OZLEM SORAN, MD, MPH, FACC, FESC

Transcription

1 The Role of Enhanced External Counterpulsation Therapy in Refractory Angina Pectoris Management OZLEM SORAN, MD, MPH, FACC, FESC Director of EECP Research Lab Associate Professor of Medicine Associate Professor of Epidemiology/Research Cardiovascular Institute University of Pittsburgh

2 Conflict of Interest Slide Present: NONE Past: Vasomedical Inc.; speaker's bureau

3 Evolution of Counterpulsation Birtwell s Arterial Counterpulsator Intra-Aortic Balloon Pump External Counterpulsation

4 Single-chamber hydraulic counterpulsation Circa 1968

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6 Postulated Mechanisms of Action Hemodynamic Effects of EECP Increase Cardiac Output Increase coronary Perfusion Improve Diastolic Filling Diastolic Augmentation Pressure Gradients Increase Venous return Systolic unloading Diastolic Retrograde Flow occlusion Remodeling Enhance Collateral capillary sprouting 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

7 EECP Hemodynamic Effects Increased Venous Return Diastolic Augmentation Control Counterpulsating Improve LV Diastolic Filling Systolic Unloading Finger Plethysmograph Duplex echocardiography of the descending aorta

8 mmhg Aortic and Intracoronary Pressure during Enhanced External Counterpulsation 2 15 Diastole 1 5 Systole Michaels AD, et al. Circulation 22; 16:

9 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

10 Exercise duration, mean (min) Exercise Times SUNY Stony Brook 12 1 P< Pre-EECP 9.72 Post-EECP Lawson WE, Hui JCK, Soroff HS, et al. Am J Cardiol 1992;7:

11 Post-EECP Pre-EECP EECP Effect on Radionuclide Stress Perfusion Stress Rest Stress Rest Lawson WE, Hui JCK, et al. J Crit Illness 2;15(11):629-36

12 Percent of patients Improvement in Perfusion (as documented by thallium perfusion imaging) Improved reversible perfusion defects Resolution of reversible perfusion defects Improved or resolved Perfusion defects Lawson WE, Hui JCK, et al. Am J Cardiol 1992;7:

13 Other Series Several studies of stable angina/refractory 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

14 Journal of the American College of Cardiology Vol. 33, No. 7, 1999 CLINICAL STUDIES The 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

15 MUST-EECP Trial EECP Therapy in Angina Time to Exercise-Induced Ischemia Mean Change from Baseline (seconds) 6 p = Sham N = EECP N = 56 EECP versus Sham EECP Overall Results EECP increased time to exerciseinduced ischemia EECP reduced occurrence of angina episodes Quality of Life Sub-study At one year post treatment, EECP improved measures of Bodily Pain Social Functioning Health & Functioning Health Transition

16 HQOL Changes Using SF36 and QL Index Instruments (Baseline to 1 Yr Follow-up) Physical Functioning (Work) Role Disability Due to Physical Health Bodily Pain General Health Vitality Social Functioning Active CP Inactive CP St. Sig. Within Group Difference St. Sig. Between Group Difference (Work) Role Disability Due to Emotional Health Mental Health Cardiac Specific Health & Functioning Magnitude of Improvement or Decline Expressed in Standard Deviation Units

17 Paresthesia Adverse Experiences* Sham (n=66) 1 EECP (n=71) 2 P Value p>.5 Edema 2 p=.5 Skin abrasion, bruise, blister 2 13 p=.5 Pain in leg or back 7 2 p=.1 Total 1 37 p<.1 # Patients reporting AEs 17 (25.8%) 39 (54.9%) p<.1 Withdrawal due to AE 1 7 * Considered by investigator as probably, possibly or definitely device related MUST-EECP Arora RR, et al. J Am Coll Cardiol 1999;33:1833-4

18 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 Soran O et al. Am J Cardiol. 26 Jan 1; 97(1): 17-2

19 Post-EECP Outcome No angina or class I/II angina % Angina reduced by at least one class % Discontinued nitroglycerin use (% of those using pre-eecp) EF < 35% (N=363) Soran O et al. Am J Cardiol. 26 Jan 1; 97(1): 17-2

20 Major Events occurring during EECP EF < 35% Death %.8 MI %.3 CABG %.3 PCI %.8 Exacerbation of heart failure % 3.3 Unstable angina % 3.6 Soran O et al. Am J Cardiol. 26 Jan 1; 97(1): 17-2

21 81% had no congestive Heart Failure exacerbation during the 2 year follow-up period.

