
There will be no assessment of compliance as the device will be implanted in the cath lab, and 
there are no further drugs that need to be administered.  
 
9- Coronary Reactivity Testing 
A full clinically indicated coronary flow evaluation will be performed in the left anterior 
descending artery (LAD) as standard of care to determine study eligibility using an 
intracoronary combined Doppler-flow and pressure wire (ComboWire XT, Philips Volcano 
Corporation, Del Mar, California) that provides iFR/FFR, HMR and CFR measurements. In 
cases in which assessment cannot be performed in the LAD, coronary reactivity testing may 
be done in the left circumflex (LCx) artery. In brief, after engaging the coronary artery of 
interest with a guiding catheter, FFR or iFR will first be done in case of moderate (>50 to 
<70%) epicardial disease to document non-obstructive CAD (FFR>0.8 or iFR>0.89) as was 
previously described in section 2.4. In cases of mild (<40%) epicardial disease by 
angiography, FFR/iFR is not recommended but may be done at the discretion of the operator. 
After confirming non-obstructive epicardial CAD (no CAD, mild CAD<40% or negative 
FFR/iFR for moderate CAD >50 but <70%), the ComboWire XT will be inserted and parked 
in the mid LAD for measurement of CFR and HMR. Intracoronary bolus injections of 
incremental doses (36, 60 and 72 μg) of adenosine will be administered until maximal 
hyperemia is achieved or the largest dose was given 11. CFR will be measured as the average 
hyperemic blood velocity post adenosine/average baseline velocity. Highest achieved CFR 

Coronary Sinus Reducer and CMD 
 
Version 4.0 9/8/2022 
 
Page 31 of 65 
 
Confidential 
 
will be used for analysis. A cine image of the LAD will be obtained after each adenosine 
administration. Coronary artery diameter will then be measured offline by an independent 
investigator in the segment 5 mm distal to the tip of the pressure-flow wire with a quantitative 
coronary angiography program (Medis Corp, Leiden, the Netherlands) as described 
previously 46, 47 and coronary blood flow (CBF) will then be calculated from the Doppler‐
derived time velocity integral and vessel diameter, where CBF=π×(coronary artery 
diameter/2)2×(average peak hyperemic velocity/2) 48. HMR will then be calculated as distal 
coronary pressure divided by coronary blood flow at maximal hyperemia. For binary analysis, 
CMD will be defined as CFR≤2.5 and/or HMR≥2.511, 12, 20, 21.    
 
10- Prior and Concomitant Therapy 
CS Reducer is being tested as an add-on therapy for ANOCA patients with microvascular 
dysfunction and ongoing refractory angina despite optimal tolerated conventional medical 
therapy. Any previously ongoing therapy for CMD or other conditions, prior to CS Reducer 
implantation, can be continued during the study. 
 
11- Study Procedures 
11.1 Visit 1: Screening Visit 
The screening visit will take place within 30 days before CS Reducer implantation, primary 
safety endpoints and secondary endpoints. Information on safety will be captured between 
visits on a diary card.  
 
Screening Visit:  
• Informed consent 

Coronary Sinus Reducer and CMD 
 
Version 4.0 9/8/2022 
 
Page 32 of 65 
 
Confidential 
 
• Demographic data 
• Medical and surgical history 
• Medication history  
• Concomitant medication 
• Concomitant procedures 
• Vital signs, including height and weight 
• 12 Lead ECG 
• Physical exam 
• Pregnancy test (blood) in reproductive-age woman  
Based on results of screening test and review of eligibility criteria, PI will assess subject’s 
eligibility for study inclusion. If deemed eligible, the patient will be enrolled in an open study 
cohort. Screening visit results will be recorded in the subjects electronic case report form and 
the subject will be scheduled for CS Reducer implantation procedure.  
11.2 Pre-Implant Days -21 to -1 
• Vital signs  
• 12-lead ECG  
• Recording of concomitant medications 
• Recording of adverse events 
• Evaluation of angina severity and frequency by CCS angina class  
• Evaluation of quality of life by SAQ 
• Standard pre-procedural laboratory tests including hematology and blood chemistry. 
• Evaluation of ischemia, exercise capacity, and left ventricular diastolic function and 
filling pressures at peak exercise on EBEST 

Coronary Sinus Reducer and CMD 
 
Version 4.0 9/8/2022 
 
Page 33 of 65 
 
Confidential 
 
11.3 Implant day 0 
• Vital signs 
• 12-lead ECG 
• Limited physical examination 
• CS Reducer implantation 
• Recording of adverse events 
• Recording of concomitant medications 
11.4 Post-Implant day 30 (±4 Days) 
• Phone call to assess: 
o CCS angina class assessment 
o SAQ assessment  
o Adverse events 
o Concomitant medications 
11.5 Post-Implant day 60 (±7 Days)  
• Phone call to assess: 
o CCS angina class assessment 
o SAQ assessment  
o Adverse events 
o Concomitant medications 
11.6 Post-Implant day 90 (± 7 Days) 
• Phone call to assess: 
o CCS angina class assessment 

Coronary Sinus Reducer and CMD 
 
Version 4.0 9/8/2022 
 
Page 34 of 65 
 
Confidential 
 
o SAQ assessment  
o Adverse events 
o Concomitant medications 
11.7 Post-Implant day 120 (± 14 days) 
• Vital signs 
• 12-lead ECG 
• CCS angina class assessment 
• SAQ assessment  
• Adverse events 
• Concomitant medications 
• Limited physical exam 
• Standard laboratory tests including hematology, blood chemistry, liver function tests, 
CRP and creatinine, urinalysis  
• Evaluation of ischemia, exercise capacity, and left ventricular diastolic function and 
filling pressures at peak exercise on EBEST 
• Coronary angiography and reactivity testing to measure CFR and HMR  
 
11.8 
Schedule of Study Procedures and Assessments 
Study 
Procedure/ 
Assessment 
Screening 
Enrolment/ 
Pre-Implant 
 
Implant 
Day 
Post-Implant 
Days 
 
 
-30 
-5 to -1 
0 
30 
60 
90 
120 

Coronary Sinus Reducer and CMD 
 
Version 4.0 9/8/2022 
 
Page 35 of 65 
 
Confidential 
 
Windows 
± 4 
±7 
±7 
±14 
Eligibility 
criteria  
X 
 
 
 
 
 
 
Informed 
consent 
X 
 
 
 
 
 
 
Medical 
history 
X 
 
 
 
 
 
 
Vital signs 
X 
X 
X 
 
 
 
X 
12-lead ECG 
X 
X 
X 
 
 
 
X 
Standard 
laboratory 
tests including 
hematology, 
blood 
chemistry, 
liver function 
tests, CRP and 
creatinine, 
urinalysis.  
 
