Coronary Sinus ReducerStent for the Treatment of Chronic Refractory Angina Pectoris

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• Coronary Sinus Reducer-Stent for the Treatment of
  Chronic Refractory Angina Pectoris
• A prospective, open label, multi-center safety
  feasibility first-in-man study

Shmuel Banai, Shmuel Ben Muvhar, Keyur H Parikh,
Aharon Medina, Horst Sievert, Ashok Seth,
Jonathan Tsehori, Gad Keren Tel Aviv, ISRAEL
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Chronic Refractory Angina Pectoris

• Patients with myocardial ischemia who have
  significant disability with limiting symptoms,
  and frequent hospital admissions despite optimal
  medical therapy
• They often have diffuse CAD, and are not amenable
  to further revascularization
• About 100,000 patients each year in the U.S, and
  50,000 in Europe have refractory or end-stage
  angina

Mannheimer C The problem of chronic refractory
angina. Eur Heart J 200223355370 Nordrehaug
JE Treatment of chronic refractory angina
pectoris. Eur Heart J 2006271007-1009 DeJongste
MJL Chronic therapeutically refractory angina
pectoris. Heart 200490225-230 Mukherjee D
DMRhow many patients might be eligible?, Am J
Cardiol 199984598600
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Refractory Angina PectorisNatural History

• Chronic disease
• No effective therapy is available today
• These patients either remain stable or
  deteriorate
• Estimated mortality rates
• 1 year 1-8 3 years up to 24

Salem M Am J Cardiol 2004 93 10861091 Aaberge
L J Am Coll Cardiol 2002 39 15881593 Schoefiel
d PM Lancet 1999 353 519524 Leon MB J Am
Coll Cardiol 2005 46 18121819 Nordrehaug JE E
Heart J 2006271007-1009
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Coronary Sinus (CS) Pressure Elevation Improves
Perfusion of Ischemic Myocardium

• In the setting of obstructive CAD
• increased CS pressure can lead to
• Redistribution of collateral blood flow from
  non-ischemic into ischemic territories of the
  myocardium
• Reduces myocardial ischemic damage and infarct
  size

Ido A Am J Physiol 2001280H1367 Sato M Am J
Physiol 1996271H1433 Kohmura C Jpn Circ J
199054924
Rouleau JR Can J Physiol Pharmacol
198563(7)787 Syeda B J Thorac Cardiovasc Surg
20041271703 Mohl, Wolner et al Am J Cardiol
198453923
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The salvage potential of CS intervention
Meta-analysis and pathophysiologic consequences

• Intermittent CSO decrease ischemic damage during
  coronary occlusion by 29 39
• Combination with retro-perfusion of arterial
  blood exhibits no additional benefit in salvaging
  the ischemic myocardium in comparison with that
  provided by ICSO alone

Syeda B J Thoracic and Cardiovasc Surgery
20041271703-1712
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Hypothesis In patients with IHD and chronic
refractory angina, who are not candidates for
revascularization procedures, implantation of a
Reducer-stent in the coronary sinus will enhance
perfusion to ischemic territories of the
myocardium and improve their symptoms
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The Device
A stainless steel balloon-expandable
over-the-wire stent Can be deployed in vessels
with diameters of 7.0-13.0 mm, using deployment
pressures between 2 to 4 bars
Neovasc Balloon
Neovasc Reducer
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Immediate (post implantation) trans-reducer
pressure gradient measurement
Mean CSp gradient (mmHg) 52.58 (n6)
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First In Man Experiment A multi center,
open-label, prospective, non-randomized,
single-arm, safety and feasibility study As the
first stage in evaluating the Neovasc CS Reducer
as a potential alternative therapy for patients
with chronic refractory angina
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• Inclusion Criteria
• Symptomatic CAD with chronic refractory angina,
  Canadian Cardiovascular Society (CCS) class II to
  IV, despite medical therapy
• Patients with CAD who are either not amenable or
  are at high risk for revascularization by CABG or
  by PCI
• Reversible ischemia of the left ventricular wall,
  as determined by myocardial perfusion scan,
  and/or by echo dobutamine
• LVEF 30

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• Exclusion Criteria
• Recent (within 3 months) MI
• Recent (within 7 months) PCI or CABG
• Severe arrhythmias, including chronic AF
• Decompensated heart failure
• Severe valvular heart disease
• Patients who have a pacemaker or any other
  electrodes in the coronary sinus
• Mean RA pressure 15 mmHg
• Patients who have undergone tricuspid valve
  replacement or repair
• Patients in whom the reversible myocardial
  ischemia is due only to RCA disease

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• Study design and follow-up
• Primary Endpoint Safety
• The absence of any Major Adverse Cardiac Events
  (MACE) related to the procedure during 6 months
  post implantation
• Adverse event death MI CS perforation CS
  occlusion need for urgent dilatation of the
  Reducer
• Secondary Endpoint Technical Success
• The successful delivery and deployment of the
  Reducer-stent in the CS as assessed by angiogram
  and/or by Cardiac CT angiography

