1. COSIRA II: Coronary Artery Sinus Reducer for Refractory Angina
Gregg W. Stone, MD
Columbia University Medical Center
NewYork-Presbyterian Hospital
The Cardiovascular Research Foundation

2. Disclosures
Gregg W. Stone: Consultant to Neovasc

3. Refractory Angina
million pts in the US have chronic angina (100, ,000 new cases every year)
Even when coronary revascularization is feasible, angina is often not relieved
COURAGE trial at 1 year: Angina in 42% of pts treated with OMT vs. 34% with PCI (p<0.001)
10% - 15% of pts with myocardial ischemia and CAD and are not good candidates for CABG/PCI
CTOs, degenerated SVGs, diffuse disease, poor distal targets, multiple restenoses, comorbidities
If this number is for MLA <=4 then the previouse prevalence was wrong
Bernstein SJ et al. Heart 1999;81:470; Brorsson B, et al Heart 2002;87:140; Mukherjee D et al. Am J Cardiol 1999; 84:598; Williams B et al. CCI 2010;75:886; Henry TD et al. Eur Heart J 2014;9:1158

4. Refractory Angina Classification
Phenotype A: Suspected syndrome X
Phenotype B: Limited territory at risk
Phenotype C: Diffuse thread-like atherosclerosis
Phenotype D: End-stage CAD

5. Claude Schaeffer Beck (1894-1971)
JAMA 1955,159 (13):
Claude Schaeffer Beck ( )

6. Mount Sinai Hospital, Cleveland, Ohio
Claude S. Beck 1955
Mount Sinai Hospital, Cleveland, Ohio
In a dog model of acute coronary artery ligation, narrowing the coronary sinus:
Reduced mortality by 43%
Reduced infarct size by 60%–70%
Doubled the degree of retrograde backflow from the distal stump of a cut LCX artery

7. Normal Perfusion of the Myocardium
Endocardium
Epicardium
LV Cavity
Subendocardial/subsepicardial blood flow ratio = 1.2

8. Subendocardial/subsepicardial blood flow ratio <1.0
Ischemic Myocardium
Subendocardial/subsepicardial blood flow ratio <1.0

9. Ischemic Myocardium with ⇑LVEDP Epicardial vasodilation
Subendocardial/subsepicardial blood flow ratio = 0.5
Two mechanisms concur: impaired epicardial vasoconstriction and increased LVEDP – both affect perfusion in the subendocardium to cause subendocardial ischemia.

10. Ischemic Myocardium with Elevated CS pressure
Subendocardial/subsepicardial blood flow ratio = 1.2
By increasing coronary sinus pressure the normal ratio of endocardial to epicardial blood flow ratio is restored. The elevated coronary sinus pressure cause a mild dilatation of the sub-endocardial capillaries and a marked reduction in the resistance to flow in those capillaries
Redistribution of collateral blood flow from non-ischemic to ischemic territories of the myocardium, with reversal of the endocardial / epicardial perfusion ratio
CS Pressure Elevation

11. The Coronary Sinus Reducer
An hour-glass shaped stainless stent implanted in the coronary sinus (CS)
Deployed in vessels with diameters mm, at 2-4 atm.
Creates controlled narrowing (3 mm) to modulate flow and elevate CS pressure
CS pressure elevation increases endocardial perfusion providing relief of ischemia and angina
Verheye S et al. NEJM 2015;372:519-27

12. Complete endothelialization by 2 months

13. Banai S et al. J Am Coll Cardiol 2007;49:1783-9
Reducer:
CT Reconstruction
Mean diameters (n=12):
Proximal 11 ± 2 mm
Distal 7.2 ± 1 mm
Mid 3.0 ± 0.2 mm
Banai S et al. J Am Coll Cardiol 2007;49:1783-9

14. Banai S et al. J Am Coll Cardiol 2007;49:1783-9
Reducer Pilot Study
Reducer implanted in 15 pts with severe angina and reversible ischemia who were not candidates for revasc. Clinical eval, dobutamine echo, thallium SPECT, and angina questionnaire at baseline and 6 mos. CT at 2 days and 6 mos after implant.
4.0
Average CCS (n=14):
Baseline: 3.07± months: 1.64±0.84 p<0.0001
3.5
3.0
Average (CCS Class)
2.5
CCS class was lower after 6 months in 12 of 14 patients (86%)
2.0
1.5
1.0 3 6
Months
Banai S et al. J Am Coll Cardiol 2007;49:1783-9

15. Banai S et al. J Am Coll Cardiol 2007;49:1783-9
Reducer Pilot Study
Reducer implanted in 15 pts with severe angina and reversible ischemia who were not candidates for revasc. Clinical eval, dobutamine echo, thallium SPECT, and angina questionnaire at baseline and 6 mos. CT at 2 days and 6 mos after implant. 34
Dobutamine stress echo (n=13 pts, 18 segments):
Baseline mean: months mean: p=0.004 32 30 28 26
Stress (18 Segments) 24 22
Stress score improved by 2 or more segments in 8/13 pts (62%) 20 18 16 6
Months
Banai S et al. J Am Coll Cardiol 2007;49:1783-9

16. Key inclusion criteria:
COSIRA: Trial Design
Prospective, randomized, double-blind, sham-controlled: 104 patients, 11 centers
Baseline
1 mo
3 mo
6 mo
Key inclusion criteria:
Stable CCS III-IV angina
Myocardial ischemia in the LCA circulation (DSE)
Limited revasc. options
Optimal medical tx
LEVF ≥25%
Reducer (n= 52) R
Sham
(n=52)
RHC and CS angiogram in all pts;
Conscious sedation or headphones;
Pts and assessors blinded during FU
Primary EP:
% pts with ≥2 CCS angina class improvement
from baseline to
6 months
CCS angina
Exercise stress test
SAQ
Echo-dobutamine
Cardiac MRI
HRQOL
CCS angina
Exercise stress test
SAQ
Echo-dobutamine
Cardiac MRI
HRQOL
In this case, the CCS angina score was assessed by a blinded investigators who was not aware of the treatment delivered to the patient
Verheye S et al. NEJM 2015;372:519-27

