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Literature Review
ANNOTATED BIBLIOGRAPHY OF EECP
prepared by
James C, Roberts MD FACC
Medical Director EECP Center of NW Ohio
SECTION ONE: CLINICAL STUDIES - ANGINA
1. Initial American Case Report on EECP ’97
2. 18 patients with refractory angina - initial outcome with EECP ’95
3. Patient status 3 years out from EECP ’95
4. Clinical status, event rate, and survival 5 years out from EECP ’00
5. Effect of EECP on quality of life ’95
6. Outcome following EECP in relation to the number of vessels blocked ’96
7. Effect of EECP in patients with occluded bypass grafts ’97
9. Effect on quality of life as measured by Canadian Functional Class ’98
10. Six to eight year outcome following EECP '99 & '90
11. EECP in widespread use - outcomes from >2000 patients treated at 84 American EECP centers '00
12. EECP in unstable angina - report from the EECP Registry '00
13. EECP for refractory angina in Indonesia ‘95
14. EECP improves stress nuclear scans and treadmill time - an international report '02
15. EECP in the Emerald Isle - post-EECP in-hospital days fall by 50% '01
SECTION TWO: CLINICAL STUDIES - HEART ATTACK
2. EECP in cardiogenic shock ’74
3. Chinese experience with EECP in the treatment of heart attack ’84
4. EECP in heart attack treated with angioplasty '00
5. EECP generates collateral flow in experimental heart attack '00
6. EECP lowers circulating and intracellular levels of Angiotensin II in experimental heart attack '02
SECTION THREE: PHYSIOLOGIC STUDIES
1. EECP triples blood flow within the Internal Mammary Artery ’98
2. EECP increases coronary artery blood flow ’98 and '02
3. Effect of EECP on diastolic and systolic blood pressure ‘98
4. Kidney function improves during EECP ’98
5. Blood flow to all internal organs increases during EECP '99
6. EECP decreases angina and increases VEGF levels ’98 & '00
7. The antioxidant effect of EECP '99
8. EECP generates Nitric Oxide '99
9. EECP generates Nitric Oxide and decreases Endothelin '99
10. Endothelial function improves following EECP in Japan '00, and in Israel '02
11. EECP improves treadmill time and PET perfusion scan findings '99
12. EECP in acute hearing loss refractory to medical therapy '00
13. Favorable effect of EECP on erectile function '00
14. Heart stiffness improves with EECP '00
15. Heparin pre-treatment enhances the patient's response to EECP '00
16. Levels of angiogenic growth factors increase during EECP '01
SECTION FOUR: CLINICAL STUDIES - HEART FAILURE
1. EECP is a safe and effective in patients with severe heart pump dysfunction '02
2. Efficacy and safety of EECP in mild to moderate heart failure: A preliminary report '99
3. Efficacy of EECP in heart failure: A feasibility study '02
4. Pump function (Ejection Fraction and contracting power) improve with EECP '00
5. Which factors predict heart failure in EECP patients? '02.
SECTION ONE: CLINICAL STUDIES - ANGINA
1. Enhanced External Counterpulsation as an Adjunct to Revascularization in Unstable Angina. Lawson WE, Hui JCK, Oster ZH, et al. Clinical Cardiology 1997; 178-180.
This case report illustrates the capacity of EECP to revascularize the heart and control symptoms in patients who have not benefited from balloon angioplasty or bypass surgery. The authors describe a 58 year old man who required two separate bypass surgeries, six rounds of angioplasty involving over 20 narrowings, and multiple heart catheterizations, all within a 26 month time period. Finally, one artery closed off completely and further angioplasty was not possible. The patient was then begun on EECP and experienced a "dramatic" reduction in symptoms within 3 weeks. Upon completion of a 120 hour course, this patient’s stress nuclear scan normalized and angina fully resolved. Three years out from EECP he remains asymptomatic.
2. Efficacy of Enhanced External Counterpulsation in the Treatment of Angina Pectoris
. Lawson WE, Hui JCK, Soroff HS, et al. American Journal of Cardiology 1992; 70:859-862.While EECP has been the standard of practice in China for some time, we American cardiologists weren’t aware of its value until this paper came out in '92. Here Lawson and associates describe the short term benefits of EECP in 18 patients with refractory angina (persisten
t symptoms despite maximum medical therapy) in patients who are not felt to be good candidates for further bypass or angioplasty. As you would predict, this was an extremely ill, actually desperate group of patients. Eight had undergone a total of 19 angioplasty or bypass procedures; seven had sustained a total of 14 heart attacks. All three coronary arteries were blocked in 4, two vessels in 8, and three patients had single vessel disease.Following an initial symptom limited nuclear stress test, all 18 patients received 35 one hour EECP treatments over a 7 week period. Anti-anginal medications were continued, but per the study protocol the doses could not be increased. Upon completion of EECP, the nuclear stress test was repeated, at the pre-treatment distance. (If the scan was done at 5 minutes of treadmill exercise pre-EECP, the post-EECP scan was carried out at 5 minutes. This way the investigators could see if EECP improved blood flow at a given level of exercise). A post-EECP symptom limited stress test was also carried out, to determine if treadmill time and exercise capacity would improve.
