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 The point of this slide is that the results of the Stony Brook case series have been replicated in a wide range of institutions and have been published in various journals. Even though these were not randomized, controlled trials, a body of highly consistent data has been made available to confirm the Stony Brook results. These were, except for one person, very sick people. Objectives 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 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

Michaels AD, et al. Circulation 2002; 106: 1237-42. Aortic and Intracoronary Pressure during Enhanced External Counterpulsation 200 Diastole 150 mmHg 100 Patient #3. 50 Systole 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 Normal regime is for the counterpulsation to be applied for 60 minutes continuously, either once or twice a day, five days a week. Usual treatment is for a minimum of 35 hours, thus a complete course of treatment lasts approximately 7 weeks for once a day therapy. The shorter 3 1/2 weeks achieved with twice/day therapy is useful for patients who are visiting a clinic away from home.

stable angina pectoris   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 baseline baseline 1 week Post EECP n=23 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) 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

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

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

IMPROVEMENTS IN LV EJECTION FRACTION AFTER EECP 60 50 * * 40 Ejection Fraction (%) 30 20 10 * p < 0.05 vs. baseline 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 * 10 PAMP (mW/cm4) 5 * p < 0.05 vs. baseline Baseline 3 Months 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, pre-proendothelin, NO), safety Echo sub-study Follow-up: 1 & 26 weeks post treatment (some items at 12 weeks) PEECH is a large study being run under an IDE from the FDA and under FDA supervision. It is the natural extensions of the pilot Feasibility study and will be used to obtain labeling for the indication through the pre-marketing approval process of the FDA. VO2 max is the primary parameter and was used to calculate the study size. There is sometimes a confusion over why patients of all etiologies are included (idiopathic) because there is a perception that EECP is basically would work only in those whose HF originates in CAD. This, of course, has no real basis because we do not know how EECP works and it might be that its main effect is to ameliorate chronic peripheral vasoconstriction. This is why I have included the next slide which shows the main result of the Feasibility study. Note that the “idiopathics” do as well as the “ischemics”. 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) 74 77 52 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 Some results . Most of the patients presenting for EECP are those with chronic coronary artery disease who have had previous treatment with conventional revascularization techniques (PTCA, STENT, CABG) but have failed these treatments, and are no longer 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 % PCI % 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

Death/MI/CABG/PCI to 2 years Event free survival at 2 years= 70 % 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 Mr Chairman, Ladies and Gentleman. On behalf of my co-authors and the investigators of the Enhanced External Counterpulsation Patient Registry I would like to present the study entitled ‘Functional Status of Patients with Chronic Angina treated with enhanced external counterpulsation

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 The operation of EECP is illustrated here. Three sets of pressure cuffs are applied to the patient, on the calves, on the thighs and on the lower buttocks. The pressure is controlled by a computer linked to he ECG signal. At the start of diastole inflation is applied to the lower cuffs, and then sequentially to the thighs and buttocks in 50 ms intervals. At the start of systole all cuffs are simultaneously deflated. This is repeated for one hoiur of treatment. Treatment is done normally once a day for 35 days.

EECP Reduced ER Visits & Hospitalizations in Patients with LVD ER Visits Hospitalizations p<0.001 p<0.001 Hospitalizations 83%  86%  83%  6-months Pre-EECP 6-months Post-EECP 6-months Pre-EECP 6-months Post-EECP 6-months Pre-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,

Petterson T, et all. Presented at the Swedish Cardiology Meeting 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. Mr Chairman, Ladies and Gentleman. On behalf of my co-authors and the investigators of the Enhanced External Counterpulsation Patient Registry I would like to present the study entitled ‘Functional Status of Patients with Chronic Angina treated with enhanced external counterpulsation 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 Normal regime is for the counterpulsation to be applied for 60 minutes continuously, either once or twice a day, five days a week. Usual treatment is for a minimum of 35 hours, thus a complete course of treatment lasts approximately 7 weeks for once a day therapy. The shorter 3 1/2 weeks achieved with twice/day therapy is useful for patients who are visiting a clinic away from home.

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 The point of this slide is that the results of the Stony Brook case series have been replicated in a wide range of institutions and have been published in various journals. Even though these were not randomized, controlled trials, a body of highly consistent data has been made available to confirm the Stony Brook results. These were, except for one person, very sick people.

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 Clear differences are seen in coronary blood flow in this experimental model of heart failure. Collateral development following counterpulsation therapy resulted in significant increased flow. 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 (%) Studies show EECP treatment with a resulting increase in growth factor (serum VEGF) that is sustained following treatment, albeit at a lower level. Kho, Liuzzo, Suresh K. Endocrine Society’s 82nd Annual Meeting; Canada

EECP: Change in Angiogenic Factors Increase (%) EECP has been shown to influence angiogenic factors in chronic stable angina. In this study, HGF, bFGF and VEGF all increased following EECP treatment (26%). Sixty-six percent of the patients increased both HGF and bFGF following EECP treatment and 33% increased MCP-1 and VEGF. It appears that patients with angina pectoris treated with EECP increased angiogenic factors, in particular HGF. These results suggest that EECP therapy may promote angiogenesis factors with shear stress and cause development of functioning collateral vessels. HGF bFGF VEGF MCP-1 Masuda D, et al. Circulation

Effects of EECP on Arteriogenesis CFI = -0.044±0.07 (Sham) +0.088 ± 0.07 (Active) p=0.00005 CFI p=0.04 p=0.0002 Collateral flow index (CFI) = ————————————————— Mean Coronary Occlusive Pressure - Central Venous Pressure Mean Aortic 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

Effect of EECP Therapy on Nitric Oxide * P < 0.01 vs baseline * Plasma Nitric Oxide (mol) In one month following EECP treatment NO levels increased to 107.9 + 59.9 mol (p<0.02 versus baseline). Masuda D, Nohara R, et al. Eur Heart J

Improvement in Neurohormonal Factors Eur Heart J 2001;22(16):1451-58 Plasma cGMP (nmol/l) p<0.001 (N=25) (N=30) Plasma cGMP AJH 2006;19:867-872 Eur Heart J 2001;22(16):1451-58 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 EECP therapy caused a modest decline in ANP levels immediately following therapy and at one month. BNP levels declined more significantly following treatment and were sustained at one month. 39

Mechanism of Action-3 EECP improves endothelial function

PEECH is a large study being run under an IDE from the FDA and under FDA supervision. It is the natural extensions of the pilot Feasibility study and will be used to obtain labeling for the indication through the pre-marketing approval process of the FDA. VO2 max is the primary parameter and was used to calculate the study size. There is sometimes a confusion over why patients of all etiologies are included (idiopathic) because there is a perception that EECP is basically would work only in those whose HF originates in CAD. This, of course, has no real basis because we do not know how EECP works and it might be that its main effect is to ameliorate chronic peripheral vasoconstriction. This is why I have included the next slide which shows the main result of the Feasibility study. Note that the “idiopathics” do as well as the “ischemics”.

How to Follow Clinical Outcomes of Patients Undergoing   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??