X* 
 
 
 
 
X 
EBEST 
 
X 
 
 
 
 
X 
CS Reducer 
Implant 
 
 
X 
 
 
 
 
CCS Angina 
Class 
 
X 
 
X 
X 
X 
X 
SAQ 
 
X 
 
X 
X 
X 
X 
Coronary 
angiography 
to measure 
CFR and 
HMR 
 
 
 
 
 
 
X 
Physical exam 
X 
 
 
 
 
 
 
Limited 
physical exam 
 
 
X 
 
 
 
 
Adverse 
events 
X 
X 
X 
X 
X 
X 
X 

Coronary Sinus Reducer and CMD 
 
Version 4.0 9/8/2022 
 
Page 36 of 65 
 
Confidential 
 
Concomitant 
medications 
X 
X 
X 
X 
X 
X 
X 
a. CS Reducer will be implanted in the coronary sinus through right (preferably, or left 
internal jugular venous access) 
b. The patient will receive a phone call from the study coordinator to collect information 
on adverse events, angina class, SAQ, and concomitant medications. 
c. Vital signs will be measured prior to implant and every 8 hours until discharge 
* Standard pre-procedural laboratory tests including hematology and blood chemistry 
including creatinine. Liver function tests, CRP, and urinalysis only at Day 120. 
 
 
12- Statistical Plan 
The effect of the CS Reducer implantation on microvascular function will be evaluated by the 
change in measured CFR and HMR at 4 months follow-up compared to baseline pre-CS 
Reducer implantation. Statistical analysis of the absolute and percent change in CFR and 
HMR measurements at follow-up will be done. Analysis of the delta change in CFR and 
HMR will also be performed. Change in angina intensity and frequency, and quality of life, 
will be evaluated by analyzing the change in CCS angina class, SAQ score in all five 
domains, and antianginals need and frequency rom baseline to follow-up. Change in 
functional capacity will be evaluated as the change in baseline to follow-up EBEST total 
exercise duration, peak exercise stage, exercise-induced symptoms, and ischemic ECG and 
echocardiographic findings. Change in diastolic function and filling pressures will be 
evaluated as baseline to follow-up change in resting and peak exercise echocardiographic E/e’ 
ratio.  
All-completed population: Only subjects who completed ALL study related procedures and 
follow-up will be included in analysis.  
13- Safety and Adverse Events 
The investigator will be responsible for the detection and documentation of any adverse 
events or serious adverse events as defined by this protocol. During the study there will be 
several safety evaluations and the investigator and/or site staff will be responsible for 

Coronary Sinus Reducer and CMD 
 
Version 4.0 9/8/2022 
 
Page 37 of 65 
 
Confidential 
 
detecting, documenting and reporting both adverse events and serious adverse events as 
defined by this protocol. These will be reported from the signing of the informed consent 
through the 4-month visit. Serious adverse events will be reported from the signing of the 
informed consent through the 4 month visit as well. Investigators will report any procedure or 
hospitalization to the Sponsor-Investigator to ensure any event needing adjudication can be 
done so in a timely fashion.  
13.1  Definitions 
Unanticipated Problems Involving Risk to Subjects or Others (UPIRTSO) 
Any unanticipated problem or adverse event that meets the following three criteria:  
• Serious: Serious problems or events that results in significant harm, (which may be 
physical, psychological, financial, social, economic, or legal) or increased risk for the 
subject or others (including individuals who are not research subjects). These include: 
(1) death; (2) life threatening adverse experience; (3) hospitalization - inpatient, new, or 
prolonged; (4) disability/incapacity - persistent or significant; (5) birth defect/anomaly; 
(6) breach of confidentiality and (7) other problems, events, or new information (i.e. 
publications, interim findings, product labeling change) that in the opinion of the local 
investigator may adversely affect the rights, safety, or welfare of the subjects or others, 
or substantially compromise the research data, AND 
• Unanticipated: (i.e. unexpected) problems or events are those that are not already 
described as potential risks in the protocol, and consent document, or not part of an 
underlying disease. A problem or event is "unanticipated" when it was unforeseeable at 
the time of its occurrence. A problem or event is "unanticipated" when it occurs at an 
increased frequency or at an increased severity than expected, AND 

Coronary Sinus Reducer and CMD 
 
Version 4.0 9/8/2022 
 
Page 38 of 65 
 
Confidential 
 
• Related: A problem or event is "related" if it is possibly related to the research 
procedures. 
• Unanticipated Adverse Device Effect: 
Any serious adverse effect on health or safety or any life-threatening problem or death 
caused by, or associated with, a device, if that effect, problem, or death was not 
previously identified in nature, severity, or degree of incidence in the investigational 
plan or application (including a supplementary plan or application), or any other 
unanticipated serious problem associated with a device that relates to the rights, safety, 
or welfare of subjects. In the event of attempted device implant with circumstances that 
prevent implant due to malfunction or deficiency the  unused devices will be retained 
until arrangements for its collection are made  and can be returned to Neovasc for 
further analysis and investigation. 
 
There are several inherent risks associated with this protocol that must be considered. There 
are risks associated with the various study procedures including cardiac catheterization, CS 
Reducer implantation, invasive coronary reactivity testing, and exercise testing.  
 
Contemporary overall rates of major complications (death/ myocardial infarction/ stroke/ 
unplanned coronary bypass grafting/ pericardial effusion) related to diagnostic cardiac 
catheterization procedures at our institution are extremely low (<1 per 1000 left heart 
catheterization) 49. Second, coronary reactivity testing is a safe procedure with <1/100 risk of 
severe adverse events (coronary artery dissection and myocardial infarction) 50. Third, in the 
largest available database (REDUCE study), CS Reducer implantation procedure was also 
shown to be a safe procedure with no CS perforations, cardiac tamponade, peri-procedural 

Coronary Sinus Reducer and CMD 
 
Version 4.0 9/8/2022 
 
Page 39 of 65 
 
Confidential 
 
death or myocardial infarction reported in the largest database available at 14 months median 
follow-up 41. Lastly, exercise testing may pose a minimal risk to patients if they were to 
develop arrhythmias during the testing. This risk is minimal, and the room in which EBEST is 
performed, and personnel performing testing will be equipped to handle any potential 
complications. 
13.2 
Adverse Event 
An adverse event will be defined as any medical occurrence in a subject or clinical investigation 
subject that is temporally associated with use of the medicinal product, whether or not it is 
considered related to the medicinal product. This is thus any unfavorable or unintended sign, 
such as abnormal symptoms, laboratory values, or new disease, which can be associated with 
the CS Reducer implantation by temporal association.  
13.3 
Serious Adverse Event 
Adverse events are classified as serious or non-serious. Serious problems/events can be well 
defined and include; 
• Death 
• Myocardial infarction 
• Stroke 
• Life threatening adverse procedural or periprocedural complications 
• Any hospitalizations post CS Reducer implantation 
• Inpatient, new, or prolonged; disability/incapacity 
 