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From October 2004 to July 2005, a single
Reducer-Stent was implanted in the coronary sinus
of 15 patients with CAD, in 3 centers in Germany
and India
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Study design and follow-up
Additional evaluation
Dobutamine echo and thallium SPECT results were
analyzed by independent physicians who were
blinded to the study design, to the nature of the
treatment given
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Reducer-stent implantation procedure One week
pre-treatment with aspirin 100mg/d and
clopidogrel 75mg/d A pre-shaped guiding sheath
was introduced into the of the CS through a right
internal jugular vein After CS pressure was
recorded, angiography of the CS was performed to
size the vessel and to locate side branches
bifurcation sites The dimensions of the proximal
segment of the CS were measured using QCA The
most suitable site for implantation was chosen
according to the vessel diameter and in order to
avoid side branch bifurcation

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Ischemic Territory
Improvement
Normal Territory
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Results Fifteen patients with CAD proven by
coronary angiography, with grade II - IV angina,
who were not candidates for revascularization
were enrolled to this study All had objective
evidence of reversible myocardial ischemia of the
LAD or LCX territories of the left ventricle by
thallium SPECT and/or by echo-dobutamine
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Baseline characteristics (n15)
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Results Primary and Secondary End Points All
Reducer-stent implantation procedures were
completed successfully in all 15 patients All
patients were discharged from the hospital 1-2
days later without clinical complications No MACE
had occurred during the peri-procedural period
and during the follow up period of 10-12 months
(mean follow up 111.03 m)
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Results CT angiography evaluation CTA was
performed in 12 patients 1-2 days and 6 months
after implantation All Reducers were well
positioned and deployed, and all were patent,
both immediately and 6 months after implantation
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• Results
• Improvement in Angina score (CCS)
• Angina score improved significantly 6 months
  following implantation
• CCS class was lower after 6 months in 12 of the
  14 patients and remained constant for 2 patients
• Average CCS was 3.07 at baseline and 1.64 at
  follow-up (plt0.0001, n14)

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Improvement in Angina
Angina Class Average
n14
P0.0064
Angina Class
Pre Implantation
3 Months Post Implantation
6 Months Post Implantation
1 Angina at intense effort 2 Angina at
moderate effort 3 Angina at minimal effort 4
Angina at rest
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• ST segment depression during exercise stress
  test
• Transient ST depression was present in 9 patients
  during baseline exercise stress test
• At 6m follow-up stress test ST depression was
  lower in 6 of these 9 patients, and was no longer
  present in 2 of the 6
• One patient had a higher ST segment depression at
  6m

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• Stress test ST segment depression
• The average ST depression
• Baseline 2.001.12 mm, mHR 11720
• 6 months 1.221.20 mm, mHR 12416
• (p0.047, n9)
• For all, exercise duration and double product
  either increased or remained constant

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Effect on Stress Test ST Depression
p0.047, n9
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Improvement in dobutamine induced Myocardial
Ischemia In 8 of 13 patients there was an
improvement when the stress images at baseline
and 6 months were compared The averageSD of the
total score of all 18 segments was Baseline-
25.084.15 6 months- 21.082.52 The analysis
was performed by 2 independent core-labs

p0.0022
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Stress Dobutamine-echo results at baseline and 6m
after Reducer implantation
Mean score baseline 25.084.15 6m
21.082.52 p0.0022, n13
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Reducer Effect on Stress Echo
8 of 13 Improved
Core Lab I
Average SD 0 months 25.084.15 6 months
21.082.52 ?4 P0.0022 0 months 21.6 2.23 6
months 18.432.23 ?3.17 p0.0063
Core Lab II
Clinical Improvement gt 2
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Improvement in Myocardial Perfusion Studies In
4 of 10 patients there was a reduction in the
extent and/or severity of myocardial
ischemia Among the remaining 6 patients, the
SPECT images were unchanged in 5 and worsened in
1 patient at 6 months The average score for the
group was Baseline 12.65.36 6 months
9.67.24 p0.042, n10 The analysis was
performed by an independent core-lab

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CS Reducer Effect on Defect Size
Pre-Reducer Implantation
Post-Reducer Implantation (6 Months)
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3D Reconstruction of the Reducer by Cardiac CT
after 6 month
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CT Angio 24 hours post implantation in human CS
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• Summary
• The CS Reducer was implanted in 15 patients with
  CAD and refractory angina pectoris, with
  objective evidence of reversible myocardial
  ischemia of the left ventricle
• All implantations were completed successfully,
  and all patients were discharged home 1-2 days
  later
• No MACE were recorded in the peri-procedural
  period, and during a follow up period of 10 -12m

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• Summary
• CT angiography proved that the Reducers were
  patent 6m post implantation and located at the
  exact site of deployment
• Angina score (CCS) improved after 6 months
• Stress test ST depression was reduced in 6 of 9
  patients and eliminated in 2 of the 6,
  accompanied by either increased or unchanged
  exercise duration and double product
• The extent and severity of myocardial ischemia
  was reduced in 8 of 13 patients as measured by
  dobutamine echo and in 4 of 10 by thallium spect

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• Conclusions
• Implantation of the CS Reducer-stent is feasible
  and safe, and carries no immediate or long term
  complications
• These findings along with the clinical
  improvement observed, support further evaluation
  of the clinical efficacy of the CS Reducer in
  patients with refractory angina

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Thank You