Angina improved substantially in all 18; 16 reported a complete
absence of pain during
their usual activities. The nuclear scan abnormality indicating ischemia (viable heart
muscle with a
compromised blood supply) fully resolved in 2/3rds of the patients, just as
it would following a successful angioplasty or bypass. In 4 patients, the scan remained
abnormal, while in 2 the scan improved without fully normalizing. Thus an objective
improvement in blood flow to the heart muscle was demonstrated in
77%
of the patients. Treadmill time increased by 1.6 min, or 20%, for the entire group, and by
1.9 min, or 22%, in the 14 patients whose flow scans improved. No side-effects were
reported.
3. Three-Year Sustained Benefit from Enhanced External Counterpulsation in Chronic Angina Pectoris
. Lawson WE, Hui JCK, Zheng ZS, et al. American Journal of Cardiology 1995; 75:840-841.
Well, if you come to my office Monday through Friday for seven weeks you ought to get better. But will the improvement hold? Will angina remain in check, or will the augmented collaterals close down, just as an artery might renarrow following an initially successful angioplasty? Will EECP provide more than transient relief ?
To answer these questions, Lawson’s group followed the course of their initial 18 patients over a three year period, and reported their findings in this ’95 article. Medication changes were permitted, and 8 patient received booster courses of EECP, but aggressive risk factor reduction maneuvers were not carried out. What happened to these patients?
Of the 4 patients with improved angina but unimproved nuclear scans, one required bypass and another a balloon angioplasty, but the other two patients remained free of disabling angina. Of the 14 whose scans improved, two sustained events - one a heart attack and one patient underwent bypass; one patient was lost to follow-up but the other 11 remained free of significant symptoms. 10 underwent a repeat stress nuclear scan; in 8 the scan remained improved.
For the group as a whole there was a 23% event rate (one heart attack and three revascularizations), no deaths, and in 60% the nuclear scan remained normal and angina remained minimal. 76% of these patients in whom standard therapy had failed remained free of disabling symptoms and event free 3 years after undergoing EECP.
Of the "responders", the 14 patients whose thallium scans improved following EECP, the three year event rate was 15%, and the thallium scan remained improved in 80% of those who remained event free.
4. Long-Term Prognosis of Patients with Angina Treated with Enhanced External Counterpulsation: Five-Year Follow-Up Study.
Lawson WE, Hui JCK, et al. Clinical Cardiology 2000 23:254-58
Three year follow-up is fine, but what’s going to happen at five years? In this report Lawson and associates summarize the five year outcome of 33 patients treated with EECP between 1989 and 1992 at the State University of New York. Keep in mind that this was a sick group of patients; 43% had multivessel disease, 45% had sustained a heart attack, 61% had undergone bypass or angioplasty, and 8 had required both. None were felt to be good candidates for further revascularization.
Angina improved in all 33 patients, 1/3rd were able to cut back on their anti-anginal medications. In 26 of the 33 patients, the post-EECP stress thallium scan showed a definite improvement; 43% of these "responders" were able to cut back on their medications. Now, how were these inoperable patients doing five years later?
Over the five year follow-up period, medication changes were
permitted, and 13 of the 33 patients underwent booster session of EECP.
For the entire group, five year survival following EECP
was 88%. 31% of the patients required a hospitalization;
14% sustained a heart attack and 21% underwent a revascularization procedure. 69% of
the patients stayed out of the hospital. Overall, 60%
of the original 33 patients undergoing EECP for refractory angina were alive and
well, event free, and remained out of the hospital
during the five year follow-up period.
Lawson found that nearly all of the events
occurred in the 7 "non-responders", those patients whose angina
improved but whose thallium scans remained abnormal. All 7 of these
patients had multivessel disease. Of the 26 inoperable patients whose
thallium scans improved following EECP, the
"responders", five year survival was 96%. Only one of these 26
patients sustained a heart attack over the five year follow-up period, and only
two required a revascularization procedure. 77% remained event free and
without a hospitalization.
