Clinical Guide. Introduction

Transcription

1 Introduction Clinical Guide Enhanced External Counterpulsation ( ) is a FDA cleared noninvasive medical device for the treatment of patients suffering from coronary artery disease (CAD). It is a device that improves cardiac output, increases circulation and pressure gradient across stenosis to recruit collaterals. It also increases shear stress on the endothelium, improving endothelial function, reduces circulating inflammatory markers and arterial stiffness, inhibits smooth muscle cells proliferation and migration. It has been demonstrated to be safe and effective in the treatment of angina pectoris as well as chronic heart failure. 1,2 Therapy Operations system consists of three sets of inflatable pressure cuffs wrapped around the calves, the lower and upper thighs, including the buttocks. The cuffs are rapidly and sequentially inflated, starting from the calves and proceeding upward to the buttocks during the relaxation (diastolic) phase of each heartbeat, creating a strong arterial retrograde flow towards the heart and significantly increasing blood flow to the coronary arteries at a time when resistance to coronary blood flow is at its lowest level. The inflation of the cuffs also simultaneously increases the volume of venous blood returned to the right side of the heart, providing greater filling of the ventricle for ejection. Just before the beginning of the next cardiac cycle when the heart begins to contract, all three cuffs simultaneously deflate, leaving an empty vascular space in the lower extremities to receive blood ejecting from the heart, thereby significantly reducing the workload of the heart. The inflation/deflation activity is monitored constantly and coordinated by a microprocessor that interprets electrocardiogram signals, monitors heart rhythm and rate information, and actuates the inflation and deflation in synchronization with each cardiac cycle (see Figure 1). The inflation/deflation cycle is repeated every heartbeat, increasing energy supply to the heart, improving cardiac output, while at the same time reducing the workload of the heart. Figure 1: The QRS complex of the electrocardiogram is used to provide a triggering signal for the calf inflation valve to open around the peak of T-wave, the lower thigh valve will open 5 ms later, to be followed by the upper thigh valve another 5 ms later. The pressure in the cuffs will hold as long as possible to allow maximization of diastolic augmentation. Then all threedeflation valves will open at the same time around the peak of P- Sequential inflation of three sets of cuffs at the Upper Thigh Cuffs Lower Thigh Calf Cuffs Simultaneous deflation of all three sets of cuffs at the Upper Thigh Lower Thigh Calf Cuffs wave to let the emptied peripheral vasculature to receive the blood ejected by the heart, leading to systolic unloading.

2 Treatment System The therapy systems are Food and Drug Administration (FDA) cleared for marketing in the treatment of stable and unstable angina, congestive heart failure, acute myocardial infarction, and cardiogenic shock. Figure 2: Lumenair system. Patient selection and contraindications as well as precautions should be followed carefully to avoid risk of adverse clinical events. Blood pressure, respiration rate, oxygen saturation and weight should be monitored during treatment to avoid exacerbation of heart failure, especially in patients with low ejection fraction. Physical assessment, especially peripheral skin condition, should be examined after every treatment session. The treatment is administered to patients on an outpatient basis, usually in daily one-hour sessions, five days per week over seven weeks for a total of 35 treatments. is equally effective if it is given twice daily, each with one-hour session separated by a minimum of 3- minutes break for a total of three and a half week. The procedure is well tolerated and most patients begin to experience relief of chest pain due to their coronary artery disease after 15 to 2 hours of therapy. Patient Selection is primary used as a non-pharmacologic outpatient therapy for patients with chronic stable angina pectoris as well as symptoms of heart failure. 3-8, Effective July 1, 1999, The Centers for Medicare and Medicaid (CMS) and other third-party insurance payers reimburse for the treatment of angina symptoms in patients who have been diagnosed with disabling angina (Class III or Class IV, Canadian Cardiovascular Society Classification or equivalent classification) who are not readily amenable to surgical intervention, such as PTCA or cardiac bypass. Patients with severe, diffuse coronary atherosclerosis and persistent angina, or significant silent ischemia burden, in whom coronary revascularization has been unsuccessful or incomplete, and symptomatic patients at high risk of adverse events related to invasive revascularization, such as elderly patients and those with diabetes, challenging coronary

