OZLEM SORAN, MD, MPH, FACC, FESC

1. OZLEM SORAN, MD, MPH, FACC, FESC Associate Professor of Medicine Associate Professor of Epidemiology/ Research Director of EECP Research Lab Cardiovascular Institute, University of Pittsburgh

3. Evolution of Counterpulsation Intra-aortic balloon pump (IABP) and external counterpulsation both work on the principle of withdrawing blood from the arterial system during systole and returning it during diastole to improve coronary perfusion and decrease cardiac workload while reducing myocardial oxygen consumption. EECP also increases venous return resulting in a greater increase in cardiac output than IABP.Intra-aortic balloon pump (IABP) and external counterpulsation both work on the principle of withdrawing blood from the arterial system during systole and returning it during diastole to improve coronary perfusion and decrease cardiac workload while reducing myocardial oxygen consumption. EECP also increases venous return resulting in a greater increase in cardiac output than IABP.

6. Aortic and Intracoronary Pressure during Enhanced External Counterpulsation Patient #3.Patient #3.

7. Treatment Procedure Counterpulsation is applied for 1 hour/day Treatment protocol is 35 days 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. 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.

8. Exercise Times18 Patients ~ SUNY Stony Brook This slide, and the two following, are details from the previous slide. When comparing maximal stress test results in the 18 patients before and after EECP treatment, there was a significant increase in mean exercise duration of 8.14 � 0.71 to 9.72 � 0.77 minutes following EECP (p<0.005).This slide, and the two following, are details from the previous slide. When comparing maximal stress test results in the 18 patients before and after EECP treatment, there was a significant increase in mean exercise duration of 8.14 � 0.71 to 9.72 � 0.77 minutes following EECP (p<0.005).

9. This is one of the scans from the trial as it continued. Bill Lawson�s patient. Myocardial perfusion improved following 35 one-hour treatment sessions with EECP treatment. Anterior and posterolateral walls showed improvement when comparing the pre-treatment panel above with the panel below showing post-treatment results with EECP.This is one of the scans from the trial as it continued. Bill Lawson�s patient. Myocardial perfusion improved following 35 one-hour treatment sessions with EECP treatment. Anterior and posterolateral walls showed improvement when comparing the pre-treatment panel above with the panel below showing post-treatment results with EECP.

10. A three-year follow-up assessment of 18 patients treated with EECP revealed sustained benefit in patients. In the original group of 14 responders, one patient was not able to be located, one sustained a myocardial infarction and one underwent revascularization during the period of three years. The remaining patients in this group continued to be free of angina. A three-year follow-up assessment of 18 patients treated with EECP revealed sustained benefit in patients. In the original group of 14 responders, one patient was not able to be located, one sustained a myocardial infarction and one underwent revascularization during the period of three years. The remaining patients in this group continued to be free of angina.

11. Other Series Non-randomized studies of angina pectoris with ETT (some radionuclide), NTG use, CCS angina Class and HQOL measures: Dresden and Erlangen, Germany Howard County General Hospital, Columbia,MD Beaumont Hospital, Dublin, Ireland Hammersmith Hospital, London, England Mayo Clinic, Rochester, MN Kyoto and Kurume, Japan Grant Hospital, Columbus, OH and Port Chester, NY Study results consistent with Stony Brook findings 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. 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.

12. CLINICAL STUDIESThe Multicenter Study of Enhanced External Counterpulsation (MUST-EECP): Effect of EECP on Exercise-Induced Myocardial Ischemia and Anginal Episodes Rohit R. Arora, MD, Tony M. Chou, MD, Diwakar Jain, MD, Bruce Fleishman, MD Lawrence Crawford, MD, Thomas McKiernan, MD Richard W. Nesto, MD for the MUST-EECP Investigators New York, New York; San Francisco, California; New Haven, Connecticut; Columbus, Ohio: Pittsburgh, Pennsylvania; Maywood, Illinois: Boston, Massachusetts The MUST-EECP trial was the first study to compare EECP treatment with a sham-control. 139 patients were randomized to either treatment consisting of 35 hours of EECP at full cuff pressure (250-300 mmHg) or a �sham� of <80 mmHg. The MUST-EECP trial was the first study to compare EECP treatment with a sham-control. 139 patients were randomized to either treatment consisting of 35 hours of EECP at full cuff pressure (250-300 mmHg) or a �sham� of <80 mmHg.

