Enhanced external counterpulsation: mechanisms of action and clinical applications

Vasiliki KITSOU1, MD; Theodoros XANTHOS1, PhD; Robin ROBERTS2, George M. KARLIS1, MD; Lila PADADIMITRIOU1, PhD 1Department of Experimental Surgery and Surgical Research, University of Athens, Greece; Medical School; 2Consultant Cardiologist London, UK. --------------------------------------------------------------------------------------------------------------------------------- Symptomatic coronary artery disease (CAD) and heart failure (HF), either of ischaemic or nonischaemic aetiology, are common medical problems. Despite optimal medical treatment and improved revascularisation techniques, a significant number of patients are not successfully managed. Among the non-pharmacological, alternative, non-invasive treatments suggested for these patients, enhanced external counterpulsation (EECP) is considered the most effective one. EECP, administered in an outpatient setting, consists of three pneumatic cuffs applied to each of the patient’s legs that are sequentially inflated and deflated synchronised with the cardiac cycle. Numerous clinical trials have shown that EECP is safe and effective in patients with ischaemic heart disease, with or without left ventricular dysfunction, improving their quality of life. EECP appears to be beneficial as an adjunctive therapy in patients with HF of any aetiology. Cardiac syndrome X has been shown to be effectively treated with EECP. Research in EECP expanded in its potential use for entities other than heart disease. More trials are necessary, including sham-controlled trials, to further establish EECP among medical society. Keywords: Enhanced external counterpulsation – angina pectoris – heart failure. ------------------------------------------------------------------------------------------------------------------------------ Address for correspondence: Theodoros Xanthos, University of Athens, Medical School, Department of Experimental Surgery and Surgical Research, 15B Agiou Thoma Street, 11527 Athens, Greece. E-mail: theodorosxanthos@yahoo.com Received 9 November 2009; revision accepted for publication 14 January 2010. Acta Cardiol 2010; 65(2): 239-247 doi: 10.2143/AC.65.2.2047060 239 --------------------------------------------------------------------------------------------------------------------------------- INTRODUCTION Coronary artery disease (CAD) is a major medical problem with a prevalence of 213 cases for every 100,000 persons over the age of 301. Heart failure (HF) affects 1-2% of the population worldwide, and in the United States it is responsible for almost 1∞∞million hospital admissions and 50,000 deaths annually2. Despite the increasing success of conventional medical treatment and improvement of mechanical revascularization approaches, a significant number of patients with CAD cannot be successfully managed, suffering from refractory angina pectoris (RAP)3,4. Moreover, for the group of patients with underlying HF, substantial unmet needs remain. As a result many patients are left to suffer their symptoms, restrict their activities and anticipate a reduced life expectancy5. Current non-pharmacological options for the treatment of patients with RAP, with or without underlying HF, have been suggested. Of these modalities enhanced external counterpulsion (EECP) therapy represents the most effective non-invasive echnique5,6. Furthermore, the role of EECP therapy has been recently investigated for the treatment of HF7. The aim of this review is to present the clinical applications of EECP therapy in RAP, HF and other clinical entities and to describe the group of patients who are eligible for this kind of treatment. DESCRIPTION AND MECHANISMS OF EECP EECP is a non-invasive procedure administered in an outpatient setting. The device consists of three pneumatic compression cuffs applied to each of the patient‘s legs - on the calves, lower thighs, upper thighs including the buttocks5,8. A computer controlled pneumatic system acts to inflate and deflate them based on the patient’s electrocardiogram(ECG).A finger plethysmogram is used throughout treatment to monitor diastolic and systolic pressure waveforms7. A course of EECP treatment typically involves 35 one-hour sessions, usually 5∞∞days a week over a 7-week period, though treatments twice per day have been effective as well9. The haemodynamic effects produced by EECP are similar to intra-aortic balloon pump (IABP)9. Sequential inflation of the cuffs, at the onset of diastole, produces aortic counterpulsation and an increase in diastolic pressure while rapid deflation of the cuffs, at the onset of systole, decreases systolic pressure in both the aorta and the coronary arteries10. Unlike IABP, EECP also increases venous return further, enhancing thus cardiac output10,11. Furthermore, as diastolic inflation pressure is increased, the preload is increased, afterload is decreased, contractility is increased and mechanical efficiency is neutral12. Since shear stress is a stimulus for the release of endothelium-derived vasodilator nitric oxide as well as a modulator of the vasoconstrictor endothelin-1 release, it has been postulated that EECP, by enhancing vascular shear stress, may favourably affect endothelial function13. Vascular mechanical forces have been suggested to initiate collateral development14. Masuda et al.15, using ammonia positron emission tomography, suggested that the development of collateral vessels is one of the mechanisms of EECP therapy. EECP was proven to exert peripheral effects similar to physical exercise16. EECP therapy exerts a ‘training’ effect decreasing thus peripheral vascular resistance and the heart rate response to exercise17. EECP effect is considered analogous to the peripheral vascular conditioning effect seen with exercise, in which improved vasomotor tone decreases the blood pressure response to exercise18. Finally, the fact that many patients experience significant symptomatic improvement, even in the absence of optimal diastolic augmentation during treatment, indicates that a placebo effect may contribute to the symptomatic benefit observed with EECP10. Evidence indicates that the use of medical devices may be associated with an enhanced placebo effect19. EECP AND ISCHAEMIC HEART DISEASE (IHD) The role of EECP in the treatment of IHD has been known since the early 1970s, however, it did not receive significant attention. The first pivotal turn of events came in 1999 when the Multicenter Study-EECP trial (MUST-EECP) was published1. MUST-EECP is the first prospective, randomized, blinded, placebo controlled trial that assessed safety and efficacy of EECP after treating outpatients with angina, documented CAD and positive exercise treadmill test. The trial concluded that EECP reduces angina and extends time to exercise-induced ischaemia20. Despite the impressive results controversy and doubt remained, mostly in regard with the role placebo played in the study. A sub-study of MUST-EECP trial21 concluded that improvements on patients’ health and quality of life were present 12∞∞months after treatment with EECP. EECP was suggested as a safe treatment option for selected symptomatic percutaneous coronary intervention (PCI) candidates with obstructive CAD22. It was further suggested that EECP, as a noninvasive treatment, could be used as a first-line treatment with invasive revascularization reserved for EECP failures, or high-risk patients23. Based on its acute haemodynamic effects, comparable to those of IABP, EECP was proposed as a potential treatment for coronary syndromes in an acute setting, as an inpatient therapy for patients with IABP contraindications24. Currently, EECP has been considered to be a more effective alternative treatment for patients with RAP who are not proper candidates for established, available non-pharmacologic options such as spinal cord stimulation25. In addition, an anti-inflammatory effect of EECP in patients with angina pectoris has been suggested when a decrease in circulating pro-inflammatory biomarker levels was demonstrated after 35 1-hour sessions26. However, in current studies, despite that endothelial improvement has been observed during the course of EECP treatment, long-term benefits of EECP could not be attributed to improved endothelial function27. Over the years, there have been many interesting studies of EECP therapy in ischaemic heart disease summarized in table 128-41 and table 242-50,13. EECP AND HEART FAILURE An interesting turn in EECP research was the prescription of the technique to patients with RAP combined with left ventricular (LV) dysfunction. The primary concern of initial researchers was that the increased venous return, resulting from EECP treatment, would precipitate pulmonary oedema in these patients and might exacerbate heart failure. Nevertheless, earlier small reports demonstrated that patients with depressed ventricular function responded to treatment with EECP considerably improving angina function and quality of life both immediately after treatment and in a 6-month follow-up51. Furthermore, benefits and safety of EECP were demonstrated to be similar in angina patients with a history of heart failure and severe systolic dysfunction with those with angina and heart failure with diastolic dysfunction25,52. More recently, Soran e t al.53 concluded that EECP offers an effective, durable therapeutic approach for refractory angina combined with high-risk LV  dysfunction. 