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nhanced External Counterpulsation:n Innovative Physical Therapy

or Refractory Angina

ebra L. Braverman, MD

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he prevalence of refractory angina in the United States is 600,000 to 1.8 million.mproved pharmacological, invasive, and surgical therapies for cardiovascular diseasesuring the last few decades have led to an increase in life expectancy of such individuals.espite treatment with multiple medications and invasive procedures, these patients

emain symptomatic and functionally limited. Enhanced external counterpulsationEECP) is a safe, noninvasive, well-tolerated, and clinically effective outpatient physicalherapy for many patients with refractory angina. Numerous trials demonstrate positivelinical responses among at least 80% of patients undergoing EECP, including reduc-ions in angina and nitrate use, increases in exercise tolerance, and enhanced quality ofife. Several mechanisms, including the promotion of collateral blood flow, improve-

ent in endothelial function, reduction in inflammation, and the production oferipheral training effects similar to exercise, are thought to be responsible for thelinical benefits of this therapy. Despite the marked success rates EECP achieves withppropriately selected patients who have end-stage coronary artery disease, the treat-ent remains largely unknown, particularly among physiatrists. This review will

ummarize the current evidence for the use of EECP and spark a better understandingf the potential role of this treatment in cardiac rehabilitation.

NTRODUCTION

pproximately 9.1 million Americans have angina pectoris, with 500,000 new caseseveloping annually. Direct and indirect costs of coronary heart disease approach $156.4illion per year [1]. Improved drug therapy and invasive procedures have increased the lifexpectancy of these patients. However, some remain severely disabled by angina despitexhausting these treatments. The prevalence of refractory angina in the United States is00,000 to 1.8 million [2]. For these individuals, daily activities such as walking, climbingteps, carrying a bag of groceries, making the bed, or mowing the lawn are impossibleithout chest pain, shortness of breath, or considerable fatigue.What remains beyond conventional surgically invasive and pharmacological treatments

s enhanced external counterpulsation (EECP). It is an innovative noninvasive therapy fororonary artery disease and angina for which a reduction of symptoms, improvement inbjective measures of myocardial ischemia, and improvement in left ventricular functionave been shown. There are more than 100 peer-reviewed articles cited by the U.S. Nationalibrary of Medicine documenting the safety and efficacy of EECP, yet this physical therapyemains largely unknown, particularly among physiatrists. This review will summarize theurrent evidence for the use of EECP and spark a better understanding of the role of thisreatment in cardiac rehabilitation.

ACKGROUND

istorical Perspective

ore than half a century ago researchers at Harvard University conducted experiments

ith counterpulsation demonstrating that this technique markedly reduces the work-

Sa

PM&R © 2009 by the American Academy of P1934-1482/09/$36.00

Printed in U.S.A.68

.L.B. Albert Einstein Medical Center, 700 Cott-an Avenue, Building B, Lower Level, Philadel-

hia, PA 19111. Address correspondence to.L.B.; e-mail: bravermd@einstein.eduisclosure: nothing to disclose

isclosure Key can be found on the Table ofontents and at www.pmrjournal.org

ubmitted for publication August 13, 2008;ccepted December 4.

hysical Medicine and RehabilitationVol. 1, 268-276, March 2009

DOI: 10.1016/j.pmrj.2008.12.002

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269PM&R Vol. 1, Iss. 3, 2009

oad, and thus oxygen consumption, of the left ventricle.n 1953, Kantrowitz described diastolic augmentation as aeans of improving coronary blood flow. Birtwell didioneering work toward the development of this tech-

Figure 1. A patient r

igure 2. Schematic of EECP cuffs. The procedure consists of se

arly diastole followed by simultaneous cuff deflation at the onset o

ique and was the first to apply this concept by developinghe initial arterial counterpulsator in the United States.heng et al reported the benefits of external counterpul-ation in the 1980s by using a pneumatic counterpulsation

ng EECP treatment.