Coronary Sinus Reducer and CMD 
 
Version 4.0 9/8/2022 
 
Page 40 of 65 
 
Confidential 
 
and/or per protocol may be problems/events that in the opinion of the sponsor-investigator 
may have adversely affected the rights, safety, or welfare of the subjects or others, or 
substantially compromised the research data. Serious adverse events are ones that may result 
in death or can be life-threatening, requires extended hospitalization, significant disability, 
meaning a substantial disruption to the person’s ability to conduct normal life functions. This 
excludes experiences of minor medical significance such as headache, nausea, vomiting, 
influenza, diarrhea, accidental trauma, which may disrupt daily functions but is not 
substantial. Medical or scientific judgment should be exercised when deciding whether 
reporting is appropriate in situations.  
 
All adverse events that do not meet any of the criteria for serious, should be regarded as non-
serious adverse events.  
13.4 
Adverse Event Reporting Period 
Serious adverse events should be reported using  the Serious Adverse Event Report Form 
within 24 hours of study personnel becoming aware of an event. This data must be entered 
into the electronic capture system within 24 hours as well.  
 
If serious adverse event results in death or is considered to be related to the study device, then 
the medical monitor must be contacted immediately. 
The follow-up period is defined as 4 months following CS Reducer implant. This is the study 
period during which adverse events must be reported.  

Coronary Sinus Reducer and CMD 
 
Version 4.0 9/8/2022 
 
Page 41 of 65 
 
Confidential 
 
13.5 
Preexisting Condition 
A preexisting condition is one that is present at the start of the study.  A preexisting condition 
should be recorded as an adverse event if the frequency, intensity, or the character of the 
condition worsens during the study period. 
13.6 
General Physical Examination Findings 
At screening, any clinically significant abnormality should be recorded as a preexisting 
condition.  At the end of the study, any new clinically significant findings/abnormalities that 
meet the definition of an adverse event must also be recorded and documented as an adverse 
event.  
13.7 
Post-study Adverse Event 
All unresolved adverse events should be followed by the sponsor-investigator until the events 
are resolved, the subject is lost to follow-up, or the adverse event is otherwise explained.  At 
the last scheduled visit, the sponsor-investigator should instruct each subject to report, to the 
sponsor-investigator, any subsequent event(s) that the subject, or the subject’s personal 
physician, believes might reasonably be related to participation in this study.  
13.8 
Patients on Anticoagulants and Antiplatelets 
Patients on warfarin will hold their medication prior to procedure or reduce their dose as 
directed by their primary provider. They will then have an INR checked on evaluation. 
Patients with an INR less than 1.4 will undergo CS Reducer implantation and invasive 
coronary reactivity testing. Those with an INR >1.4, will be asked to hold their warfarin for 
additional time until the INR is less than 1.4, and then the procedure will be undertaken.  

Coronary Sinus Reducer and CMD 
 
Version 4.0 9/8/2022 
 
Page 42 of 65 
 
Confidential 
 
Novel anticoagulant medications will be held 3-5 days prior to procedure as mandated by 
laboratory protocol.  
 
While antiplatelet therapy may increase the bleeding risk, it will not preclude enrollment in 
the study. Given the nature of patients seen in the cardiac catheterization laboratory, many are 
on antiplatelet therapy, and it is preferred that patients have antiplatelet therapy prior to 
initiation of the procedure. For these reasons we will plan on continuing antiplatelet therapy.  
13.9 
Hospitalization, Prolonged Hospitalization or Surgery 
Any adverse event that results in hospitalization or prolonged hospitalization should be 
documented and reported as a serious adverse event unless specifically instructed otherwise in 
this protocol. Any condition responsible for surgery should be documented as an adverse 
event if the condition meets the criteria for an adverse event.  
 
Neither the condition, hospitalization, prolonged hospitalization, nor surgery are reported as 
an adverse event in the following circumstances. Hospitalizations that do not  necessitate 
reporting as adverse events, including those that are scheduled as a part of the study or as a 
part of the predetermined care of the patient, or hospitalization for preexisting conditions, 
including elective surgical procedures. These include: 
• Hospitalization or prolonged hospitalization for diagnostic or elective surgical 
procedures for a preexisting condition. Surgery should not be reported as an outcome of 
an adverse event if the purpose of the surgery was elective or diagnostic and the outcome 
was uneventful. 
• Hospitalization or prolonged hospitalization required to allow efficacy measurement for 
the study. 

Coronary Sinus Reducer and CMD 
 
Version 4.0 9/8/2022 
 
Page 43 of 65 
 
Confidential 
 
• Hospitalization or prolonged hospitalization for therapy of the target disease of the study, 
unless it is a worsening or increase in frequency of hospital admissions as judged by the 
clinical investigator. 
13.10  Recording of Adverse Events 
At each contact with the subject, the study team must seek information on adverse events by 
specific questioning and, as appropriate, by examination. Information on all adverse events 
should be recorded immediately in the source document, and also in the appropriate adverse 
event section of the case report form (CRF) or in a separate adverse event worksheet. All 
clearly related signs, symptoms, and abnormal diagnostic, laboratory or procedure results 
should be recorded in the source document. 
 
All adverse events occurring during the study period must be recorded.  The clinical course of 
each event should be followed until resolution, stabilization, or until it has been ultimately 
determined that the study device or participation is not the probable cause.  Serious adverse 
events that are still ongoing at the end of the study period must be followed up, to determine 
the final outcome.  Any serious adverse event that occurs after the study period and is 
considered to be at least possibly related to the study treatment or study participation should 
be recorded and reported immediately. 
13.11  Reporting of Serious Adverse Events and Unanticipated Problems 
When an adverse event has been identified, the study team will take appropriate action 
necessary to protect the study participant and then complete the Study Adverse Event 
Worksheet and log.  The sponsor-investigator will evaluate the event and determine the 
necessary follow-up and reporting required. 