240 V. Kitsou et al. Clinical applications of EECP 241 Currently, systolic blood pressure improvements have been documented during and after EECP treatment, as well as after a 6-week follow-up54. However, EECP did not improve any measurements of LV systolic or diastolic function, performed by two-dimensional and Doppler echocardiography55. Unlike the efficacy and safety of EECP treatment in RAP evidence regarding the efficacy of the procedure in patients with HF is just beginning to emerge56. In an earlier study57, in patients with class II or III heart failure and ejection fraction less than 35%, EECP treatment was associated with a significant improvement in LV function, as measured by an increase in ejection fraction, and a significant decrease in heart rate. It was further demonstrated by later studies that EECP can be safe and well tolerated in patients with relatively stable heart failure and no fluid overload. Also, according to a pilot study, in these patients EECP can improve exercise capacity, quality of life and functional status, both in the short term and for a period of 6∞∞months 58. Nevertheless, the results of this pilot study should be interpreted with caution given the small sample size. Nevertheless, these promising results revealed the need for a randomized control study to ascertain the efficacy of EECP as an adjunctive therapy in the management of patients with chronic stable heart failure. The Prospective Evaluation of EECP in Heart Failure (PEECH) trial concluded that EECP improved exercise tolerance, quality of life and New York Heart Association (NYHA) functional classification without an accompanying increase in peak oxygen consumption in patients with HF59,60. Futhermore, a subgroup analysis of the PEECH trial61 confirmed the beneficial  effects of EECP in elderly patients, older than 65, with chronic, stable mild-to-moderate heart failure. EECP can benefit patients with HF who already receive optimal medical therapy without achieving the desired effects. Yet, only when the haemodynamic effects of EECP during diastole and during systole are synchronised properly will the increase in venous return be compensated and not result in pulmonary congestion or even pulmonary oedema. However, while the safety of EECP in patients without significant fluid overload has been demonstrated, further studies are needed to guide the use of the technique in patients with more severe overload or acute decompensated heart failure62. EECP appears to be relatively safe in heart failure patients but the treatment‘s efficacy is more nebulous and more research is  necessary63. PATIENT SELECTION AND LIMITATIONS EECP is a Food and Drug Administration approved class IIb-recommended treatment for refractory angina63. Indications for EECP therapy include stable and unstable angina, class II-III stable congestive heart failure, acute myocardial infarction, and Cardiogenic shock62. As more is learned about EECP, patients once excluded from early clinical trials are now able to take advantage of EECP. Nevertheless, EECP is not suitable for some patients64,65,66 (table 3). Furthermore, another impediment to the widespread use of EECP is that many cardiologists are not fully informed about the concept of EECP as well as about the technique itself. Physicians and patients are eager to see quick results and fast improvement of their health status, whereas with EECP therapy a considerable amount of time is needed in order to observe results9. Contraindications Arrhythmias that interfere with machine triggering (atrial fibrillation) Decompensated heart failure Severe uncontrolled hypertension (> 180/110∞∞mmHg) Cardiac catheterization or arterial puncture within 2∞∞weeks Severe pulmonary hypertension Severe aortic insufficiency Severe peripheral arterial disease with rest claudication ornon-healing ulcers Venous diseases (thrombophlebitis, deep venous thrombosis) Bleeding diathesis or warfarin therapy Pregnancy Aortic aneurysm or dissection Side effects Skin abrasion Haematoma of the legs Severe pain of the legs FURTHER CLINICAL APPLICATIONS There has been much concern over other potential clinical applications of EECP. Kronhaus et al.67 treated with EECP 30∞∞patients with refractory angina due to cardiac syndrome X. There was a significant reduction in angina class and in inducible ischaemia. The effect Clinical applications of EECP 243 following treatment was durable, with a low incidence of recurrent angina. Investigating the hypothesis that symptom improvement from EECP is related to improved heart rate variability (HRV). To assess the efficacy of EECP in relieving angina and improving objective measures of myocardial ischaemia. There was no significant change in the time- or frequency-domain HRV measures after EECP. In diabetic individuals, there was an increase in low frequency HRV, which has been associated with reduced mortality. The results of this study suggested that EECP is a safe, well tolerated, and significantly effective treatment for angina pectoris. Improvement of endothelial dysfunction was suggested as the underlying mechanism of action; however, the efficacy of EECP in syndrome X remains unknown68. Further studies investigate the benefits of EECP on entities other than cardiac disease. EECP improved skin oxygenation and decreased carbon dioxide load. These effects were attributed to microcirculation improvements caused by the increase of concentration and the decrease of velocity of moving blood cells observed during counterpulsation69. Also, Werner et al. used EECP in an effort to improve renal dysfunction of liver cirrhosis. They observed that EECP improved diuresis, but did not influence the vasoconstrictive dysregulation of the kidneys in liver cirrhosis70. Furthermore, it was suggested that EECP could be a clinically useful and safe procedure in patients with acute central retinal artery occlusion or branch retinal artery occlusion71. Rajaram et al. found some patients who underwent EECP for angina or congestive heart failure who also coincidently had severe restless leg syndrome (RLS). They concluded that EECP improved RLS symptoms significantly; still, a larger number of patients should be investigated to draw further conclusions72. The effect of EECP was assessed on ischaemic heart disease associated erectile dysfunction. Although preliminary results indicated an improvement, large scale trials and long-term data are needed73,74. An interesting study by Werner et al. Demonstrated that cerebral autoregulation ensures the constancy of cerebral blood flow even though EECP creates marked systemic changes. The decrease of blood pressure (BP) after EECP with maintained cerebral flow velocity (CBFV) indicates an improved BP/CBFV relation75. Experimental studies have demonstrated that EECP results in endothelium-dependent vasorelaxation in the carotid arteries of hypercholesterolaemic pigs76. Furthermore, it was suggested that  EECP does not compromise cerebral autoregulation and, therefore, does not seem to bear cerebrovascular risks77. These data suggest that EECP might be useful in the treatment of stroke patients, as it improves neurological functional outcome78, increased power in paretic extremities and decreased spasticity79. However, randomized-controlled trials with a large sample size are needed to further define the efficacy and safety of EECP in acute stroke management. CONCLUSION Safety and immediate benefits of the technique as well as the achievement of sustained symptomatic benefits and quality of life have been confirmed in most patients for up to three years80. However, patients with more severe angina and without history of HF are more likely to gain immediate symptomatic benefit whereas patients with more severe angina, diabetes, and a history of HF are more likely to suffer from unfavourable long-term outcome and major adverse cardiovascular events81,82. Furthermore, residual high-grade angina after EECP can occur, though uncommon, in patients with more severe angina at baseline48. More trials are necessary, including sham-controlled trials, to further establish among medical society the mechanisms, the benefits as well as the short and long-term outcome of the procedure in a variety of pathologies. Conflict of interest: none declared. REFERENCES 1. DeMaria A. A historical overview of enhanced external counterpulsation. Clin Cardiol 2002; 25(12∞∞suppl): II3-II5. 2. Braunwald E. Heart failure and cor pulmonale, Harrison’s principals of internal medicine - 16th edition. Edited by Kasper DL, Fauci AS, Longo DL, Braunwald E, Hauser SL, Jameson JL, United States, McGraw Hill Professional, 2005:1367-78. 3. Sinvhal RM, Gowda RM, Khan IA. Enhanced external counterpulsation for refractory angina pectoris. Heart 2003; 89: 830-3. 4. Gowda RM, Khan IA, Punukollu G, Vasavada BC, Nair CK. Treatment of refractory angina pectoris. Int J Cardiol 2005; 101: 1-7. 5. Manchanda A, Soran O. Enhanced external counterpulsation and future directions: step beyond medical management for 244 V. Kitsou et al. patients with angina and heart failure. J Am Coll Cardiol 2007; 50: 1523-31. 6. Holmes DR Jr. Treatment options for angina pectoris and the future role of enhanced external counterpulsation. Clin Cardiol 2002; 25(12 Suppl 2): II22-II25. 7. Soran O. A new treatment modality in heart failure enhanced external counterpulsation (EECP). Cardiol Rev 2004; 12: 15-20. 8. Shea ML, Conti RC, Arora RR. An update on enhanced external counterpulsation. Clin Cardiol 2005; 28: 115-8. 9. Brosche TA, Middleton SK, Boogaard RG. Enhanced external counterpulsation. Dimens Crit Care Nurs 2004; 23: 208-14. 10. Bonetti PO, Holmes DR Jr, Lerman A, Barsness GW. Enhanced external counterpulsation for ischemic heart disease: what’s behind the curtain? J Am Coll Cardiol 2003; 41: 1918-25. 11. Michaels AD, Accad M, Ports T, Grossman W. Left ventricular systolic unloading and augmentation of intracoronary pressure and Doppler flow during enhanced external counterpulsation. Circulation 2002; 106: 1237-42. 12. Michaels AD, Tacy T, Teitel D, Shapiro M, Grossman W. Invasive left ventricular energetics during enhanced external counterpulsation. Am J Ther 2009; 16: 239-46. 