tial leg compression by the EECP cuffs at 50-ms intervals during

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270 Braverman ENHANCED EXTERNAL COUNTERPULSATION

evice [3]. Interest in EECP grew in the United Stateshen multiple open-label studies in the 1990s showed

esolution of coronary perfusion defects associated withmprovement in exercise tolerance on stress tests. In 1995he U.S. Food and Drug Administration approved theECP device to treat stable angina, cardiogenic shock, andcute myocardial infarction and, in 1999, the Centers foredicare and Medicaid Services approved coverage ofECP for Medicare recipients with disabling angina. Be-ause of its effects on the venous system, EECP therapynitially was considered contraindicated in patients witheart failure. However, recent studies showed the safetynd effectiveness of the system in heart failure treatmenthich subsequently led the Food and Drug Administra-

ion to expand its approval of the EECP device to treatongestive heart failure in 2002 [4-7].

emodynamic Effects of EECP

uring EECP the patient’s lower extremities are wrapped in 3

Cardiac Effects

Afterload Coronary blood flow

Open preexisting collaterals

Oxygen consumption

Placebo effect

Growth factor

Collaterali

Perfusion

Ischem

Clinical B

Endothelial progenitor cells

Cardiac orkload

ArteriogeneAngiogene

Figure 3. Mecha

ompressive pneumatic cuffs applied to the calves, lower thighs, I

nd upper thighs (Figure 1). Electrocardiogram (ECG)-gatedequential leg compression occurs as these cuffs are inflatedrom distal to proximal in early diastole and then rapidly de-ated at the onset of systole (Figure 2), analogous to the intra-ortic balloon pump (IABP). The rapid inflation increases dia-tolic pressure (diastolic augmentation) by 93%, increasingoronary perfusion pressure and myocardial perfusion. Peakoronary flow velocity increases by 109%. The rapid cuff defla-ion promotes lower extremity arterial “runoff” and leads to aecrease in systolic pressure (systolic unloading) by 15% in theorta and coronary arteries and improved ventricular unloading8]. Unlike the IABP, EECP also increases venous return, furtherromoting an increase in cardiac output.

ISCUSSION

echanism of Action

here are several possible mechanisms of action of EECPFigure 3) put forth by numerous studies (Table 1) [9-15].

Peripheral Effects

ar stress

Vasodilation

it Peripheral conditioning

“Passive exercise”

Endothelial function Inflammation ( nitric oxide) ( endothelin-1)

f action of EECP.

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nitially, the prevailing theory was that EECP increased cor-

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271PM&R Vol. 1, Iss. 3, 2009

nary collateral circulation. An illustration of this was ob-erved in a study in which patients underwent maximaladionuclide perfusion treadmill stress tests (RPSTs) beforend after EECP that showed significant improvement inxercise duration (12%, P � .0001) after EECP withouthange in the double product. The improvement in RPST wasot caused by an alteration in myocardial oxygen demandut by expanded myocardial perfusion (increased supply byollateralization). Another group of patients underwent

able 1. Mechanism of Action of EECP

Study[Ref.] Methods

tys et al2002 [9]

175 patients had baseline maximalradionuclide perfusion treadmillstress test (RPST) and follow-up RPSTwithin 6 mos of completing courseof EECP (97 had same level RPSTand 78 had maximal RPST).

Improimprwithhadin pedoub

hanget al2007 [10]

35 pigs in 3 groups (high-cholesteroldiet, high-cholesterol diet plusEECP, usual diet); histopathologicaland immunohistochemicalanalyses of coronary arteries andaortas.

EECPintimpigsdecrcholendoandof exkinasreve

khtaret al2006 [11]

Plasma nitrate and nitrite (NOx) andendothelin-1 (ET-1) levels measuredserially in 13 EECP patients.

Afterincredecrremaandbase

onettiet al2003 [12]

Reactive hyperemia-peripheralarterial tonometry (RH-PAT)measured in 23 patients before,during, and after a course of EECP.

RH-PAtreatfollowexpefrom

icholset al2006 [13]

Radial artery pressure waveformsrecorded by applanationtonometry and central aorticpressure waveforms generatedusing a mathematical transferfunction in 20 EECP patients.

