OZLEM SORAN, MD, MPH, FACC, FESC

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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

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Effects of EECP therapy on CAD and
heart failure treatment and integration of
endothelial function measurement to follow
clinical outcomes

• Objectives
• Brief history of counterpulsation
• Hemodynamic effects of EECP
• Summary of recent clinical trials
• Mode of Action
• Need for endothelial function measurement

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Postulated Mechanisms of Action
Hemodynamic Effects of EECP
Increase Cardiac Output
Increase coronary Perfusion
Diastolic Augmentation
Pressure Gradients
Improve Diastolic Filling
Diastolic Retrograde Flow
occlusion
Increase Venous return
Systolic unloading
Enhance Collateral capillary sprouting
Remodeling
Increase Shear Stress on endothelium
Neurohormonal Release Increases NO,
ANP Deceases BNP, ET-1, ACE,
ANG II
Angiogenesis and Arteriogenesis
Release of Growth Factors
Improve Endothelial Function
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Aortic and Intracoronary Pressure during Enhanced
External Counterpulsation
200
Diastole
150
mmHg
100
50
Systole
0
Michaels AD, et al. Circulation 2002 106
1237-42.
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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

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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

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FDA approved indications -1995

• stable angina pectoris
• unstable angina pectoris
• acute myocardial infarction
• cardiogenic shock

 

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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
19995(3)53(195)
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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)204-208
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Heart Failure Feasibility Study Mean Exercise
Duration (sec)
Plt0.001
P0.028
baseline
baseline
1 week Post EECP n23
6 mos Post EECP n19
Soran O, et al Congest Heart Fail 2002
8(4)204-208
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Heart Failure Feasibility StudyMean Peak O2
Uptake (ml/kg/min)
Plt0.001
P0.05
baseline
baseline
1 week Post EECP n23
6 mos Post EECP n19
Soran O, et al Congest Heart Fail 2002
8(4)204-208
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Minnesota Living with Heart Failure Questionnaire
QOL score Improved 35.3 after EECP Tx
Quality of life (QOL) score
A FEASIBILITY STUDY
Soran O, et al Congest Heart Fail 2002
8(4)204-208
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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
199831861-868
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IMPROVEMENTS IN LV EJECTION FRACTION AFTER EECP
60
50


40
Ejection Fraction ()
30
20
10

p lt 0.05 vs. baseline
0
Baseline
3 Months
6 Months
Gorcsan III J, et al. J Cardiac Failure
200035(2)230A 901-5
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INCREASE IN LEFT VENTRICULAR MAXIMAL POWER
AFTER EECP

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PAMP (mW/cm4)
5

p lt 0.05 vs. baseline

0
Baseline
3 Months
6 Months
Gorcsan III J, et al. J Cardiac Failure
200035(2)230A 901-5
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Prospective New IndicationsCongestive 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 gt20 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
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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
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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
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Post-EECP Outcome
EF lt 35 (N363)
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
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Major Events occurring during EECP
EF lt 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
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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
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Patients with LVD Death/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
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THE IMPACT OF ENHANCED EXTERNAL
COUNTERPULSATION TREATMENT ON EMERGENCY ROOM
VISITS AND HOSPITALIZATIONSSoran et al,
Congest Heart Fail. 200713(1)36-40
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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. 200713(1)36-40

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EECP Reduced ER Visits Hospitalizations in
Patients with LVD
Hospitalizations
ER Visits
plt0.001
plt0.001
Hospitalizations
83 ?
86 ?
83 ?
6-months Pre-EECP
6-months Post-EECP
6-months Pre-EECP
6-months Pre-EECP
6-months Post-EECP
6-months Post-EECP
Presented at the European Society of Cardiology -
Heart Failure, Lisbon, June, 2005 Published in
Congestive Heart Failure - Soran et al - Jan
2007,
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RESULTSHospitalization 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

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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

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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

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• Research More than 15.000 patients have
• been treated with EECP for research purpose
• Routine Practice Currently gt 300 000 patients
  have been treated with EECP

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Mechanism of Action
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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

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Collateral Development in Experimental Heart
(Dog) Following Counterpulsation
After
Before
Jacobey JA, Taylor WJ, et al. Am J Cardiol
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Influence of EECP on Serum VEGF
During EECP
After EECP
Increase in serum VEGF from baseline ()
Kho, Liuzzo, Suresh K. Endocrine Societys 82nd
Annual Meeting Canada
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EECP Change in Angiogenic Factors
Increase ()
HGF
bFGF
VEGF
MCP-1
Masuda D, et al. Circulation
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Effects of EECP on Arteriogenesis
?CFI -0.0440.07 (Sham) 0.088 0.07
(Active) p0.00005
Gloekler S et al Heart 2010
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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

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Effect of EECP Therapy on Nitric Oxide
P lt 0.01 vs baseline

Plasma Nitric Oxide (?mol)
Masuda D, Nohara R, et al. Eur Heart J
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Improvement in Neurohormonal Factors
Eur Heart J 200122(16)1451-58
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Mechanism of Action-3

• EECP improves endothelial function

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How to Follow Clinical Outcomes of Patients
Undergoing EECP in the Routine Clinical
Practice
Easy /on the spot Assessment of Functional
Capacity Symptom and QoL 6 min test Endothelial
Function Measurement (non-invasive,
accurate, reliable, easy to use, inexpensive ,
done in 10-15 min) Somewhat time consuming
and/or costly Echo MPI/ Stress Test Invasive Cath
??