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 Table of Contents  
REVIEW ARTICLE
Year : 2017  |  Volume : 5  |  Issue : 2  |  Page : 55-60

Enhanced external counterpulsation as an effective nonsurgical solution for ischemic heart disease patients


Department of Cardiovascular and Thoracic Surgery, Institute of Medical Sciences, Banaras Hindu University, Varanasi, Uttar Pradesh, India

Date of Web Publication20-Jun-2017

Correspondence Address:
Sanjay Kumar
Department of Cardiovascular and Thoracic Surgery, Institute of Medical Sciences, Banaras Hindu University, Varanasi - 221 005, Uttar Pradesh
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/heartindia.heartindia_15_17

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  Abstract 

Stable angina is managed primarily through lifestyle advice, medication therapy, and coronary revascularization procedures. Some patients with refractory angina exhibit symptoms that are not optimally controlled with the optimal medication and revascularization options available. Enhanced external counterpulsation (EECP) is a technique that can be used to improve symptoms in chronic stable angina. However, the role of EECP has also been investigated following positive outcomes in patients with both angina and heart failure in multicenter studies. We performed a systematic review of the evidence of the clinical effectiveness of EECP. EECP has been approved by the United States Food and Drug Administration (FDA) for the management of refractory angina (Class IIb). About 200 hospitals across India have adopted this technique. EECP uses three sets of pneumatic cuffs that sequentially contract during diastole, increasing aortic diastolic pressure, augmenting coronary blood flow, and central venous return. EECP improves anginal symptoms and exercise tolerance, and reduces nitroglycerin use in patients with chronic, stable angina. EECP has also been shown to be safe and beneficial in patients with symptomatic stable congestive heart failure. It has been postulated that cardiac benefits of EECP are mediated through vascular endothelial growth factor, and nitric oxide-mediated vasodilatation and angiogenesis. In June 2002, the FDA also approved EECP therapy for heart failure patients. EECP is cost-effective if the observed quality of life benefits are assumed to continue throughout a patient's lifetime. However, there remain uncertainties around the long-term effects of the intervention.

Keywords: Angina, enhanced external counterpulsation, ischemic heart disease, refractory angina


How to cite this article:
Kumar S, Lahiri T K. Enhanced external counterpulsation as an effective nonsurgical solution for ischemic heart disease patients. Heart India 2017;5:55-60

How to cite this URL:
Kumar S, Lahiri T K. Enhanced external counterpulsation as an effective nonsurgical solution for ischemic heart disease patients. Heart India [serial online] 2017 [cited 2017 Oct 20];5:55-60. Available from: http://www.heartindia.net/text.asp?2017/5/2/55/208551


  Introduction Top


There is a high prevalence of symptomatic coronary artery disease (CAD) affecting approximately 6.9 million patients in the United States, with an annual incidence of about 400,000.[1] A conservative estimate indicates that there could be 30 million CAD patients in India, of which 14 million are in urban and 16 million in rural areas. According to the WHO prediction, if the current trend continues by the year 2020, the burden of atherothrombotic cardiovascular disease (CVD) in India will surpass other regions of the world. The mortality attributable to CVD in India is expected to rise by 103% in men and 90% in women from 1985 to 2018.[2]

In a subset of these patients, angina is not optimally controlled despite optimal medical management and coronary revascularization. This condition is termed refractory angina.[3] The Scottish Intercollegiate Guidelines Network for the management of refractory angina include education, rehabilitation, cognitive behavioral therapy, spinal cord stimulation, transcutaneous electrical nerve stimulation, left stellate ganglion block, thoracoscopic sympathectomy, angiogenesis, and surgical transmyocardial revascularization, among others.[4]

In 1953, Kantrowitz demonstrated that coronary blood flow can be increased 20%–40% by increasing diastolic blood pressure.[5] Intraaortic balloon pump (IABP) counterpulsation is an invasive method of increasing coronary blood flow, while enhanced external counterpulsation (EECP) is a noninvasive method. EECP therapy has been approved by the United States Food and Drug Administration (FDA) (Class IIb) for the management of refractory angina and heart failure.

