OZLEM SORAN, MD, MPH, FACC, FESC

Director of EECP Treatment Lab

Associate Professor of Medicine

Associate Professor of Epidemiology/Research

Heart and Vascular Institute

University of Pittsburgh

Effects of EECP therapy on CAD and heart failure treatment and integration of

endothelial function measurement to

follow clinical outcomesObjectives–Brief history of counterpulsation–Hemodynamic effects of EECP–Summary of recent clinical trials –Mode of Action–Need for endothelial function measurement

Neurohormonal ReleaseIncreases: NO, ANPDeceases: BNP, ET-1, ACE, ANG II

Hemodynamic Effects of EECPIncrease Cardiac Output

Systolic unloading

Increase Venous return

DiastolicRetrograde Flow

Diastolic Augmentation

Increase Shear Stress on endothelium

Increase coronary Perfusion

Pressure Gradients

occlusion

Enhance Collateral capillary sprouting

Improve Diastolic Filling

Remodeling

Release of Growth Factors

Angiogenesis andArteriogenesis

Improve Endothelial Function

Postulated Mechanisms of Action

Aortic and Intracoronary Pressure during Aortic and Intracoronary Pressure during Enhanced External CounterpulsationEnhanced External Counterpulsation

Michaels AD, et al. Circulation 2002; 106: 1237-42.

mm

Hg

0

50

100

150

200

Systole

Diastole

EECP Therapy Treatment Regimen

Outpatient therapy

Standard treatment is 1 hour per day

5 days per week for 7 weeks

A total of 35 treatment sessions

Benefits associated with EECP – including Placebo Controlled Clinical Trials and

International Registry Results

Significant•angina reduction, - in some cases no angina•improvement in quality of life,•prolongation of the time to exercise induced ST segment depression, •improvement in exercise capacity and duration,•improvement in myocardial perfusion,•reduction in nitrate use

stable angina pectoris unstable angina pectoris acute myocardial

infarctioncardiogenic shock 

FDA approved indications -1995

EECP in Heart Failure: Results of a Pilot Study

Ozlem Z. Soran†, Teresa De Marco‡, Lawrence E. Crawford†, Virginia Schneider†, Paul-André de Lame+, Bruce Fleishman*, William Grossman‡,

Arthur M. Feldman†

† University of Pittsburgh Medical Center, Pittsburgh, PA; ‡ University of California San Francisco, San Francisco, CA; * Cardiovascular Research

Institute, Columbus, OH; + Anabase International Corp., Stockton, NJ

Soran OZ, et al. J Cardiac Failure 1999;5(3):53(195)

Enhamced External Counterpulsation in Patients with

Heart Failure : A Multicenter Feasibility Study

Ozlem Z. Soran†, Bruce Fleishman *, Teresa De Marco‡, William Grossman‡, Virginia Schneider†, Karen Manzo *, Paul-André de Lame+,

Arthur M. Feldman†

† University of Pittsburgh Medical Center, Pittsburgh, PA; ‡ University of California San Francisco, San Francisco, CA; * Cardiovascular Research

Institute, Columbus, OH; + Anabase International Corp., Stockton, NJ

Soran O, et al Congest Heart Fail 2002; 8(4):204-208Soran O, et al Congest Heart Fail 2002; 8(4):204-208

637.13

715.17

580

600

620

640

660

680

700

720

740

Heart Failure Feasibility Study Mean Exercise Duration (sec)

627.63

732.96

550

600

650

700

750

P<0.001P=0.028

Soran O, et al Congest Heart Fail 2002; 8(4):204-208Soran O, et al Congest Heart Fail 2002; 8(4):204-208

baseline 1 weekPost EECP

n=23

baseline 6 mosPost EECP

n=19

Heart Failure Feasibility StudyMean Peak O2 Uptake (ml/kg/min)

14.99

15.98

14.414.614.8

1515.215.415.615.8

1616.2

P=0.0514.78

18.41

0

5

10

15

20 P<0.001

Soran O, et al Congest Heart Fail 2002; 8(4):204-208Soran O, et al Congest Heart Fail 2002; 8(4):204-208

baseline 1 weekPost EECP

n=23

baseline 6 mosPost EECP

n=19

Minnesota Living with Heart Failure Questionnaire

A FEASIBILITY STUDY Soran O, et al Congest Heart Fail 2002; 8(4):204-208Soran O, et al Congest Heart Fail 2002; 8(4):204-208

36.3

22.3

0

5

10

15

20

25

30

35

40

45

50BaselinePost-EECP

Qua

lity

of li

fe (

QO

L) s

core

QOL scoreImproved35.3% afterEECP Tx

ASSESSMENT OF LV FUNCTION

• Preload-Adjusted Maximal Power (PAMP) was calculated as a relatively load-independent measure of LV function: Power = Pressure x Flow

• Echocardiographic Automated Border Detection measures of mid-LV cross-sectional area as a surrogate for LV volume (H-P Sonos 2500). Simultaneous noninvasive arterial pressure was estimated by finger photoplethysmography.