Reflecfrom(p�.decraugm18�9(p�.

aseyet al2008 [14]

12 EECP patients vs 9 sham patients;Plasma tumor necrosis factor-�́(TNF), monocyte chemoattractantprotein-1 (MCP), and solublevascular cell adhesion molecule-1(VAM) were measured before andafter course of EECP.

EECPin TNp �MCPpg/mcontNo c

arsheshetet al2008 [15]

25 EECP patients vs 10 controls;number of endothelial progenitorcells (EPCs) positive for CD34 andkinase insert domain receptor(KDR) determined by flowcytometry and number of colony-forming units (CFUs) assessed in a7-day culture, before and aftercourse of EECP.

EECP(10.2p �11.0;cont

PSTs at the same level of exercise before and after EECP that p

howed an even greater improvement in post-EECP perfu-ion. At the same cardiac workload, they achieved a lowerouble product (5%, P � .05), reflecting a decrease inyocardial oxygen demand. This is analogous to peripheral

ascular conditioning found with exercise, in which im-roved vasomotor tone decreases the blood pressure re-ponse to exercise [9].

Recent advances in the understanding of vascular ho-eostasis include an understanding that the endothelium

ResultsMechanism of Action

of EECP

erfusion and 12%nt in exercise durational RPST; same level RPSTarger improvement

and 5% lowerduct.

EECP leads to expandedmyocardial perfusion viaincreased collateralizationand decrease inmyocardial oxygendemand.

ses arterial shear stress;erplasia in high-cholesteroltima-to-media area ratio42% in EECP group; high-pigs had attenuated

l nitric oxide synthaseced phosphorylationlular signal-regulatednd 2 which werey EECP.

Chronic exposure of vascularendothelial cells andvascular smooth musclecells to high physiologicalshear stress during EECPhas antiproliferative andvasoprotective effects.

EECP there was a 62�17%NOx and a 36�8%

n ET-1. At 3 mos, NOx2�11% above baselinemained 11�10% below

Neurohormonal evidencethat EECP improvesendothelial function.

x increased after eachand at one monththose patients who

d clinical benefit

EECP enhances peripheralendothelial function.

ave amplitude decreased1mmHg to 8.7�6.8mmHgausing a significantn central aortiction index fromHg to 12�8.4mmHg

EECP improves wavereflection characteristicsand reduces arterial stiffnessby 30%.

ts had a 29% reduction2.7 vs. 4.9�2.5 pg/ml,nd a 19% reduction in�55.9 vs. 190.4�47.601) as compared to

in VAM for either group.

EECP decreased circulatinglevels of proinflammatorybiomarkers.

sed EPC number by 75%8/105 mononuclear cells;nd CFUs by 214% (3.5 to).These parameters in theup did not change.

EECP is associated withincreased number andcolony-forming capacityof circulating EPCs.

ved povememaximeven lrfusionle pro

increaal hypand ineasedesterolthelia

enhantraceles 1 arsed b36 hrsase inease iined 1ET-1 reline.T indement,-up in

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001).patienF (6.9�0.01) a(254.9l, p�.

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lays a critical role. Basic science research in a pig model

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272 Braverman ENHANCED EXTERNAL COUNTERPULSATION

ocumented that increased peak diastolic arterial wall sheartress during EECP (107%, P � .001) reduces endothelialamage in coronary artery disease. This augmented sheertress also mitigates cellular changes by arresting vascularmooth muscle cell proliferation and migration, decreasingroliferating cell nuclear antigen proliferative index, sup-ressing extracellular matrix formation, and inhibiting inti-al hyperplasia and the development of atherosclerosis by

ctivating endothelial nitric oxide synthase [10].Endothelial dysfunction is known to be an early step in

therogenesis and is characterized by impaired bioavail-bility of endothelium-derived nitric oxide (NO), whichas vasodilatory, antiproliferative, anti-inflammatory, an-ithrombotic, and antiplatelet properties. Endothelial dys-unction also is marked by an increase in production ofndothelin-1 (ET-1), a vasoconstrictor with prothrom-otic, proinflammatory, and mitogenic effects. This imbal-nce between vasodilators and vasoconstrictors leads tompaired endothelium-dependent vasodilation, the func-ional characteristic of endothelial dysfunction. There is