While traditional treatment for ischemic heart disease usually involves bypass surgery or the use of stents to correct blocked arteries, these procedures present a significant risk, besides being costly. The need for cost-effective therapies for heart diseases is likely to be met by the ECP, which benefits the body by artificially emulating the benefits of exercise.

External counterpulsation therapy was first developed over half a century ago as a resuscitative tool to support the failing heart and was based on hemodynamic principles of the IABP. Over the course of last few decades, it has evolved into the modern EECP therapy, which has proven to be a safe, effective, and low-cost, noninvasive treatment for patients with debilitating angina and chronic heart failure who are poor candidates for revascularization procedures and have suboptimal results from other therapies. Although the EECP is not considered an alternative to traditional treatments, it may delay the need for these invasive procedures, and in many cases, relief will be sufficient to render them unnecessary.

A systematic review of the evidence of the clinical effectiveness of EECP was performed. Searches were undertaken to identify relevant published and unpublished clinical and cost-effectiveness literature. The website of the main EECP manufacturer, Vasomedical, was also searched. Update searching was conducted in November 2016 on selected databases.

Randomized controlled trials (RCTs), non-RCTs, cohort studies with a contemporaneous control group, and case–control studies of patients with refractory stable angina or heart failure were included in this study. Standard care (drugs, cardiac rehabilitation, and revascularization) or placebo (sham EECP) was the comparators. The results of the included studies were discussed in a narrative synthesis.


  Procedure Top


EECP is a registered trademark (timing mechanism of the machine) of Vasomedical, Inc., Westbury, New York, which manufactures EECP equipment in the United States. Most published studies have used vasomedical EECP equipment. EECP therapy consists of three sets of pneumatic cuffs attached to each of the patient's legs at the calf and lower and upper thigh [Figure 1]. Sensors are placed on the chest to detect the heartbeat. The inflation of the cuffs is triggered by a computer, and timing of the inflation is based on the R-wave of the electrocardiogram. The EECP therapist adjusts the inflation and deflation timing to provide optimal blood movement per a finger plethysmogram waveform reading. This produces a retrograde flow of blood in the aorta (aortic counterpulsation), resulting in a diastolic augmentation of blood flow and also an increase in venous return, which leads to an improved coronary perfusion pressure during diastole. Shortly afterward, the cuffs simultaneously deflate before the onset of systole, thereby decreasing vascular resistance, assisting with systolic unloading, and decreasing cardiac workload. The inflation of the cuffs squeezes blood from the lower legs up toward the heart, thus improving blood flow in and around the heart. The rhythmic pulsing of the cuffs is firm, yet comfortable and patients find it soothing and relaxing. The treatment takes approximately 1 h and is repeated over a series of about 35 daily sessions. About 200 hospitals across India have adopted this technique.
Figure 1: The placement of cuff during enhanced external counterpulsation

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Chronic stable angina patients who respond well to ECP therapy often experience:

  • A reduction in symptoms: Shortness of breath, dizziness, fatigue, weakness, pain or pressure in chest, back, neck, jaw, shoulders, or arms providing an overall improvement to quality of life
  • An increase in energy and exercise tolerance
  • Results that can last for years.



  Indication Top


The EECP counterpulsation system is intended for the treatment of chronic stable angina that is refractory to optimal antianginal medical therapy and without options for revascularization. In addition, it is intended for use in healthy controls to provide an improvement in vasodilation, increased VO2, and increased blood flow. It is intended for use under the oversight of a health-care professional. To date, more than 300 studies have been published showing the benefits of ECP therapy. Numerous studies for other disease indications are ongoing.