17. COSIRA: Change in CCS Angina Class from Baseline to 6 Months
Improvement in CCS Class
Mean ∆ in CCS Class
Treatment
Control
Baseline
6 Months 40
4.0
P∆ =0.001 35
37/52
71%
3.5 30
3.2
3.1
3.0
± 0.4
± 0.3 25
Primary EP
P=0.02
P=0.003
2.6
Patients (%) 20
Class (no. of Points)
2.5
± 0.9
22/52
42%
18/52
35%
2.1 15
2.0
± 1.0 10
Figure 2 Change in Canadian Cardiovascular Society (CCS) Angina Class, According to Study Group. The proportion of patients with improvement of at least two CCS angina classes (primary end point) and the proportion with improvement of at least one CCS class were significantly higher in the group that received the active treatment than in the group that underwent the sham procedure (at least two CCS classes, P=0.02; at least one CCS class, P=0.003) (Panel A). CCS classes range from I to IV, with higher classes indicating greater limitations on physical activity owing to angina. The mean (±SD) CCS class was reduced from 3.2±0.4 at baseline to 2.1±1.0 at 6 months of follow-up in the treatment group, as compared with a reduction from 3.1±0.3 to 2.6±0.9 in the control group (P=0.001) (Panel B).
1.5
8/52
15% 5
1.0
≥2 Classes
≥1 Class
Treatment
Control
Verheye S et al. NEJM 2015;372:519-27

18. COSIRA: Bicycle Ergometry and Dobutamine Echocardiography
Exercise Duration (seconds)
Reducer
(N = 42)
Control
(N = 48)
Baseline – mean (SD)
441.3 (193.7)
463.7 (256.8)
6-month follow-up – mean (SD)
499.8 (194.3)
467.3 (245.7)
∆ (baseline to 6MFU) – mean (SD)
58.5 (161.3)
3.6 (125.8)
% ∆ (baseline to 6MFU)
13.3%
0.8%
t-Test: ∆ in Baseline to 6 Mo FU Control vs. Reducer group
p=0.07
DSE – WMSI (LCA)
Reducer
(N = 48)
Control
(N = 46)
Baseline – mean (SD)
1.50 (0.53)
1.30 (0.43)
6-month follow-up – mean (SD)
1.31 (0.46)
1.26 (0.44)
∆ (baseline to 6MFU) – mean (SD)
-0.19 (0.41)
-0.04 (0.35)
% ∆ (baseline to 6MFU)
-12.7%
-3.2%
t-Test: ∆ in Baseline to 6 Mo FU Control vs. Reducer group
Figure 3 CCS Angina Class at Baseline and 6 Months after Randomization, According to Study Group. At baseline, no patient in either study group had a CCS angina class of I or II, according to the inclusion criteria for the trial.
p=0.06

19. COSIRA: Technical Success and Safety
Technical success rate (device successfully implanted): 50/52 (96.2%)
Major Adverse Events at 6 Months
Reducer
Sham-Control
Cardiac Death 1 MI 2 3
No MACE were adjudicated by the CEC as related to the device
3-year FU: No device related AEs; no Reducer migration. CCS grade improved 2 grades in 8 pts, 1 grade in 5 pts and was unchanged in 1 pt vs. baseline.
Figure 3 CCS Angina Class at Baseline and 6 Months after Randomization, According to Study Group. At baseline, no patient in either study group had a CCS angina class of I or II, according to the inclusion criteria for the trial.
Verheye S et al. NEJM 2015;372:519-27

20. COSIRA II: Efficacy of the COronary SInus Reducer in Patients with Refractory Angina II
Prospective, randomized, double-blind, sham-controlled trial ~380 patients, up to 35 centers in North America
Days
Years
Key inclusion criteria:
Stable CCS III-IV angina
Myocardial ischemia + severe CAD in the LCA circulation
Max tolerated guideline directed med tx
No revasc. options
LEVF ≥30%
Baseline 30 90
180 1* 2 3 4 5
Reducer (n= 190)
*XO allowed R
Sham
(n=190)
At varying intervals
CCS angina/meds
ETT (6, 12 mo)
SAQ and EQ-5D-5L
2 week angina diary
Blinding/perception
questionnaire
PET substudy (tentative)
RHC and CS angiogram in all pts;
Conscious sedation or headphones;
Pts and assessors blinded during FU
- CCS angina/meds
- Echo/angio/RHC
- ETT (mod Bruce)
- SAQ and EQ-5D-5L
- 2 week angina diary
- Central Screening
Eligibility Committee
Pending FDA approval
PIs: Timothy D. Henry and Gregg W. Stone
ARO: The Cardiovascular Research Foundation; Sponsor: Neovasc

21. COSIRA II: Efficacy of the COronary SInus Reducer in Patients with Refractory Angina II
Prospective, randomized, double-blind, sham-controlled trial ~380 patients, up to 35 centers in North America
Primary endpoints
Effectiveness (superiority):
Change in total exercise duration in modified Bruce treadmill ETT at 6 months post-procedure compared to baseline
Safety (non-inferiority):
Composite rate of death, MI, pericardial effusion requiring surgical or percutaneous intervention, device embolization, or BARC 3 or 5 bleeding within 12 months post-procedure
Pending FDA approval
PIs: Timothy D. Henry and Gregg W. Stone
ARO: The Cardiovascular Research Foundation; Sponsor: Neovasc