13. Akhtar M,Wu GF, Du ZM, Zheng ZS, Michaels AD. Effect of external counterpulsation on plasma nitric oxide and endothelin-1 levels. Am J Cardiol 2006; 98: 28-30. 14. Kersten JR, Pagel PS, Chilian WM, Warltier DC. Multifactorial basis for coronary collateralization: a complex adaptive response to ischemia. Cardiovasc Res 1999;43: 44-57. 15. Masuda D, Nohara R, Inada H, Hirai T, Li-Guang C, Kanda H, Inubushi M, Tadamura E, Fujita M, Sasayama S. Improvement of regional myocardial and coronary blood flow reserve in a patient treated with enhanced external counterpulsation: evaluation by nitrogen-13 ammonia PET.Jpn Circ J 1999; 63: 407-11. 16. Bonetti PO, Barsness GW, Keelan PC, Schnell TI, Pumper GM, Kuvin JT, Schnall RP, Holmes DR, Higano ST, Lerman A. Enhanced external counterpulsation improves endothelial function in patients with symptomatic coronary artery disease. J Am Coll Cardiol 2003; 41: 1761-8. 17. Lawson WE, Hui JCK, Zheng ZS, Burger L, Jiang L, Lillis O, Oster Z, Soroff H, Cohn PF. Improved exercise tolerance following enhanced external counterpulsation: cardiac or peripheral effect? Cardiology 1996; 87: 271-5. 18. Stys TP, Lawson WE, Hui JCK, Fleishman B, Manzo K, Strobeck JE, Tartaglia J, Ramasamy S, Suwita R, Zheng ZS, Liang H, Werner D. Effects of enhanced external counterpulsation on stress radionuclide coronary perfusion and exercise capacity in chronic stable angina pectoris. Am J Cardiol 2002; 89: 822-4. 19. Kaptchuk TJ, Goldman P, Stone DA, Stason WB. Do medical devices have enhanced placebo effects? J Clin Epidemiol 2000; 53: 786-92. 20. Arora RR, Chou TM, Jain D, Fleishman B, Crawford L,  McKiernan T, Nesto R. The multicenter study of enhanced external counterpulsation (MUST-EECP): effect of EECP on exercise-induced myocardial ischemia and anginal episodes. J Am Coll Cardiol 1999; 33: 1833-40. 21. Arora RR, Chou TM, Jian D, Fleishman B, Crawford L, McKiernan T, Nesto R, Ferrans CE, Keller S. Effects of enhanced external counterpulsation on Health-Related Quality of Life continue 12∞∞months after treatment: a sub-study  of the Multicenter Study of Enhanced External Counterpulsation. J Investig Med 2002; 50: 25-32. 22. Holubkov R, Kennard ED, Forris JM, Kelsey SF, Soran O, Williams DO, Holmes Jr. DR. Comparison of patients undergoing enhanced external counterpulsation and percutaneous coronary intervention for stable angina pectoris. Am J Cardiol 2002; 89: 1182-6. 23. Fitzgerald CP, Lawson WE, Hui JC, Kennard ED; IEPR Investigators. Enhanced external counterpulsation as initial revascularization treatment for angina refractory to medical therapy. Cardiology 2003; 100: 129-35. 24. Cohen J, Grossman W, Michaels AD. Portable enhanced external counterpulsation for acute coronary syndrome and Cardiogenic shock: a pilot study. Clin Cardiol2007; 30: 223-8. 25. Bondesson S, Pettersson T, Erdling A, Hallberg IR, Wackenfors A, Edvisson L. Comparison of patients undergoing enhanced external counterpulsation and spinal stimulation for refractory angina pectoris. Coron Artery Dis 2008; 19: 627-34. 26. Casey DP, Conti CR, Nichols WW, Choi CY, Khuddus MA, Braith RW. Effect of enhanced external counterpulsation on inflammatory cytokines and adhesion molecules in patients with angina pectoris and angiographic coronary artery disease. Am J Cardiol 2008; 101: 300-2. 27. Hashemi M, Hoseinbalam M, Khazaei M. Long-term effect of enhanced external counterpulsation on endothelial function in the patients with intractable angina. Heart Lung Circ 2008; 17: 383-7. 28. Lawson WE, Hui JC, Lang, G. Treatment benefit in the enhanced external counterpulsation consortium. Cardiology 2000; 94: 31-5. 29. Lakshmi MV, Kennard ED, Kelsey SF, Holubkov R, Michaels AD. Relation of the pattern of diastolic augmentation during a course of enhanced external counterpulsation (EECP) to clinical benefit (from the International EECP Patient Registry [IEPR]). Am J Cardiol 2002; 89: 1303-5. 30. Lawson WE, Kennard ED, Hui JC, Holubkov R, Kelsey SF; IEPR Investigators. Analysis of baseline factors associated with reduction in chest pain in patients with angina pectoris treated by enhanced external  counterpulsation. Am J Cardiol 2003; 92: 439-43. 31. Linnemeier G, Michaels AD, Soran O, Kennard ED; International Enhanced External Counterpulsation Patient Registry Investigators. Enhanced external counterpulsation in the management of angina in the elderly. Am J Geriatr Cardiol 2003; 12: 90-4. 32. Linnemeier G, Rutter MK, Barsness G, Kennard ED, Nesto RW; IEPR Investigators. Enhanced External Counterpulsation for the relief of angina in patients with diabetes: safety, efficacy and 1-year clinical outcomes. Am Heart J 2003; 146: 453-8. 33. Tartaglia J, Stenerson J Jr, Charney R, Ramasamy S, Fleishman BL, Gerardi P, Hui JCK. Exercise capability and myocardial perfusion in chronic angina patients treated with enhanced external counterpulsation. Clin Cardiol 2003; 26: 287-90. 34. Lawson WE, Hui JC, Barsness GW, Kennard ED, Kelsey SF; IEPR Investigators. Effectiveness of enhanced external counterpulsation in patients with left main disease and angina. Clin Cardiol 2004; 27: 459-63. 35. Henrikson CA, Chandra-Strobos N. Enhanced external counterpulsation therapy: significant clinical improvement without electrophysiologic remodelling. Ann Noninvasive Electrocardiol 2004; 9: 265-9. 36. Bagger JP, Hall RJ, Koutroulis G, Nihoyannopoulos P. Effect of enhanced external counterpulsation on dobutamineinduced left ventricular wall motion abnormalities in severe chronic angina pectoris. Am J Cardiol 2004; 93: 465-7. 37. Masuda D, Fujita M, Nohara R, Matsumori A, Sasayama S. Improvement of oxygen metabolism in ischemic myocardium as a result of enhanced external counterpulsation with heparin pretreatment for patients with stable angina. Heart Vessels 2004; 19: 59-62. 38. Michaels AD, Linnemeier G, Soran O, Kelsey SF, Kennard ED. Two-year outcomes after enhanced external counterpulsation for stable angina pectoris (from the international EECP patient registry [IEPR]). Am J Cardiol 2004; 93: 461-4. 39. Taguchi I, Ogawa K, Kanaya T, Matsuda R, Kuga H, Nakatsugawa M. Effects of enhanced external counterpulsation on hemodynamics and its mechanism. Circ J2004; 68: 1030-4. 40. Arora R, Chen HJ, Rabbani L. Effects of enhanced external counterpulsation on vascular cell release of coagulation factors. Heart Lung 2005; 34: 252-6. 41. Michaels AD, Raisinghani A, Soran O, de Lame PA, Lemaine ML, Kligfield P, Watson DD, Conti CR, Beller G. The effects of enhanced external counterpulsation on myocardial perfusion in patients with stable angina: a multicenter radionuclide study. Am Heart J 2005; 150: 1066-73. 42. Lawson WE, Hui JC, Kennard ED, Kelsey SF, Michaels AD, Soran O; International Enhanced External Counterpulsation Patient Registry Investigators. Two-year outcomes in patients with mild refractory angina treated with enhanced external counterpulsation. Clin Cardiol 2006; 29: 69-73. 43. Loh PH, Louis AA, Windram J, Rigby AS, Cook J, Hurren S, Nikolay NP, Caplin J, Cleland JG. The immediate and long-term outcome of enhanced external counterpulsation in treatment of chronic stable refractory angina. J Intern Med 2006; 259: 276-84. 44. Nichols WW, Estrada JC, Braith RW, Owens K, Conti CR. Enhanced external counterpulsation treatment improves arterial wall properties and wave reflection characteristics in patients with refractory angina. J Am Coll Cardiol 2006; 48: 1208-14. 45. Novo G, Bagger JP, Carta R, Koutroulis G, Hall R, Nihoyannopoulos P. Enhanced external counterpulsation for treatment of refractory angina pectoris. J Cardiovasc Med 2006; 7: 335-9. 46. Soran O, Kennard ED, Kfoury AG, Kelsey SF; IEPR investigators. Two-year clinical outcomes after enhanced external counterpulsation (EECP) therapy in patients with refractory angina pectoris and left ventricular dysfunction (report from The International EECP Patient Registry). Am J Cardiol 2006; 97: 17-20. 47. Arora RR, Bergmann S. Effects of enhanced external counterpulsation (EECP) on myocardial perfusion. Am J Ther 2007; 14: 519-23. 48. McCullough PA, Henry TD, Kennard ED, Kelsey SF, Michaels AD. Residual high-grade angina after enhanced external counterpulsation therapy. Cardiovasc Revasc Med 2007; 8: 161-5. 49. Michaels AD, Bart BA, Pinto T, Lafferty J, Fung G, Kennard ED. The effects of enhanced external counterpulsation on time- and frequency-domain measures of heart rate variability. J Electrocardiol 2007; 40: 515-21. 50. Yavari M, Montazeri HR. Effects of enhanced external counterpulsation on anginal symptoms and improvements in objective measures of myocardial ischaemia.Cardiovasc J Afr 2007; 18: 154-6. 51. Soran O, Kennard ED, Kelsey SF, Holubkov R, Strobeck J, Feldman AM. Enhanced external counterpulsation as treatment for chronic angina in patients with left ventricular dysfunction: a report from the International EECP Patient Registry (IEPR). Congest Heart Fail 2002; 8: 297-300. 52. Lawson WE, Silver MA, Hui JC, Kennard ED, Kelsey SF. Angina patients with diastolic versus systolic heart failure demonstrate comparable immediate and one-year benefit from enhanced external counterpulsation. J Card Fail 2005; 11: 61-6. 53. Soran O, Kennard ED, Kfoury AG, Kelsey SF. Refractory angina pectoris and left ventricular dysfunction (report from the international EECP patient registry. Am J Cardiol 2006; 97: 17-20. 54. Campbell AR, Satran D, Zenovich AG. Enhanced external counterpulsation improves systolic blood pressure in patients with refractory angina. Am Heart J 2008; 156: 1217-22. 55. Kumar A, Aronow WS, Vadnerkar A, Sindhu P, Mittal S, Kasliwal RR, Trehan N. Effect of enhanced external counterpulsation on clinical symptoms, quality of life, 6-minute walking distance, and echocardiographic measurements of left ventricular systolic and diastolic function after 35∞∞days of treatment and at 1-year follow up in 47∞∞patients with chronic refractory angina pectoris. Am J Ther 2009; 16: 116-8. 