3 anatomies, or debilitating heart failure, renal failure, or pulmonary disease, have also been shown to derive benefit from therapy. 1, 2, 23 therapy has also been shown to be effective in relieving angina symptoms in patients with cardiac syndrome X. 22 Benefits of have also been determined in the management of angina in the elderly, 24 angina patients with left main disease, 27 and in patients with mild refractory angina (CCS Class II). 8 therapy is equally effective in reducing angina symptoms in patients with or without diabetes, 25 and in patients with all ranges of body mass index. 26 therapy has also been shown to improve exercise capacity in heart failure patients with NYHA Class II/III, and in exercise peak oxygen consumption in older patients with heart failure. 15 therapy has also been demonstrated to be equally effective in providing symptomatic benefits in angina patients with either systolic or diastolic heart failure. 16 For patients with left ventricular dysfunction, the beneficial effects of therapy has been shown to sustain up to 2-year at follow-up Contraindications According to the current FDA labeling, Therapy System should not be used for the treatment of patients with: 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. Precautions Patients with blood pressure higher than 18/11 mmhg should be controlled prior to treatment with enhanced external counterpulsation. Patients with a heart rate more than 12 bpm should be controlled prior to treatment with enhanced external counterpulsation. Patients at high risk of complications from increased venous return should be carefully chosen and monitored during treatment with enhanced external counterpulsation. Decreasing cardiac afterload by optimizing diastolic augmentation may help minimize increased cardiac filling pressures due to venous return. Patients with clinically significant valvular disease should be carefully chosen and monitored during treatment with enhanced external counterpulsation. Certain valve conditions, such as significant aortic insufficiency, or severe mitral or aortic stenosis, may prevent the patient from obtaining benefit from diastolic augmentation and reduced cardiac afterload in the presence of increased venous return.

4 Special clinical issues Elderly patients with age 8 years or older can be treated with with angina classification reduced by at least 1 class and quality of life improved in 76%. At 1 year, 81% reported maintenance of angina improvement. 24 Diabetes: CAD patients with diabetes can safely and effectively be treated with comparable results to non-diabetic CAD patients. 25 Obesity: treatment is equally safe and effective across patients with diverse range of body mass index, including obese patients (BMI > 3 kg.m 2 ) and morbidly obese (BMI > 4 kg.m 2 ). 26 Peripheral vascular disease: listed as precaution due to inadequate diastolic augmentation can gain benefits from treatment similar to all other CAD patients. 1 Abdominal aortic aneurysm (AAA) with increased risk of rupture or retrograde thromboembolic events has not been reported with treatment. AAA larger than 4. cm should be referred to vascular surgeon for evaluation. 1 Atrial fibrillation can be treated with with rate control between 4-1 bpm Pacemakers and defibrillators could undergo safely and derive clinical benefits with appropriate monitoring. Rate-adaptive pacemaker may lead to trigger a paced tachycardia due to patient s body motion and can be turned off during. Treatment protocol: the 35 hours daily treatment is associated with angina reduction and improved exercise tolerance in at least 75% of patients. Extension of therapy by 1-12 hours is associated with further improvement. 1 Repeat therapy: within 2 years after initial treatment, 18% of patients undergo another course of re-treatment due to recurrent angina, persistent angina with benefit 34, 35 similar to patients who respond to their first course. Evidence-Based Clinical Results There are more then 15 papers published in peer reviewed medical journals documenting therapy is a noninvasive, safe, low-cost and highly effective treatment for patients with coronary artery disease. For a list of all published paper, visit: Major results of a few selected papers are summarized below: 1. There are two randomized controlled trials, one for patients with chronic angina pectoris and one for patients with chronic heart failure. Changes in Time to Exercise-induced ST-segment Depression se 6 p= The Multicenter Study of Enhanced External Counterpulsation (MUST- ECP): Effect of on Exercise- Induced Myocardial Ischemia and Anginal Episodes 3 A multicenter (7 university hospitals), prospective, randomized, blinded, control trial in 139 angina patients sec Sham n=56 37 sec n=56

