Efficacy of the COronary SInus Reducer in Patients With Refractory Angina II

Inclusion Criteria:

1. Subject is older than 18 years of age

2. Symptomatic coronary artery disease (CAD) with greater than or equal to 90 days ofpersistent refractory angina pectoris classified as CCS Grade III or IV despitemaximally tolerated guideline directed medical therapy as determined by the localheart team and confirmed by a Central Screening Eligibility Committee Note: subjectsmay also have exertional dyspnea, but the symptoms that limit activity must beanginal in nature (including chest pain, pressure, heaviness, discomfort, with orwithout radiation to the neck, jaw, shoulders, arms, or other location) and notdyspnea

3. Must have attempted treatment with the maximally tolerated dose of at least three ofthe four (preferably all four) approved classes of anti-anginal agents: long-actingnitrates, calcium channel blockers (either a dihydropyridine or anon-dihydropyridine), beta blockers, and ranolazine. The regimen must be stable forat least 30 days prior to enrollment, must remain stable from enrollment torandomization, and there must be no intent to change the medical regimen for atleast 12 months after randomization Note: If the dose of a medication was increasedor decreased for a temporary period and then returned to the original dose, whichwill then be continued for at least 12 months after randomization, the subject maybe immediately enrolled without needing to otherwise requalify

4. Subject has either no treatment options for revascularization by coronary arterybypass grafting or by percutaneous coronary intervention, or is otherwise unsuitableor high risk for revascularization as determined by the local heart team, andconfirmed by a Central Screening Eligibility Committee

5. Evidence of either exercise or pharmacologically induced reversible ischemiaseverity by stress echo, nuclear study, PET, perfusion MRI, CT perfusion, FFR-CT,FFR, iFR, or other non-hyperemic FDA approved tests (such as diastolic hyperaemiafree ratio [DRF] or resting full-cycle ratio [RFR] in the distribution of the leftcoronary artery (LCA), performed within 12 months prior to enrollment and while thepatient is maintained on their stable regimen of maximally tolerated doses ofanti-anginal medications Note: If the subject has evidence of ischemia in both theLCA and RCA distributions, the extent of ischemia must be greater in the LCAdistribution Note: The qualifying assessment must be performed after any myocardialinfarction, CABG, or successful PCI within the prior 12 months. If the anti-anginalmedication regimen is permanently changed after the assessment of ischemia, the testmust be repeated. For subjects with multiple assessments, the one performed closestto enrollment will serve as the qualifying study

6. Functional limitation due to refractory angina as defined by a modified Bruceexercise tolerance test duration of greater than or equal to 2 minutes but less thanor equal to 10 minutes, performed while the subject is maintained on their stableregimen of maximally tolerated doses of anti-anginal medications Note: The ETTvariability must be less than 20% between last two ETTs performed.

7. Left ventricular ejection fraction (LVEF) greater than or equal to 30% within the 12-months prior to enrollment Note: The LVEF must be reassessed after anyintervening myocardial infarction. For subjects with multiple assessments, the mostrecent LVEF assessment is used as the qualifying test.

8. Subject is willing and able to sign informed consent

9. Subject is willing to comply with the specified follow-up evaluations

Angiographic Inclusion Criteria:

1. Three-vessel coronary angiography performed within 12 months prior to enrollment demonstrating obstructive CAD (visually estimated diameter stenosis of ≥70% or ≥50% - <70% with fractional flow reserve (FFR) value of ≤0.80 or an iFR or other FDA-approved/cleared non-hyperemic physiological assessment (such as DFR or RFR) of ≤0.89 in one or more lesions) in the left coronary artery (main epicardial vessels or branches) that is not suitable for and will not be treated with PCI or CABG as determined by the local heart team Note: The qualifying 3-vessel angiogram must be performed after any myocardial infarction, PCI, or CABG within the 12 months prior to enrollment. For patients with multiple 3-vessel angiograms, the one performed closest to enrollment will serve as the qualifying study

Exclusion Criteria:

1. Recent (within 30 days prior to enrollment) troponin or CKMB positive acute coronarysyndrome (NSTEMI or STEMI) Note: subjects with an elevated troponin or CKMB withoutacute coronary syndrome may still be enrolled

2. Recent successful revascularization by either CABG or PCI within six months prior toenrollment Note: Successful revascularization is defined as any CABG procedure, or any PCIprocedure with a reduction of one or more lesions to <50% diameter stenosis Note: Subjects with successful revascularization by either CABG or PCI that occurredless than six months prior to enrollment may still be approved for participation inthe trial if revascularization was completed six months prior to procedure and CSECapproves subject participation