13. Exercise Results* There was not a significant difference in the before and post-EECP treatment results for exercise duration (42 + 11 versus 26 + 12 seconds), p > 0.3. The lack of significance might have been due to having been no pre-baseline exercise test to reduce training effect. There was however, a significant difference before and following EECP treatment in the change in time to exercise induced ischemia (37 + 11 versus �4 + 12 seconds), p=0.01. Note that the sham group had a slight deterioration in time to ST depression. The investigators note that the results were similar to those of most drug trials.There was not a significant difference in the before and post-EECP treatment results for exercise duration (42 + 11 versus 26 + 12 seconds), p > 0.3. The lack of significance might have been due to having been no pre-baseline exercise test to reduce training effect. There was however, a significant difference before and following EECP treatment in the change in time to exercise induced ischemia (37 + 11 versus �4 + 12 seconds), p=0.01. Note that the sham group had a slight deterioration in time to ST depression. The investigators note that the results were similar to those of most drug trials.

14. Angina Counts (daily episodes) There was a reduction of angina counts in both the intention-to-treat analysis and also on a per-protocol basis, suggesting, as expected, that for those receiving a full course are more likely to have better antianginal outcomes.There was a reduction of angina counts in both the intention-to-treat analysis and also on a per-protocol basis, suggesting, as expected, that for those receiving a full course are more likely to have better antianginal outcomes.

15. Adverse Experiences* There were significantly more adverse events particularly those of a musculoskeletal nature in the EECP treatment group as compared to sham. However, withdrawals due to AE were few, suggesting that the AEs were generally tolerable. There were significantly more adverse events particularly those of a musculoskeletal nature in the EECP treatment group as compared to sham. However, withdrawals due to AE were few, suggesting that the AEs were generally tolerable.

16. Note that there is a greater improvement from Baseline to 12-months follow-up than from baseline to EOT. Was this due to an increased ability of some patients to exercise and help themselves (hope effect) or was is due to the triggering of a �healing� process that continued after treatment was over? Note that there is a greater improvement from Baseline to 12-months follow-up than from baseline to EOT. Was this due to an increased ability of some patients to exercise and help themselves (hope effect) or was is due to the triggering of a �healing� process that continued after treatment was over?

17. Organized in 1998 to document patterns of use, safety and efficacy of EECP in consecutive series of patients Open to all centers using EECP for treatment of angina pectoris Voluntary registry (no payment to patients or centers) Phase 1 planned to enroll 5000 consecutive patients with follow-up for minimum of three years INTERNATIONAL EECP PATIENT REGISTRY [IEPR] The IEPR is conducted by the Department of Epidemiology, Graduate School of Public Health, University of Pittsburgh, a center with long experience of registry keeping. Centers offering EECP to their patients are invited to join and having done so, commit to entering all consecutive patients. A patient log is kept to monitor entry. The IEPR is a multicenter study of consecutive patients undergoing EECP at member cardiology hospitals and clinics. Measures are at baseline (before starting treatment) and at end of treatment with follow-up for clinical events, anginal symptoms and QOL questions by telephone at 6 months and annually for 3 years. Written informed consent and IRB approvals are required. The IEPR is conducted by the Department of Epidemiology, Graduate School of Public Health, University of Pittsburgh, a center with long experience of registry keeping. Centers offering EECP to their patients are invited to join and having done so, commit to entering all consecutive patients. A patient log is kept to monitor entry. The IEPR is a multicenter study of consecutive patients undergoing EECP at member cardiology hospitals and clinics. Measures are at baseline (before starting treatment) and at end of treatment with follow-up for clinical events, anginal symptoms and QOL questions by telephone at 6 months and annually for 3 years. Written informed consent and IRB approvals are required.