56. Blazing MA, Crawford LE. Enhanced external counterpulsation (EECP): Enough evidence to support this and the next wave? Am Heart J 2003; 146: 383-4. 57. Gorscan J III, Crawford L, Soran O, Wang H, Severyn D, de Lame PA, Schneider V, Feldman AM. Improvement in left ventricular performance by enhanced external counterpulsation in patients with heart failure. J Am Coll Cardiol 2000; 35(2 Suppl A): 230A: 901-5. 58. Soran O, Fleishman B, Demarco T, Grossman W, Schneider VM, Manzo K, de Lame PA, Feldman AM. Enhanced external counterpulsation in patients with heart failure: a multicenter feasibility study. Congest Heart Fail 2002; 8: 204-8. 59. Feldman AM, Silver MA, Francis GS, De Lame PA, Parmley WW. Treating heart failure with enhanced external counterpulsation (EECP): Design of the prospective evaluation of EECP in heart failure (PEECH) trial. J Card Fail 2005; 11: 240-5. 60. Feldman AM, Silver MA, Francis GS, Abbottsmith CW, Fleishman BL, Soran O, de Lame PA, Varricchione T; PEECH Investigators. Enhanced external counterpulsation improves exercise tolerance in patients with chronic heart failure. J Am Coll Cardiol 2006; 48: 1198-205. 61. Abbottsmith CW, Chung ES, Varricchiose T, de Lame PA, Silver MA, Francis GS, Feldman AM. Prospective evaluation of EECP in congestive heart failure investigators. Enhanced external counterpulsation improves exercise duration and peak oxygen consumption in older patients with heart failure: a subgroup analysis of the PEECH trial. Congest Heart Fail 2006; 12: 307-11. 62. Silver MA. Mechanisms and evidence for the role of enhanced external counterpulsation in heart failure management. Curr Heart Fail Rep 2006; 3: 25-32. 63. Arora RR, Shah AG. The role of enhanced external counterpulsation in the treatment of angina and heart failure. Can J Cardiol 2007; 23: 779-81. 64. Lawson WE. Current use of enhanced external counterpulsation and patient selection. Clin Cardiol 2002; 25 (12 Suppl 2): II16-II21. 65. Michaels AD, McCullough PA, Soran OZ, Lawson WE, Barsness GW, Henry TD, Linnemeier G, Ochoa A, Kelsey SF, Kennard ED. Primer: practical approach of patients for 246 V. Kitsou et al. and application of EECP. Nat Clin Pract Cardiovasc Med 2006; 3: 623-32. 66. Werner D, Kropp J, Schellong S, Friedel C, Voigt JU, Ludwig J, Daniel WG, Flachskampf FA. Practicability and limitations of enhanced external counterpulsation as an additional treatment for angina. Clin Cardiol 2003; 26: 525-9. 67. Kronhaus KD, Lawson WE. Enhanced external counterpulsation is an effective treatment for syndrome X. Int JCardiol 2009; 135: 256-7. 68. Celik T, Iyisoy A, Yuksel UC, Amasyali B. A new treatment modality in management of patients with cardiac syndrome X: Enhanced external counterpulsation. Int J Cardiol 2008 Dec 29 [Epub ahead of print]. 69. Hilz MJ, Werner D, Marthol H, Flachskampf FA, Daniel WG. Enhanced external counterpulsation improves skin oxygenation and perfusion. Eur J Clin Invest 2004;34: 385-91. 70. Werner D, Trägner P, Wawer A, Porst H, Daniel WG, Gross P. Enhanced external counterpulsation: a new technique to augment renal function in liver cirrhosis.Nephrol Dial Transplant 2005; 20: 920-6. 71. Werner D, Michalk F, Harazny J, Hugo C, Daniel WG, Michelson G. Accelerated reperfusion of poorly perfused retinal areas in central retinal artery occlusion and branch retinal artery occlusion after a short treatment with enhanced external counterpulsation. Retina 2004; 24: 541-7. 72. Rajaram SS, Shanahan J, Ash C, Walters AS, Weisfogel G. Enhanced external counter pulsation (EECP) as a novel treatment for restless legs syndrome (RLS): a preliminary test of the vascular neurologic hypothesis for RLS. Sleep Med 2005; 6: 101-6. 73. El-Sakka A, Morsy A, Fagih B. Enhanced external counterpulsation in patients with coronary artery disease-associated erectile dysfunction. Part I: effects of risk factors. J Sex Med 2007; 4: 771-9. 74. El-Sakka AI, Morsy AM, Fagih BI. Enhanced external counterpulsation in patients with coronary artery diseaseassociated erectile dysfunction. Part II: impact of disease duration and treatment courses. J Sex Med 2007; 4: 1448- 53. 75. Werner D, Marthol H, Brown CM, Daniel WG, Hilz MJ. Changes of cerebral blood flow velocities during enhanced external counterpulsation. Acta Neurol Scand 2003;107: 405-11. 76. Tao J, Tu C, Yang Z, Zhang Y, Chung XL, Ma H, Zhen ZS. Enhanced external counterpulsation improves endothelium dependent vasorelaxation in the carotid arteries of hypercholesterolemic pigs. Int J Cardiol 2006; 112: 269-74. 77. Marthol H, Werner D, Brown CM, Hecht M, Daniel WG, Hilz MJ. Enhanced external counterpulsation does not compromise cerebral autoregulation. Acta Neurol Scand 2005; 111: 34-41. 78. Han JH, Leung TW, Lam WW, Soo YO, Alexandrov AW, Mok V, Leung YF, Lo R,Wong KS. Preliminary findings of external counterpulsation for ischemic stroke patient with large artery occlusive disease. Stroke 2008; 39: 1340-3. 79. Han JH, Wong KS. Is counterpulsation a potential therapy for ischemic stroke? Cerebrovasc Dis 2008; 26: 97-105. 80. Loh PH, Cleland JG, Louis AA, Kennard ED, Cook JF, Caplin JL, Barsness GW, Lawson WE, Soran OZ, Michaels AD. Enhanced external counterpulsation in the treatment of chronic refractory angina: a long-term follow-up outcome from the International Enhanced External Counterpulsation Patient Registry. Clin Cardiol 2008; 31: 159-64. 81. Lawson WE, Hui JC, Kennard ED, Barsness G, Kelsey SF. Predictors of benefit in angina patients one year after completing enhanced external counterpulsation: initial responders to treatment versus nonresponders. Cardiology 2005; 103: 201-6. 82. Lawson WE, Kennard ED, Holubkov R, Kelsey SF, Strobeck JE, Soran O, Feldman AM. Benefit and safety of enhanced external counterpulsation in treating coronary artery disease patients with a history of congestive heart failure. Cardiology 2001; 96:78-84. Clinical applications of EECP 247 http://bphospital.net/articles/mechanisms-of-action-and-clinical-applications.htm

Enhanced External Counterpulsation and Future Directions: Step Beyond Medical Management for Patients With Angina and Heart Failure

STATE-OF-THE-ART PAPER Aarush Manchanda, MD,* Ozlem Soran, MD, MPH, FACC, FESC† Washington, DC; and Pittsburgh, Pennsylvania J Am Coll Cardiol 2007; : 1523–31) © 2007 by the American College of Cardiology Foundation Between 25,000 and 75,000 new cases of angina refractory to maximal medical therapy and standard coronary revascularization procedures are diagnosed each year. In addition, heart failure also places an enormous burden on the U.S. health care system, with an estimated economic impact ranging from $20 billion to more than $50 billion per year. The technique of counterpulsation, studied for almost one-half century now, is considered a safe, highly beneficial, low-cost, noninvasive treatment for these angina patients, and now for heart failure patients as well. Recent evidence suggests that enhanced external counterpulsation (EECP) therapy may improve symptoms and decrease long-term morbidity via more than 1 mechanism, including improvement in endothelial function, promotion of collateralization, enhancement of ventricular function, improvement in oxygen consumption (VO2), regression of atherosclerosis, and peripheral training effects similar to exercise. Numerous clinical trials in the last 2 decades have shown EECP therapy to be safe and effective for patients with refractory angina with a clinical response rate averaging 70% to 80%, which is sustained up to 5 years. It is not only safe in patients with coexisting heart failure, but also is shown to improve quality of life and exercise capacity and to improve left ventricular function long-term. Interestingly, EECP therapy has been studied for various potential uses other than heart disease, such as restless leg syndrome, sudden deafness, hepatorenal syndrome, erectile dysfunction, and so on. This review summarizes the current evidence for its use in stable angina and heart failure and its future directions. An estimated 6.4 million patients in the U.S. suffer from symptomatic coronary artery disease (CAD), and about 400,000 new cases develop each year (1). Despite optimal medical therapy and invasive procedures, such as angioplasty and cardiac bypass surgery, there are an estimated 300,000 to 900,000 patients in the U.S. who have refractory angina pectoris (RAP). About 25,000 to 75,000 new cases of RAP are diagnosed each year (1). Daily tasks such as climbing a flight of stairs, walking a dog, or mowing the lawn become impossible without experiencing chest pain for these difficult-to-treat patients. In addition, despite advances in medical therapy for the treatment of heart failure (HF) over the past decade, substantial unmet needs remain, particularly in patients with moderate to severe HF. Heart failure is the number 1 diagnosis in Medicare patients and approximately 5 million Americans experience HF, with 550,000 new cases per year reported (1). It has been estimated that in 2005, the total direct and indirect cost of HF in the U.S. will be equal to $27.9 billion, and approximately $2.9 billion annually is spent on drugs for the treatment of HF (1). Only a few consensus therapies exist to treat HF beyond medical management, and many patients now are left to suffer their symptoms and restrict their activities chronically, and anticipate a reduced life expectancy. Current nonpharmacological options available for these patients with RAP with or without underlying HF include neurostimulation (transcutaneous electrical nerve stimulation and spinal cord stimulation), enhanced external counterpulsation (EECP) therapy, laser revascularization techniques, gene therapy, and newer interventional procedures such as percutaneous in situ coronary venous arterialization or percutaneous in situ coronary artery bypass (2). Of these modalities, EECP