3. Recent unsuccessful PCI (e.g., failed attempt to open a chronic total occlusion)within 30 days prior to enrollment Note: Subjects with unsuccessful PCI that occurred less than 30 days prior toenrollment may still be approved for participation in the trial if PCI was completed 30 days prior to procedure and CSEC approves subject participation

4. The predominant manifestation of angina is dyspnea Note: some dyspnea may be present with exertion, but the predominant symptom thatlimits activity must be angina (i.e., chest pain, pressure, tightness, heaviness, ordiscomfort, with or without radiation to the neck, jaw, shoulders, arms, or otherlocation)

5. Has extra-coronary contributory causes of angina - e.g., untreated hyperthyroidism,untreated anemia (hgb <10 g/dL), uncontrolled hypertension (systolic blood pressure >160 mmHg or diastolic blood pressure >100 mmHg despite medications), atrialfibrillation with rapid ventricular response (consistently >100 bpm despitemedications) or other tachyarrhythmia, severe aortic stenosis, hypertrophiccardiomyopathy with left ventricular outflow tract obstruction or asymmetric septalhypertrophy (concentric left ventricular hypertrophy is not an exclusion criterion),or epicardial vasospasm disease/coronary artery vasospasm (CAS)/vasospastic angina (VSA)

6. NYHA Class III or IV heart failure (HF), decompensated HF or hospitalization due toHF during the 90 days prior to enrollment

7. Life threatening rhythm disorders or any rhythm disorders that would require futureplacement of an internal defibrillator and/or pacemaker

8. Severe chronic obstructive pulmonary disease (COPD) as indicated by a forcedexpiratory volume in one second (FEV1) that is less than 55% of the predicted value,or need for home daytime oxygen or oral steroids

9. Severe valvular heart disease (any valve)

10. Moderate or severe RV dysfunction by echocardiography

11. Pacemaker electrode/lead is present in the coronary sinus

12. A Class I indication is present for an implantable defibrillator or cardiacresynchronization therapy according to ACCF/AHA/HRS guidelines

13. Recent implantation of a new pacemaker or defibrillator lead with electrode in theright atrium within 90 days of enrollment

14. Chronic severe renal failure (estimated eGFR less than 30 mL/min/1.73m2 by the MDRDformula) or subjects on chronic dialysis

15. Known allergy to stainless steel or nickel

16. Any clinical condition that might interfere with the trial protocol or the subject'sability to be compliant with the trial protocol (e.g., active alcohol or drug abuse,dementia, magnetic resonances imaging (MRI) planned within 8 weeks of procedure)

17. Currently enrolled in another investigational device or drug trial that has notreached its primary endpoint or that might clinically interfere with the currenttrial endpoints or procedures

18. Pregnant or planning pregnancy within the next 12 months (women of reproductivepotential must have a negative pregnancy test within 7 days of the procedure)

19. Subject is part of a vulnerable population who, in the judgment of the investigator,is unable to give Informed Consent for reasons of incapacity, immaturity, adversepersonal circumstances or lack of autonomy. This may include individuals with mentaldisability, persons in nursing homes, children, impoverished persons, persons inemergency situations, homeless persons, nomads, refugees, and those incapable ofgiving informed consent. Vulnerable populations also may include members of a groupwith a hierarchical structure such as university students, subordinate hospital andlaboratory personnel, employees of the Sponsor, members of the armed forces, andpersons kept in detention.

20. Inability to tolerate dual antiplatelet therapy for 6 months if not on a chronicoral anticoagulant, or inability to tolerate a P2Y12 inhibitor for at least 6 monthsif on a chronic oral anticoagulant

21. Comorbidities limiting life expectancy to less than one year

22. Subject is currently hospitalized for definite or suspected COVID-19

23. Subject has previously been symptomatic with or hospitalized for COVID-19 and hasbeen asymptomatic for <8 weeks prior to enrollment or has not returned to his or herprior baseline (pre-COVID-19) clinical condition

24. Subject is asymptomatic but has had a positive PCR or antigen test for COVID-19within the past 4 weeks prior to enrollment

Angiographic/Hemodynamic Exclusion Criteria:

1. Coronary anatomy amenable to revascularization of ischemic myocardial territory by either PCI or CABG with at least moderate likelihood of long-term alleviation of angina or angina equivalent symptoms, as per the assessment of the local heart team.