Dr. Roberts’ Comments: We in EECP aren’t "competing" with invasive cardiology and bypass surgery. (I’ve done well over 2,000 cardiac catheterization and routinely refer patients for angioplasty or bypass). Our focus is to use EECP when bypass or angioplasty are not possible at a reasonable risk. Still, as we evaluate the three and five year follow-up results of EECP in refractory angina patients who were not felt to be reasonable candidates for bypass surgery, it is useful to look at post-bypass outcome in angina patients who were felt to have an acceptable surgical risk. While reviewing this outcome data, keep in mind that the per patients cost of EECP to the Medicare program is about one tenth the per patient cost of bypass surgery.
A. In the Randomized Intervention Treatment of Angina, or RITA trial, patients with symptomatic coronary disease were randomized to undergo bypass surgery or balloon angioplasty. Of the patients treated with bypass, 11% required a repeat revascularization procedure, sustained a heart attack, or died within the first two years following surgery.
B. During the first year of follow-up in the German Austrian Bypass Investigation trial, 18% of the patients undergoing multivessel bypass required a repeat intervention, sustained a heart attack, or died.
C. In the Bypass Angioplasty Revascularization Investigation, or BARI study, 20% of bypass patients sustained a heart attack or died during the first five years of post-surgical follow-up.
This chart depicts five year survival in patients felt to be
suitable candidates for bypass, who underwent either medical therapy or a
revascularization procedure as part of a clinical study. The last column shows
five
year survival in patients not felt to be suitable candidates for
revascularization, who were treated with external counterpulsation. From
the perspective of five-year survival, EECP, carried out in patients who could
not undergo bypass or angioplasty
with an acceptable risk, worked just as well as did bypass or angioplasty in
patients who were felt to be good candidates for these procedures.
Now, don’t think for a minute that I am anti-bypass. The "my way is the only way and all else is second rate" attitude is intellectually foolish and has no place in health care. Hundreds of my patients are alive only because they underwent bypass surgery. The point here is that short-term, 3 year, and 5 year outcome following EECP in patients who are not good candidates for further surgery is similar to that of acceptable candidates for surgery who do undergo bypass.
Fricchione GL, et al. Psychosomatics 1995;36:494-97.5. Psychosocial Effects of Enhanced External Counterpulsation in the Angina Patient.
So far we have talked about thallium scans, event rates, and mortality, the "hard data" that we cardiologists like to read about in our journals. This information is important to us, but as a patients you will be more concerned with the effect a treatment has on your quality of life. In this study, Fricchione and associates looked at the effect of EECP on a "hard" endpoint, the cardiac nuclear scan, and several "human" endpoints, such as the patient's stress level and quality of life. Let’s see what they found.
The nuclear scans normalized in 75% of the patients, not a surprise to you at this point. The researchers also showed that patients did not experience significant stress in association with their EECP treatments. Following EECP, average angina frequency fell from 3.9 to 0.6 episodes per three months. NTG requirement decreased from 2.3 to 0.1 tablets over the same time period. Chest pain severity on a four point scale fell from 2.9 to 1.7. Each patient was questioned as to the effect EECP had on their quality of life and the group responses are listed below:
Parameter |
Worsened |
Unchanged |
Improved |
| Sexual activity | 0% |
67% |
33% |
| Family life | 0% |
33% |
67% |
| Health condition | 0% |
0% |
100% |
| Sense of well-being | 0% |
0% |
100% |
| Social life | 0% |
33% |
67% |
| Ability to work | 0% |
0% |
100% |
| Energy level | 0% |
0% |
100% |
Research tells us that intimacy with one’s spouse, interaction with family members, and involvement with others in our work, community, and church activities has a positive effect on our health and sense of well being. EECP seems to help here, improving our quality of life, not just the "hard end points".
Results section). All three had refractory symptoms due to three vessel coronary disease, and were undergoing EECP only because no other treatment options were available.6. Can Angiographic Findings Predict Which Coronary Patients Will Benefit from Enhanced External Counterpulsation?
Lawson WE, Hui JCK, Zheng ZS, et al. American Journal of Cardiology 1996;77:1107-09.It certainly seems that patients with symptomatic coronary disease will benefit from EECP, but which patients will benefit the most? Will patients with two vessel blockage fare as well as those with single vessel disease? What happens when all three arteries are blocked? Common sense provides an answer to these questions, but we cardiologists needed a heart catheterization study to see it. Lawson and associates treated 50 angina patients with a standard 35 hour course of EECP. As in prior studies, stress nuclear scans were performed before and after EECP, to document objectively that an improvement in blood flow had occurred. A pre-EECP cardiac catheterization was also carried out; the patients were classified as having one, two, or three vessel coronary artery disease, depending on how many arteries were blocked. The point of the study was to determine if the number of vessels blocked could predict which patients would improve the most with EECP. Dr. Lawson's findings are presented in both graphic and table form below. Before looking at this information, please take a moment to think this over and predict what Dr. Lawson found. Remember that EECP works by recruiting and then enlarging collaterals from a good artery to a blocked artery.