Coronary Sinus Reducer and CMD 
 
Version 4.0 9/8/2022 
 
Page 44 of 65 
 
Confidential 
 
13.12  Sponsor-Investigator reporting: notifying the Mayo IRB 
The sponsor-investigator will report to the Mayo IRB any UPIRTSOs and Non-UPIRTSOs 
according to the Mayo IRB Policy and Procedures. All serious adverse events must be 
reported in writing to both the Institutional Review Board by the investigator himself as 
institutional policies mandate. The investigator must then provide a summary describing the 
SAE in detail and his assessment of how related the event is to the study device. The 
documentation related to the SAE must follow the initial SAE report immediately as 
available. As new information becomes available to the investigator, the investigator must 
continue to collect and forward this information,and provide a corresponding follow-up 
summary.  
 
Information collected on the adverse event worksheet (and entered in the research database):  
• Subject’s name:  
• Medical record number:  
• Disease/histology (if applicable):  
• The date the adverse event occurred:  
• Description of the adverse event:  
• Relationship of the adverse event to the research (device, procedure):  
• If the adverse event was expected:  
• The severity of the adverse event: (use a table to define severity scale 1-5) 
• If any intervention was necessary:  
• Resolution: (was the incident resolved spontaneously, or after discontinuing treatment) 
• Date of Resolution:  
 

Coronary Sinus Reducer and CMD 
 
Version 4.0 9/8/2022 
 
Page 45 of 65 
 
Confidential 
 
The sponsor-investigator will review all adverse event reports to determine if specific reports 
need to be made to the IRB and FDA. The sponsor-investigator will sign and date the adverse 
event report when it is reviewed. For this protocol, only directly related SAEs/UPIRTSOs will 
be reported to the IRB. 
13.13 Sponsor-Investigator reporting: Notifying the FDA 
The sponsor-investigator will report to the FDA any unanticipated adverse device events and 
the reviewing IRB as well as all participating investigators within 10 working days after the 
Sponsor-Investigator is aware of the occurrence. 
 
The sponsor-investigator will submit annual progress reports to FDA which will include a 
summary of progress to date, a summary of results, a summary of anticipated and 
unanticipated adverse effects, any deviation from the protocol, any minor change to the 
protocol, and any changes to the risk analysis. State any future plans including any anticipated 
changes to the investigation and include any resulting publications from the study.  
 
 
 
Any clinically important increase in the rate of serious suspected adverse reactions over those 
listed in the protocol or product insert will be reported as a serious suspected adverse reaction.  
This will be reported to both the Institutional Review Board by the investigator himself as 
institutional policies mandate  after the sponsor-investigator’s initial receipt of the information 
about the event. 
 

Coronary Sinus Reducer and CMD 
 
Version 4.0 9/8/2022 
 
Page 46 of 65 
 
Confidential 
 
13.14  Stopping Rules  
The principal investigator will review all serious adverse events and be involved in the 
decision to stop the study. The study will be stopped if 3/5 patients experience serious adverse 
events deemed secondary to the study device, including death, cardiovascular mortality, 
bleeding, stroke or sepsis thought to be secondary to CS Reducer implantation. Given that the 
CS Reducer has no FDA approved indication yet, and to ensure independent review and 
reporting of adverse events and determine if study stopping criteria have been met, a DSMB 
committee will be formed. The committee will be formed of 3 independent members: Dr. 
Charanjit S. Rihal, an independent interventional and structural heart disease expert will be a 
member and chair the committee, and the remaining 2 members will be an independent 
cardiologist who evaluates and manages patients with coronary microvascular dysfunction at 
Mayo Chest Pain Clinic, and an independent Mayo Clinic statistician. These members will be 
named prior to initiation of the study.  
 
13.15  Medical Monitoring 
It is the responsibility of the sponsor-investigator to oversee the safety of the study. This 
safety monitoring will include careful assessment and appropriate reporting of adverse events 
as noted above, as well as the construction and implementation of a site data and safety-
monitoring plan (see section 17 below; Study Monitoring, Auditing, and Inspecting). Medical 
monitoring will include a regular assessment of the number and type of serious adverse 
events. 

Coronary Sinus Reducer and CMD 
 
Version 4.0 9/8/2022 
 
Page 47 of 65 
 
Confidential 
 
14- Data Handling and Record Keeping 
The data collection tool for this study will be sponsor-investigator defined case report forms. 
The investigator will maintain complete and accurate study documentation in a separate file. 
Study documentation may include medical records, records detailing the progress of the study 
for each subject, signed informed consent forms, study device disposition records, 
correspondence with the study coordinator study monitor/sponsor, screening and consent 
information, severe adverse event reports, laboratory reports, subject diaries, data clarifications 
requested by the sponsor, and any other documentation deemed relevant and pertinent to the 
study and the study subjects.  Subject data necessary for analysis and reporting will be entered 
into a validated database or data system in accordance. Clinical data management will be 
performed in accordance with applicable data management vendor standards and data cleaning 
procedures. The investigator is responsible for the procurement of data and for the quality of 
data recorded on the CRFs. The handling of data by the sponsor-investigator, including data 
quality assurance, will comply with regulatory guidelines (e.g., ICH GCP) and the standard 
operating procedures of the sponsor. 
14.1  Confidentiality 
Information about study subjects will be kept confidential and managed according to the 
requirements of the Health Insurance Portability and Accountability Act of 1996 (HIPAA). 
Those regulations require a signed subject authorization informing the subject of the 
following:  
• What protected health information (PHI) will be collected from subjects in this study 
• Who will have access to that information and why 
• Who will use or disclose that information 

Coronary Sinus Reducer and CMD 
 
Version 4.0 9/8/2022 
 
Page 48 of 65 
 
Confidential 
 
• The rights of a research subject to revoke their authorization for use of their PHI.  
In the event that a subject revokes authorization to collect or use PHI, the investigator, by 
regulation, retains the ability to use all information collected prior to the revocation of subject 
authorization. For subjects that have revoked authorization to collect or use PHI, attempts 
should be made to obtain permission to collect at least vital status (long term survival status 
that the subject is alive) at the end of their scheduled study period. 
14.2  Source Documents 
Source data is all information, original records of clinical findings, observations, or other 
activities in a clinical trial necessary for the reconstruction and evaluation of the trial. Source 
data are contained in source documents. Examples of these original documents, and data 
records include: hospital records, clinical and office charts, laboratory notes, memoranda, 
subjects’ diaries or evaluation checklists, pharmacy dispensing records, recorded data from 
automated instruments, copies or transcriptions certified after verification as being accurate 
and complete, microfiches, photographic negatives, microfilm or magnetic media, x-rays, 
subject files, and records kept at the pharmacy, at the laboratories, and at medico-technical 
departments involved in the clinical trial. 
14.3  Case Report Forms 
The study case report form (CRF) is the primary data collection instrument for the study. All 
data requested on the CRF must be recorded. All missing data must be explained. If a space 
on the CRF is left blank because the procedure was not done or the question was not asked, 
write “N/D”. If the item is not applicable to the individual case, write “N/A”. All entries 
should be printed legibly in black ink. If any entry error has been made, to correct such an 
error, draw a single straight line through the incorrect entry and enter the correct data above it. 