5 with documented coronary artery disease and positive exercise treadmill test were treated with either active counterpulsation (applied cuff pressure up to 35 mm Hg), and inactive counterpulsation (<75 mm Hg). Exercise duration increased in both groups, with time to 1-mm ST-segment depression increased significantly from baseline in the active group compared with the inactive group (p=.1), as well as a significant reduction in the number of angina episodes (p<.5). 1.2a Prospective Evaluation of in Heart Failure (PEECH): 13, subjects with mild-to-moderate symptoms of heart failure were randomized to either treatment with protocol-defined pharmacologic therapy (PT) or PT alone. 35% in the therapy group and 25% in control group increased their exercise time by at least 6 sec (p=.16) at 6 months. However, there was no between group difference in the percentage of subjects with at least 1.25 ml/kg/min increase in peak volume of oxygen uptake. New York Heart Association (NYHA) functional class improved in the active treatment group at 1- week (p<.1), 3 months (p<.2), and 6 months (p<.1). The Minnesota Living with Heart Failure score also improved significantly in the treated group at 1 week % Subjects Who Met Threshold 4. p= (p<.2) and 3 months (p=.1) after treatment, versus no significant changes in the control group % N= % N=94 Exercise Duration Increase 6 sec from baseline 22.8% N=93 Contro l p=ns 24.1% N=94 Peak VO 2 Increase 1.25 ml/kg/min from baseline % responders at 6-month follow-up 1.2b A Subgroup Analysis of the PEECH Trial: Improves Exercise Duration and Peak Oxygen Consumption in Older Patients With Heart Failure 15 This paper reports the results of a prespecified subgroup analysis of 85 elderly patients (65 years or older) enrolled in the PEECH trial. At 6- months post treatment, the percentage of subjects with >6-second increase in exercise duration was significantly higher in patients compared with the control group (p=.8). Moreover, in contrast to the overall PEECH study (see above), the older % Subjects Who Met Threshold % 13/37 p= % 11/44 Exercise Duration Increase 6 sec from baseline 29.7% 11/37 Control p= % 5/44 Peak VO 2 Increase 1.25 ml/kg/min from baseline

6 patient group demonstrated a significantly higher percentage of responders with >1.25 ml/kg/min increase in peak volume of oxygen consumption (p=.17). In addition, the mean changes in exercise duration and peak oxygen consumption from baseline were significantly increased compared with the control group at 1 week, 3 months and 6 months following completion of treatment. 2. Two International Patient Registries (IEPR I with 5, patients and IEPR II with 2,5 patients) have been completed in July 21 and Oct 24 respectively by the Epidemiology Data Center of the University of Pittsburgh to determine the patterns of use, safety and efficacy of for a period of 2-3 years post treatment. Data collected were patients demographics, medical history, CAD status, quality of life, CCS Classification, medication, angina frequency and adverse clinical events before, post, and during follow-up periods At Baseline, patients treated with therapy have an average age of 67 years old, with significant risk factors (43% diabetes, 84% hyperlipidemia and 75% hypertension) and suffered from severe CAD (87% with prior PCI/CABG, 69% with prior MI, 31% heart failure), 86% of patients were Canadian Cardiovasular Society (CCS) angina class III and IV patients. 29 Post- therapy, 81% of the patients improved with reduction of at least one CCS class. 3 The benefits were sustained at 1-year (75%), 3 2-year (73%), 32 and 3-year (74%) 33 follow-up (see figures for the Distribution of the percent of patients according to their CCS angina class). The percent of patients in CCS class III and IV reduced from 86% at baseline to 25% at 1- year, 24% at 2-year and 21% at 3-year follow-up, with 27%, 3% and 35% of patients had no angina during the 1, 2 and 3-year follow-up period N=4, Baseline year follow-up 6 2-year Follow-up 6 3-year Follow-up Canadian Cardiovascular Society angina class No Angina I II III IV Mechanisms of Action There are many pathophysically pathways by which therapy achieves its longterm beneficial effects. There is evidence of improved endothelial function via the hemodynamic effects of increased shear stress on the arterial wall, reducing arterial stiffness and providing