therapy represents the only truly noninvasive technique for which both a reduction of angina symptoms, improvement in objective measures of myocardial ischemia, and improvement in left ventricular function (both systolic and diastolic) have been shown (3–5). From the *Department of Internal Medicine, The George Washington University, Washington, DC; and the †Cardiovascular Institute, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania. Dr. Soran serves on the Speakers’ Bureau of Vasomedical, Inc. Manuscript received April 2, 2007; revised manuscript received May 25, 2007, accepted July 17, 2007. Journal of the American College of Cardiology Vol. 50, No. 16, 2007 © 2007 The American College of Cardiology Foundation ISSN 0735-1097/07/$32.00 Published by Elsevier Inc. doi:10.1016/j.jacc.2007.07.024 Downloaded from content.onlinejacc.org by on May 10, 2011 Historical Perspective Almost one-half century ago, researchers at Harvard Universityconducted experiments with counterpulsation showing that this technique markedly reduces the workload, and thus oxygen consumption, of the left ventricle. In 1953, Kantrowitz and Kantrowitz (6) described diastolic augmentation as a means of improving coronary blood flow. Birtwell et al. (7) did pioneering work toward the development of this technique and were first to apply this concept by developing the initial arterial counterpulsator in the U.S. Zheng et al. (8) were the first to report the benefits of external counterpulsation in the 1980s by using the first pneumatic counterpulsation device. Lawson et al. (9–13) at the State University of New York, Stony Brook, undertook a number of open-label studies with the enhanced system, EECP, between 1989 and 1998 using both objective and subjective end points. These studies, although open and nonrandomized, showed statistical improvement in exercise tolerance by patients as evidenced by thallium-stress testing and partial or complete resolution of coronary perfusion defects as evidenced by radionuclide imaging studies. In 1999, Arora et al. (14) reported results of the first double blind randomized placebo-controlled multicenter trial (MUST-EECP [Multicenter Study of Enhanced External Counterpulsation]) (14). Since then, EECP therapy has emerged as an effective, noninvasive, and durable therapeutic option for patients not only with angina but also with HF. Technique The technique of EECP therapy consists of electrocardiogram-gated rapid, sequential compression of the lower extremities taking place during diastole, followed by simultaneous decompression during systole. These actions produce hemodynamic effects similar to those of an intraaortic balloon pump, but unlike an intra-aortic balloon pump, EECP therapy also increases venous return (Fig. 1). Cuffs resembling oversized blood pressure cuffs—on the calves, the lower thighs, and the upper thighs, including the buttocks, inflate rapidly and sequentially—via computer interpreted electrocardiogram signals—starting from the calves and proceeding upward to the buttocks (Fig. 1) during the resting phase of each heartbeat (diastole). This has the effect of creating a strong retrograde counterpulse in the arterial system, forcing freshly oxygenated blood toward the heart and coronary arteries, while simultaneously increasing the volume of venous blood return to the heart under increased pressure. Just before the next heartbeat, before the systole, all 3 cuffs simultaneously deflate, significantly reducing the workload of the heart. This is achieved because the vascular beds in the lower extremities are relatively empty when the cuffs are deflated, significantly lowering the resistance to blood ejected by the heart, reducing the amount of work the heart must do to pump oxygenated blood to the rest of the body. The inflation-deflation activity is monitored with the help of a finger plethysmogram and coordinated by a microprocessor that interprets electrocardiogram signals from the patient’s heart and actuates the inflation and deflation cycles. The end result of this sequential squeezing of the legs is to create a pressure wave that significantly increases peak diastolic pressure, benefiting circulation to the heart muscle and other organs, while also reducing systolic pressure and systemic vascular resistance to the general benefit of the vascular system. A typical treatment course consists of 35 outpatient treatments administered as 1 h per day over 7 weeks. Three pairs of pneumatic cuffs are applied to the calves, lower thighs, and upper thighs. The cuffs are inflated sequentially during diastole, distal to proximal. The compression of the lower-extremity vascular bed increases diastolic pressure and flow and increases venous return. The pressure is then released at the onset of systole. Inflation and deflation are timed according to the R-wave on the patient’s cardiac monitor. The pressures applied and the inflation– deflation timing can be altered by using the pressure waveforms and electrocardiogram on the enhanced external counterpulsation (EECP) therapy monitor. Mechanism of Action of EECP Recent advances in the understanding of coronary arterial physiology and response to EECP therapy have provided some insight into possible modes of effect and an explanation for the benefits seen with EECP therapy (Fig. 2.) However, most of the experience is from small animal or human uncontrolled studies, and the mechanism of the sustained antianginal benefit with EECP remains unclear. Development of new functional collateral vessels by increasing nitric oxide and decreasing endothelin-1 levels to the ischemic myocardium was postulated as the mechanism of action for EECP therapy by many early studies conducted. Masuda et al. (15) reported that the development of functional collateral vessels is one of the mechanisms of EECP therapy using ammonia positron emission tomography. Endothelial shear stress from increased diastolic augmentation after EECP therapy was shown to augment endothelium-derived relaxing factor/nitric oxide production (16) and to cause down-regulation of endothelin-1 levels, thereby recruiting more collateral vessels (17). Akhtar et al. (18) recently showed that EECP therapy has a sustained, dose-related effect in stimulating endothelial cell production of the vasodilator nitric oxide and in decreasing production of endothelin-1. However, an increase in myocardial perfusion on nuclear stress tests was inconsistent with improvement in symptoms (Table 1), making it unlikely as a sole mechanism of benefit. In recent studies by Tao et al. (19,20), EECP therapy demonstrated stabilization of coronary endothelium, an effect very similar to that of athletic training. These recent studies confirm the earlier results by Bonetti et al. (21); they had seen improvement in the peripheral endothelial function (RH-PAT) in their patients after 35 h of EECP treatment. Zhang et al. (22) also showed retardation of the atherosclerosis process by the metabolic effects of external counterpulsation therapy on the NF-kappa signaling pathways. Recently Levenson et al. (23) postulated that an increase in cyclic guanosine monophosphate (cGMP) acutely after EECP therapy might in part be responsible for the improved peripheral arterial function. Cyclic guanosine monophosphate regulates vascular smooth muscle tone, which may improve arterial function. Fifty-five subjects were randomized into 2 groups to receive either sham (control) or active EECP therapy during 1 h. Plasma and platelet cGMP were measured immediately before and after EECP therapy by radioimmunoassay. One hour of EECP therapy increased cGMP plasma concentration by 52% and platelet content by 19%. This theory of endothelial stabilization has attracted the most attention in the recent past as one of the primary mechanisms of action, with more clinical trials needed to further understand it completely. Arora et al. (24) showed a trend toward increased vascular endothelial growth factor levels after EECP therapy in human subjects, thereby confirming the findings of Chen et al. (25) in the canine model. Vascular endothelial growth factor, along with other growth factors such as fibroblast growth factor, is the most widely studied in gene therapy for RAP. It is considered important in promoting angiogenesis or neorevascularization of the ischemic myocardium. However, failure to show consistent improvement in myocardial perfusion as discussed above makes neorevascularization unlikely, an argument similar to the one against collateralization. Ochoa et al. (26) recently reported the acute effects of EECP therapy on oxygen uptake: VO2 at rest in adults with symptomatic CAD compared with healthy volunteers using sham control group. They measured VO2 continuously in 20 adults during a single treatment session of EECP therapy, including 10 subjects with previous coronary revascularization who were referred for EECP therapy for refractory angina and 10 healthy, sedentary volunteers. Both groups showed a small, sustained increase in VO2 during EECP Possible Mechanisms Responsible for the Clinical Benefit Associated With EECP Therapy Acute afterload reduction decreases myocardial demand. By increasing coronary blood flow, enhanced external counterpulsation (EECP) therapy is thought to promote myocardial collateralization via opening of preformed collateral vessels, arteriogenesis, and angiogenesis. Increased blood flow and shear stress also may improve coronary endothelial function, favoring vasodilation and myocardial perfusion. In addition, improvement in endothelial function may further promote collateral formation by arteriogenesis and angiogenesis. In addition to a peripheral training effect, a minor placebo effect is considered to contribute to the symptomatic benefit of Treatment Duration (h) Angina Relief (% >1 CCS Class1) Nitroglycerine Use Versus Frequency Exercise Capacity (%) Time to ST-Segment Depression on Stress Test Cardiac Perfusion (% of Patients) Other Findings Zheng et al. (8) 1983 200 12 2(97%) NA NA NA NA — Lawson et al. (10) 1992 18 36 2(100%) 2 167 NA 1(78%) — Lawson et al. (11,12) 1996 27 35 NA NA 181 NA 1(78%) In addition, EECP therapy seemed to decrease PVR and HR response to exercise, the so-called training effect Lawson et al. (13) 1998 60 35 2 NA 1 NA 1(75%) Benefit sustained at 2-yr follow-up Arora et al. (14) 1999 139 35 2 2 1 1 NA Only double-blind trial to date using sham controls Lawson et al. (27)  2000 33 35 2(100%) 2 NA NA 1(79%) Benefit sustained at 5-yr follow-up Lawson et al. (28)  2000 2,289 35 2(74%) NA NA NA NA EECP consortium. Efficacy was independent of provider setting or experience Masuda et al. (29) 2001 11 35 NA NA 1 1 1 Coronary perfusion increased both at baseline and during dipyridamole Provocation Stys et al. (30) 2001 395 35 2(88%) NA NA NA NA EECP was equally effective in men and women and young and elderly (65 yrs) Barsness et al. (31) 2001 978 35 2 (81%) 2 NA NA NA EECP therapy can be used for those who prefer noninvasive treatment to avoid revascularization Stys et al. (32) 2002 175 35 2 (85%) NA 1 NA 1(83%) — Fitzgerald et al. (33) 2003 4,454 35 2* 2* NA NA 1 *Comparable benefit seen for both previously revascularized and PUMPERS Tartaglia et al.  (34) 2003 25 35 2 (93%) NA 1 1(80%) NA — Lawson et al. (35) 2006 363 35 2 (72%)* 2 52* NA NA NA *Benefit sustained at 2 yrs Lawson et al. (36) 2005 746 32 2 (72%) 2 NA NA NA Equal benefit in both systolic and diastolic heart failure Novo et al. (37) 2006 25 35 2 (84%) NA NA NA 1(36%) dobutamine stress if possible echocardiography Maximal benefit seen in patients with worst systolic failure Lawson et al. (38) 2006 1,458 35 2 2 1 NA NA EECP therapy was found to be equally beneficial in mild vs. severe anginal symptoms Loh et al. (39) 2006 58 35 2 (86%)* 2 1 NA NA *Sustained improvement in 78% at 1-yr follow-up treatment. Because VO2 is an independent predictor of increased exercise capacity, it led them to conclude that increase in VO2 may also in part be one of the mechanisms by which EECP therapy increases exercise tolerance in stable angina patients (26). In summary, further studies are needed to elucidate both the mechanism of action and the overall effects of EECP therapy, or a combination of the above mechanisms may explain the sustained benefit from EECP therapy in the clinical trials (27). EECP and Angina Several nonrandomized and randomized trials have shown a consistently positive clinical response among patients of RAP treated with EECP therapy (Table 1) (8 –14,28 –39). Benefits associated with EECP therapy include reduction of angina and nitrate use, increased exercise tolerance, favourable psychosocial effects and enhanced quality of life, as well as prolongation of the time to exercise-induced ST-segment depression and an accompanying resolution of myocardial perfusion defects (Table 1). Patients with severely disabling angina at baseline and those without a history of smoking are more likely to improve their angina class after EECP therapy (40). Most of the studies on EECP therapy cannot be double blind and lack good control groups because of technical limitations, which have frequently raised questions of operator bias in the past. But the MUST-EECP study, a randomized, double-blind, sham-controlled trial, also showed the clinical benefit of EECP therapy in patients with chronic stable angina and positive exercise stress tests (14). In this study, 139 patients (mean age 63 years, range 35 years to 81 years) with angina pectoris (typical Canadian Cardiovascular Society classes I, II, and III angina) and documented coronary ischemia were equally randomized to hemodynamically inactive counterpulsation with EECP versus active counterpulsation. Patients in the active EECP therapy group showed a statistically significant increase in time to exercise-induced ST-segment depression when compared with sham and baseline, and reported a statistically significant decrease in the frequency of angina episodes when compared with sham and baseline. Exercise duration increased significantly in both groups; however, the increase was greater in the active EECP group. Moreover, a MUSTEECP sub-study showed a significant improvement in quality-of-life parameters in patients assigned to active treatment, which was sustained during a 12-month follow-up period (41). Results from the International EECP Patient Registry (31,33,35) and the EECP Clinical Consortium (28) have shown that the symptomatic benefit observed in controlled studies also translates to the heterogeneous patient population seen in clinical practice. Moreover, follow-up data indicate that the clinical benefit may be maintained for up to 5 years in patients with a favorable initial clinical response (27,35). One of the ongoing debates with most of the published trials discussed earlier (Table 1) is that the increased exercise tolerance reported after EECP therapy may, at least in part, be attributed to a training effect. EECP in Angina with Left Ventricular Dysfunction When providing EECP therapy to the HF population, the primary concern of the initial researchers was that the increased venous return resulting from EECP therapy could precipitate pulmonary edema in angina patients with severe left ventricular dysfunction (LVD). Soran et al. (42,43) evaluated the safety and efficacy of EECP therapy in patients with angina and severe LVD (ejection fraction [EF] _35%). The outcomes of EECP treatment were followed up in 363 patients enrolled in the International EECP Patient Registry, an international multicenter study of EECP therapy for the treatment of patients with chronic angina. The EECP therapy was observed to be a safe and effective treatment of angina in patients with severe LVD who were not considered good candidates for revascularization by coronary artery bypass graft or percutaneous coronary intervention (43). After completion of treatment, there was a significant reduction in severity of angina: 72% improved from severe angina to no angina or mild angina. Fifty-two percent of patients discontinued nitroglycerin use. Quality of life showed a significant increase. At 2-year follow-up, this angina reduction was maintained in 55%, 83% survived, and event-free (death/myocardial infarction/ percutaneous coronary intervention/coronary artery bypass graft) survival rate was 70%. Forty-three percent had no cardiac hospitalization; 81% had no congestive HF event (43). Lawson et al. (44) also evaluated RAP patients with preserved left ventricular function (EF _35%) and with severe left ventricular dysfunction (EF _35%) who were treated with a 35-h course of EECP therapy. Bioimpedance measurements of cardiovascular function were obtained before the first and again after the 35th hour of EECP therapy. Twenty-five patients were enrolled, 20 with preserved left ventricular function and 5 with severe left ventricular dysfunction. Angina class improved similarly in both groups. The severe left ventricular dysfunction group, in contrast to the preserved left ventricular function group, increased cardiac power, stroke volume, and cardiac index and decreased systemic vascular resistance with treatment. This study suggests that EECP could benefit patients experiencing CAD with severe left ventricular dysfunction directly by improving cardiac power and indirectly by decreasing systemic vascular resistance (44). EECP Therapy in HF Most of the data to date on the efficacy and safety of EECP therapy in HF are from small studies (45,46). In a pilot study of clinically stable patients diagnosed with mild to moderate HF (New York Heart Association [NYHA] JACC Vol. 50, No. 16, 2007 Manchanda and Soran 1527 October 16, 2007:1523–31 EECP and Future Directions Downloaded from content.onlinejacc.org by on May 10, 2011 functional class II or III) and a left ventricular EF _35%, Soran et al. (45) found EECP treatment to be safe with no unexpected adverse events during the application of EECP treatment. Soran et al. (45) also conducted a multicenter feasibility study in which stable HF (New York Heart Association functional class II to III, ischemic and nonischemic etiology) patients with left ventricular EF _35% were treated with 35 1-h sessions of EECP therapy over a 7-week period and followed up over a 6-month period. The mean EF for the ischemic and nonischemic groups was 25.6 _ 7.1% and 18.7 _ 7.4%, respectively. Mild to moderate valvular heart disease was the most common etiology for the group with nonischemic etiology. Study results showed that EECP therapy was safe and well-tolerated in this group of patients (46). In addition, EECP therapy was associated with significant improvements in exercise capacity as measured by peak oxygen uptake and exercise duration and in quality of life at 1 week and 6 months after EECP treatment. Although safety was the primary end point of this feasibility study, the efficacy results suggest that EECP therapy can increase peak oxygen uptake, improve exercise capacity and functional status, as well as improve the patient’s quality of life, for both the short term and long term (6 months) after the completion of EECP therapy. Although study subjects benefited from EECP therapy to a similar degree regardless of ischemic or nonischemic etiology of their HF, because of a small number of patients in the nonischemic group, further studies need to be conducted to evaluate the effectiveness of EECP in patients  with a nonischemic etiology (46). Based on these results, a larger, controlled study of EECP therapy in patients with stable HF (NYHA functional classes II and III) and LVD was undertaken called the PEECH (Prospective Evaluation of EECP in Heart Failure) trial (47), results of which were recently published. It was a controlled, randomized, single-blind, parallel-group, multicenter study of 187 patients with symptomatic but stable HF (NYHA functional classes II and III, ischemic and nonischemic etiology) and a left ventricular EF _35% was designed to assess the efficacy of EECP therapy in patients with stable HF. Medical therapy is optimized in all patients based on the recommendations of the Heart Failure Society of America (usual care), and then randomized between 2 treatment groups, usual care or EECP therapy (35 h over 7 weeks). The EECP therapy improved exercise tolerance, quality of life, and NYHA functional class without an accompanying increase in peak VO2. Investigators also assessed whether differences existed in response to EECP therapy in patients with HF secondary to either ischemic or nonischemic dilated cardiomyopathy. Albeit in a relatively small sample size, subgroup analysis based on etiology of disease showed benefit in patients with ischemic cardiomyopathy, whereas this difference was not seen in the small number of patients with nonischemic disease. Because patients were not blinded to therapy, these benefits of EECP therapy may be attributable to a placebo effect. However, the usefulness of EECP therapy by physicians must be individualized based on their assessment of the totality of EECP therapy data. Further studies may help elucidate both the mechanism of action and the overall effects of EECP therapy.  