Coronary Sinus Reducer and CMD 
 
Version 4.0 9/8/2022 
 
Page 49 of 65 
 
Confidential 
 
All such changes must be initialed and dated. Do not erase or use “white-out” for errors. For 
clarification of illegible or uncertain entries, print the clarification above the item, then initial 
and date it. If the reason for the correction is not clear or needs additional explanation, neatly 
include the details to justify the correction. 
15- Data Management 
15.1  Data Quality Assurance 
There will be computerized checks that ensure data integrity. These will be reviewed by a 
clinical research coordinator for fidelity. Source document verification will be performed to 
ensure data fidelity as well. To ensure compliance with GCP and all applicable regulatory 
requirements, the sponsor-investigator or designee may conduct a quality assurance audit. 
Regulatory agencies may also conduct a regulatory inspection of this study. 
 
Such audits/inspections can occur at any time during or after completion of the study. If an 
audit or inspection occurs, the investigator and institution agree to allow the auditor/inspector 
direct access to all relevant documents and to allocate his/her time and the time of his/her staff 
to the auditor/inspector to discuss findings and any relevant issues. 
15.2  Data Clarification Process 
All data queries will be recorded by the clinical study coordinator and reviewed by the study 
investigator.  
15.3  Records Retention 
The sponsor-investigator will maintain records and essential documents related to the conduct 
of the study. These will include subject case histories and regulatory documents. These will 

Coronary Sinus Reducer and CMD 
 
Version 4.0 9/8/2022 
 
Page 50 of 65 
 
Confidential 
 
be in the form of locked excel files and on a secure server that is password protected. Subject 
names or other directly identifiable information will not appear on any reports, publications or 
other disclosures of clinical study outcomes. These materials will be coded by a subject 
identification code list, and will be stored on a single secure server, to protect the subjects’ 
confidentiality.  
 
The sponsor-investigator will retain the specified records and reports for; 
1. Up to 2 years after the marketing application is approved for the device; or, if a 
marketing application is not submitted or approved for the device, until 2 years after 
shipment and delivery of the device for investigational use is discontinued and the FDA 
has been so notified. OR 
2. As outlined in the Mayo Clinic Research Policy Manual –“Retention of and Access to 
Research Data Policy” http://mayocontent.mayo.edu/research-policy/MSS_669717   
16- Study Monitoring, Auditing, and Inspecting 
16.1  Study Monitoring Plan 
The investigator will allocate adequate time for such monitoring activities. The Investigator 
will also ensure that the monitor or other compliance or quality assurance reviewer is given 
access to all the study-related documents and study related facilities (e.g. catheterization 
laboratory, etc.), and has adequate space to conduct the monitoring visit. 
 
All SAEs will be reported to the IRB within 24 hours. Based on our previous studies we 
anticipate rate of approximately 1% risk of mainly a reversible coronary spasm and 

Coronary Sinus Reducer and CMD 
 
Version 4.0 9/8/2022 
 
Page 51 of 65 
 
Confidential 
 
hematomas and less than 1% for bleeding. Screening and application of exclusion criteria will 
minimize potential risks. 
 
As a service to the sponsor-investigator, this study may be monitored during the conduct of 
the trial by staff from the Mayo Clinic Office of Research Regulatory Support. Clinical trial 
monitoring may include review of the study documents and data generated throughout the 
duration of the study to help ensure the validity and integrity of the data along with the 
protection of human research subjects. This will assist sponsor-investigators in complying 
with Food and Drug Administration regulations. 
16.2  Auditing and Inspecting 
The investigator will permit study-related monitoring, audits, and inspections by the IRB, , 
and government regulatory agencies, of all study related documents (e.g. source documents, 
regulatory documents, data collection instruments, study data etc.). The investigator will 
ensure the capability for inspections of applicable study-related facilities (e.g. catheterization 
laboratory, etc.). 
 
Participation as an investigator in this study implies acceptance of potential inspection by 
government regulatory authorities and applicable compliance offices. 
17- Ethical Considerations 
This study is to be conducted according to United States government regulations and 
Institutional research policies and procedures. 
 

Coronary Sinus Reducer and CMD 
 
Version 4.0 9/8/2022 
 
Page 52 of 65 
 
Confidential 
 
This protocol and any amendments will be submitted to a properly constituted local 
Institutional Review Board (IRB), in agreement with local legal prescriptions, for formal 
approval of the study. The decision of the IRB concerning the conduct of the study will be 
made in writing to the sponsor-investigator before commencement of this study. 
 
All subjects for this study will be provided a consent form describing this study and providing 
sufficient information for subjects to make an informed decision about their participation in 
this study. This consent form will be submitted with the protocol for review and approval by 
the IRB for the study. The formal consent of a subject, using the Approved IRB consent form, 
must be obtained before that subject undergoes any study procedure. The consent form must 
be signed by the subject or the subject’s legally authorized representative, and the individual 
obtaining the informed consent. 
18- Study Finances 
18.1  Funding Source 
This study is financed by a Small Business Innovation Research Grant through the National 
Institute of Health.  
18.2  Conflict of Interest 
Royalties, or financial gain greater than the minimum allowable by their institution, etc.) must 
have the conflict reviewed by a properly constituted Conflict of Interest Committee with a 
Committee-sanctioned conflict management plan that has been reviewed and approved by the 
study sponsor-investigator prior to participation in this study. 

Coronary Sinus Reducer and CMD 
 
Version 4.0 9/8/2022 
 
Page 53 of 65 
 
Confidential 
 
19- Publication Plan 
There are no specific publication policy requirements of the sponsor-investigator, other 
investigators or funding agency. The primary responsibility for publication of the results of 
the study belongs to the Principal Investigator. Any information from this study can be used 
or passed onto a third party only after approval from the principal investigator. The 
registration of the study to ClinicalTrials.gov will occur prior to subject recruitment and 
enrollment. Posting of results to ClinicalTrials.gov will be done within 12 months of final 
data collection for the primary outcome. 
 