7 protective effects against inflammation, thereby inhabits intima hyperplasia. There is also evidence to suggest that therapy triggers a neurohomonal response that induces the production of growth and vasodilatation factors, which together with the hemodynamic effects of increasing pressure gradient across the occlusive site during therapy, promotes recruitment of new arteries, while dilates and normalizes the function of existing blood vessels. The recruitment of new arteries, known as collateral blood vessels, bypass blocked or narrowed vessels and increase blood flow to ischemic areas of the heart muscle that are receiving an inadequate supply of blood. Mechanisms of Action Improve Neurohormonal Factors BNP and ANP Angiotensin II Acute Hemodynamic Effects Systolic Unloading Diastolic Augmentation Increase Cardiac Output Collaterals Development Blood flow to ischemic region Vascular growth factors Capillary density Reduce Proinflammatory Cytokines and Adhesion Molecules Tumor necrosis factor - Monocyte chemoattractant protein 1 Improve Endothelial Function Vasodilation Intimal Hyperplasia Release of Endothelial Progenitor Cell Reduce Arterial Stiffness Blood pressure Vascular resistance Cardiac efficiency Improve blood flow to ischemic regions Clinical Benefits Hemodynamic Effects during treatment has been documented in the descending aorta with increased stroke volume and presence of retrograde flow, 37 as well as significant increase of blood flow in the coronary arteries using intracoronary Doppler. 38 The increase in flow velocity increases shear stress on the endothelium and improves endothelial functions with significant increase of plasma nitric oxide level 43 and improvement in flow-mediated vasodilatation. 44 In addition, significant decrease (29%) of inflammatory cytokines Descending Aorta Nitric Oxide * Baseline 1hr 12hr 24hr 36hr 1-mo 3-mo *p=.14; p<.1; p=.2 vs baseline Plasma Tumor Necrosis Factor N=12-29% p<. 5 Sham N=9 + 5 % Intracoronary flow N= Brachial Artery Flow-mediated dilatation p = NS Control Baseline p =.43 Sham (N=1) Baseline p<.1 EEC 2-month P after Endothelial Progenitor Cells p=.49 Post- (N=15)

8 tumor necrosis factor- in patients with angina, and increase of circulating plasma endothelial progenitor cell after 41, 4 therapy have been reported. The long-term benefits of therapy from improvement in endothelial functions lead to inhibition of vascular smooth muscle cells migration and proliferation, Scanning Electron attenuation of oxidative stress and Scale 1 µm inflammation and inhibits intimal hyperplasia as demonstrated by the experimental work on hypercholesterolemic pigs in which the coronary arteries and aortas of 35 male pigs randomly assigned to control, high-cholesterol diet (HCD) and HCD+. The group enjoyed a reduction of intima-tomedia area ratio by 42% compared 5µm with HCD group. treated group also increased the protein expression of endothelial nitric oxide synthase and suppressed the phosphorylation of extracellular signal-regulated 5µm kinases ½. 46 In patients suffering from angina pectoris, 34 1-hour treatments 3 in 2 patients caused a significant decline in the augmentation index and an increase in reflected wave travel time, demonstrating a reduction of arterial stiffness, resulting in a decrease in left ventricular afterload, myocardial oxygen demand and angina episodes and improved Canadian Cardiovascular Society functional class. 42 Augm entatio n Index (%) Control High Cholesterol diet (HCD) HCD % Pre- Arterial Stiffness p= % Post- In summary, the acute hemodynamic effects during Therapy of systolic unloading and diastolic augmentation not only provide a chance for myocardial muscle to rest and accumulate energy reserve, the higher pressure gradient across stenosis generated during diastolic when resistance to coronary flow is at its minimum would help to enhance collateral generation, while the increased cardiac output and promotion of retrograded flow induce higher shear stress on the endothelium, improve endothelial functions and increase release of neurohomonal and vascular growth factors that induce vasodilatation, inhibit intima hyperplasia and develop collateral circulation to achieve long-term clinical benefits. There are several review papers on therapy expanding these concepts. 47,48