22 Patients with LVD Death/MI/CABG/PCI to 2 years Event free survival at 2 years= 7 % Soran O et al. Am J Cardiol. 26 Jan 1; 97(1): 17-2

23 THE IMPACT OF ENHANCED EXTERNAL COUNTERPULSATION TREATMENT ON EMERGENCY ROOM VISITS AND HOSPITALIZATIONS Soran O et al, Congest Heart Fail. 27;13(1):36-4

24 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. 27;13(1):36-4

25 EECP Reduced ER Visits & Hospitalizations in Patients with RAP and LVD ER Visits Hospitalizations p< p<.1 86% 83% 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, 25 Published in Congestive Heart Failure - Soran et al - Jan 27,

26 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,25

27 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

28 Research: More than 15. patients have been treated with EECP for research purpose Routine Practice: Currently > 2 patients have been treated with EECP

29 FDA Indications for EECP Therapy March 1995 stable and unstable angina, acute myocardial infarction, cardiogenic shock, June 22 Clinical indications are expanded to include congestive heart failure

30 The Therapeutic Conundrum: How does EECP Work?

31 Hypothesis 1: Enhanced diastolic flow increases shear stress Increased shear stress activates the release of growth factors Augmentation of growth factor release activates angiogenesis

32 Collateral Development in Experimental Heart (Dog) Following Counterpulsation Before After Jacobey JA, Taylor WJ, et al. Am J Cardiol

33 Increase in serum VEGF from baseline (%) Influence of EECP on Serum VEGF 25 During EECP After EECP Baseline 1 Hour 17 Hours 35 Hours 1 Week I Month Kho, Liuzzo, Suresh K. Endocrine Society s 82 nd Annual Meeting; Canada

34 Increase (%) EECP: Change in Angiogenic Factors HGF bfgf VEGF MCP-1 Masuda D, et al. Circulation

35 Effects of EECP on Arteriogenesis CFI = -.44±.7 (Sham) +.88 ±.7 (Active) p=.5.25 p=.2.2 p=.4 CFI Sham-ECP Active-ECP Baseline Post-ECP Mean Coronary Occlusive Pressure -Central Venous Pressure Collateral flow index (CFI) = Mean Aortic Pressure -Central Venous Pressure Gloekler S et al; Heart 21

36 Hypothesis 2: EECP enhances vascular reactivity Like athletic training, the vascular effects of EECP might be mediated through changes in the neurohormonal milieu

37 Nitric Oxide ( mol/l) Effect of EECP on NO Control Pre- 6 wk Pre- 1 h 12 h 24 h 36 hr Medical Therapy EECP Treatment Qian XX, et al. J Heart Dis

38 Plasma Nitric Oxide ( mol) Effect of EECP Therapy on Nitric Oxide * P <.1 vs baseline 17.9 Control Day 1 After 1 wk After 1 mo * Masuda D, Nohara R, et al. Eur Heart J

39 Plasma cgmp (nmol/l) Improvement in Neurohormonal Factors p<.1 High Risk (N=25) Placebo Plasma cgmp Eur Heart J 21;22(16): CAD Eur Heart J 21;22(16): (N=3) 1-Hr EECP p<.1 AJH 26;19: pg/ml Plasma ANG II Activity * * * p<.1 vs normal p<.1 vs baseline CAD * * * Baseline 1 hr 12 hrs 24 hrs 36 hrs Normal Volunteers (N = 17) EECP treated pts (N = 2) European Society Cardiol Congress 21

