Enhanced External Counterpulsation

Discussed during the "Cardiology Update, 1997" October 16-18, 1997
at the Carmel Valley Ranch Resort, Carmel, CA
Directed by William W. Parmley, MD, FACC
and Kanu Chatterjee, MBBS, FRCP, FACC

Introduction

Since the advent of bypass surgery in 1966 and coronary angioplasty in 1977, there has been an explosion in the arena of coronary revascularization for atherosclerotic disease. Yet, in every cardiology clinic there is an increasing population of patients who have persistent anginal symptoms who have exhausted the standard revascularization armamentarium and remain severely restricted. Following bypass surgery, only 75% of patients are symptom free from ischemic events for 5 years or more and only 50% after 10 years or more (1). Even with the successes of reoperation and catheter-based revascularization techniques, the population of patients with intractable angina and no conventional revascularization options is increasing.

Enhanced external counterpulsation, or "EECP", has been used as a treatment for angina in China for two decades but has only recently sparked interest in the U.S. Refinements in the technology utilized in this old concept has led to increasing promise for this treatment. This noninvasive technique provides augmentation of diastolic blood flow and coronary blood flow similar to the intra-aortic balloon pump, utilizing the serial inflation of three sets of cuffs which wrap around the calves, thighs and buttocks. Inflation and deflation is timed to the patient's ECG and the arterial pressure waveform is monitored noninvasively. The overall hemodynamic effect is to provide diastolic augmentation and thus increase coronary perfusion pressure; to unload systolic cardiac workload and therefore decrease myocardial oxygen demand; and to increase venous return and subsequently, cardiac output. This exciting new therapy is presently being explored as a treatment for chronic angina, but has many possible therapeutic utilities in acute ischemic syndromes and cardiac dysfunction.

The History of Counterpulsation

In 1953, Kantrowitz and Kantrowitz initially described the concept of diastolic augmentation as a technique to improve coronary flow which had been known to be primarily diastolic. Early work by Birtwell and others showed that the ECG QRS complex could be utilized to time an external pumping device that provided a synchronous pulse wave thereby increasing the development of coronary collaterals in experimental models. In the 1960's, Dr. S.D. Malopoulis at the Cleveland Clinic developed an experimental protocol of the intra-aortic balloon pump where a pulse wave was delivered via intra-aortic balloon device timed to the cardiac cycle to increase diastolic pressure and flow. Soroff and colleagues then described how these types of assist devices could not only produce increased coronary flow, but also reduce left ventricular work and oxygen demand (2).

Gorlin first coined the term "counterpulsation" to describe the two-fold effect of the rapid displacement and reduced resistant of volume in the lower arterial circuit. The principle thought to be in effect is that via persistent augmentation of diastolic flow, stimulation of collaterals to ischemic territories occurs with improvement in symptoms and clinical measures of ischemia. It has been shown that external counterpulsation improves ischemic physiology by increasing myocardial oxygen supply (with increased diastolic perfusion pressure) and reducing cardiac workload by decreasing left-ventricular afterload (3).

Adrian Kantrowitz began initial clinical work with an internal system in 1968 with a 15 French device which was employed via a surgical approach using a chimney graft on the femoral artery (4). This technique developed into the modern intra-aortic balloon pump which is part of the standard armamentarium of cardiologists and cardiovascular surgeons today (4). The present day intra-aortic balloon pump is available in 8 French and 9 French sizes and can be placed via a transfemoral approach in 90-95% of patients where coronary perfusion or cardiac assist is needed.

Soroff and Birtwell first described how the application of a positive pressure pulse to the lower extremities during diastole could raise diastolic pressures by 40 to 50% and lower systolic pressures by up to 30% (5, 6). By the early 1960's, three groups (Birtwell and Soroff, Dennis, and Osborn) independently developed hydraulically activated external counterpulsation devices. They found that the technique was effective in improving survival after myocardial infarction complicated by cardiogenic shock (5, 6). Initial experience with a crude external counterpulsation device used in stable angina saw relief of angina symptoms with angiographic evidence of increased vascularity (7). In a large randomized trial, 258 acute myocardial infarction patients were assigned to treatment with external counterpulsation for three hours within 24 hours of presentation reduced mortality significantly in patients over 46 years of age (8.3% vs. 17.5%, p < 0.05) (8). Despite some of these very positive early findings, other studies showed no benefit with external counterpulsation as it was studied in the 1970's and 1980's. The great variability in the clinical benefit found seemed to correlate with the level of diastolic augmentation achieved.