9 Cost Effectiveness 1. Reimbursement for refractory angina There are approximately 6.8 million people in the United States suffering from angina, with 4, new cases diagnosed annually, and 8-1, patients suffered from refractory angina. Effective July 1, 1999, the Centers for Medicare and Medicaid Services (CMS ) and many other third-party insurance payers provide coverage for patients who have been diagnosed with disabling angina (Class III or Class IV, Canadian Cardiovascular Society Classification or equivalent classification) who, in the opinion of a cardiologist or cardiothoracic surgeon, are not readily amenable to surgical intervention, such as PTCA or cardiac bypass because: (1) Their condition is inoperable, or at high risk of operative complications or post-operative failure, (2) Their coronary anatomy is not readily amenable to such procedures; or (3) They have co-morbid states, which create excessive risk. Ø 2. Heart Failure patients with ischemic etiology In addition, there are 5 million patients in the United States and approximately 22 million worldwide suffering from heart failure. It is the leading cause of hospitalization in patients over age 65, and is one of the largest burdens on the U.S. healthcare system, costing in excess of $2 billion annually. therapy offers an opportunity to redefine the standard of care in how this group of patients is treated and has been demonstrated to reduce both emergency room (ER) visits and hospitalizations in heart failure patients with left ventricular dysfunction by 86% and 83% respectively, from 1.4 to.2 ER visits and 2.4 to.4 hospitalizations per patient per year months Pre- ER Visits p<.1 Hospitalizations 86% 83% 6-months Post- 6-months Pre- p<.1 6-months Post- Reference Clinical Practice 1. Primer: Practical Approach to the Selection of Patients for and Application of Michaels AD, McCullough PA, Soran OZ, Lawson WE, Barsness GW, Henry TD, Linnemeier G, Ochoa A, Kelsey SF, Kennard ED. Nature Clinical Practice Cardiovascular Medicine. 26 Nov;3(11):

10 2. Enhanced External Counterpulsation for Chronic Myocardial Ischemia. Lawson WE, Hui JCK. The Journal of Critical Illness. 2 Nov;15(11): Angina Pectoris 3. The Multicenter Study of Enhanced External Counterpulsation (MUST-): Effect of on Exercise-Induced Myocardial Ischemia and Anginal Episodes. Arora RR, Chou TM, Jain D, Fleishman B, Crawford L, McKiernan T, Nesto R. The Journal of the American College of Cardiology Jun;33(7): Efficacy of Enhanced External Counterpulsation in the Treatment of Angina Pectoris Lawson WE, Hui JCK, Soroff HS, Zheng ZS, Kayden DS, Sasvary D, Atkins H, Cohn PF. American Journal of Cardiology Oct 1;7(9): Effects of Enhanced External Counterpulsation on Stress Radionuclide Coronary Perfusion and Exercise Capacity in Chronic Stable Angina Pectoris. Stys TP, Lawson WE, Hui JCK, Fleishman B, Manzo K, Strobeck JE, Tartaglia J, Ramasamy S, Suwita R, Zheng ZS, Liang H, Werner D. American Journal of Cardiology. 22 Apr 1;89(7): Exercise Capability and Myocardial Perfusion in Chronic Angina Patients Treated with Enhanced External Counterpulsation. Tartaglia J, Stenerson Jr J, Charney R, Ramasamy S, Fleishman BL, Gerardi P, Hui JCK. Clinical Cardiology. 23 Jun;(26): Enhanced External Counterpulsation as Initial Revascularization Treatment for Angina Refractory to Medical Therapy. Fitzgerald CP, Lawson WE, Hui JC, Kennard ED; IEPR Investigators. Cardiology. 23 Nov;1(3): Two-Year Outcomes in Patients with Mild Refractory Angina Treated with Enhanced External Counterpulsation. Lawson WE, Hui JCK, Kennard ED, Kelsey SF, Michaels AD, Soran O. Clinical Cardiology. 26 Feb;29(2): Quality of Life 9. Effects of Enhanced External Counterpulsation on Health-Related Quality of Life Continue 12 Months After Treatment: A Substudy of the Multicenter Study of Enhanced External Counterpulsation. Arora RR, Chou TM, Jain D, Fleishman B, Crawford L, McKiernan T, Nesto R, Ferrans CE, Keller S. Journal of Investigative Medicine. 22 Jan;5(1): Psychosocial Effects of Enhanced External Counterpulsation in the Angina Patient: A Second Study. Springer S, Fife A, Lawson W, Hui JCK, Jandorf L, Cohn PF, Fricchione G. Psychosomatics. 21 Mar-Apr;42(2): Heart Failure 11. Benefit and Safety of Enhanced External Counterpulsation in Treating Coronary Artery Disease Patients with a History of Congestive Heart Failure. Lawson WE, Kennard ED, Holubkov R, Kelsey SF, Strobeck JE, Soran O, Feldman AM. Cardiology. 21;96(2):78-84.