 

Coronary Sinus Reducer and CMD 
 
Version 4.0 9/8/2022 
 
Page 54 of 65 
 
Confidential 
 
20- References  
1. 
Jespersen L, Hvelplund A, Abildstrom SZ, Pedersen F, Galatius S, Madsen JK, 
Jorgensen E, Kelbaek H and Prescott E. Stable angina pectoris with no obstructive 
coronary artery disease is associated with increased risks of major adverse 
cardiovascular events. European heart journal. 2012;33:734-44. 
2. 
Patel MR, Peterson ED, Dai D, Brennan JM, Redberg RF, Anderson HV, Brindis 
RG and Douglas PS. Low diagnostic yield of elective coronary angiography. The New 
England journal of medicine. 2010;362:886-95. 
3. 
Ford TJ, Yii E, Sidik N, Good R, Rocchiccioli P, McEntegart M, Watkins S, Eteiba 
H, Shaukat A, Lindsay M, Robertson K, Hood S, McGeoch R, McDade R, McCartney 
P, Corcoran D, Collison D, Rush C, Stanley B, McConnachie A, Sattar N, Touyz RM, 
Oldroyd KG and Berry C. Ischemia and No Obstructive Coronary Artery Disease: 
Prevalence and Correlates of Coronary Vasomotion Disorders. Circ Cardiovasc Interv. 
2019;12:e008126. 
4. 
Sara JD, Widmer RJ, Matsuzawa Y, Lennon RJ, Lerman LO and Lerman A. 
Prevalence of Coronary Microvascular Dysfunction Among Patients With Chest Pain 
and Nonobstructive Coronary Artery Disease. JACC Cardiovascular interventions. 
2015;8:1445-53. 
5. 
Herrmann J, Kaski JC and Lerman A. Coronary microvascular dysfunction in 
the clinical setting: from mystery to reality. European heart journal. 2012;33:2771-
2782b. 
6. 
AlBadri A, Bairey Merz CN, Johnson BD, Wei J, Mehta PK, Cook-Wiens G, Reis 
SE, Kelsey SF, Bittner V, Sopko G, Shaw LJ, Pepine CJ and Ahmed B. Impact of 

Coronary Sinus Reducer and CMD 
 
Version 4.0 9/8/2022 
 
Page 55 of 65 
 
Confidential 
 
Abnormal Coronary Reactivity on Long-Term Clinical Outcomes in Women. Journal of 
the American College of Cardiology. 2019;73:684-693. 
7. 
Britten MB, Zeiher AM and Schachinger V. Microvascular dysfunction in 
angiographically normal or mildly diseased coronary arteries predicts adverse 
cardiovascular long-term outcome. Coronary artery disease. 2004;15:259-64. 
8. 
Marinescu MA, Loffler AI, Ouellette M, Smith L, Kramer CM and Bourque JM. 
Coronary microvascular dysfunction, microvascular angina, and treatment strategies. 
JACC Cardiovascular imaging. 2015;8:210-20. 
9. 
Marks DS, Gudapati S, Prisant LM, Weir B, diDonato-Gonzalez C, Waller JL 
and Houghton JL. Mortality in patients with microvascular disease. Journal of clinical 
hypertension (Greenwich, Conn). 2004;6:304-9. 
10. 
Pepine CJ, Anderson RD, Sharaf BL, Reis SE, Smith KM, Handberg EM, 
Johnson BD, Sopko G and Bairey Merz CN. Coronary microvascular reactivity to 
adenosine predicts adverse outcome in women evaluated for suspected ischemia 
results from the National Heart, Lung and Blood Institute WISE (Women's Ischemia 
Syndrome Evaluation) study. Journal of the American College of Cardiology. 
2010;55:2825-32. 
11. 
Widmer RJ, Samuels B, Samady H, Price MJ, Jeremias A, Anderson RD, Jaffer 
FA, Escaned J, Davies J, Prasad M, Grines C and Lerman A. The functional 
assessment of patients with non-obstructive coronary artery disease: expert review 
from an international microcirculation working group. EuroIntervention. 2019;14:1694-
1702. 

Coronary Sinus Reducer and CMD 
 
Version 4.0 9/8/2022 
 
Page 56 of 65 
 
Confidential 
 
12. 
Taqueti VR and Di Carli MF. Coronary Microvascular Disease Pathogenic 
Mechanisms and Therapeutic Options: JACC State-of-the-Art Review. Journal of the 
American College of Cardiology. 2018;72:2625-2641. 
13. 
Camici PG and Crea F. Coronary microvascular dysfunction. The New England 
journal of medicine. 2007;356:830-40. 
14. 
Ford TJ, Stanley B, Good R, Rocchiccioli P, McEntegart M, Watkins S, Eteiba 
H, Shaukat A, Lindsay M, Robertson K, Hood S, McGeoch R, McDade R, Yii E, Sidik 
N, McCartney P, Corcoran D, Collison D, Rush C, McConnachie A, Touyz RM, Oldroyd 
KG and Berry C. Stratified Medical Therapy Using Invasive Coronary Function Testing 
in Angina: The CorMicA Trial. Journal of the American College of Cardiology. 
2018;72:2841-2855. 
15. 
Ford TJ, Stanley B, Sidik N, Good R, Rocchiccioli P, McEntegart M, Watkins S, 
Eteiba H, Shaukat A, Lindsay M, Robertson K, Hood S, McGeoch R, McDade R, Yii E, 
McCartney P, Corcoran D, Collison D, Rush C, Sattar N, McConnachie A, Touyz RM, 
Oldroyd KG and Berry C. 1-Year Outcomes of Angina Management Guided by Invasive 
Coronary Function Testing (CorMicA). JACC Cardiovasc Interv. 2020;13:33-45. 
16. 
Davies JE, Sen S, Dehbi HM, Al-Lamee R, Petraco R, Nijjer SS, Bhindi R, 
Lehman SJ, Walters D, Sapontis J, Janssens L, Vrints CJ, Khashaba A, Laine M, Van 
Belle E, Krackhardt F, Bojara W, Going O, Harle T, Indolfi C, Niccoli G, Ribichini F, 
Tanaka N, Yokoi H, Takashima H, Kikuta Y, Erglis A, Vinhas H, Canas Silva P, Baptista 
SB, Alghamdi A, Hellig F, Koo BK, Nam CW, Shin ES, Doh JH, Brugaletta S, Alegria-
Barrero E, Meuwissen M, Piek JJ, van Royen N, Sezer M, Di Mario C, Gerber RT, 
Malik IS, Sharp ASP, Talwar S, Tang K, Samady H, Altman J, Seto AH, Singh J, 
Jeremias A, Matsuo H, Kharbanda RK, Patel MR, Serruys P and Escaned J. Use of 