In the early 1980's, a Chinese group lead by Z.S. Zheng began reporting a large experience using a sequential three-cuff external counterpulsation system which provided a pressure wave by sequentially inflating from calf to thigh to buttock (Figure 1) (9, 10). Their clinical experience led to the installation of more than 1,500 external counterpulsation units in China during the past 15 years leading to the development and refinement of the EECP technique and device.

Stony Brook Experience

A commercially available EECP system (EECP, Vasomedical Inc., Westbury, NY) similar to the Chinese device has been FDA approved as of 1995 and has been recently utilized in clinical studies by Lawson and Cohn and the group at the State University of New York at Stony Brook. Lawson et al examined this outpatient therapy when performed for an hour each day for 7 weeks in 18 patients. Subjects had symptomatic angina despite medical and surgical interventions and evidence of ischemia by exercise thallium testing. In all 18 patients, there was symptomatic improvement in angina and in 16 of 18, activities of daily living could be performed asymptomatically. Thallium-201 imaging showed resolution of thallium defects in 12 patients (67%), a decrease in ischemic area in 2 (11%) and no change in 4 patients (22%) (11). Exercise treadmill tests saw an improvement in exercise duration without a significant change in double product(11). A sustained benefit was seen in most of these patients as 13 of 18 patients reported being angina free at three year follow-up without interval coronary events(12). Repeat thallium in 10 of the 14 original improved patients showed persistent improvement in comparison to pre-EECP studies in 8 patients and worsening in only 2. Recently reported unpublished five year follow-up data on 33 patients treated at Stony Brook suggests that this positive effect continues in the long term.

It has been postulated that this collateral development is dependent upon the patency of neighboring vessels. It appears that an open non-obstructed conduit, either via native coronary flow or via bypass graft, provides the milieu for greatest benefit from EECP thus placing greater importance in the angiographic findings in patients in predicting who will benefit most from this treatment(13). In analyzing the 50-patient experience at the SUNY Stony Brook Medical Center, it appears that patients with residual 1- or 2-vessel coronary artery disease appear to derive the most benefit from EECP and those with residual 3-vessel disease may derive less benefit when only 35 hours of therapy are applied. The clinical benefit seen in 80% of patients in this series was inversely related to the extent of residual coronary disease(13). Thus it appeared that transmission of diastolic pressure and distal vessel effects are dependent upon a patent proximal conduit.

MUST-EECP

The first multicenter randomized sham-controlled trial was recently completed comparing the effect of full EECP treatment versus sham on exercise treadmill scores and subjective angina in stable chronic angina patients, the Multi-center Study of Enhanced External Counterpulsation (MUST-EECP) study were presented at the annual scientific meeting of the American Heart Association in November of 1997 and published(14). Seven centers enrolled into this study: University of California, San Francisco Moffitt-Long Hospitals; Columbia Presbyterian Medical Center; Yale New Haven Medical Center; and Beth Isreal Deaconess Hospitals of Harvard Medical School; University of Pittsburgh Medical Center; and Grant/Riverside Methodist Hospitals of Columbus, Ohio.

