1. Lasers, Tights, and Bayers…Oh My!!!: Part II Dwight A. Dishmon, MD Morbidity and Mortality Conference April 6, 2006

2. Introduction There is an increasing population of patients who have persistent anginal symptoms despite maximal therapy Following CABG, only 75% of patients are symptom free from ischemic events for 5+ years and only 50% after 10+ years

3. As the survival of patients with primary coronary events continues to increase, the number of patients with CAD unsuitable to further revascularization and symptoms refractory to medical therapy also continues to rise Enhanced external counterpulsation (EECP) is one of the treatment strategies that is finding a role in the treatment of patients with refractory angina

4. EECP is a noninvasive outpatient treatment used for intractable angina EECP uses an acute hemodynamic effect that is presumed to be similar to that produced by the intra-aortic balloon pump (IABP) By applying a series of compressive cuffs sequentially from the calves to the thigh muscles upon diastole and rapidly deflating the cuffs in early systole, an increase in diastolic and decrease in systolic pressure is created

5. History In 1953, Kantrowitz and Kantrowitz initially described the concept of diastolic augmentation as a technique to improve coronary blood flow Birtwell and others showed that the ECG QRS complex could be used to time an external pumping device that provided a synchronous pulse wave thereby increasing coronary collaterals

6. Gorlin coined the term “counterpulsation” to describe the two- fold effect of the rapid displacement and reduced resistance of volume in the lower arterial circuit Soroff and Birtwell first described how the application of a positive pressure pulse to the lower extremities during diastole could raise diastolic pressures by 40-50% and lower systolic pressures by up to 30%

7. In the 1960’s, S.D. Malopoulis developed an experimental protocol of the IABP where a pulse wave was delivered via an intra-aortic balloon device timed to the cardiac cycle

8. By the early 1960’s, 3 groups independently developed hydraulically activated external couterpulsation devices Initial experience with a crude external counterpulsation device used in stable angina saw relief of angina symptoms with angiographic evidence of increased vascularity

10. In the early 1980’s, a Chinese group lead byZ.S. Zheng began using a sequential three cuff external counterpulsation method Their positive clinical experience led to the installation of more than 1500 external counterpulsation units in China

12. Technique EECP is offered exclusively by Vasomedical Inc. Involves the use of three paired inflatable cuffs wrapped around the patient’s lower extremities The patient is connected to an ECG monitor and a finger plethysmograph

13. The R wave of the ECG is used as the trigger for inflation and deflation

14. The cuffs are sequentially inflated (calves  lower thighs  upper thighs) during diastole

15. All pressure is released at the onset of systole

16. The diastolic augmentation increases coronary perfusion pressure and provides improved afterload reduction and increased venous return Systolic unloading is enhanced and cardiac workload is decreased via decrease in PVR

18. Retrograde aortic pressure wave  diastolic pressure  intracoronary perfusion pressure  myocardial perfusion  venous return  preload  cardiac output  systemic vascular resistance  cardiac workload  myocardial O 2 consumption  afterload

19. Pressures in the range of 250-275 mmHg applied Treatment course consists of 35 one- hour sessions

20. Patient Selection Patients with angina or angina equivalents who: No longer respond to medical therapy Restrict their activities to avoid angina Are unwilling to undergo addt’l procedures Are high risk for revascularization Have coronary anatomy unsuitable for revascularization Suffer with microvascular angina

21. Contraindications Arrhythmias that interfere with machine triggering Bleeding diathesis Active thrombophlebitis Severe lower extremity vaso-occlusive disease Presence of a documented aortic aneurysm requiring surgical repair Pregnancy

22. Precautions BP > 180/110 should be controlled HR >120 bpm Pulmonary congestion Significant valvular disease

23. Mechanism of Action Several theories have been postulated The hemodynamic effects of EECP have been theorized to simulate the IABP where CO, SV, and retrograde aortic diastolic flow are enhanced and myocardial O 2 demand is decreased

24. Potential for increased transmyocardial pressure to open collaterals

25. In 1973, Banas demonstrated that EECP increased angiographically visible collateralization in patients with chronic stable angina It has been postulated that collateral development is dependent upon the patency of neighboring vessels An open non-obstructed conduit provides the milieu for greatest benefit