11 12. Enhanced External Counterpulsation in Patients with Heart Failure: A Multicenter Feasibility Study. Soran O, Fleishman B, Demarco T, Grossman W, Schneider VM, Manzo K, de Lame PA, Feldman AM. Congestive Heart Failure. 22 Jul-Aug;8(4)24-28, Treating Heart Failure With Enhanced External Counterpulsation (): Design of the Prospective Evaluation of in Heart Failure (PEECH) Trial. Feldman AM, Silver AM, Francis GS, de Lame P, Parmley WW. Journal of Cardiac Failure. 25 Apr;11(3): Enhanced External Counterpulsation Improves Exercise Tolerance in Patients With Chronic Heart Failure. Feldman AM, Silver MA, Francis GS, Abbottsmith CW, Fleishman BL, Soran O, de Lame PA, Varricchione T for the PEECH Investigators. Journal of the American College of Cardiology. 26 Sep 19;48(6): Epub 26 Aug Enhanced External Counterpulsation Improves Exercise Duration and Peak Oxygen Consumption in Older Patients With Heart Failure: A Subgroup Analysis of the PEECH Trial. Abbottsmith CW, Chung ES, Varricchione T, de Lame PA, Silver MA, Francis GS, Feldman AM; Prospective Evaluation of in Congestive Heart Failure (PEECH) Investigators. Congestive Heart Failure. 26 Nov-Dec;12(6): Angina Patients with Diastolic Versus Systolic Heart Failure Demonstrate Comparable Immediate and One-Year Benefit from Enhanced External Counterpulsation. Lawson WE, Silver MA, Hui JCK, Kennard ED, Kelsey SF. Journal of Cardiac Failure. 25 Feb;11(1): External Counterpulsation as Treatment for Chronic Angina in Patients with Left Ventricular Dysfunction: A Report from the International Patient Registry (IEPR). Soran O, Kennard ED, Kelsey SF, Holubkov R, Strobeck J, Feldman AM. Congestive Heart Failure. 22 Nov-Dec;8(6): Two-Year Clinical Outcomes After Enhanced External Counterpulsation () Therapy in Patients with Refractory Angina Pectoris and Left Ventricular Dysfunction (Report from The International Patient Registry). Soran O, Kennard ED, Kfoury AG, Kelsey SF; IEPR Investigators. American Journal of Cardiology. 26 Jan 1;97(1):17-2. Epub 25 Nov 2. Acute Coronary Syndrome 19. New Sequential External Counterpulsation for the Treatment of Acute Myocardial Infarction. Zheng ZS, Yu LQ, Cai SR, Kambic H, Li TM, Ma H, Chen PZ, Huang BJ, Nose Y. Transactions of the American Society of Artificial Internal Organs Nov;8(4): Comparison of Hemodynamic Effects of Enhanced External Counterpulsation and Intra- Aortic Balloon Pumping in Patients with Acute Myocardial Infarction. Taguchi I, Ogawa K, Oida A, Abe S, Kaneko N, Sakio H. American Journal of Cardiology. 2 Nov 15;86(1):