Coronary Sinus Reducer and CMD 
 
Version 4.0 9/8/2022 
 
Page 57 of 65 
 
Confidential 
 
the Instantaneous Wave-free Ratio or Fractional Flow Reserve in PCI. The New 
England journal of medicine. 2017;376:1824-1834. 
17. 
De Bruyne B, Fearon WF, Pijls NH, Barbato E, Tonino P, Piroth Z, Jagic N, 
Mobius-Winckler S, Rioufol G, Witt N, Kala P, MacCarthy P, Engstrom T, Oldroyd K, 
Mavromatis K, Manoharan G, Verlee P, Frobert O, Curzen N, Johnson JB, Limacher 
A, Nuesch E and Juni P. Fractional flow reserve-guided PCI for stable coronary artery 
disease. The New England journal of medicine. 2014;371:1208-17. 
18. 
Gotberg M, Christiansen EH, Gudmundsdottir IJ, Sandhall L, Danielewicz M, 
Jakobsen L, Olsson SE, Ohagen P, Olsson H, Omerovic E, Calais F, Lindroos P, 
Maeng M, Todt T, Venetsanos D, James SK, Karegren A, Nilsson M, Carlsson J, Hauer 
D, Jensen J, Karlsson AC, Panayi G, Erlinge D and Frobert O. Instantaneous Wave-
free Ratio versus Fractional Flow Reserve to Guide PCI. The New England journal of 
medicine. 2017;376:1813-1823. 
19. 
Tonino PA, De Bruyne B, Pijls NH, Siebert U, Ikeno F, van' t Veer M, Klauss V, 
Manoharan G, Engstrom T, Oldroyd KG, Ver Lee PN, MacCarthy PA and Fearon WF. 
Fractional flow reserve versus angiography for guiding percutaneous coronary 
intervention. The New England journal of medicine. 2009;360:213-24. 
20. 
Eshtehardi P, Luke J, McDaniel MC and Samady H. Intravascular imaging tools 
in the cardiac catheterization laboratory: comprehensive assessment of anatomy and 
physiology. J Cardiovasc Transl Res. 2011;4:393-403. 
21. 
Williams RP, de Waard GA, De Silva K, Lumley M, Asrress K, Arri S, Ellis H, Mir 
A, Clapp B, Chiribiri A, Plein S, Teunissen PF, Hollander MR, Marber M, Redwood S, 
van Royen N and Perera D. Doppler Versus Thermodilution-Derived Coronary 
Microvascular Resistance to Predict Coronary Microvascular Dysfunction in Patients 

Coronary Sinus Reducer and CMD 
 
Version 4.0 9/8/2022 
 
Page 58 of 65 
 
Confidential 
 
With Acute Myocardial Infarction or Stable Angina Pectoris. Am J Cardiol. 2018;121:1-
8. 
22. 
Anderson JL, Adams CD, Antman EM, Bridges CR, Califf RM, Casey DE, Jr., 
Chavey WE, 2nd, Fesmire FM, Hochman JS, Levin TN, Lincoff AM, Peterson ED, 
Theroux P, Wenger NK, Wright RS, Smith SC, Jr., Jacobs AK, Adams CD, Anderson 
JL, Antman EM, Halperin JL, Hunt SA, Krumholz HM, Kushner FG, Lytle BW, 
Nishimura R, Ornato JP, Page RL and Riegel B. ACC/AHA 2007 guidelines for the 
management of patients with unstable angina/non-ST-Elevation myocardial infarction: 
a report of the American College of Cardiology/American Heart Association Task Force 
on Practice Guidelines (Writing Committee to Revise the 2002 Guidelines for the 
Management of Patients With Unstable Angina/Non-ST-Elevation Myocardial 
Infarction) developed in collaboration with the American College of Emergency 
Physicians, the Society for Cardiovascular Angiography and Interventions, and the 
Society of Thoracic Surgeons endorsed by the American Association of Cardiovascular 
and Pulmonary Rehabilitation and the Society for Academic Emergency Medicine. 
Journal of the American College of Cardiology. 2007;50:e1-e157. 
23. 
Fraker TD, Jr., Fihn SD, Gibbons RJ, Abrams J, Chatterjee K, Daley J, 
Deedwania PC, Douglas JS, Ferguson TB, Jr., Gardin JM, O'Rourke RA, Williams SV, 
Smith SC, Jr., Jacobs AK, Adams CD, Anderson JL, Buller CE, Creager MA, Ettinger 
SM, Halperin JL, Hunt SA, Krumholz HM, Kushner FG, Lytle BW, Nishimura R, Page 
RL, Riegel B, Tarkington LG and Yancy CW. 2007 chronic angina focused update of 
the ACC/AHA 2002 guidelines for the management of patients with chronic stable 
angina: a report of the American College of Cardiology/American Heart Association 
Task Force on Practice Guidelines Writing Group to develop the focused update of the 

Coronary Sinus Reducer and CMD 
 
Version 4.0 9/8/2022 
 
Page 59 of 65 
 
Confidential 
 
2002 guidelines for the management of patients with chronic stable angina. Journal of 
the American College of Cardiology. 2007;50:2264-74. 
24. 
Bairey Merz CN, Pepine CJ, Walsh MN and Fleg JL. Ischemia and No 
Obstructive Coronary Artery Disease (INOCA): Developing Evidence-Based Therapies 
and Research Agenda for the Next Decade. Circulation. 2017;135:1075-1092. 
25. 
Maas AH, Milasinovic D, Berry C and Escaned J. Microvascular Angina: 
Diagnosis, Assessment, and Treatment. 
26. 
Lerman A, Burnett JC, Jr., Higano ST, McKinley LJ and Holmes DR, Jr. Long-
term L-arginine supplementation improves small-vessel coronary endothelial function 
in humans. Circulation. 1998;97:2123-8. 
27. 
Beck CS and Leighninger DS. Scientific basis for the surgical treatment of 
coronary artery disease. J Am Med Assoc. 1955;159:1264-71. 
28. 
Wising PJ. THE BECK-I OPERATION FOR ANGINA PECTORIS: MEDICAL 
ASPECTS. Acta Med Scand. 1963;174:93-8. 
29. 
Mohl W. The development and rationale of pressure-controlled intermittent 
coronary sinus occlusion--a new approach to protect ischemic myocardium. Wien Klin 
Wochenschr. 1984;96:20-5. 
30. 
Mohl W, Simon P, Neumann F, Schreiner W and Punzengruber C. Clinical 
evaluation of pressure-controlled intermittent coronary sinus occlusion: randomized 
trial during coronary artery surgery. Ann Thorac Surg. 1988;46:192-201. 
31. 
Verheye S, Jolicoeur EM, Behan MW, Pettersson T, Sainsbury P, Hill J, Vrolix 
M, Agostoni P, Engstrom T, Labinaz M, de Silva R, Schwartz M, Meyten N, Uren NG, 
Doucet S, Tanguay JF, Lindsay S, Henry TD, White CJ, Edelman ER and Banai S. 

