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: firstname.lastname@example.org
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
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.
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
Aortic aneurysm or dissection
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
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.
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