12 21. Portable Enhanced External Counterpulsation for Acute Coronary Syndrome and Cardiogenic Shock: A Pilot Study Cohen J, Grossman W, Michaels AD. Clinical Cardiology. 27 May;3(5): Co-Morbidities 22. Enhanced External Counterpulsation is an Effective Treatment for Syndrome X. Kronhaus KD, Lawson WE. International Journal of Cardiology. 28 Jun 3. [Epub ahead of print]. 23. Residual High-Grade Angina After Enhanced External Counterpulsation Therapy. McCullough PA, Henry TD, Kennard ED, Kelsey SF, Michaels AD; IEPR Investigators. Cardiovascular Revascularization Medicine: Including Molecular Interventions. 27 Jul- Sep;8(3): Enhanced External Counterpulsation in the Management of Angina in the Elderly Linnemeier G, Michaels AD, Soran O, Kennard ED; International Registry (IEPR) Investigators. American Journal of Geriatric Cardiology. 23 Mar-Apr;12(2): Enhanced External Counterpulsation for the Relief of Angina in Patients with Diabetes: Safety, Efficacy and 1-Year Clinical Outcomes. Linnemeier G, Rutter MK, Barsness G, Kennard ED, Nesto RW; IEPR Investigators. American Heart Journal. 23 Sep;146(3): Impact of Body Mass Index on Outcomes of Enhanced External Counterpulsation Therapy. McCullough PA, Silver MA, Kennard ED, Kelsey SF, Michaels AD; IEPR Investigators. American Heart Journal. 26 Jan;151(1):139 e9-e Effectiveness of Enhanced External Counterpulsation in Patients with Left Main Disease and Angina. Lawson WE, Hui JCK, Barsness GW, Kennard ED, Kelsey SF for the IEPR Investigators. Clinical Cardiology. 24 Aug;27(8): International Patient Registry/ Consortium 28. Treatment Benefit in the Enhanced External Counterpulsation Consortium. Lawson WE, Hui JCK, Lang G. Cardiology. 2;94(1): The International Patient Registry (IEPR): Design, Methods, Baseline characteristics and Acute Results. Barsness G, Feldman AM, Holmes Jr. DR, Holubkov R, Kelsey SF, Kennard ED. Clinical Cardiology. 21 Jun;24(6): Clinical Cardiology. 27 May;3(5): Predictors of Benefit in Angina Patients One Year After Completing Enhanced External Counterpulsation: Initial Responders to Treatment Versus Nonresponders. Lawson WE, Hui JCK, Kennard ED, Barsness G, Kelsey SF. Cardiology. 25 Apr 13;13(4):21-26.

13 31. External Counterpulsation as Treatment for Chronic Angina in Patients with Left Ventricular Dysfunction: A Report from the International Patient Registry (IEPR). Soran O, Kennard ED, Kelsey SF, Holubkov R, Strobeck J, Feldman AM. Congestive Heart Failure. 22 Nov-Dec;8(6): Two-Year Outcomes After Enhanced External Counterpulsation for Stable Angina Pectoris (from the International Patient Registry [IEPR]). Michaels AD, Linnemeier G, Soran O, Kelsey SF, Kennard ED. American Journal of Cardiology. 24 Feb 15;93(4): Enhanced External Counterpulsation in the Treatment of Chronic Refractory Angina: A Long-term Follow-up Outcome from the International Enhanced External Counterpulsation Patient Registry. Loh PH, Cleland JG, Louis AA, Kennard ED, Cook JF, Caplin JL, Barsness GW, Lawson WE, Soran OZ, Michaels AD. Clinical Cardiology. 28 Apr 1;31(4 34. Frequency and Efficacy of Repeat Enhanced External Counterpulsation for Stable Angina Pectoris (from the International Patient Registry). Michaels AD, Barsness GW, Soran O, Kelsey SF, Kennard ED, Hui JCK, and Lawson WE for the International Patient Registry Investigators. American Journal of Cardiology. 25 Feb;95(3): Effectiveness of Repeat Enhanced External Counterpulsation for Refractory Angina in Patients Failing to Complete an Initial Course of Therapy. Lawson WE, Barsness G, Michaels AD, Soran O, Kennard ED, Kelsey SF, Hui J CK. Cardiology. 26 Nov 1;18(3): [Epub ahead of print] 36. Impact of External Counterpulsation Treatment on Emergency Department Visits and Hospitalizations in Refractory Angina Patients with Left Ventricular Dysfunction. Soran O, Kennard ED, Bart BA, Kelsey SF. Congestive Heart Failure. 27 Jan-Feb;13(1):36-4 Hemodynamics 37. Acute Hemodynamic Effects and Angina Improvement with Enhanced External Counterpulsation. Stys T, Lawson WE, Hui JCK, Lang G, Liuzzo J, Cohn PF. Angiology. 21 Oct;52(1): Left Ventricular Systolic Unloading and Augmentation of Intracoronary Pressure and Doppler Flow During Enhanced External Counterpulsation. Michaels AD, Accad M, Ports TA, Grossman W. Circulation. 22 Sep 3;16(1): Effects of Enhanced External Counterpulsation on Hemodynamics and its Mechanism- Relation to Neurohormonal Factors. Taguchi I, Ogawa K, Kanaya T, Matsuda R, Kuga H, Nakatsugawa M. Circulation Journal. 24 Nov;68(11):