EFFECT OF EECP ON NUCLEAR STRESS SCAN ABNORMALITIES
# Blocked Vessels
Unimproved
Less Severe
Normalized
Improved
One
5%
21%
74%
95%
Two
10%
32%
58%
90%
Three
59%
8%
33%
41%
You were right. When only one artery is blocked, we have two good arteries to grow collaterals from, allowing us to "surround" the blocked artery with an exuberant growth of collateral vessels. A 95% scan improvement rate makes sense. These are the patients who note a reduction in angina during their second week of treatment. Conversely, when all three arteries are blocked, we can grow collaterals only from the diseased vessels themselves, proximal to their point of obstruction. This gives us fewer potential collaterals to work with, a less efficient EECP, and less complete revascularization.
Keep in mind that while the nuclear scan improved in only 41% of the patients with three vessel disease, all of these patients experienced a reduction in angina. Also, a 41% scan improvement rate is better than no improvement at all in a patient with persistent angina who cannot be treated with angioplasty or bypass.
This study tells us that patients with one or two vessel blockage, who are otherwise technically good candidates for EECP, typically do well with EECP. Patients with three vessel disease may improve, but here we expect less. In this patient population, we might extend their course of EECP to 45 or 50 hours, to get the most we can out of this technique. Of the first 50 patients to complete a full course of EECP at our center, one man did not experience a reduction in angina. Two others improved but died of cardiovascular disease later on (see Patient
We expect a lot from EECP in patients with one or two vessel disease; patients with three vessel blockage may still benefit, but most of the time their nuclear scan will remain abnormal. What about patients with angina related to closure of their bypass grafts? This is a group that we’d really like to help. Often, a second bypass isn’t technically possible, and when it is the risk may be twice that of the first surgery. Will EECP help these people?
To answer this question, Dr. Lawson and his colleagues at Stony Brook Medical Center provided EECP to 25 patients with angina due to clogged bypass grafts, and compared their response to that of 35 never bypassed angina patients. Pre-EECP coronary angiograms were carried out in both groups. Post-bypass one or two vessel disease was said to be present if one or two grafts contained a ³ 70% narrowing; patients with three narrowed grafts were designated as having post-bypass three vessel disease. Pre and post-EECP stress nuclear scans were carried out in all patients. The investigators looked for a relationship between the number of vessels blocked, either native vessels or bypass grafts, and the percentage of patients in each category whose nuclear scans improved. We already know that nuclear scans improve following EECP in less than half of the patients with native three vessel disease, but what will happen in the post-bypass population? The results may surprise you.
The difference between 88 and 80% was not statistically meaningful, so from this study we learn that patients with narrowings in one or two bypass grafts typically do as well as never bypassed patients with one or two artery blockage - good news. The really good news is that patients with post-bypass three vessel disease seem to do just as well. We aren’t sure why post-bypass triple vessel disease patients do better than never bypassed triple vessel disease patients. It may be that a 70% narrowing in a bypass graft allows more flow than a 70% narrowing in a native artery, allowing us to counterpulse enough pressure through the graft to grow collaterals from the vessel it is attached to. There may be other reasons. I’m supposed to be the local expert, and I really don’t know. What I do know is what I need to know, that post-bypass patients usually respond well to EECP, regardless of the number of vessels blocked. In these patients, we can typically omit a pre-EECP coronary angiogram. (Why put the patient through the risk and expense of an angiogram if the results will not alter our treatment; we can always do an angiogram if the patient continues to experience symptoms after completing a course of EECP)
8. The Multicenter Study of Enhanced External Counterpulsation (MUST-EECP): Effect of EECP on Exercise-Induced Myocardial Ischemia and Anginal Episodes. Aurora, R, et al Circulation Abstracts 10/97 and Journal of the American College of Cardiology 1999;33:1833-40
I found the above articles to be rather convincing. I read them front to back five times, spoke with other physicians who were using EECP, and then ordered our first EECP machine. Good results and a backlog of patients in need led to the addition of two more machines, and a commitment on my part to "get the word out" to patients and doctors. Patients are sure interested, but their physicians were initially skeptical regarding the benefits of EECP. They question whether the positive results of EECP could be simply a "placebo effect", a positive change in one’s health that occurs simply because the patient believes that he or she will get better. They criticize the published EECP studies for not including a "blinded control group" in their research. In a "controlled" study, patients are randomly divided into a "treatment group", which receives the therapy under study, and a "control group" that receives a biologically inactive placebo or sham treatment. The study is "blinded", in that neither the patients nor the researchers know who is receiving the real or sham therapy, until the study has been completed and the "blinding code" broken.