18. 92 Centers 82 United States 5 Europe 5 Other international 5222 patients in current enrollment 5718 courses of EECP therapy INTERNATIONAL EECP PATIENT REGISTRY [IEPR]Phase I Katherine Detre, MD, DrPH - Sheryl Kelsey, PhD -Elizabeth Kennard, PhD - Richard Holubkov, PhD are responsible for the IEPR at the Department of Epidemiology, University of Pittsburgh Graduate School of Public Health, Pittsburgh, Pennsylvania USA. Phase I was completed in 2001. Phase II began in January 2002. Probably constitutes one third to one half the patients treated with EECP during the last 4 years. Information is collected at time points: baseline, at the last treatment session. 6 months post-treatment, 12 months post-treatment, annually. Baseline items are:- Age, Race, Weekly angina, Weekly NTG, Medications, Prior EECP, Time of diagnosis. MI/PTCA/CABG/CHF/ Other, Risk factors, Angiogram results, LVEF, Stress test METS, Revascularization Status, QoL questions. Post treatment: Hrs. of EECP, Peak & area diastolic/systolic ratios, Tx completion?, Reason stopped, CCS angina Class, Medications, Clinical events, weekly angina counts, NTG, QoL questions Follow-up: CCSC, Weekly angina counts, NTG, Medications, repeat EECP, Reasons?, Clinical events, Stress test METS, QoL questions Katherine Detre, MD, DrPH - Sheryl Kelsey, PhD -Elizabeth Kennard, PhD - Richard Holubkov, PhD are responsible for the IEPR at the Department of Epidemiology, University of Pittsburgh Graduate School of Public Health, Pittsburgh, Pennsylvania USA. Phase I was completed in 2001. Phase II began in January 2002. Probably constitutes one third to one half the patients treated with EECP during the last 4 years. Information is collected at time points: baseline, at the last treatment session. 6 months post-treatment, 12 months post-treatment, annually. Baseline items are:- Age, Race, Weekly angina, Weekly NTG, Medications, Prior EECP, Time of diagnosis. MI/PTCA/CABG/CHF/ Other, Risk factors, Angiogram results, LVEF, Stress test METS, Revascularization Status, QoL questions. Post treatment: Hrs. of EECP, Peak & area diastolic/systolic ratios, Tx completion?, Reason stopped, CCS angina Class, Medications, Clinical events, weekly angina counts, NTG, QoL questions Follow-up: CCSC, Weekly angina counts, NTG, Medications, repeat EECP, Reasons?, Clinical events, Stress test METS, QoL questions

19. This slide shows the patient characteristics for the first year of the IEPR. Over time, perhaps because of Medicare coverage provisions or perhaps because of greater willingness to treat sicker patients, there has been a tendency for patients to be sicker. Otherwise there has been little change.This slide shows the patient characteristics for the first year of the IEPR. Over time, perhaps because of Medicare coverage provisions or perhaps because of greater willingness to treat sicker patients, there has been a tendency for patients to be sicker. Otherwise there has been little change.

20. INTERNATIONAL EECP PATIENT REGISTRY [IEPR]Change in CCS Angina Class (1998 Cohort Intention-To-Treat) The main efficacy parameters of the IEPR are CCSC and QOL. The CCSC changes are similar to those seen in other EECP studies. About 75 % improve by one class, 40 % by two classes and 20 % three classes Improvements are usually maintained for at least 12 months. 13 % of patients experience and event including repeat EECP, PCI, CABG, CHF, unstable angina or death during one year. The main efficacy parameters of the IEPR are CCSC and QOL. The CCSC changes are similar to those seen in other EECP studies. About 75 % improve by one class, 40 % by two classes and 20 % three classes Improvements are usually maintained for at least 12 months. 13 % of patients experience and event including repeat EECP, PCI, CABG, CHF, unstable angina or death during one year.