Note: If a pathway to coronary revascularization is present which, in the opinion of the local heart team, is reasonably low risk and reasonably likely to provide long-term symptom relief and the subject refuses the revascularization procedure, the patient is ineligible for randomization

Procedural Angiographic/Hemodynamic Randomization Exclusion Criteria:

1. Mean right atrial pressure greater than 15 mmHg assessed during the final screeningprocedure for eligibility assessment and potential randomization

2. Anomalous or abnormal CS anatomy (e.g., tortuosity, aberrant branch, persistent leftsuperior vena cava [SVC]) as demonstrated by angiogram

3. The CS diameter at the most proximal end of the planned implant region (2-4 cmdistal to the coronary sinus ostium) is less than 9.5 mm or greater than 13.0 mm

Single-arm Registry (Unblinded, Non-Randomized Treatment Arm) Inclusion/Exclusion Criteria:

Subject can be included in the single-arm registry if they fall into one of the three categories with inclusions and exclusion criteria as described below.

Predominant right coronary disease subjects (RCA):

1. Reversible ischemia: Subjects with evidence of either exercise or pharmacologicallyinduced reversible ischemia by stress echo, nuclear study, PET, perfusion MRI, CTperfusion, FFR-CT, FFR, iFR, or other non-hyperemic FDA approved or cleared tests (such as DFR or RFR) in the distribution of the right coronary artery (RCA),performed within 12 months prior to enrollment. Note: If the subject has evidence of ischemia in both the LCA and RCA distributions,the extent of ischemia must be greater in the RCA distribution Note: The qualifying assessment must be performed after any myocardial infarction,CABG, or successful PCI within the prior 12 months. If the anti-anginal medicationregimen is permanently changed after the assessment of ischemia, the test must berepeated. For subjects with multiple assessments, the one performed closest toenrollment will serve as the qualifying study

2. Obstructive CAD: Three-vessel coronary angiography performed within the 12 monthsprior to enrollment demonstrating obstructive CAD (visually assessed diameterstenosis of ≥70% or ≥50% - <70% with fractional flow reserve (FFR) value of ≤0.80 oran iFR or other FDA-approved/cleared non-hyperemic physiological assessment (such asDFR or RFR) of ≤0.89 in one or more lesions) in the RCA (main epicardial vessels orbranches) that is not suitable for and will not be treated with PCI or CABG asdetermined by the local heart team. Note: The qualifying assessment must be performed after any myocardial infarction,PCI or CABG within the prior 12 months. For subjects with multiple assessments, theone performed closest to enrollment will serve as the qualifying study

3. In addition to the above inclusion criteria, subjects must meet all inclusioncriteria (except clinical inclusion #5 and angiographic inclusion #1) and none ofthe exclusion criteria of the main randomized trial

Non-obstructive coronary artery disease subjects (ANOCA)

1. Abnormal Coronary Flow Reserve (CFR): subjects must have either abnormal PET CFR (< 2.0) or abnormal invasive CFR (<2.5) in at least one main epicardial coronary arteryperformed within 12 months prior to enrollment Note: Subjects may or may not have evidence of either exercise or pharmacologicallyinduced reversible ischemia by stress echo, nuclear study, PET, perfusion MRI, or CTperfusion

2. Non-obstructive CAD: subjects have non-obstructive coronary disease (estimateddiameter stenosis in all coronary lesions is <50% and (if performed) FFR ≥0.81 or anon-hyperemic test is ≥0.90) demonstrated on three-vessel coronary angiographyperformed within the 12 months prior to enrollment. If an estimated diameterstenosis is ≥50% to <70%, the patient may still qualify if FFR ≥0.81 or anon-hyperemic test is ≥0.90 in that vessel. If both FFR and a non-hyperemic test areperformed, both must be negative. Note: The qualifying 3-vessel angiogram must be performed after any myocardialinfarction, PCI or CABG within the 12 months prior to enrollment. For patients withmultiple 3-vessel angiograms, the one performed closest to enrollment will serve asthe qualifying study

3. In addition to the above inclusion criteria, subjects must meet all inclusioncriteria (except clinical inclusion #5 and angiographic inclusion #1) and none ofthe exclusion criteria of the main randomized trial

Subjects unable to complete ETT

1. Subjects must be unable to complete the required COSIRA-II exercise tolerance testdue to lower limb amputation (above the ankle) or other physiologic condition withdocumented chronic mobility or balance issues that require the use of a walking aid (e.g., wheelchair, cane, rollator, crutches, or knee walker).

2. In addition to the above inclusion criteria, subjects must meet all inclusioncriteria (except clinical inclusion #6) and none of the exclusion criteria of themain randomized trial

Prior to inclusion in single-arm registry, all subjects will be reviewed by the Central Screening Eligibility Committee to ensure that they meet registry inclusion criteria and are not eligible for enrollment into the randomized study.