In my opinion, it is inappropriate to ignore the positive results of the early refractory angina EECP research, simply because a control group was not included. First of all, while I personally and professionally respect the healing powers of belief, I don’t think that belief alone could improve the nuclear scans in 90% of patients with 1 or 2 vessel disease and previously refractory symptoms. Second, in this situation a control group would be unethical. How could you withhold a low-risk, potentially beneficial therapy from patients with severe chest pain and no where else to go? Third, how could you "fake" EECP in the control group?
Now, there has never been (nor should there ever be) a randomized, blinded, controlled study of coronary bypass surgery versus fake surgery. To do this, the surgeon would have to remove the leg veins from an anesthetized cardiac patient, open up his chest and look at his heart, and then throw away the veins and sew the patient up. Long-term outcome of these patient would then be compared to a group of patients undergoing real bypass surgery. Pretty stupid idea, right? A blinded, controlled study of angioplasty would involve the cardiologist passing the balloon catheter across a symptomatic narrowing without inflating the balloon to dilate the vessel. Outcome of the "sham angioplasty" patients would be compared against that of a group of patients undergoing real angioplasty.
What was actually done to prove the value of bypass surgery was to take a group of patients with coronary artery disease, randomly divide them into a group that underwent bypass surgery and a group that remained on medical therapy, and to compare outcomes at three to five years. This type of research showed that patients with certain clinical and angiographic characteristics (Left main coronary artery blockage or three vessel disease with a prior heart attack, unstable symptoms with certain angiographic and clinical findings, etc.) did better with surgery than with medical therapy alone. Based on these studies, we will recommend bypass surgery to patients when their situation is identical or similar to that of patients for whom bypass surgery has been shown to produce a benefit. This type of comparative outcome study can move medicine forward without denying therapy to patients in need.
We in EECP are typically using EECP to treat patients with medically refractory symptoms who cannot safely undergo bypass surgery or angioplasty, or in whom blockages have recurred following an invasive procedure; withholding EECP from these patients simply to get your "controlled" research published would be unethical. Aurora and the other MUST-EECP investigators found a way to ethically carry out a controlled study of EECP, by studying patients with significant but stable symptoms, using EECP and a clever "sham" EECP procedure. These patients were not experiencing debilitating symptoms, so withholding EECP from the control group was not unethical. The study was carried out between 5/95 and 7/97. 139 angina patients at five different medical centers were randomly divided into a "treatment" group, that received 35 hours of EECP, and a "control" group that received 35 hours of sham EECP. Here, the EECP cuffs were placed over the patient’s lower extremities and inflated only minimally. This minimal cuff inflation didn’t raise the patient’s diastolic pressure and thus could not promote collateral flow, but the patients didn’t know this. They didn’t know what to expect and couldn’t tell whether they were receiving fake or real EECP. So now we have two groups of angina patients, one treated with EECP and the other thinking that they were treated with EECP but in reality undergoing only a sham or placebo therapy. Treadmill stress tests were carried out before and after treatment in both groups, and all study patients kept a diary of angina frequency and NTG use. Preliminary data from the first 84 patients studied was reported by Aurora et. al. at the American Heart Association annual meeting in late ‘97. Treatment results for the 115 patients who completed a full course of either active or sham EECP were reported in this June '99 article. What did the MUST-EECP investigators find?
The baseline characteristics of the MUST-EECP subjects are given below. While the subjects were assigned to receive sham or active EECP on a random basis, you can see that those assigned to active EECP were actually a sicker group, with a longer duration of angina, higher frequency of prior heart attack or bypass, and a greater percentage with multivessel disease.
|
|
SHAM EECP |
REAL EECP |
| Years of Angina | 4.5 | 8.6 |
| Prior Heart Attack |
41% |
56% |
| Prior Bypass | 38% | 47% |
| Multivessel Disease | 48% | 61% |
| Class II or III | 74% | 73% |
| Abnormal Stress EKG | 100% | 100% |
The post-treatment outcome results are presented in table form below:
SHAM EECP |
REAL EECP |
|
| Treadmill Time | 432 ® 464 seconds |
426 ® 470 seconds |
| Time to ST Depression | no change |
337 ® 379 seconds |
| Angina episodes/week | no change |
5.3 ® 3.8 |
| NTG use/week | no change |
3.3 ® 1.3 |
| Complications | none |
none |
Treadmill time did increased in the sham EECP group. This is the "placebo" effect. When you think you are going to get better, in many ways you will get better; these patients thought they were getting an active treatment and walked 32 seconds farther after sham EECP. However, treadmill time until ST depression, the objective EKG sign telling us that the heart muscle is not getting enough blood and oxygen, didn’t change in the sham EECP group, and improved by 46 seconds in the real EECP patients. Angina frequency and NTG requirement decreased significantly following real EECP, but weren’t effected by the sham treatment. Treatment related complications did not occur in either group.