• Flow was calculated as dA/dt from the LV area signal. Maximum area was aligned with minimum arterial pressure to correct for the delay in the pressure signal.

• PAMP: (Pressure x Flow) / (End-diastolic Area) 3/2.

Mandarino et al. J Am Coll Cardiol 1998;31:861-868

Baseline 3 Months 6 Months0

10

20

30

40

50

60

p < 0.05 vs. baseline

Eje

cti

on

Fra

cti

on

(%

)

* *

*

IMPROVEMENTS IN LV EJECTION FRACTION AFTER EECP

Gorcsan III J, et al. J Cardiac Failure 2000;35(2):230A 901-5

Baseline 3 Months 6 Months0

5

10

* p < 0.05 vs. baseline

*

INCREASE IN LEFT VENTRICULAR MAXIMAL

POWER AFTER EECPP

AM

P (

mW

/cm

4 )

Gorcsan III J, et al. J Cardiac Failure 2000;35(2):230A 901-5

Prospective New Indications:Congestive Heart Failure

Prospective Evaluation of EECP in Congestive Heart Failure (PEECH)

A multicenter, prospective, randomized, single blind, controlled trial

Purpose: Conclusively to determine efficacy of EECP as treatment for chronic congestive heart failure (NYHA II/III)

Method: Randomize (50/50), at >20 centers, 180 evaluable subjects with NYHA class II/III heart failure, LVEF ≤ 35%, ischemic or idiopathic, under optimal medical care to either 35 hours of EECP or continued medical care

Testing: Peak VO2, exercise duration, NYHA class change, HQoL (SF36 & MLWHF questionnaire), circulating markers (PNE, AII, BNP, CRP, pre-proendothelin, NO), safety Echo sub-study

Follow-up: 1 & 26 weeks post treatment (some items at 12 weeks)

J Am Coll Cardiol. 2006

PEECH: Conclusions

• Primary end point for statistical improvement to exercise capacity was met

• The addition of a standard regimen of EECP to optimal pharmacologic therapy improves exercise time for at least 6 months

• Consistent with the improvement in exercise time, there was an improvement in QoL and NYHA classification

• Changes to pVO2 although positive at 1 week and 3 months did not demonstrate statistically significant differences at 6 months

• EECP therapy is well tolerated in this group of patients

• These results suggest that EECP provides adjunctive therapy in patients with NYHA Class II-III heart failure receiving optimal pharmacologic therapy

J Am Coll Cardiol. 2006

Clinical Outcomes, Event Free Survival Rates and Incidence of Repeat Enhanced

External Counterpulsation in CAD Patients with Left Ventricular Dysfunction

- A 2 Year Cohort Study

Soran O et al. Am J Cardiol. 2006 Jan 1; 97(1): 17-20

Post-EECP Outcome

EF < 35%(N=363)

No angina or class I/II angina %

74

Angina reduced by at least one class %

77

Discontinued nitroglycerin use (% of those using pre-EECP)

52

Soran O et al. Am J Cardiol. 2006 Jan 1; 97(1): 17-20

Major Events occurring during EECP

EF < 35%

Death % 0.8

MI % 0.3

CABG % 0.3

PCI % 0.8

Exacerbation of heart failure % 3.3

Unstable angina % 3.6

Soran O et al. Am J Cardiol. 2006 Jan 1; 97(1): 17-20

81% had no congestive Heart Failure exacerbation during the 2

year follow-up period.

Soran O et al. Am J Cardiol. 2006 Jan 1; 97(1): 17-20

Patients with LVDDeath/MI/CABG/PCI to 2 years

Event free survival at 2 years= 70 %

Soran O et al. Am J Cardiol. 2006 Jan 1; 97(1): 17-20

•

THE IMPACT OF ENHANCED EXTERNAL

COUNTERPULSATION TREATMENT ON

EMERGENCY ROOM VISITS AND

HOSPITALIZATIONS

Soran et al, Congest Heart Fail. 2007;13(1):36-40

Methods

• Clinical outcomes, number of ER visits and hospitalizations within the six months prior to EECP therapy were compared with those at 6 month follow up. Statistical analysis was performed using paired t-tests and chi-square tests.