40 LVEDP (mmhg) Left Ventricular End-Diastolic Pressure Plasma BNP positively correlated with LVEDP ==.44, p<.5) P <.5 Pre-EECP Post-EECP Urano H, et al. J Am Coll Cardiol

41 Units x 1 2 Dynes-sec-cm 2 x 1 2 Blood Pressure (mm Hg) Effects on Blood Pressure and Myocardial Oxygen Consumption p=.1 Brachial Blood Pressure Aortic p= p= p= Systolic Pressure Pulse Pressure Systolic Pressure Pulse Pressure Pre-EECP Post-EECP Pre-EECP Post-EECP Indexes of Myocardial Oxygen Demand Tension-Time-Index p<.1 23 ± ± Wasted LV Energy 56 ± 16 p<.1 36 ± 13 Baseline EECP Baseline EECP N=2 patients with refractory angina Wilmer Nichols, et al: JACC doi:1.116/j.jacc

42 Hypothesis 3: EECP improves endothelial function Enhanced External Counterpulsation Treatment Improves Arterial Wall Properties and Wave Reflection Characteristics in Patients With Refractory Angina J Am Coll Cardiol, 26; 48:

43 Pressure Wave Travel Time (msec ) Augmentation Index (%) Effects of EECP on Pulse Wave Velocity and Arterial Stiffness Travel Time of Reflected Wave Decreased PWV Increased t p / 2 Arterial Stiffness Arterial Stiffness Augmentation Index 74 p= % p= % Pre-EECP Post-EECP Pre-EECP Post-EECP Ps Pi Pulse Pressure = ( Pi Pd ) Augmentation Index = (Ps Pi) / (Ps Pd) Pressure without reflection Time for pressure wave to travel from aortic root and back = t p Wasted LV pressure energy = 2.9 X tp * (Ps Pi) Pd LV Workload = Tension Time Index = area under systolic wave J Am Coll Cardiol 26;48:

44 PAT Index Improvement in Endothelial Function % FMD EECP Improves Endothelial Functions Determined by Reactive-Hyperemia Peripheral Arterial Tonometry (PAT) 2. Normal PAT Index: 1.77 ±.18 * * * N=18 pt 1 st hr 17 th hr 35 th hr Pre-EECP Post-EECP 1-month follow-up *p<.5; p<.5 vs pre EECP index on 1 st, 17 th and 35 th hr J Am Col Cardiol 23:41,1, Brachial Artery Flow-mediated dilation (FMD) 12 1 p< Control EECP N=2 N=2 Baseline 2-month after Enrollment J Am Coll Cardiol 23;42:29-5

45 Effects of EECP on Peripheral Endothelial Function Control (Sham) EECP (n=1) Active EECP (n=2) Parameters Baseline Post p Baseline Post- p Sham EECP BFMD (%) NS <.5 FFMD (%) NS <.5 FBF (ml/min/1ml) NS <.5 CBF (ml/min/1ml) NS <.5 Ala (%) NS <.5 T p (ms) NS <.5 LV we (msec-mm Hg -2 ) NS <.5 CF-PWV (m/sec) NS <.5 Plasma Nox ( mol/l) NS <.5 ADMA ( mol/l) NS <.5 ED (sec) NS <.5 Time to angina (sec) NS <.5 VO 2peak (ml/kg/min) NS <.5 Braith: 58 Annual Scientific Session ACC Orlando, 29

46 Circulating Endothelial Progenitor Cells (EPC) in Patients with Angina Pectoris Number of CD34+/KDR+ Cells per 1 5 peripheral blood mononuclear cells p=.43 p= Control (N=1) Treated (N=15) Assessed by flow activated cell sorter Baseline per well Post-treatment EPC Colony Forming Unit p=.557 p=.1 Control (N=1) Treated (N=15) Cardiology 28;11:16-166

47 Effects of EECP on Vascular Endothelial Cell Morphology Scanning Electron Micrographs Scale 1 µm (amplification x5) The luminal surface was covered with many adherent cells. The endothelial cells were in disarray. Less cellular adherence Endothelial cells align parallel to direction of blood flow Circulation 27;116:

48 Intima/media area ratio Effects of EECP on Intimal Hyperplasia Left Anterior Descending Coronary Artery magnification 4 5µm 5µm * magnification 4 2 5µm 1 5µm Control CHOL CHOL+ EECP N=7 N=11 N=17 CHOL group fed with high cholesterol atherogenic diet for 15 weeks EECP started at 7½ wks, treated for 7 ½ wks Intimal Area = (Internal elastic laminal lumen area) Control CHOL CHOL + EECP There was no significant difference between Control and CHOL+EECP * p<.5 for CHOL vs Control p <.5 for CHOL+EECP vs CHOL Media Area = (External elastic laminal internal elastic laminal) Circulation 27;116:

49 enos protein level (% of control) Shear stress (dynes/cm 2 ) Effect of EECP on enos Protein Expression A B C D Control (n=7) CHOL (n=11) CHOL+ EECP (N=17) *p<.5 versus Control * p<.5 versus CHOL group Control CHOL CHOL +EECP A - C: Immunohistochemistry of enos localized in endothelial cells (brown) D: Bar chart showing fluorescence intensity of enos as % of control in the three groups E: Peak diastolic arterial wall shear stress ( ) in the Brachial arteries is calculated using = 4 V / ID Circulation 27;116: E ± 7.28 Baseline (p<.1) ± 1.71 During EECP

50 svcam-1 (% change from baseline) TNF- (% change from baseline) MCP-1(% change from baseline) Decrease Circulating Level of Proinflammatory Biomarkers Plasma Tumor Necrosis Factor EECP -29% N=12 p<.5 6.9±2.7 to 4.9±2.5 pg/ml, p<.1 N=9 Sham 5 % 6.4±1.9 to 6.7±1.9 pg/ml, p=.54 Soluble Vascular Cell Adhesion Molecule EECP -6 % NS 776±28 to 726±278 ng/ml, p=.14 Sham 1.4% 847±177 to 859±16 ng/ml, p=.81 Monocyte Chemoattractant Protein EECP -2% p<.5 255±56 to 19±48 pg/ml, p<.1 Sham -.5% 27±82 to 264±66 pg/ml, p=.51 Clinical Improvement Post EECP Canadian Cardiovascular Society Angina Class Baseline Post EECP 3.1±.5 1.2±.4 <.1 Angina Episodes 1.6±1.4.4±.6 <.5 Nitroglycerin use/day.5±.7.1±.2 <.5 p -2 Casey, Conti: Am J Cardiol 28;11:3-32

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52 Review of the Mechanisms of Action of EECP Therapy Acute Effects during EECP treatment as a Circulatory Assisted Device Workload of the heart Coronary blood flow Systemic circulation Improve Endothelial Functions Nitric oxide Endothelin Intimal hyperplasia Arterial stiffness Improve Ischemic Heart Disease & Heart Failure Exercise Capacity Quality of Life Medications Coronary collateral flow Ejection Fraction Functional Class Neurohormonal Deactivation Angiotension, ANP, BNP Reduce Proinflammatory Cytokines TNF-, MCP-1 Regulates smooth muscle tone cgmp

53 Patients Selection FDA Labeling for EECP Intended Use stable or unstable angina pectoris congestive heart failure acute myocardial infarction cardiogenic shock Contraindications arrhythmias that interfere with machine triggering bleeding diathesis active thrombophlebitis severe lower extremity vascular occlusive disease presence of a documented aortic aneurysm requiring surgical repair pregnancy Current Clinical Criteria Indications CCS class II-IV angina Pectoris refractory to medical therapy and revascularization NYHA or CCS Class II-III heart failure Contraindications decompensated heart failure (i.e. central venous pressure > 7 mm Hg, and pulmonary edema) uncontrolled systemic hypertension (> 18/11 mm Hg) severe aortic insufficiency warfarin therapy with INR>3.