21. EECP in Heart Failure: Results of a Pilot Study Ozlem Z. Soran�, Teresa De Marco�, Lawrence E. Crawford�, Virginia Schneider�, Paul-Andr� 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

22. 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-Andr� 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

23. Heart Failure Feasibility Study  Mean Exercise Duration (sec)

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

25. Minnesota Living with Heart Failure Questionnaire

26. 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.

29. 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�. 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�.

30. PEECH: Hypothesis Based on the known hemodynamic effects of enhanced external counterpulsation, the use of EECP therapy can improve: Exercise performance Symptom status and Quality of life in patients with: Non-ischemic or ischemic cardiomyopathy Stable heart failure symptoms Optimal medical therapy

33. The PEECH Trial: Study Plan 187 subjects (180 planned) randomized in a 1-to-1 ratio to either Optimal Medical Therapy per HFSA guidelines or EECP� Therapy + Optimal Medical Therapy Stratification by etiology, age, gender, use of ACEI/ARB, use of beta-blocker 35 sessions, 1 hour each, over 7 weeks Sample size calculated to provide 90% power. Analysis by intent to treat Comment on reason; comment on assumptions including VO9708 resultsComment on reason; comment on assumptions including VO9708 results

34. PEECH: Change in Exercise Duration

35. PEECH: Improvement in NYHA Class Key Points: There were no statistically significant differences between the three study arms either in the outcome of death or death/MI. For both outcomes, there were slight, though non-statistically significant increases with the 48 hour regimen. It is important to note that the majority of the effect of abciximab on platelet inhibition comes from the bolus and after around 12 hours, even with the infusion running, platelet inhibition begins to drop off. This may explain the lack of efficacy at 24 and 48 hours in ACS patients.Key Points: There were no statistically significant differences between the three study arms either in the outcome of death or death/MI. For both outcomes, there were slight, though non-statistically significant increases with the 48 hour regimen. It is important to note that the majority of the effect of abciximab on platelet inhibition comes from the bolus and after around 12 hours, even with the infusion running, platelet inhibition begins to drop off. This may explain the lack of efficacy at 24 and 48 hours in ACS patients.

36. PEECH: Change in Peak VO2

37. 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

38.  Clinical Outcomes, Event Free Survival Rates and Incidence of Repeat Enhanced External Counterpulsation in Refractory Angina Patients with Left Ventricular Dysfunction - A 2 Year Cohort Study 

39. Post-EECP Outcome 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 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

40. Major Events occurring during EECP

41. 81% had no congestive Heart Failure exacerbation during the 2 year follow-up period.

42.

43. THE IMPACT OF ENHANCED EXTERNAL COUNTERPULSATION TREATMENT ON EMERGENCY ROOM VISITS AND HOSPITALIZATIONSCongest 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 counterpulsationMr 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

44. 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. 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. 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.

45. ER Visits

46. Hospitalization

47. 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,2005 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 counterpulsationMr 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

48. The Therapeutic Conundrum: How does EECP Work?

49. Data from several studies are depicted here demonstratinghe mechanisms involved in EECP treatment. Endothelin levels diminish while nitric oxide levels increase, resulting in benefits for patients. Growth factors are increased while brain natriuretic peptide levels fall. PET studies have shown an increase in myocardial perfusion.Data from several studies are depicted here demonstratinghe mechanisms involved in EECP treatment. Endothelin levels diminish while nitric oxide levels increase, resulting in benefits for patients. Growth factors are increased while brain natriuretic peptide levels fall. PET studies have shown an increase in myocardial perfusion.