Transcript The treatment of symptomatic CAD

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 outcomes
Objectives
–
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–
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–
Brief history of counterpulsation
Hemodynamic effects of EECP
Summary of recent clinical trials
Mode of Action
Need for endothelial function measurement
Postulated Mechanisms of Action
Hemodynamic Effects of EECP
Increase Cardiac Output
Increase coronary Perfusion
Diastolic
Augmentation
Improve
Diastolic
Filling
Increase
Venous return
Systolic
unloading
Diastolic
Retrograde
Flow
Pressure Gradients
occlusion
Enhance Collateral
capillary sprouting
Remodeling
Increase Shear Stress on endothelium
Neurohormonal Release
Increases: NO, ANP
Deceases: BNP, ET-1,
ACE, ANG II
Improve
Endothelial
Function
Release of
Growth
Factors
Angiogenesis
and
Arteriogenesis
Aortic and Intracoronary Pressure during
Enhanced External Counterpulsation
200
Diastole
mmHg
150
100
50
Systole
0
Michaels AD, et al. Circulation 2002; 106: 1237-42.
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
FDA approved indications -1995
stable angina pectoris
unstable angina pectoris
acute myocardial
infarction
cardiogenic shock
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):204-208
Heart Failure Feasibility Study
Mean Exercise Duration (sec)
P<0.001
P=0.028
732.96
750
700
650
627.63
600
550
baseline
1 week
Post EECP
n=23
740
720
700
680
660
640
620
600
580
715.17
637.13
baseline
6 mos
Post EECP
n=19
Soran O, et al Congest Heart Fail 2002; 8(4):204-208
Heart Failure Feasibility Study
Mean Peak O2 Uptake (ml/kg/min)
16.2
16
15.8
15.6
15.4
15.2
15
14.8
14.6
14.4
P=0.05
15.98
20
P<0.001
18.41
14.78
15
10
14.99
5
0
baseline
1 week
Post EECP
n=23
baseline
6 mos
Post EECP
n=19
Soran O, et al Congest Heart Fail 2002; 8(4):204-208
Quality of life (QOL) score
Minnesota Living with Heart
Failure Questionnaire
50
45
40
35
30
25
20
15
10
5
0
A FEASIBILITY STUDY
Baseline
Post-EECP
36.3
22.3
QOL score
Improved
35.3% after
EECP Tx
Soran O, et al Congest Heart Fail 2002; 8(4):204-208
ASSESSMENT OF LV FUNCTION
•
Preload-Adjusted Maximal Power (PAMP) was calculated as a relatively loadindependent 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
IMPROVEMENTS IN LV EJECTION
FRACTION AFTER EECP
Ejection Fraction (%)
60
50
*
40
*
30
20
10
*p < 0.05 vs. baseline
0
Baseline
3 Months 6 Months
Gorcsan III J, et al. J Cardiac Failure 2000;35(2):230A 901-5
INCREASE IN LEFT VENTRICULAR
MAXIMAL
POWER AFTER EECP
PAMP (mW/cm4)
*
10
5
*
0
Baseline
3 Months
p < 0.05 vs. baseline
6 Months
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, preproendothelin, 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 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
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 & Hospitalizations
in Patients with LVD
1.4
ER Visits
Hospitalizations
p<0.001
1.2
1
p<0.001
0.8
86% 
0.6
83% 
0.4
0.2
0
6-months
Pre-EECP
6-months
Post-EECP
6-months 6-months
Pre-EECP Post-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 ActionI
• 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
After
Jacobey JA, Taylor WJ, et al. Am J Cardiol
Influence of EECP on Serum VEGF
During EECP
After EECP
Increase in serum VEGF
from baseline (%)
25
20
15
10
5
0
Baseline
1 Hour
17 Hours
35 Hours
1 Week
I Month
Kho, Liuzzo, Suresh K. Endocrine Society’s 82nd Annual Meeting; Canada
EECP: Change in Angiogenic
Factors
Increase (%)
30
26.6
25
18.8
20
15.6
15
10
5
0
0
HGF
bFGF
VEGF
MCP-1
Masuda D, et al. Circulation
Effects of EECP on Arteriogenesis
CFI = -0.044±0.07 (Sham)
0.25
+0.088 ± 0.07 (Active) p=0.00005
p=0.0002
0.2
p=0.04
CFI 0.15
0.1
0.05
0
Sham-ECP
Baseline
Collateral flow index (CFI)
Active-ECP
Post-ECP
Venous Pressure
Mean Coronary Occlusive PressureCentral
-
= —————————————————
Mean Aortic Pressure -Central Venous Pressure
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
Plasma Nitric Oxide (mol)
Effect of EECP Therapy on Nitric Oxide
160
* P < 0.01 vs baseline
140
107.9 *
120
100
75.8
80
60
53.7
49.9
40
20
0
Control
Day 1
After 1 wk
After 1 mo
Masuda D, Nohara R, et al. Eur Heart J
Improvement in Neurohormonal Factors
Plasma cGMP
Eur Heart J 2001;22(16):1451-58
7
6
p<0.001
p<0.001
Plasma cGMP (nmol/l)
5
4
3
2
1
0
High Risk
(N=25)
Placebo
CAD
Eur Heart J 2001;22(16):1451-58
(N=30)
pg/ml
1-Hr EECP
Plasma ANG II Activity
160.00
AJH 2006;19:867-872
140.00
*†
*
* p<0.001 vs normal
† p<0.001 vs baseline CAD
120.00
*
100.00
*
*†
80.00
60.00
40.00
20.00
0.00
Baseline
1 hr
12 hrs
Normal Volunteers (N = 17)
24 hrs
36 hrs
EECP treated pts (N = 20)
European Society Cardiol Congress 2001
Mechanism of Action-3
EECP improves endothelial function
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??