able 2. Published Trials of EECP in Patients with Stable Angina

Study [Ref.] Year N

heng et al [16] 1983 200awson et al [17] 1992 18awson et al [18] 1996 27awson et al [19] 1996 50

awson et al [20] 1998 60rora et al [21] 1999 139

awson et al [22] 2000 33awson et al [23] 2000 2,289rano et al [24] 2001 12asuda et al [25] 2001 11

tys et al [26] 2001 395

arsness et al [27] 2001 978tys et al [9] 2002 175

itzgerald et al [28] 2003 4,454

artaglia et al [29] 2003 25awson et al [30] 2005 746awson et al [31] 2006 1,458

ovo et al [32] 2006 25oh et al [33] 2006 58ettersson et al [34] 2006 55oran et al [35] 2007 450

asey et al [14] 2008 21

arsheshet et al [15] 2008 25

oh et al [36] 2008 1,427

CS � Canadian Cardiovascular Society; ED � emergency department; EECheart rate; PUMPERS � candidates for percutaneous coronary intervention

s initial revascularization treatment; pts � patients; PVR � peripheral vasc

eurohormonal evidence that EECP improves endothelial r

unction in humans. After 36 hours of EECP, there was a2% increase in plasma NO and a 36% decrease in ET-1ompared with baseline. Three months later, NO re-ained 12% above and ET-1 remained 11% below base-

ine [11]. Patients who experienced a favorable clinicalesponse with EECP demonstrated a significant increase25%, P � .05) in their endothelial function as measuredy reactive hyperemia-peripheral arterial tonometry indexfter 1 hour of treatment and at 1-month follow-up [12].

The likely mechanism of improvement from EECP is thatt mimics the vascular effects of aerobic exercise. The repeti-ive inflation and deflation of the cuffs echoes the cyclic strainn leg arteries from intermittent skeletal muscle contractionnd relaxation, although the EECP effect is more dramatic ashe applied circumferential pressure of the cuffs is 260 � 20m Hg. Also, both aerobic exercise and EECP increase

rterial blood flow and wall shear stress. Together the cyclictrain and increased shear stress improve endothelial func-ion, stimulate NO release, and cause vasodilation. Suchhanges in arterial wall properties from EECP decrease arte-

tmenttion (h)

Angina(% > 1 CCS Class) Nitrate Use

12 2 (97) N/A36 2 (100) 235 N/A N/A35 2 (100) 2

35 2 N/A35 2 25-36 2 (100) 235 2 (74) N/A35 N/A N/A35 N/A N/A

35 2 (88) N/A

35 2 (81) 235 2 (85) N/A

35 2 2

35 2 (93) N/A32 2 (72) 235 2 2

35 2 (84) N/A35 2 (86) 235 2 (79) 235 2 (72) 2

35 2 2

35 2 N/A

33 2 (78) 2

hanced external counterpulsation; EPCs � endothelial progenitor cells; HRcoronary artery bypass graft and chose enhanced external counterpulsationistance.

TreaDura

3

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ial stiffness by 30% (P � .001), resulting in a decrease in left

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273PM&R Vol. 1, Iss. 3, 2009

entricular afterload, myocardial oxygen demand, and num-er of angina episodes [13].

Cardiovascular disease is associated with chronic inflam-ation, and studies suggest that inflammation can be sup-ressed under conditions of high endothelial shear stress.ECP reduces levels of the circulating proinflammatory bi-markers tumor necrosis factor-� (TNF-�, -29%, P � .01)nd monocyte chemoattractant protein-1 (MCP, -19%, P �01) in patients with angina. Interestingly, the percentageeduction in TNF from EECP is similar to what has beeneported with exercise in cardiovascular disease. IncreasedNF and MCP predict future coronary events and, therefore,reduction may have clinical significance with regard to

educing forthcoming risk [14]. Another marker of cardio-ascular disease risk is the number of circulating endothelialrogenitor cells (EPCs). The improvement of angina afterECP treatment is associated with an increased number (by5%, P � .05) and colony-forming units (by 214%, P � .01)f circulating EPCs [15], again linking EECP to improved