  Contraindications Top


ECP therapy is contraindicated in the treatments of patients who have a history of the following:

  • Any surgical intervention within 6 weeks
  • Cardiac catheterization within 1–2 weeks
  • Uncontrolled arrhythmia or controlled arrhythmias that could interfere with ECP inflation and deflation triggering
  • Dual chamber pacemakers with atrial pacing may interfere with ECP inflation timing sequence. This should be addressed before treatment
  • Aortic insufficiency (regurgitation can prevent diastolic augmentation)
  • Severe pulmonary disease
  • Limiting peripheral vascular disease involving the iliofemoral arteries
  • Deep-vein thrombophlebitis (risk of thromboembolism)
  • Severe hypertension (≥180 mmHg systolic or ≥110 diastolic)
  • Limiting peripheral vascular disease involving the iliofemoral arteries
  • Deep-vein thrombophlebitis (risk of thromboembolism)
  • Bleeding disorders
  • Patients undergoing major anticoagulation therapy (such as heparin therapy) with prothrombin time >1.5
  • Heart rates <35 or more than 125 beats/min (patients with these heart rates should be evaluated and treated before ECP treatments)
  • The presence of abdominal aortic aneurysm
  • The presence of local infection, vasculitis of the extremities
  • Pregnant women and women of childbearing age who do not have a negative pregnancy test
  • The presence of a burn, open wound, or bone fracture on any limb subject to ECP treatment.



  Role of Enhanced External Counterpulsation in Angina Top


The multicenter study-EECP (MUST-EECP)[9] was the landmark prospective, blinded, multicenter study that randomly assigned 139 patients with chronic stable angina and positive exercise stress tests to full-dose EECP or a sham method with minimal pressures. The study showed significant increase in exercise time post-EECP from baseline (426 ± 20–470 ± 20 s, P< 0.001) versus the sham group (432 ± 22–464 ± 22 s, P< 0.03), and significant improved time to ≥1 mm ST-segment depression in the EECP group (337 ± 18–379 ± 18 s, P< 0.002) compared with the sham group (326 ± 21–330 ± 20 s, P< 0.74). These results were maintained 12 months after EECP treatment.[6],[7]

The International EECP Patient Registry (IEPR) demonstrated that 78% of patients had a reduction of ≥1 angina class, and 38% of patients had improvement of at least two classes. At least, a 50% reduction in the frequency of angina was experienced by 76% of patients as well as improvement in quality-of-life assessment that was sustained for at least 2 years.[7],[8] Loh et al.[8] conducted a follow-up review in 2008 that followed 1061 patients from the IEPR-1 (previously described) who maintained significant improvements in both weekly anginal events and quality of life at 3 years following completion of EECP therapy, compared with data obtained 1-week posttherapy.

A 5-year, single-center, nonrandomized study in 33 patients with CAD, treated with EECP, and grouped as responders versus nonresponders found that major adverse cardiovascular events or mortality occurred in 6 of 7 patients (86%) in the nonresponder group and 6 of 26 patients (23%) in the responder group.[9] The overall 5-year survival of EECP-treated patients was 88%, comparable to that seen with medical and revascularization therapies. At 5 years of follow-up, 64% of patients were alive without interim cardiovascular events or need for revascularization.[9]

The IEPR data also demonstrated an 83% reduction in hospitalization rates, compared to 6 months before EECP. About 86% of IEPR patients completed the 35-h treatment.[10],[11] The EECP completion rate was a major indicator for benefit from EECP; there were significantly lower rates of myocardial infarction, coronary artery bypass grafting, and percutaneous coronary intervention (PCI) mortality at 1-year among those who completed the 35-h EECP therapy compared to those who did not.[12],[13],[14] At 5 years, major adverse cardiovascular events (death, acute myocardial infarction, new coronary artery bypass grafting, new PCI, valve replacement, and unstable angina) were significantly lower among EECP responders (23%) compared to nonresponders (86%).[9] EECP responders also have significant posttherapy improvements in perfusion defects on radionucleotide stress tests performed to the same cardiac workload and double product.[9],[12],[13],[14] EECP also has shown positive psychosocial effects among recipients.[15]


  Mechanism of Action Top


Numerous studies have shown ECP to be efficacious in patients with chronic angina, with its effects lasting for several years after completion of therapy. Besides being safe in patients with coexisting left ventricular dysfunction, there is emerging evidence that ECP therapy may result in improvement in exercise capacity and oxygen consumption in heart failure patients. Several mechanisms have been postulated to explain the therapeutic effects of ECP, including improvement in endothelial function, promotion of angiogenesis and new collaterals, reduction in atherosclerotic burden, improvement in ventricular function, and peripheral training effects analogous to that of exercise. With a greater understanding of these complex mechanisms, possible applications of ECP have broadened in recent years, with its use being studied in conditions such as hepatorenal syndrome, erectile dysfunction, and restless leg syndrome.