The MUST-EECP study proves beyond all doubt that EECP is an effective approach to coronary insufficiency and angina, even in patients with a prior heart attack, failed bypass, or vessel renarrowing following angioplasty. This is not due to expectation or a placebo effect; EECP works!
What effect does EECP have on a heart patient’s quality of life? That’s a fair question. After all, you’re not coming here to increase your treadmill time. You’re interested in EECP because you want to feel better. Fricchione’s study (article 5) described the beneficial effects of EECP on life style parameters such as sense of well being, ability to work, and sexual function. Lawson’s group takes a different approach in this article, measuring the effect of EECP on Canadian Functional Class, a sort of global rating of a cardiac patient’s functional status. Functional Class was assessed before and after treatment, in 670 patients undergoing EECP at 41 centers throughout the US. (Note that 25% of the patients enrolled in the EECP Registry came from your EECP Center, The EECP Center of Northwest Ohio.) A decrease in functional class is considered to be a beneficial outcome. Conversely, if functional class increases, that means that the patient got worse. First the definitions, then the results:9. Quality of Life Benefits in the International EECP Registry Study. Lawson et al 20th Congress of the European Society of Cardiology Abstract P505 September ’98 Vienna, Austria
Class 1: Ordinary physical activity (such as walking or climbing stairs) does not cause angina. Angina may occur with strenuous, rapid, or prolonged exertion (work or recreation).
Class 2: There is a slight limitation of ordinary activity. Angina may occur with walking or climbing stairs rapidly; walking uphill; walking or stair climbing after meals or in the cold, in the wind, or under emotional stress; walking more than two blocks on the level and climbing one flight of stairs at a normal pace under normal conditions.
Class 3: There is a marked limitation of ordinary physical activity. Angina may occur after walking one or two blocks on the level or climbing one flight of stairs in normal conditions at a normal pace.
Class 4: There is inability to carry on any physical activity without discomfort; angina may be present at rest.
Pre-EECP Post-EECP Functional Class |
||||
| Class 4 - 31 | Class 3 - 61 | Class 2 -169 | Class 1-204 | |
| Class 4 - 86 | 31 |
26 |
20 |
9 |
| Class 3 - 176 | 0 |
35 |
87 |
54 |
| Class 2 - 153 | 0 |
0 |
62 |
91 |
| Class 1 - 50 | 0 |
0 |
0 |
50 |
From the table you can see that no patient deteriorated. That is, no patient experienced an increase in functional class following EECP. 69% of the patients in Classes 1-3 improved by at least one level and 20% improved by two or more. All 50 patients who began EECP in functional class 1 stayed there; none worsened.
0. Enhanced External Counterpulsation Protects Coronary Artery Disease Patients from Future Cardiac Events. S. Karim et al 1st International Congress on Heart Disease - New Trends in Research, Diagnosis, and Treatment. The Journal of Heart Disease 1:1 May ’99External Counterpulsation - Review Article. Xu-Yu-yun, Hu Da-yi, & Zheng Zhen-sheng. Chinese Medical Journal 103(9): 762-71,1990
The published studies of EECP give us a clear message: EECP is an effective treatment for angina. In each study, be it American, Chinese, or Indonesian, just over 90% of patients improve. That EECP works well short term is now clearly established, but can EECP, or a program of EECP, have an effect on long term outcome? Dr. Lawson’s paper, which we reviewed as article 4, showed us that five year outcome following EECP, when used to treat refractory symptoms in inoperable patients, was similar to that of low risk patients who underwent elective bypass surgery. But Lawson’s study involved only 33 patients. What effect will EECP have when larger groups of patients are studied, and for longer periods of time? Can a program based on EECP make a long term difference?
Karim and associates treated 117 patients with EECP between 1/92 and 12/97. Their outcome through 12/98 was then compared with that of 198 coronary patients who were treated over the same time period with standard drug therapy. The number of cardiac events (cardiac death, heart attack, need for invasive revascularization) occurring in each group over the seven year follow-up period was recorded. The average number of days elapsing between the initiation of therapy and the development of an event was calculated. Here’s what Karim found:
Drug Group |
EECP Group |
|
| Mean # Event Free Days | 958 |
1,010 |
| Cardiac Death | 9.6% |
4.3% |
| Heart Attack | 4.5% |
1.7% |
| Revascularization | .5% |
1.7% |
Karim found that patients treated with drug therapy alone were 2.3 times more likely to experience an adverse event during the seven year follow-up period. Unlike the MUST-EECP study (Article 8), Karim’s study was not randomized or double-blind. The EECP patients knew they had received EECP. The drug group knew that they hadn’t. Still, the results are impressive, and I like the idea of my patients being 2.3 times less likely to experience an adverse cardiac event.
