New Therapeutic Option in Managing Chronic Angina: Role of Extracorporeal Shockwave Myocardial Revascularization (ESMR)

Gil Hakim
Director of New Product Development Medispec LTD.

Background
The majority of patients suffering from IHD can be adequately treated by drug therapy and revascularization procedures, i.e, CABG and PTCA. However, there are still patients who remain severely disabled by myocardial ischemia related symptoms, i.e, angina pectoris and dyspnea. As a result of the improvements in cardiovascular care this patient group is rapidly growing. (COURAGE study, ~25% not free from angina 1,3 and 5 years post therapy) Current therapy options for these patients are limited and mostly highly invasive.

Persistent Angina despite revascularization procedures

Previous Medical intervention
No prior procedure Prior PCI only Prior CABG ALL
Am Heart J. 2002;23:1546-1555

n
2357 823 661 3841

Angina
471 210 200 880

%
20.0% 25.5% 30.3% 22.9%

PCI + Medical Therapy

Baseline 1 year 3 year 5 year Medical Therapy only Baseline 1 year 3 year 5 year N Engl J Med 2007;356

n
1149 1031 820 423 n 1137 1010 824 406

Angina
1014 351 218 107 Angina 989 415 266 110

%
88% 34% 27% 25% % 87% 41% 32% 27%

Published in major cardiology journals Over 5,500 patients evaluated Angina prevalence: PCI: 20%-41%; CABG: ~30%

Background
Shockwaves are special acoustics waves that can be targeted and focused non-invasively to a selected area inside the patient body. Shock wave therapy have been used in the last decades in Urology (kidney stone lithotripsy) and Orthopedics (plantar facilities) applications. In-vitro and animal data show an increase of angiogenic factors and neo-vascularization after treatment of low intensity shock waves (1/10 of the energy of lithotripsy). Therapeutic effect is localized, precise (<2 mm precision) and controlled.

Aim
Treatment for patients no longer benefit from current revascularization methods Inducing Local Angiogenesis at Myocardial Ischemic Areas Using Low Intensity, Non Invasive, Focused Shockwaves

Angioplasty

CABG

ESMR

Why ESMR?
1. Occlusions in a small artery (< 2.5 mm) that cannot be treated with Anti Angina medication, CABG or Angioplasty

3
2

2. Large number of occluded small arteries (<2 mm) that supply a myocardial area (micro-vessels disease) 3. Chronic Total Occlusion (CTO) in one major coronary artery

Technology - SWs Characteristics

Technology - From physics to clinical practice

Generated by Electro-hydraulic effect: High voltage creates electric spark discharge The water vaporizes and creates an explosion Generating high energy Shock Waves Reflected by the Semi-Ellipsoid Focused onto the Ischemic Area
Water Spark High Voltage Line Electrode Ischemic Area Shock waves Semi-Ellipsoid

Technology Patient set-up

Main Arm Lock/Unlock Button Shock Wave Applicator ECG Monitor

Ultrasound Probe Holder User Control Panel

ECG Remote Control Unit

Energy Level: 0.09 mJ/mm2; ~1000 shocks per tx

Technology Focal Zone Calibration

Cardiospec - ESMR device

Clinical Data
Multi Center Feasibility study
PI Naber CK. Vainer J. Vasyuk Y. Takayama T. Faber L. Lyadov K. Ge J. Zuoziene G. Samad A. oltunov I. AZM Moscow State University Nighon School of Medicine Heart and Diabetes Center, NRW Medical and Rehabilitation Center Zhongshan Hospital Vilnius University Karachi Institute of Heart Diseases Hospital number 33 Hospital Essen University Hospital Essen Maastricht Moscow Tokyo Bad Oeynhausen Moscow Shanghai Vilnius Karachi Moscow City Country Germany Netherlands Russia Japan Germany Russia China Lithuania Pakistan Russia n 24 14 26 17 16 13 14 10 24 20

Total of 178 patients

Patient Selection
Inclusion
Reversible ischemia or hybernation. CCS of III or IV PCI or CABG not applicable stable symptoms life expectancy of >12 months

Exclusion
Severe COPD Acute MI < 3 months prior to treatment Heart valve disease > grade II Intraventricular thrombus Pregnancy Malignancy

Shockwave Treatment Protocol

Week 1 Week 2 Week 3

Week 4

Week 5

Week 6

Week 7

Week 8

Week 9

At each treatment session shock waves should be delivered to the border of the ischemic area triggering the viable tissue for angiogenesis

AP-CCS class (n=178)

oltunov I. ,2008 (20) Samad A. ,2008 (24) Zuoziene G. ,2009 (10) Ge J. ,2009 (14) Lyadov K. ,2006 (13) Faber L. ,2008 (16) Vasyuk Y. ,2009 (26) Vainer J. ,2008 (14) Naber CK. ,2006 (24) 0.0% 10.0% 20.0% 30.0% 40.0% 50.0% 60.0%

Mean Improvement 34.2% 3.000.33 to 2.040.36

Myocardial Perfusion (n=124)

Faber L. ,2008

Vasyuk Y. ,2009

Mean Improvement (*) 60%

Vainer J. ,2008

Naber CK. ,2006

0%
(*)

10%

20%

30%

40%

50%

60%

70%

80%

Mean improvement is presented in % as different analysis methods were used.

Takayama T. ,2008; Lyadov K. ,2006; Ge J. ,2009 reported as well improved myocardial perfusion (no data available)

16

Treated vs. Untreated areas (n=16)

Regional myocardial blood flow at the treated and untreated areas
180
[ Ml / min / 100g ]

150 120 90 60 30 0

P=0.9

P=0.04

Untreated areas

Treated areas
Baseline Follow-up

Typical SPECT Results

6 months follow-up
Pre CCS class IV
EG, 62, male 3 Diseased vessels Hypertension CABG X 2 Post MI PTCA & Stent

Post CCS class III

Courtesy of Prof. R. Erbel, Essen, Germany

Exercise Tolerance Capacity (n=117)

Samad A. ,2008 Lyadov K. ,2006 Faber L. ,2008 Vasyuk Y. ,2009 Vainer J. ,2008 Naber CK. ,2006 0.0%
(*)

Mean Improvement (*) 32%

10.0%

20.0%

30.0%

40.0%

50.0%

60.0%

70.0%

Mean improvement is presented in % as different analysis methods were used.

Weekly Nitrate Intake (n=50)

Zuoziene G. ,2009

Vasyuk Y. ,2009

Mean Improvement 76% From 18.811.5 times a week to 3.91.6

0% 20% 40% 60% 80% 100%

Vainer J. ,2008

Safety Troponin I levels (n=78)

0.10
p=NS; n=24

Troponin I ng/ml

0.08 0.06 0.04 0.02 0.00 baseline 1st 2nd 3rd

Normal Values < 0.1 ng/ml

Average values

Therapy course
Faber L. ,2008; Vainer J. ,2008 Takayama T. ,2008, and Samad A. ,2008 reported no change in cardiac markers between baseline and post treatments as well (no data available)

Summary
Non-invasive treatment for patients with myocardial reversible ischemia untreatable by conventional methods Echo-based and echo-guided treatment delivering low intensity, focused shockwaves into the Myocardium Triggering local, precise and controlled angiogenesis to the treatment area Increasing perfusion and restoring LV function Painless, safe, 15 min treatment without reported side-effects

Future Plans
Current indication is: Chronic Angina Pectoris (IDE approval) Future plans:
CHF (ischemic etiology) Acute MI remodeling Other Ischemic and non ischemic related cardiac conditions

Thank you for your attention

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