Endothelium

EECP responders have significant immediate increase in the reactive hyperemia-peripheral arterial tonometry (a noninvasive method of measuring peripheral endothelial function) index after each treatment and at 1-month.[19] Endothelium plays an integral part in vascular homeostasis, and its dysfunction leads to imbalance between nitric oxide – a potent vasodilator, antiproliferative, anti-inflammatory molecule – and endothelin-1 – a potent vasoconstrictor, mitogen, pro-inflammatory molecule.[20] A prospective study of 25 patients by Barsheshet et al.[21] demonstrated EECP-related increase in median number of endothelial progenitor cells (10.2–17.8 cells, P< 0.001) and colony forming units (3.5–11, P= 0.01). EECP leads to improved coronary blood flow derived from increased shear stress,[22] which leads to increased endothelial nitric oxide release and resultant vasodilatation.[23] Patients with CAD have been noted to have a significant increase in the levels of plasma nitric oxide levels and a significant decrease in plasma endothelin-1 levels, 1-month after a course of EECP.[24],[25] In a prospective study by Shechter et al.[26] in 2003 of 20 patients with CAD, EECP resulted in significant improvement in flow-mediated dilatation of the brachial artery (8.2% ±2.2%, P= 0.01) compared to controls (3.1% ±2.2%, P= 0.78).

A randomized, controlled study of 42 patients with symptomatic CAD (35 1-h EECP [n = 28] and sham-EECP [n = 14]) by Braith et al.[27] showed significant increase in flow-mediated dilatation of brachial arteries (51% vs. 2%) and femoral arteries (31% vs. 5%), while reducing endothelin-1 (−25% vs. +5%) and nitric oxide synthase inhibitor asymmetric dimethylarginine (−28% vs. +0.2%).

Oxidative stress

Oxidative stress is associated with various cardiovascular risk factors and plays a key role in the etiology of atherogenesis and endothelial dysfunction.[28] Furthermore, Braith et al.[27] showed EECP-mediated reduction in pro-inflammatory cytokines (tumor necrosis-α [−16% vs. +12.1%], monocyte chemoattractant protein-1 [−13% vs. +0.2%], vascular cell adhesion molecule-1 [−6% vs. +1%], hs C-reactive protein [−32% vs. +5%], and lipid peroxidation marker 8-isoprostane platelet growth factor 2α [ −21% vs. +1.3%]) with treatment versus sham.

Angiogenesis

Shear stress is a known stimulus for coronary collateral development and recruitment.[29] Vascular endothelial growth factors (VEGFs) and platelet-derived growth factors that are crucial in angiogenesis are upregulated by vascular shear stress.[30],[31] A course of EECP has shown to increase the plasma levels of VEGF, basic fibroblast growth factor, and hepatocyte growth factor in a study of 11 patients with stable angina.[32] VEGF is known to induce nitric oxide synthase expression and activity. Endothelial nitric oxide stimulates the effect of VEGF on endothelial cells and their organization in network like structures.[33] In a study of 6-week EECP on 12 beagle dogs, Wu et al.[31] demonstrated a significant increase in the microvessels density per mm 2 in the infarcted regions (vWF, 15.2 ± 6.3 vs. 4.9 ± 2.1, P< 0.05; alpha-actin, 11.8 ± 5.3 versus 3.4 ± 1.2, P< 0.05) of EECP group compared to control group, respectively. There was also a significant increase in VEGF expression, and they demonstrated that an increase in capillary density corresponded to improved myocardial perfusion by 99 mTc-sestamibi single-photon emission computed tomography.[34]