14 Mechamisms of Action 4. The Effects of External Counter Pulsation Therapy on Circulating Endothelial Progenitor Cells in Patients with Angina Pectoris. Barsheshet A, Hod H, Shechter M, Sharabani-Yosef O, Rosenthal E, Barbash IM, Matetzky S, Tal R, Bentancur AG, Sela BA, Nagler A, Leor J. Cardiology. 28;11(3): Epub 27 Dec Effect of Enhanced External Counterpulsation on Inflammatory Cytokines and Adhesion Molecules in Patients with Angina Pectoris and Angiographic Coronary Artery Disease. Casey DP, Conti CR, Nichols WW, Choi CY, Khuddus MA, Braith RW. American Journal of Cardiology. 28 Feb 1;11(3):3-32. Epub 27 Dec Enhanced External Counterpulsation Treatment Improves Arterial Wall Properties and Wave Reflection Characteristics in Patients With Refractory Angina. Nichols WW, Estrada JC, Braith RW, Owens K, Conti CR. Journal of the American College of Cardiology. 26 Sep 19;48(6): Epub 26 Aug Effect of External Counterpulsation on Plasma Nitric Oxide and Endothelin-1 Levels. Akhtar M, Wu GF, Du ZM, Zheng ZS, Michaels AD. American Journal Cardiology. 26 Jul 1;98(1):28-3. Epub 26 May Successful Treatment of Symptomatic Coronary Endothelial Dysfunction with Enhanced External Counterpulsation.Bonetti PO, Gadasalli SN, Lerman A, Barsness GW. Mayo Clinic Proceedings. 24 May;79(5): Experimental 45. Angiogenic Effects of Long-term Enhanced External Counterpulsation in a Dog Model of Myocardial Infarction. Wu G, Du Z, Hu C, Zheng Z, Zhan C, Ma H, Fang D, Ahmed KT, Laham RJ, Hui JCK, Lawson WE. American Journal of Physiology Heart and Circulatory Physiology. 26 Jan;29(1):H Epub 25 Aug Enhanced External Counterpulsation Inhibits Intimal Hyperplasia by Modifying Shear Stress Responsive Gene Expression in Hypercholesterolemic Pigs. Zhang Y, He X, Chen X, Ma H, Liu D, Luo J, Du Z, Jin Y, Xiong Y, He J, Fang D, Wang K, Lawson WE, Hui JC, Zheng Z, Wu G. Circulation. 27 Jul 31;116(5): Epub 27 Jul 9. Review Papers 47. Enhanced External Counterpulsation and Future Directions: Step Beyond Medical Management for Patients with Angina and Heart Failure. Manchanda A, Soran O. Journal of the American College of Cardiology. 27 Oct 16;5(16): Epub 27 Oct Enhanced External Counterpulsation for Ischemic Heart Disease: What s Behind the Curtain? Bonetti PO, Holmes DR Jr, Lerman A, Barsness GW. Journal of the American College of Cardiology. 23 Jun 4;41(11):