Exercise Tolerance(% of pts)

Time to STDepression

Cardiac Perfusion(% of pts)

N/A N/A N/A1 (67) N/A 1 (78)1 (81) N/A 1 (78)

N/A N/A 1 (80)

1 N/A 1 (75)1 1 N/A

N/A N/A 1 (79)N/A N/A N/A1 1 11 1 1

N/A N/A N/A

N/A N/A N/A1 N/A 1 (83)

N/A N/A 1

1 1 (80) 1 (80)N/A N/A N/A1 N/A N/A

N/A N/A 11 N/A N/A

N/A N/A N/AN/A N/A N/A

N/A N/A N/A

N/A N/A N/A

N/A N/A N/A

ascular health and diminished vascular risk. l

Because the similarities between exercise and EECP areubstantial, one might argue that EECP is not necessaryecause exercise itself can achieve these desired outcomes.owever, most of these patients are so symptomatic and

unctionally limited that they cannot exercise to the degree itould take to achieve the aforementioned cardiovascularenefits. They use EECP as a bridge to regain an active

ifestyle. EECP provides passive exercise, making patientseel better, and allowing them to engage in a more intensective exercise program thereafter.

linical Studies

umerous trials (Table 2) [16-36] demonstrate positive clin-cal responses among approximately 80% of patients under-oing EECP, including reductions in angina and nitrate use,ncrease in exercise tolerance, enhanced quality of life, im-roved exercise stress tests, and resolution of myocardialerfusion defects (Figure 4). In 1999, Arora et al. [21] pub-

Other Findings

–Benefits sustained at 3-yr follow-upDecrease PVR and HR response to exercise (training effect)The presence of a patent vascular conduit (native coronaryor bypass graft) predicts a favorable response to EECP

Benefit sustained at 2-yr follow-upDouble-blind placebo controlled trialBenefit sustained at 5-yr follow-upEfficacy independent of provider setting or experienceImproved left ventricular diastolic fillingCoronary perfusion increased at baseline and duringdipyridamole provocation

EECP equally effective in men and women, young andelderly (65yrs)

EECP can be used to avoid revascularizationLower double product at same level of exercise showingperipheral vascular conditioning

Comparable benefit for both previously revascularized andnon-revascularized patients

–Equal benefit in systolic and diastolic heart failureBenefit sustained at 2-yr follow-up; EECP equally beneficialin mild vs. severe angina

Maximal benefit seen in pts with worst systolic failureSustained improvement in 78% at 1-yr follow-upBenefits sustained at 1-yr follow-upRefractory angina pts with LV dysfunction had 18%reduction in all-cause ED visits and 33% reduction inhospitalization rates at 6-mos follow-up

Single-blind placebo controlled trial; EECP decreasedcirculating levels of pro-inflammatory biomarkers

Placebo controlled trial; EECP increases number andcolony-forming capacity of circulating EPCs

Benefits sustained at 3-yr follow-up

ished the first randomized, placebo-controlled, double-

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lind trial of EECP. A total of 139 patients were randomizedo receive EECP or a sham treatment. Only the EECP groupad significant (12%, P � .01) improvement in time toT-segment depression on exercise stress tests and decreasen angina episodes (38%, P � .05) compared with no changen the sham group. Using the Medical Outcomes Study6-Item Short-Form Health Survey and the Quality of Lifendex-Cardiac Version III to assess the effects of EECP onealth-related quality of life, the EECP group reportedreater improvements in all 9 quality of life scales, mostignificantly in bodily pain, social functioning, and quality ofife specific to cardiac patients at the end of the treatment and

year later [37].EECP is safe, well-tolerated, and provides sustained favor-

ble results. A recent study illustrating this was done by Thenternational EECP Patient Registry at the Epidemiology Dataenter of the University of Pittsburgh. They followed 1427ECP patients prospectively from 36 centers for a median of7 months. Multivessel coronary artery disease was present

n 76% for 11 � 8 years. Eighty-eight percent had previousurgical or percutaneous revascularization, 82% were un-uitable for further coronary intervention, and 89% hadanadian Cardiovascular Angina Classification (CCS) III/IV.dverse events during the treatment period were musculo-keletal discomfort (1.5%), skin breakdown (2.5%), heartailure (2.2%), and unstable angina (4.5%). Major adverseardiac events (MACEs) were rare and included myocardialnfarction (0.8%), percutaneous coronary intervention (0.8%),oronary artery bypass surgery (0.6%), and death (0.5%).