A 2013 prospective interventional study of 50 patients by Eslamian et al.[35] demonstrated a significant difference between perfusion scan ischemia severity before and 1-month post-EECP completion (P = 0.04). A prospective study by Buschmann et al.[36] showed significant improvement in coronary flow index (from 0.08 ± 0.01 to 0.15 ± 0.02; P< 0.001) and fractional flow reserve (from 0.68 ± 0.03 to 0.79 ± 0.03; P= 0.001) in EECP-treated patients (n = 16) compared to none in the control group (n = 7), indicating the stimulation of coronary arteriogenesis through EECP in patients with stable CAD.[36]

Exercise capacity

EECP may promote improvement in exercise duration with no change in peak double product by reduction in peripheral vascular resistance.[37]


  Controversies Top


Limited data from well-designed, multicenter, randomized, and prospective data are available on the efficacy and efficiency of EECP. Both randomized-controlled trials (MUST-EECP [6] and PEECH [17]) received sponsorship from Vasomedical, the EECP manufacturer. These studies included patients with chronic stable angina, and refractoriness to standard anginal treatment was not a mandatory requirement. In addition, patients with Class IV angina, overt heart failure, unstable angina, and myocardial infarction within 3 months were excluded from the study. The MUST-EECP [9] intervention group had longer duration of angina and higher incidence of prior myocardial infarction, and personnel administering the EECP were not blinded.

Most available studies have critical limitations such as conclusions based on subjective assessment, failure to complete the entire 35 1-h EECP course, and lack of comparison group. The PEECH [17] trial failed to maintain a statistically significant improvement in the quality of life after 6 months. The EECP group had a higher attrition rate (23.7%) compared to control group (13.85) due to adverse events.[3]

A prospective study by Dockery et al.[38] did not show a significant change in arterial stiffness parameters as measured by carotid-radial pulse wave velocity and aortic augmentation index, despite a significant improvement in treadmill exercise time and blood pressure reduction after a 7-week EECP therapy. Hence, the study suggests that factors besides change in arterial wall mechanics could be contributing to the sustained clinical benefit seen by EECP.[38] Available data are unclear on whether EECP in nonresponders contributed to a higher incidence of adverse cardiac events than responders. A small subgroup analysis of the PEECH trial showed that the EECP benefit seen in patients with ischemic cardiomyopathy was not seen in patients with nonischemic cardiomyopathy. This may have been attributed to low patient numbers and nonblinding of patients to therapy, hence leading to a placebo effect.[18]

Some data from IEPR reveal that in patients with ejection fraction ≤35%, there is a significant increase in adverse cardiac events, death, congestive heart failure, and hospitalization after 6 months.[16] Nonrandomized trials conducted with limited patients and at a limited number of institutions usually run the risk of selection bias and placebo effect influencing the outcome of the trial. Data on long-term cardiac mortality are unavailable; hence, symptomatic improvement with EECP does not guarantee improved survival or reduced cardiovascular mortality.

In 2010, Braith et al.'s randomized controlled trial of 42 patients demonstrated significant EECP-mediated dilation of brachial and femoral arteries and release of vasoactive agents reduction of pro-inflammatory markers. However, the small patient number affects the power and generalizability of the study. In addition, the clinical significance of peripheral flow dynamics and endovascular chemicals is largely unknown.[27]


  Cost-effectiveness Top


If the quality of life benefits of EECP are assumed to be maintained for no more than 1 year after treatment, EECP does not appear to be cost-effective, as defined by the National Institute for Health and Clinical Excellence's cost-effectiveness threshold range (National Institute for Clinical Excellence, 2004). In contrast, if the quality of life benefits are maintained over a lifetime, the cost-effectiveness of EECP appears clear, with a resulting incremental cost-effectiveness ratio well below conventional thresholds.[39]


  Conclusion Top


EECP has been used in the treatment of angina for the past two decades with a record of safety, and more recently, several publications support its efficacy. It is approved by the FDA for the treatment of chronic or unstable angina and in patients with congestive heart failure. Treatment has been associated with improved exercise tolerance and myocardial perfusion, as evidenced by nuclear imaging and positron emission tomography. More research will hopefully shed additional light on the mechanism of action and verify the long-term attenuation of symptoms in patients with unstable angina pectoris and in those with congestive heart failure.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

 
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Introduction
Procedure
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Role of Enhanced...
Mechanism of Action
Controversies
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References
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