Clinical Trials

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 of
persistent refractory angina pectoris classified as CCS Grade III or IV despite
maximally tolerated guideline directed medical therapy as determined by the local
heart team and confirmed by a Central Screening Eligibility Committee.

Note: subjects may also have exertional dyspnea, but the symptoms that limit activity
must be anginal in nature (including chest pain, pressure, heaviness, discomfort, with
or without radiation to the neck, jaw, shoulders, arms, or other location) and not
dyspnea

3. Must have attempted treatment with the maximally tolerated dose of at least three of
the four (preferably all four) approved classes of anti-anginal agents: long-acting
nitrates, calcium channel blockers (either a dihydropyridine or a
non-dihydropyridine), beta blockers, and ranolazine. The regimen must be stable for at
least 60 days prior to enrollment, must remain stable from enrollment to
randomization, and there must be no intent to change the medical regimen for at least
12 months after randomization Note: If the dose of a medication was increased or
decreased for a temporary period and then returned to the original dose, which will
then be continued for at least 12 months after randomization, the subject may be
immediately enrolled without needing to otherwise requalify.

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

5. Evidence of either exercise or pharmacologically induced reversible ischemia severity
by stress echo, nuclear study, PET, perfusion MRI, CT perfusion, FFRCT, FFR, iFR, or
other non-hyperemic FDA approved tests in the distribution of the left coronary artery
(LCA), performed within 12 months prior to enrollment and while the patient is
maintained on their stable regimen of maximally tolerated doses of anti-anginal
medications.

Note: If the subject has evidence of ischemia in both the LCA and RCA distributions,
the extent of ischemia must be greater in the LCA 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 medication
regimen is permanently changed after the assessment of ischemia, the test must be
repeated. For subjects with multiple assessments, the one performed closest to
enrollment will serve as the qualifying study.

6. Functional limitation due to refractory angina as defined by a modified Bruce exercise
tolerance test duration of greater than or equal to 2 minutes but less than or equal
to 8 minutes, performed while the subject is maintained on their stable regimen of
maximally tolerated doses of anti-anginal medications.

Note: The ETT variability 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 any intervening
myocardial infarction. For subjects with multiple assessments, the most recent 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 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
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 coronary
syndrome (NSTEMI or STEMI).

Note: subjects with an elevated troponin or CKMB without acute coronary syndrome may
still be enrolled

2. Recent successful revascularization by either CABG or PCI within six months prior to
enrollment Note: Successful revascularization is defined as any CABG procedure, or any
PCI procedure with a reduction of one or more lesions to <50% diameter stenosis

3. Recent unsuccessful PCI (e.g., failed attempt to open a chronic total occlusion)
within 30 days prior to enrollment

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

5. Has extra-coronary contributory causes of angina - e.g., untreated hyperthyroidism,
anemia (hgb <10 g/dL), uncontrolled hypertension (systolic blood pressure >160 mmHg or
diastolic blood pressure >100 mmHg despite medications), atrial fibrillation with
rapid ventricular response (consistently >100 bpm despite medications) or other
tachyarrhythmia, severe aortic stenosis, hypertrophic cardiomyopathy with left
ventricular outflow tract obstruction or asymmetric septal hypertrophy (concentric
left ventricular hypertrophy is not an exclusion criterion).

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

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

8. Severe chronic obstructive pulmonary disease (COPD) as indicated by a forced
expiratory 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 cardiac
resynchronization therapy according to ACCF/AHA/HRS guidelines

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

14. Chronic severe renal failure (estimated eGFR less than 30 mL/min/1.73m2 by the MDRD
formula) 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's
ability to be compliant with the trial protocol (e.g., active alcohol or drug abuse,
dementia, magnetic resonances imaging (MRI) planned within 8 weeks of randomization.)

17. Currently enrolled in another investigational device or drug trial that has not
reached its primary endpoint or that might clinically interfere with the current trial
endpoints or procedures

18. Pregnant or planning pregnancy within the next 12 months (women of reproductive
potential must have a negative pregnancy test within 7 days of the randomization
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, adverse
personal circumstances or lack of autonomy. This may include individuals with mental
disability, persons in nursing homes, children, impoverished persons, persons in
emergency situations, homeless persons, nomads, refugees, and those incapable of
giving informed consent. Vulnerable populations also may include members of a group
with a hierarchical structure such as university students, subordinate hospital and
laboratory personnel, employees of the Sponsor, members of the armed forces, and
persons kept in detention.

20. Inability to tolerate dual antiplatelet therapy for 6 months if not on a chronic oral
anticoagulant, or inability to tolerate a P2Y12 inhibitor for at least 6 months if 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 has been
asymptomatic for <8 weeks prior to enrollment or has not returned to his or her prior
baseline (pre-COVID-19) clinical condition

24. Subject is asymptomatic but has had a positive PCR or antigen test for COVID-19 within
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 screening
procedure for eligibility assessment and potential randomization

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

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

Single Arm Registry Inclusion Criteria:

The subject must meet all inclusion and exclusion criteria for the main randomized trial,
except for three possible specific conditions as follows:

1. Subjects with evidence of either exercise or pharmacologically induced reversible
ischemia by stress echo, nuclear study, PET, perfusion MRI, CT perfusion, FFRCT, FFR,
iFR, or other non-hyperemic FDA approved or cleared tests in the predominate (RCA >
LCA ischemia) or sole distribution of the right coronary artery

2. Subjects with evidence of either exercise or pharmacologically induced reversible
ischemia by stress echo, nuclear study, PET, perfusion MRI, CT perfusion, CFR, or IMR
without documented obstructive coronary disease (i.e. estimated diameter stenosis in
all coronary lesions is <50%)

3. Subjects who are unable to complete the required COSIRA-II exercise tolerance test due
to lower limb amputation (above the ankle).

Single-Arm Registry Angiographic Inclusion Criteria

1. Obstructive CAD: Three-vessel coronary angiography performed within the 12 months
prior to enrollment demonstrating obstructive CAD (visually assessed diameter stenosis
of ≥70%) in the RCA if it is single vessel disease, or the ischemia in the territory
of the RCA is greater than the ischemia in the territory of the LCA when it is >2
vessel coronary disease, or a fractional flow reserve (FFR) value of ≤0.80 or an iFR
(or other FDA-approved/cleared non-hyperemic physiologic assessment) of ≤0.89 in an
RCA lesion with a visually assessed diameter stenosis of ≥50% in single RCA coronary
disease, that is not suitable for and will not be treated with PCI or CABG as
determined by the local heart team.

2. Non-obstructive CAD: Patients with non-obstructive CAD (coronary narrowing of <50%,
and/or FFR ≥0.81) Note: The qualifying 3-vessel angiogram must be performed after any
myocardial infarction 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.

Note: Other protocol defined Inclusion/Exclusion criteria may apply.

Eligibility last updated 4/18/23. Questions regarding updates should be directed to the study team contact.