Limitations of the Technique It is important to point out that EECP therapy is not for everyone. This noninvasive outpatient procedure can be somewhat uncomfortable for patients because of the high pressure sequential compression of the cuffs. It is not recommended for certain types of valvular heart disease Side Effects and Contraindications of Enhanced External Counterpulsation Side Effects of Enhanced External Counterpulsation Leg or waist pain Skin abrasion or ecchymoses Bruises in patients using Coumadin when INR dosage is not adjusted Paresthesias Worsening of heart failure in patients with severe arrhythmias (especially aortic insufficiency), or for those with recent cardiac catheterization, an irregular heart rhythm, severe hypertension, significant blockages in the leg arteries, or a history of deep venous thrombosis (Table 2). For anyone else, however, the procedure seems to be quite safe. Contraindications of Enhanced External Counterpulsation Coagulopathy with an INR of prothrombin time _2.5 Arrhythmias that may interfere with triggering of EECP system (uncontrolled atrial fibrillation, flutter, and very frequent premature ventricular contractions) Within 2 weeks after cardiac catheterization or arterial puncture (risk of bleeding at femoral puncture site) Decompensated heart failure Moderate to severe aortic insufficiency (regurgitation would prevent diastolic augmentation) Severe peripheral arterial disease (reduced vascular volume and muscle mass may prevent effective counterpulsation, increased risk of thromboembolism) Severe hypertension _180/110 mm Hg (the augmented diastolic pressure may exceed safe limits) Aortic aneurysm (_5 mm) or dissection (diastolic pressure augmentation may be deleterious) Pregnancy or women of childbearing age (effects of EECP therapy on fetus have not been studied) Venous disease (phlebitis, varicose veins, stasis ulcers, prior or current deep vein thrombosis or pulmonary embolism) Severe chronic obstructive pulmonary disease (no safety data in pulmonary hypertension) Future Directions and Potential Uses of EECP Future Directions and Potential Uses of EECP Potential Uses of EECP Therapy in Conditions Other Than RAP and HF Remarks Werner et al. (48) 2005/Germany 19 2 Hepatorenal syndrome Safety: EECP therapy was tolerated by healthy and cirrhotic patients alike Efficacy: EECP therapy increased MAP and increased urinary production (urinary flow rate) in patients with end-stage cirrhosis and hepatorenal syndrome. Potential role of EECP therapy in diuresis and increased urinary flow in patients with end-stage liver disease who are awaiting transplant Rajaram et al. (49) 2005/U.S. 6 35 Restless leg syndrome Relief of symptoms and change in the IRLS score from 28.8 to 6.0 after EECP therapy Benefit sustained for 6 months; IRLS score was 3.3 at the end of 6 months It was a small, uncontrolled case series Hilz et al. (50) 2004/Germany 38 1 Peripheral vasodilatation and skin effects similar to those during exercise Potential role of EECP therapy in improving vascular flow in mild nonulcerative peripheral vascular disease Nike Sports Research Lab (51) 2004/U.S. 19 vigorously active men in training 35 Improvement in postural instability and ataxia in EECP treatment group as compared with control EECP therapy had no significant effect on the physiological parameters considered to be the best for predicting performance in endurance-type sportsmen: VO2, lactate levels, work tolerance time Erectile dysfunction Froschermaier et al. (52) 1998/Germany 13 35 Increase in the penile artery flow by 200%, and 11 of 13 reported improved erectile function Case series looking at EECP therapy and erectile Sudden deafness and tinnitus (vascular in origin) Dysfunction Offergeld et al. (53) 1998/Germany 30 5–10 Treatment of sudden deafness and tinnitus (vascular in origin) Hearing threshold increased in 28%, on average by 19 dB Tinnitus decreased in 47% of the patients by an average of 16 dB Improvement persisted at 1-year follow-up Future Directions and Conclusions Throughout the world, EECP therapy has been studied for various potential uses other than heart disease (48 –53) (Table 3). Its role in improving endothelial function might be beneficial in the treatment of patients with Cardiac Syndrome X, which is marked by severe chest pain caused by myocardial dysfunction, often without detectable atherosclerosis. Mayo Clinic investigators have reported successful treatment of Cardiac Syndrome X with severely symptomatic coronary endothelial dysfunction in the absence of obstructive CAD with standard 35-h course of EECP therapy (54). However, it is important to realize that EECP therapy is an option for patients with angina refractory to medical treatment who are not candidates for interventional or surgical revascularization. The American Heart Association recommends it as a Class IIb (Level of Evidence: B) intervention for treatment of RAP, among other nonpharmacological approaches such as neurostimulation (Class IIb, Level of Evidence: B) and transmyocardial laser revascularization (Class IIa, Level of Evidence: A) (55). The European Society of Cardiology views EECP therapy as an interesting modality available for treatment of RAP with more clinical trials needed to define its role in treating RAP (56). Enhanced external counterpulsation therapy is a valuable outpatient procedure providing acute and long-term relief of anginal symptoms and improved quality of life among a group of patients with symptomatic ischemic heart disease with or without congestive HF. Reprint requests and correspondence: Dr. Ozlem Soran, University of Pittsburgh Cardiovascular Institute, 200 Lothrop Street, UPMC, Presbyterian Hospital, F-748, Pittsburgh, Pennsylvania 15213. E-mail: soranzo@upmc.edu. REFERENCES 1. American Heart Association. Heart Disease and Stroke Statistics. Dallas, TX: American Heart Association, 2005. 2. Kim MC, Kini A, Sharma SK. Refractory angina pectoris: mechanism and therapeutic options. J Am Coll Cardiol 2002;39:923–34. 3. Urano H, Ikeda H. Enhanced external counter pulsation improves exercise tolerance, reduces exercise-induced myocardial ischemia and improves left ventricular diastolic filling in patients with coronary artery disease. J Am Coll Cardiol 2001;37:93–9. 4. Cohen J, Grossman W, Michaels AD. Portable enhanced external counterpulsation for acute coronary syndrome and cardiogenic shock: a pilot study. Clin Cardiol 2007;30:223– 8. 5. Lawson WE, Silver MA, Hui JC, Kennard ED, Kelsey SF. Angina patients with diastolic versus systolic heart failure demonstrate comparable immediate and one-year benefit from enhanced external counterpulsation. J Card Fail 2005;11:61– 6. 6. Kantrowitz A, Kantrowitz A. Experimental augmentation of coronary flow by retardation of coronary artery pressure pulse. Surgery 1953;34: 678–87. 7. Birtwell WC, Ruiz U, Soroff HS, DesMarais D, Deterling RA Jr. Technical consideration in the design of a clinical system for external left ventricular assist. Trans Am Soc Artif Intern Organs 1968;14: 304–10. 8. Zheng ZS, Li TM, Kambic H, et al. Sequential external counterpulsation (SECP) in China. Trans Am Soc Artif Intern Organs 1983; 29:599–603. 9. Lawson WE, Hui JC, Zheng ZS, et al. Improved exercise tolerance following enhanced external counterpulsation: cardiac or peripheral effect? Cardiology 1996;87:271–5. 10. Lawson WE, Hui JCK, Soroff HS, et al. Efficacy of enhanced external counterpulsation in the treatment of angina pectoris. Am J Cardiol 1992;70:859–62. 11. Lawson WE, Hui JCK, Zheng ZS, et al. Can angiographic findings predict which coronary patients will benefit from enhanced external counterpulsation? Am J Cardiol 1996;77:1107–9. 12. Lawson WE, Hui JCK, Zheng ZS, et al. Improved exercise tolerance following enhanced external counterpulsation: cardiac or peripheral effect? Cardiology 1996;87:271–5. 13. Lawson WE, Hui JCK, Guo T, Burger L, Cohn PF. Prior revascularization increases the effectiveness of enhanced external counterpulsation. Clin Cardiol 1998;21:841– 4. 14. Arora RR, Chou TM, Jain D, et al. The Multicenter Study of Enhanced External Counterpulsation (MUST-EECP): effect of EECP on exercise-induced myocardial ischemia and anginal episodes. J Am Coll Cardiol 1999;33:1833– 40. 15. Masuda D, Nohara R, Inada H, et al. Improvement of regional myocardial and coronary blood flow reserve in a patient treated with enhanced external counterpulsation: evaluation by nitrogen-13 ammonia PET. Jpn Circ J 1999;63:407–11. 