Soran et al, Congest Heart Fail. 2007;13(1):36-40

EECP Reduced ER Visits & Hospitalizationsin Patients with LVD

0

0.2

0.4

0.6

0.8

1

1.2

1.4

86% 83%

6-monthsPre-EECP

6-monthsPost-EECP

p<0.001

p<0.001

ER Visits Hospitalizations

6-monthsPre-EECP

6-monthsPost-EECP

Presented at the European Society of Cardiology - Heart Failure, Lisbon, June, 2005

Published in Congestive Heart Failure - Soran et al - Jan 2007,

RESULTS

Hospitalization for angina pectoris decreased with 82%, 12 month after treatment compared to 6 month before. CCS class

improved with persistent benefit 6 and 12 month after treatment. No patient deteriorated in CCS class. One

patient experienced pain along the ischias nerve; otherwise no adverse events were recorded.

Petterson T, et all. Presented at the Swedish Cardiology Meeting

FDA Indications for EECP Therapy

• March 1995 – stable and unstable angina, acute myocardial infarction

and cardiogenic shock

• June 2002– Clinical indications are expanded to include

congestive heart failure

Benefits associated with EECP – including Placebo Controlled Clinical Trials and

International Registry Results• angina reduction, • improvement in quality of life,• prolongation of the time to exercise induced ST

segment depression, • resolution of myocardial perfusion defects,• reduction of nitrate use• reduction in hospitalization• improvement in LV Functions• Low MACE rates at long term follow up

Research: More than 15.000 patients have

been treated with EECP for research purpose

Routine Practice: Currently > 300 000 patients have been treated with EECP

Mechanism of Action

Mechanism of Action-I

• Enhanced diastolic flow increases shear stress

• Increased shear stress activates the release of growth factors

• Augmentation of growth factor release activates angiogenesis

Collateral Development in Experimental Heart (Dog) Following Counterpulsation

Before AfterJacobey JA, Taylor WJ, et al. Am J Cardiol

Influence of EECP on Serum VEGF

0

5

10

15

20

25

Baseline 1 Hour 17 Hours 35 Hours 1 Week I Month

Incr

ea

se in

se

rum

VE

GF

fr

om

ba

selin

e (

%)

Kho, Liuzzo, Suresh K. Endocrine Society’s 82nd Annual Meeting; Canada

During EECP After EECP

EECP: Change in Angiogenic Factors

26.6

18.8

15.6

0

0

5

10

15

20

25

30

Incr

ease

(%

)

HGF bFGF VEGF MCP-1

Masuda D, et al. Circulation

Effects of EECP on Arteriogenesis

Collateral flow index (CFI) = ————————————————— Mean Coronary Occlusive Pressure -Central Venous Pressure

Mean Aortic Pressure - Central Venous Pressure

0

0.05

0.1

0.15

0.2

0.25

Sham-ECP Active-ECP

Baseline Post-ECP

CFI

p=0.04

p=0.0002

CFI = -0.044±0.07 (Sham) +0.088 ± 0.07 (Active) p=0.00005

Gloekler S et al; Heart 2010

Mechanism of Action-2

• EECP enhances vascular reactivity

• Like athletic training, the vascular effects of EECP might be mediated through changes in the neurohormonal milieu

Pla

sma

Nit

ric

Oxi

de (m

ol)

Masuda D, Nohara R, et al. Eur Heart J

Effect of EECP Therapy on Nitric Oxide

53.7 49.9

75.8

107.9

0

20

40

60

80

100

120

140

160

Control Day 1 After 1 wk After 1 mo

* P < 0.01 vs baseline

*

Improvement in Neurohormonal Factors

Eur Heart J 2001;22(16):1451-58

Eur Heart J 2001;22(16):1451-58

0

1

2

3

4

5

6

7

High Risk CAD

Placebo 1-Hr EECP

Plas

ma

cGM

P (n

mol

/l)

p<0.001 p<0.001

(N=25) (N=30)

Plasma cGMP

AJH 2006;19:867-872

0.00

20.00

40.00

60.00

80.00

100.00

120.00

140.00

160.00

Normal Volunteers (N = 17) EECP treated pts (N = 20)

pg/ml

*

*†

*†

European Society Cardiol Congress 2001

Baseline 1 hr 12 hrs 24 hrs 36 hrs

* p<0.001 vs normal† p<0.001 vs baseline CAD

Plasma ANG II Activity

* *

Mechanism of Action-3

EECP improves endothelial function

Easy /on the spot:Assessment of Functional CapacitySymptom and QoL6 min testEndothelial Function Measurement (non-invasive, accurate,reliable, easy to use, inexpensive , done in 10-15 min)

Somewhat time consuming and/or costlyEchoMPI/ Stress Test

InvasiveCath??

 

How to Follow Clinical Outcomes of Patients Undergoing EECP in the Routine Clinical Practice