In this study, 139 patients (mean age 63 years/ range 35-81 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 (inactive-CP) with EECP versus active counterpulsation (active-CP). End-points on exercise treadmill testing included time to ST segment depression by ECG, frequency of angina attacks by questionnaire and on-demand oral nitrate use. Time to ST segment depression was significantly different between groups (p=0.01) with active-CP patients improving (337 ± 18 to 379 ± 18 seconds (mean ± SEM); p<0.0016) versus no improvement for sham (326 ± 21 sec to 330 ± 20 sec, p=0.7395). Total exercise duration in the active-CP group were significantly higher after treatment (426 ± 20 sec to 470 ± 20 sec; p<0.0004) and inactive-CP (432 ± 22 to 464 ± 22 seconds; p<0.0279). Between group difference was not significant at (p=0.3043). Angina episodes in the active-CP were decreased (0.756 ± 0.146 to 0.545 ± 0.272; p= 0.0001) but not in inactive-CP (0.760 ± 0.1129 to 0.765 ± 0.196; p= 0.41). More active-CP patients saw a decreased and fewer experienced an increase in angina as compared to inactive-CP (p=0.41). Nitroglycerine usage did not change in inactive-CP (0.0510 ± 0.151 to 0.447 ± 0.188; p=407) but decreased in active-CP (0.474 ± 0.129 to 0.188 ± 0.066; p=0.0003); the difference was not significant (p=0.5). There were no serious complications from treatment in either group. Initial data on one year follow-up inply a sustained effect.

The MUST-EECP data indicate that the experience of the Chinese investigators as well as the preliminary results from Stony Brook are accurate. In a well controlled, randomized clinical trial, multi-center data now suggests that EECP can effectively and safely improve exercise treadmill parameters as well as medication usage and subjective angina pectoris complaints in patients with chronic stable angina.

Current and Future Directions

Currently, the primary indication for EECP treatment is chronic stable angina. Patients who are accepted for treatment must be prepared to undergo 35 hours of EECP therapy. Treatment is administered one or two hours daily at least 5 days per week. If two hours daily is planned, the first week of treatment is best limited to one hour daily to facilitate familiarization and monitor patient tolerance before increasing the daily treatment time. Two hours of treatment on the same day should be separated by a rest period. Precautions for therapy (see Table 1) include recent catheterization, arrhythmia which would preclude accurate timing of the device, active cardiac dysfunction, aortic insufficiency and limiting peripheral vascular disease.

Clearly, EECP may be used as a potential treatment modality for angina patients, in whom invasive revascularization procedures do not offer a survival benefit, or as an alternative to PTCA or CABG. EECP may be particularly useful in patients considered high risk for revascularization procedures or in whom revascularization is not technically possible.

Potential use of the current EECP system in chronic heart failure, unstable cardiogenic shock syndromes and in acute ischemic syndromes are also being explored. Historical data suggests that there is great potential for acute coronary syndromes. Application in the field, in the emergency ward and in the intensive care unit requires the development of a smaller mobile system which replicates the dependable augmentation which the present system produces. Such as system is currently under development.

Conclusions

The intractable angina patient who fails to respond to conventional treatment with bypass surgery or catheter-based techniques has options. EECP is a non-invasive technique which has a long experience in China of providing relief from angina and has shown promise in U.S. experience to date. Recently completed randomized trial data suggests that EECP is a real and viable alternative for those who have no further interventional options. More trials are underway to evaluate the true efficacy of this exciting technology and the precise role it will play in the broader treatment of coronary artery disease.

Figure 1. Enhanced External Counterpulsation (EECP) Device

Figure 2. Sequential application of cuff inflations. Series of three cuffs inflate at the calf, thigh and buttock level timed with the cardiac cycle.

Table 1. Precautions for EECP treatment

• Cardiac catheterization within 1-2 weeks to minimize the likelihood of bleeding at the femoral puncture site.
• Arrhythmia that might interfere with the triggering of the EECP system e.g. atrial fibrillation, atrial flutter, ventricular tachycardia.
• Congestive heart failure. In some patients, left ventricular unloading may be insufficient to compensate for increased venous return during EECP.
• Aortic insufficiency where regurgitation would prevent diastolic augmentation.
• Limiting peripheral vascular disease (PVD) and/or phlebitis because of increased risk of thromboembolus. Severe PVD with reduced vascular volume and diminished musculature of the lower extremities can compromise effective counterpulsation.
• Severe hypertension (ò 180/110mmhg). Under these circumstances, EECP could produce diastolic blood pressure levels surpassing acceptable limits.
• Bleeding diathesis, coumadin therapy with PT ³ 15, because the pressure of cuff inflations might cause bleeding in muscles of the leg.
• Pregnant women, and women of childbearing potential who do not employ a reliable contraceptive method to avoid possible danger to fetus.

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