26. Huang, W, et al. J of Eur Soc of Cardio. 1999.

27. The less the CAD, the greater the therapeutic benefit from EECP

29. Michaels et al measured left ventricular and intracoronary hemodynamics directly in patients undergoing EECP Aortic pressure, intracoronary pressure, and intracoronary Doppler flow velocity were measured at baseline and during EECP 93% increase in diastolic pressure 16% increase in mean intracoronary pressure 15% decrease in systolic pressure 28% increase in coronary blood flow

31. Central aortic pressure

32. Intracoronary phasic and mean pressures

33. Hemodynamic improvement in terms of diastolic augmentation, improved coronary perfusion and systolic unloading are supplemented by neurohormonal factors Diastolic augmentation causes increased shear stress  endothelial growth factors  angiogenesis

34. Endothelial Cell

35. With exposure to the augmented blood flow and endothelial shear stress, there is elaboration of NO, MMPs, and VEGF

36. Masuda et al examined the effect of EECP on the angiogenic factors

40. Garlichs et al found that EECP reduced serum endothelin-1 concentrations

41. Masuda et al showed that EECP induced an increase in concentrations of NO and a decrease in BNP and ANP

43. Within the endothelial cells, angiotensin II is an oxidative stressor promoting superoxide formation, NO degradation, and endothelial dysfunction

45. Effects on Perfusion Lawson et al studied patients with chronic stable angina and compared the extent of CAD with results of radionuclide stress testing after EECP There was significant improvement in the perfusion defects after EECP The benefits were sustained at five years’ follow-up which showed a significant improvement in stress thallium perfusion and limiting angina

48. “The Pressure” Suresh et al examined the optimal pressures to maximize the hemodynamic benefit of EECP EECP effectiveness ratios (ratio between diastolic augmentation and systolic unloading) in the range of 1.5-2.0 were found to be optimal

49. 200 mm Hg pressure ARTERY% INCREASE IN FLOW Left main coronary18% Carotid artery19% Vertebral artery12% Renal artery21% 300 mmHg pressure ARTERY% INCREASE IN FLOW Left main coronary42% Carotid artery26%

50. Another study analyzed the data from an EECP registry examining the effect of diastolic augmentation on the efficacy of EECP Patients with higher diastolic augmentation tended to have a greater reduction in angina class at 6 months There is evidence that higher diastolic augmentation ratios are associated with improved short or long-term clinical outcomes

51. Efficacy There are reported benefits derived from the use of EECP The first multicenter randomized sham- controlled trial was the MUlticenter STudy of Enhanced External CounterPulsation (MUST-EECP) MUST-EECP compared full EECP treatment –vs- sham on exercise treadmill scores and subjective angina

52. In this trial conducted in 7 centers, 139 outpatients with angina, documented CAD, and (+) ETT were randomly assigned to receive 35 hrs of active or inactive counterpulsation 59 patients in the active and 65 in the inactive group completed the study Outcome was measured in terms of exercise duration, time to 1 mm ST segment depression, avg daily anginal attacks, and NTG use

55. MUST-EECP was a small trial and was not powerful enough to recommend EECP for routine use Follow-up analysis of patients in the MUST-EECP trial at 1 yr showed greater improvement in the health-related quality of life measures in the active treatment group

56. In January 1998, Phase 1 of the International EECP Patient Registry (IEPR) was established to document patient characteristics, safety, efficacy, and long-term outcomes of EECP therapy Analysis of long-term outcomes demonstrates that the clinical benefits achieved with EECP are sustained up to at least 24 months

59. More Studies…

60. In Summary…

61. References Sinvhal, RM, et al. EECP for Refractory Angina Pectoris. Heart. Aug 2003. Parmley, WW and Chatterjee, K. Enhanced External Counterpulsation. Cardiology Update. Oct 1997. The Physician’s Guide to EECP Therapy. Vasomedical Inc. Masuda, D, et al. EECP Promotes Angiogenesis Factors in Patients with Chronic Stable Angina. Circulation. 2001.

62. Quan, XX, et al. Effect of EECP on Nitric Oxide Production in Coronary Disease. J of Heart Disease. May 1999. Werner, D, et al. Pneumatic External Counterpulsation– A New Treatment for Selected Patients with Symptomatic CAD. Circulation supplement. Nov 1998. Werner, D, et al. A New Noninvasive Method to Improve Organ Perfusion. Am J Cardio. 1999.