Coronary Sinus Reducer and CMD 
 
Version 4.0 9/8/2022 
 
Page 60 of 65 
 
Confidential 
 
Efficacy of a device to narrow the coronary sinus in refractory angina. The New 
England journal of medicine. 2015;372:519-27. 
32. 
Giannini F, Baldetti L, Ielasi A, Ruparelia N, Ponticelli F, Latib A, Mitomo S, 
Esposito A, Palmisano A, Chieffo A and Colombo A. First Experience With the 
Coronary Sinus Reducer System for the Management of Refractory Angina in Patients 
Without Obstructive Coronary Artery Disease. JACC Cardiovascular interventions. 
2017;10:1901-1903. 
33. 
De Maria GL, Alkhalil M, Borlotti A, Wolfrum M, Gaughran L, Dall'Armellina E, 
Langrish JP, Lucking AJ, Choudhury RP, Kharbanda RK, Channon KM and Banning 
AP. Index of microcirculatory resistance-guided therapy with pressure-controlled 
intermittent coronary sinus occlusion improves coronary microvascular function and 
reduces infarct size in patients with ST-elevation myocardial infarction: the Oxford 
Acute Myocardial Infarction - Pressure-controlled Intermittent Coronary Sinus 
Occlusion study (OxAMI-PICSO study). EuroIntervention. 2018;14:e352-e359. 
34. 
Ido A, Hasebe N, Matsuhashi H and Kikuchi K. Coronary sinus occlusion 
enhances coronary collateral flow and reduces subendocardial ischemia. Am J Physiol 
Heart Circ Physiol. 2001;280:H1361-7. 
35. 
Giannini F, Palmisano A, Baldetti L, Benedetti G, Ponticelli F, Rancoita PMV, 
Ruparelia N, Gallone G, Ancona M, Mangieri A, Tzanis G, De Cobelli F, Del Maschio 
A, Colombo A and Esposito A. Patterns of Regional Myocardial Perfusion Following 
Coronary Sinus Reducer Implantation. Circ Cardiovasc Imaging. 2019;12:e009148. 
36. 
Konigstein M, Bazan S, Revivo M and Banai S. Coronary Sinus Reducer 
implantation improves symptoms, ischaemia and physical capacity in patients with 

Coronary Sinus Reducer and CMD 
 
Version 4.0 9/8/2022 
 
Page 61 of 65 
 
Confidential 
 
refractory angina unsuitable for myocardial revascularisation: a single-centre 
experience. EuroIntervention. 2018;14:e452-e458. 
37. 
Konigstein M, Meyten N, Verheye S, Schwartz M and Banai S. Transcatheter 
treatment for refractory angina with the Coronary Sinus Reducer. EuroIntervention. 
2014;9:1158-64. 
38. 
Szekely Y, Topilsky Y, Bazan S, Revivo M, Banai S and Konigstein M. The 
impact of coronary sinus narrowing on diastolic function in patients with refractory 
angina. Int J Cardiol. 2019;291:8-12. 
39. 
Gori T. Coronary sinus reducer for microvascular angina. PCR Online. 2020. 
40. 
Giannini F, Aurelio A, Jabbour RJ, Ferri L, Colombo A and Latib A. The coronary 
sinus reducer: clinical evidence and technical aspects. Expert Rev Cardiovasc Ther. 
2017;15:47-58. 
41. 
Giannini F, Baldetti L, Konigstein M, Rosseel L, Ruparelia N, Gallone G, 
Colombo A, Banai S and Verheye S. Safety and efficacy of the reducer: A multi-center 
clinical registry - REDUCE study. Int J Cardiol. 2018;269:40-44. 
42. 
Giannini F, Aurelio A, Jabbour RJ, Ferri L, Colombo A and Latib A. The coronary 
sinus reducer: clinical evidence and technical aspects. Expert review of cardiovascular 
therapy. 2017;15:47-58. 
43. 
Giannini F, Tzanis G, Ponticelli F, Baldetti L, Demir OM, Mitomo S, Gallone G, 
Banai S and Colombo A. Technical aspects in coronary sinus Reducer implantation. 
EuroIntervention. 2020;15:1269-1277. 
44. 
Konigstein M, Giannini F and Banai S. The Reducer device in patients with 
angina pectoris: mechanisms, indications, and perspectives. European heart journal. 
2018;39:925-933. 

Coronary Sinus Reducer and CMD 
 
Version 4.0 9/8/2022 
 
Page 62 of 65 
 
Confidential 
 
45. 
Konigstein M, Verheye S, Jolicoeur EM and Banai S. Narrowing of the Coronary 
Sinus: A Device-Based Therapy for Persistent Angina Pectoris. Cardiol Rev. 
2016;24:238-43. 
46. 
Al Suwaidi J, Higano ST, Holmes DR, Jr., Rihal CS and Lerman A. Measuring 
maximal percent area stenosis poststent placement with intracoronary Doppler and the 
continuity equation and correlation with intracoronary ultrasound and angiography. Am 
J Cardiol. 1999;84:650-4. 
47. 
Corban MT, Prasad A, Nesbitt L, Loeffler D, Herrmann J, Lerman LO and 
Lerman A. Local Production of Soluble Urokinase Plasminogen Activator Receptor and 
Plasminogen Activator Inhibitor-1 in the Coronary Circulation Is Associated With 
Coronary Endothelial Dysfunction in Humans. J Am Heart Assoc. 2018;7:e009881. 
48. 
Doucette JW, Corl PD, Payne HM, Flynn AE, Goto M, Nassi M and Segal J. 
Validation of a Doppler guide wire for intravascular measurement of coronary artery 
flow velocity. Circulation. 1992;85:1899-911. 
49. 
Al-Hijji MA, Lennon RJ, Gulati R, El Sabbagh A, Park JY, Crusan D, Kanwar A, 
Behfar A, Lerman A, Holmes DR, Bell M and Singh M. Safety and Risk of Major 
Complications With Diagnostic Cardiac Catheterization. Circ Cardiovasc Interv. 
2019;12:e007791. 
50. 
Wei J, Mehta PK, Johnson BD, Samuels B, Kar S, Anderson RD, Azarbal B, 
Petersen J, Sharaf B, Handberg E, Shufelt C, Kothawade K, Sopko G, Lerman A, Shaw 
L, Kelsey SF, Pepine CJ and Merz CN. Safety of coronary reactivity testing in women 
with no obstructive coronary artery disease: results from the NHLBI-sponsored WISE 
(Women's Ischemia Syndrome Evaluation) study. JACC Cardiovascular interventions. 
2012;5:646-53. 

Coronary Sinus Reducer and CMD 
 
Version 4.0 9/8/2022 
 
Page 63 of 65 
 
Confidential