16. Tseng H, Peterson TE, Berk BC. Fluid shear stress stimulates mitogen-activated protein kinase in endothelial cells. Circ Res 1995; 77:869 –78. 17. Garlichs CD, Zhang H, Werner D, John A, Trägner P, Daniel WG. Reduction of serum endothelin-1 levels by pneumatic external counterpulsation (abstr). Can J Cardiol 1998;14 Suppl:87F. 18. Akhtar M, Wu GF, Du ZM, Zheng ZS, Michaels AD. Effect of external counterpulsation on plasma nitric oxide and endothelin-1 levels. Am J Cardiol 2006;98:28 –30. 19. Sessa WC, Pritchard K, Seyedi N, Wang J, Hintze TH. Chronic exercise in dogs increases coronary vascular nitric oxide production and endothelial cell nitric oxide synthase gene expression. Circ Res 1994;74:349 –53. 20. Tao J, Tu C, Yang Z, Zhang Y, Chung XL. Enhanced external counterpulsation improves endothelium-dependent vasorelaxation in the carotid arteries of hypercholesterolemic pigs. Int J Cardiol 2006; 112:269 –74. 21. Bonetti PO, Barsness GW, Keelan PC, et al. Enhanced external counterpulsation improves endothelial function in patients with symptomatic coronary artery disease. J Am Coll Cardiol 2003;41:1761– 8. 22. Zhang Y, Chen XL, He XH, et al. Effects of enhanced external counterpulsation in atherosclerosis and NF-kappaB expression: a pig model with hypercholesterolemia. Zhonghua Bing Li Xue Za Zhi 2006;35:159–64. 23. Levenson J, Pernollet MG, Iliou MC, Devynck MA, Simon A. Cyclic GMP release by acute enhanced external counterpulsation. Am J Hypertens 2006;19:867–72. 24. Arora R, Chen HJ, Rabbani L. Effects of enhanced counterpulsation on vascular cell release of coagulation factors. Heart Lung 2005;34: 252–6. 25. Chen XL, He XH, Zhang Y, et al. (Effect of chronic enhanced external counterpulsation on arterial endothelial cells of porcine with hypercholesteremia). Di Yi Jun Yi Da Xue Xue Bao 2005;25:1491–3. 26. Ochoa AB, Dejong A, Grayson D, Franklin B, McCullough P. Effect of enhanced external counterpulsation on resting oxygen uptake in patients having previous coronary revascularization and in healthy volunteers. Am J Cardiol 2006;98:613–5. 27. Lawson WE, Hui JCK, Cohn PF. Long-term prognosis of patients with angina treated with enhanced external counterpulsation: five-year follow-up study. Clin Cardiol 2000;23:254–8. 28. Lawson WE, Hui JCK, Lang G. Treatment benefit in the enhanced external counterpulsation consortium. Cardiology 2000;94:31–5. 1530 Manchanda and Soran JACC Vol. 50, No. 16, 2007 EECP and Future Directions October 16, 2007:1523–31 Downloaded from content.onlinejacc.org by on May 10, 2011 29. Masuda D, Nohara R, Hirai T, et al. Enhanced external counterpulsation improved myocardial perfusion and coronary flow reserve in patients with chronic stable angina. Eur Heart J 2001;22:1451– 8. 30. Stys T, Lawson WE, Hui JCK, Lang G, Liuzzo J, Cohn PF. Acute hemodynamic effects and angina improvement with enhanced external counterpulsation. Angiology 2001;52:653– 8. 31. Barsness G, Feldman AM, Holmes DR, Holubkov R Jr., Kelsey SF, Kennard ED. The International EECP Patient Registry (IEPR): design, methods, baseline characteristics, and acute results. Clin Cardiol 2001;24:435– 42. 32. Stys TP, Lawson WE, Hui JCK, et al. Effects of enhanced external counterpulsation on stress radionuclide coronary perfusion and exercise capacity in chronic stable angina pectoris. Am J Cardiol 2002;89:822– 82. 33. Fitzgerald CP, Lawson WE, Hui JC, Kennard ED, IEPR Investigators. Enhanced external counterpulsation as initial revascularization treatment for angina refractory to medical therapy. Cardiology 2003; 100:129 –35. 34. Tartaglia J, Stenerson J Jr., Charney R, Ramasamy S, Fleishman BL, Gerardi P. Exercise capability and myocardial perfusion in chronic angina patients treated with enhanced external counterpulsation. Clin Cardiol 2003;26:287–90. 35. Lawson WE, Hui JC, Kennard ED, Kelsey SF, Michaels AD, Soran O. Two-year outcomes in patients with mild refractory angina treated with enhanced external counterpulsation. Clin Cardiol 2006;29:69–73. 36. Lawson WE, Silver MA, Hui JC, Kennard ED, Kelsey SF. Angina patients with diastolic versus systolic heart failure demonstrate comparable immediate and one-year benefit from enhanced external counterpulsation. J Card Fail 2005;11:61– 6. 37. Novo G, Bagger JP, Carta R, Koutroulis G, Hall R, Nihoyannopoulos P. Enhanced external counterpulsation for treatment of refractory angina pectoris. J Cardiovasc Med 2006;7:335–9. 38. Lawson WE, Hui JC, Kennard ED, Kelsey SF, Michaels AD, Soran O, IEPR Investigators. Two-year outcomes in patients with mild refractory angina treated with enhanced external counterpulsation. Clin Cardiol 2006;29:69 –73. 39. Loh PH, Louis AA, Windram J, et al. The immediate and long-term outcome of enhanced external counterpulsation in treatment of chronic stable refractory angina. J Intern Med 2006;259:276–84. 40. Lawson WE, Kennard ED, Hui JC, Holubkov R, Kelsey SF, IEPR Investigators. Analysis of baseline factors associated with reduction in chest pain in patients with angina pectoris treated by enhanced external counterpulsation. Am J Cardiol 2003;92:439–43. 41. Arora RR, Chou TM, Jain D, et al. 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. J Investig Med. 2002;50:25–32. 42. Soran OZ, Kennard ED, Kelsey SF, Holubkov R, Strobeck J, Feldman AM. Enhanced external counterpulsation as treatment for chronic angina in patients with left ventricular dysfunction: a report from the International EECP Patient Registry (IEPR). Congest Heart Fail 2002;8:297–302. 43. Soran O, Kennard ED, Kfoury AG, Kelsey SF, IEPR investigators Two-year clinical outcomes after enhanced external counterpulsation (EECP) therapy in patients with refractory angina pectoris and left ventricular dysfunction (report from The International EECP Patient Registry). Am J Cardiol 2006;97:17–20. 44. Lawson WE, Kennard ED, Holubkov R, et al., IEPR investigators. Benefit and safety of enhanced external counterpulsation in treating coronary artery disease patients with a history of congestive heart failure. Cardiology 2001;96:78–84. 45. Soran OZ. Efficacy and safety of enhanced external counterpulsation in mild to moderate heart failure: a preliminary report (abstr). J Card Fail 1999;3 Suppl 1:195. 46. Soran OZ. Enhanced external counterpulsation in patients with heart failure: a multicenter feasibility study. Congest Heart Fail 2002;8: 204–8. 47. Feldman AM, Silver MA, Francis GS, et al., for the PEECH Investigators. Enhanced external counterpulsation improves exercise tolerance in patients with chronic heart failure. J Am Coll Cardiol 2006;48:1198 –205. 48. Werner D, Tragner P, Wawer A, Porst H, Daniel WG, Gross P. Enhanced external counterpulsation: a new technique to augment renal function in liver cirrhosis. Nephrol Dial Transplant 2005;20: 920–6. 49. Rajaram SS, Shanahan J, Ash C, Walters AS, Weisfogel G. Enhanced external counter pulsation (EECP) for restless legs syndrome (RLS): preliminary negative results in a parallel double-blind study. Sleep Med 2006;7:390 –1. 50. Hilz MJ, Werner D, Marthol H, Flachskampf FA, Daniel WG. Enhanced external counterpulsation improves skin oxygenation and perfusion. Eur J Clin Invest 2004;34:385–91. 51. Myhre LG, Muir I, Schutz RW, Rantala B, Thigpen T. Enhanced external counterpulsation for improving athletic performance. Paper presented at: Experimental Biology 2004; April 17–21, 2004; Washington, DC. 52. Froschermaier SE, Werner D, Leike S, Schneider M, Waltenberger J, Daniel WG, Wirth MP. Enhanced external counterpulsation as a new treatment modality for patients with erectile dysfunction. Urol Int 1998;61:168 –71. 53. Offergeld C, Werner D, Schneider M, Daniel WG, Hüttenbrink KB. Pneumatic external counterpulsation (PECP): a new treatment option in therapy refractory inner ear disorders? Laryngorhinootologie 2000; 79:503–9. 54. Bonetti PO, Gadasalli SN, Lerman A, Barsness GW. Successful treatment of symptomatic coronary endothelial dysfunction with enhanced external counterpulsation. Mayo Clin Proc 2004;79:690 –2. 55. Gibbons RJ, Abrams J, Chatterjee K, et al. ACC/AHA 2002 guideline update for the management of patients with chronic stable angina— summary article: a report of the American College of Cardiology/ American Heart Association Task Force on Practice Guidelines (Committee on the Management of Patients With Chronic Stable Angina). Circulation 2003;107:149 –58. 56. Fox K, Garcia MAA, Ardissino D, et al. Guidelines on management of stable angina pectoris: executive summary: the Task Force on the Management of Stable Angina Pectoris of the European Society of Cardiology. Eur Heart J 2006;27:1341– 81. J. Am. Coll. Cardiol. 2007;50;1523-1531; originally published online Oct 1, 2007; Aarush Manchanda, and Ozlem Soran Medical Management for Patients With Angina and Heart Failure Enhanced External Counterpulsation and Future Directions: Step Beyond This information is current as of May 10, 2011 CORRECTION Manchanda A, Soran O. Enhanced external counterpulsation and future directions: step beyond medical management for patients with angina and heart failure. J Am Coll Cardiol 2007;50:1523–31. Figure 2 from this article on page 1525 had previously appeared in a 2003 article in the Journal. The final line of this figure caption should have contained the following credit line: Reproduced with permission from Bonetti et al. Enhanced external counterpulsation for ischemic heart disease: what’s behind the curtain? J Am Coll Cardiol 2003;41:1918 –25. The authors apologize for this omission. doi:10.1016/j.jacc.2007.11.023 Journal of the American College of Cardiology Vol. 50, No. 25, 2007 © 2007 by the American College of Cardiology Foundation ISSN 0735-1097/07/$32.00 Published by Elsevier Inc. Downloaded from content.onlinejacc.org by on May 10, 2011 http://bphospital.net/articles/Patients-With-Angina-and-Heart-Failure.htm