A total of 1061 patients (74.4%) completed follow-up,hereas 220 patients (15.4%) died. Immediately after EECP,

he proportion of those with severe angina was reduced from9% to 25% (P � .001.) The CCS class was improved by at

east 1 class in 78% of patients and by at least 2 classes in8%; this functional improvement was maintained 3 years

ater in 74% of patients. At follow-up, 36% of patients hadCS II or less angina (better than pre-EECP) without a MACE

igure 4. Positron emission tomography scans demonstratingaseline ischemia (left) and improved myocardial perfusionfter EECP (right).

36]. This is thought-provoking outcome data when one r

onsiders that all the patients had advanced symptomaticoronary artery disease.

riteria for Patient Selection for EECP

he overall data support the use of EECP in patients withoronary artery disease with CCS functional class III-IV an-ina or angina equivalent syndrome, who are not candidatesor surgical revascularization, and who are receiving optimalharmacological management [38]. The American Heart As-ociation recommends EECP as a Class IIb intervention forhe treatment of refractory angina pectoris (level of evidence:

indicates data from randomized trials with high false-ositive [alpha] or high false-negative [beta] errors) [39]. Inarticular, patients who have had incomplete or unsuccessfulevascularization and have persistent angina or significantilent ischemic burden have favorable outcomes with EECP.ymptomatic individuals who are unable to undergo invasiveevascularization as the result of high risk co-morbid statesi.e., renal failure, advanced pulmonary disease, elderly andrail, diabetes, and advanced heart failure) or anatomic con-traints making them unsuitable for surgical or catheter-ased revascularization likewise do well with EECP. Patientsith New York Heart Association function class II-III heart

ailure caused by ischemic heart disease who are stable,ell-compensated, and in a euvolemic state also derive ben-

fit from EECP.The procedure is safe and well-tolerated for most patients.

nfrequent side effects include discomfort, skin abrasions,cchymoses, and/or paresthesias in the lower extremitiesoverall incidence 0.8%), angina or silent ischemia (inci-ence 0.2%), arrhythmia (0.07%), and pulmonary edema0.03%) [23]. Contraindications for EECP include arrhyth-ias that interfere with machine triggering, bleeding diathe-

is or warfarin therapy with an international normalized ratio3.0, current or recent (within 2 months) lower-extremity

hrombophlebitis or deep venous thrombosis, severe lower-xtremity peripheral vascular disease with rest claudicationr nonhealing ischemic ulcers, aortic aneurysm requiringurgical repair, pregnancy, severe pulmonary hypertension,ecompensated heart failure, uncontrolled systemic hyper-ension, and severe aortic insufficiency [38].

roviding and Monitoring Patients DuringECP

he typical course of treatment is 35 sessions of 1 hour inuration, once a day, 5 days per week over the course of 7eeks. EECP generally is provided by a nurse or cardiac

echnician, and each procedure is performed under directhysician supervision. Before beginning the program, eachatient should have a comprehensive cardiac assessment,

ncluding noninvasive testing to evaluate left ventricularunction, valvular competence, and myocardial ischemicurden. Once in the EECP program, patients are clinicallyssessed daily before and after treatment and vital signs are

ecorded. During the treatment hour, the magnitude of he-

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275PM&R Vol. 1, Iss. 3, 2009

odynamic change is estimated noninvasively several timesy measuring the diastolic-to-systolic effectiveness ratio viahe use of finger plethysmography. Upon completion of theherapy course, patients may undergo repeat nuclear stressesting to document the objective benefits of EECP. EECP isovered by Medicare under the HCPCS (Healthcare Com-on Procedure Coding System) code GO166 with the ICD-9

International Statistical Classification of Diseases and Re-ated Health Problems) code 413.9 for other and unspecifiedngina pectoris. The treatment is also reimbursed by mostrivate insurers.