In China, medical records are centralized, and standard measures are used to asses symptom severity and a patient’s response to treatment. By 1990, 1,800 EECP centers were up and running in China. In this 1990 paper, Dr. Xu Yu-yun and colleagues describe the short term effects of EECP in just over 6,000 patients. Long term outcome of 102 patients treated with EECP is compared with that of a similar group of coronary patients who received standard drug therapy alone. Here’s what they found:
Short-term effects on symptoms and EKG appearance were assessed in 6,116 patients treated with EECP
|
Short-term |
Symptoms |
EKG |
| Significant Improvement | 52.6% |
20.5% |
| Improvement | 30.3% |
47.8% |
| No Change | 8.0% |
30.5% |
| Deterioration | 0.2% |
1.2% |
| Total Effective Rate | 92% |
68.3% |
Here again, just over 90% of patients treated with EECP improved.
Long-term results were measured in 102 EECP patients; 23, 39, & 53 were followed for 7, 6, & 5 years post EECP respectively. 19, 32, & 52 patients treated solely with medication were followed over the same time periods.
Total Effective Rate - Symptoms
| Long-term: Symptoms | EECP Group |
Drug Group |
| 5 year follow-up | 55.8% |
33.3% |
| 6 year follow-up | 67.9% |
48.1% |
| 7 year follow-up | 73.9% |
21.3% |
Total Effective Rate - EKG
|
Long-term: EKG |
EECP Group |
Drug Group |
| 5 year follow-up | 63.6% |
31.2% |
| 6 year follow-up | 67.9% |
20% |
| 7 year follow-up | 61.5% |
46.8% |
Cardiac Death Rate
|
Cardiac Death |
EECP Group |
Drug Group |
| First Year | 4.9% |
13.5% |
| By Eighth Year | 7.7% |
30.3% |
| Overall | 8.8% |
30.3% |
I think I’d want to be in the EECP group. Again, this was not a randomized, double blind study, but it involved a large number of patients and points to a definite, beneficial effect of EECP on long term outcome. In interpreting these numbers, keep in mind that in China EECP is often not just a one time treatment; Chinese patients not infrequently receive booster and maintenance sessions. In China the goal is to keep people healthy and out of the hospital, at the lowest possible cost, so they’re not shy about the use of EECP. They know that EECP helps long term. The question for us is, just why does EECP help long term? Could EECP have a favorable effect on atherosclerosis? Could EECP be altering our biochemistry in a positive way? Articles
6 through10 in the physiology section discuss the favorable effect of EECP on several of the angiochemicals that regulate cardiovascular health.
11.
Treatment Benefit
in the Enhanced External Counterpulsation Consortium.
Lawson, W, et al Cardiology
2000;94:31-35
The American outcome studies have all been positive, but these studies were carried out at medical school affiliated cardiology programs, involving selected cohorts of patients, in the controlled, university hospital setting. Some treatments, especially new treatments, certainly seem to work well when carried out by super specialists at academic centers, but then not so well, when carried out by general cardiologists, on the patients we see in the community setting. Could EECP be such a phenomenon – only of academic benefit? Is it going to work on a large scale, outside of the university hospital setting
The International EECP Registry was founded to help answer these questions;
through 3/00, 3,788 EECP patients have been entered.
In this report from the registry, involving 2,991 patients treated
between 1/97 and 3/00 at 84 American EECP centers, outcome data from 2,289
with complete follow-up is analyzed. EECP
providers ranged from solo practitioners to large multispecialty groups to
university hospitals. All
patients had angina upon entry, with an average Canadian Functional Class of
2.8. What happened with EECP
performed in the community setting?
First of all, the treatment was well tolerated and patients rarely
deteriorated. 0.2% of the 2,289
patients deteriorated by 1 functional class.
Of the 91 adverse events experienced amongst these 2,991 individuals
during their course of EECP, the vast majority were musculoskeletal,
cutaneous, or non-cardiovascular and totally unrelated to their EECP
treatments- see chart below.
|
Adverse
events among 2,991 EECP patients |
||
|
Category
of Events |
Number |
Percentage |
|
Total |
91 |
3
% |
|
Musculoskeletal
& Skin |
23 |
0.8 % |
|
Non
CV & Unrelated to EECP |
52 |
1.7
% |
|
Myocardial
Infarction |
8 |
0.3
% |
|
Angina
or Silent Ischemia |
5 |
0.2 % |
|
Arrhythmia |
2 |
0.07
% |
|
Pulmonary
Edema |
1 |
0.03 % |
While
only 0.2% of patients deteriorated during EECP, of those in classes II-IV
pre-EECP, 73.4% improved by at least one level while 26.5% remained in their
pre-treatment class. Overall,
mean functional class improved from 2.78 to 1.81.