EECP is painless for most patients. Some individuals, suchs those with severe peripheral vascular disease and ad-anced degenerative lumbosacral spine and hip disease,ight experience pain or discomfort during treatment. Thisain can usually be managed with individualized paddingnd positioning techniques that often alleviate the sorenessnd allow for favorable clinical outcomes [40].

he Future of EECP

s patients live longer with coronary artery disease, they haveore complex comorbidities and are at greater risk for inva-

ive procedures, making EECP an attractive treatment alter-ative. As a noninvasive modality, it should perhaps beonsidered as first-line treatment with invasive revasculariza-ion reserved for EECP failures. Patients who choose EECP asrst-line therapy have similar favorable results comparedith those who were previously revascularized and then haveECP [28]. Because the scientific evidence of EECP efficacy isrowing, it should be considered to be integrated into cardiacehabilitation programs as a jump-start to enable these pa-ients to attain their maximal functional capacity.

Looking beyond angina, it is known that EECP increaseslood flow throughout the body, not only to the heart. Asuch, there are numerous conditions associated with circula-ory compromise where EECP may play a therapeutic role.urther investigation is warranted in this arena [40].

As the basic science and clinical research of EECP contin-es to grow, physician acceptance of this unique physicalherapy will expand and allow access for more patients to thisaluable outpatient treatment that provides long-term relieff anginal symptoms and improved quality of life for thoseith symptomatic ischemic heart disease.

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training in refractory angina. BMJ 2008;336:338-339.3. Manchanda A, Soran O. Enhanced external counterpulsation and fu-

ture directions: Step beyond medical management for patients withangina and heart failure. J Am Coll Cardiol 2007;50:1523-1531.

4. Soran O, Demarca T, Crawford L, et al. Efficacy and safety of enhancedexternal counterpulsation in mild to moderate heart failure: A prelimi-

nary report. J Cardiac Failure 1999;5(3 Suppl 1):53(195).

5. Soran O, Fleishman B, Demarco T, et al. Enhanced external counter-pulsation in patients with heart failure: A multi-center feasibility study.Congest Heart Fail 2002;8:204-208.

6. Soran O, Kennard ED, Kelsey SF, Holubkov R, Strobeck J, FeldmanAM. Enhanced external counterpulsation as treatment for chronic an-gina in patients with left ventricular dysfunction: A report from theInternational EECP Patient Registry (IEPR). Congest Heart Fail 2002;8:297-302.

7. Feldman AM, Silver MA, Francis GS, et al. Enhanced external counter-pulsation improves exercise tolerance in patients with chronic heartfailure. J Am Coll Cardiol 2006;48:1198-1205.

8. Michaels AD, Accad M, Ports TA, Grossman W. Left ventricular systolicunloading and augmentation of intracoronary pressure and Dopplerflow during enhanced external counterpulsation. Circulation 2002;106:1237-1242.

9. Stys TP, Lawson WE, Hui JCK, et al. Effects of enhanced externalcounterpulsation on stress radionuclide coronary perfusion and exer-cise capacity in chronic stable angina pectoris. Am J Cardiol 2002;89:822-824.

0. Zhang Y, He X, Chen X, et al. Enhanced external counterpulsationinhibits intimal hyperplasia by modifying shear stress responsive geneexpression in hypercholesterolemic pigs. Circulation 2007;116:526-534.

1. Akhtar M, Wu GF, Du ZM, Zheng ZS, Michael AD. Effect of externalcounterpulsation on plasma nitric oxide and endothelin-1 levels. Am JCardiol 2006;98:28-30.

2. Bonetti PO, Barsness GW, Keelan PC, et al. Enhanced external coun-terpulsation improves endothelial function in patients with symptom-atic coronary artery disease. J Am Coll Cardiol 2003;41:1761-1768.

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