As you would expect, the relative gain from EECP was proportionate to the severity of symptoms pre-treatment. Amongst patients with class III-IV symptoms pre-treatment, mean functional class improved from 2.99 to 1.84. Anginal class improved by 2 or more levels in 49% of those in class IV pre-EECP, and in 34.9% of those in class III. Women did just as well as men, and patients treated in their physician’s office did just as well as those treated at a university hospital EECP program.
12.
The Safety and Efficacy of
Enhanced External Counterpulsation as Therapy for Unstable Angina. Arora, A, et al Circulation
102:18 Supplement II Oct. '00 Abstract 2982
We have a few studies demonstrating the benefit of EECP in heart attack (acute MI), while the majority of American papers deal with the effects of EECP in persistent but stable angina. Will EECP be effective in unstable angina, chest pain that is of new onset, or suddenly worse than that previously experienced by the patient? EECP takes weeks to have an effect, so we really can’t treat unstable angina with EECP in the office setting, but EECP is available at many American hospitals, so looking at its effect in unstable angina is reasonable. Of the first 832 patients included in the International EECP Registry, 21 carried the diagnosis of unstable angina. Prior CABG was more prevalent in the unstable group, ejection fraction was lower (36 vs. 46%), and multivessel disease was more frequent (95 vs. 77%), while risk factors and many other clinical parameters were similar.
83% of the stable angina patients completed an average 34.3 hours of treatment, while 73% of the unstable patients completed an average 30.9 hours. The degree of diastolic augmentation was higher in the stable patients. Adverse events during treatment were not statistically different between the groups. Both groups showed substantial reduction in angina, with 74% of the stable patients improving by at least one functional class, and 80% of the unstable patients improving to the same degree. NTG requirement and quality of life parameters improved to a similar degree.
EECP may thus be of value in dealing with the patient with unstable angina. The papers by Taguchi (Heart Attack section – article 4) and Fujita (Physiology section – article 15) tell us that heparin anticoagulation is not a contraindication to EECP, and we know from clinical experience that EECP does not interfere with the action of anti-anginal medications. Formal clinical studies of EECP in unstable angina are on the drawing board. In the future, we may be using EECP to “cool down” the unstable angina patient, or to “tune-up” their status in preparation for angiography or revascularization.
13. Enhanced External Counterpulsation in the Treatment and Rehabilitation of Coronary Patients in Indonesia. Karim et al. Asian Cardiovascular & Thoracic Annals 1995, Vol. 3, No. 1
External counterpulsation started out as an American idea. 25 years of Chinese clinical research and improvements in engineering have given us the Enhanced External Counter Pulsation device that we use today. EECP is the standard of care in China; somewhere between 500,000 and a million patients have been treated. While the "return" of external counterpulsation is new to the US, EECP is already an international treatment. Karim’s article tells us that EECP works just as well in Indonesia as it does in the US. Using the same protocol as in the American studies, Karim’s group demonstrated a 26% increase in treadmill exercise time following EECP. Nuclear stress scans improved in 87% of their patients, fully normalizing in 24%. Angina and functional class improved in all.
14. Effects of Enhanced External Counterpulsation on Stress Radionuclide Coronary Perfusion and Exercise Capacity in Chronic Stable Angina Pectoris. Stys, P, et al. Am. J. Cardiology 2002;89:822-24.
Dr. Lawson (article 7 - this section) showed us, in angina patients with 1 or 2 vessel disease, that same distance nuclear perfusion scans improve in 95 and 90% of patients respectively. In his group's initial report on the effects of EECP on 18 patients with refractory angina (article 2), average treadmill time increased by 96 seconds for the entire group, and by 114 seconds in patients whose nuclear scans improved. In the MUST-EECP study, treadmill times improved by 44 seconds and time to ST depression (the EKG signal that coronary blood flow is strained) by 42 seconds. These are benchmarks against which we in the medical community can compare our own work (We do not routinely carry out pre- and post-EECP stress tests on all of our patients. Nearly all of our patients had a pre-EECP stress test, and we repeat the study post-EECP only when we have a patient care related question that needs to be answered. Some patients can't exercise due to orthopedic limitations, while others were doing so well that we don't need to re-stress them. 61 of our first 181 patients underwent serial pre- and post-EECP stress studies. Of these 61 patients, treadmill time increased in 90%, on average by 94 seconds, a 22% increase from baseline - please see Patient Outcomes section for more information).
In this study, Stys and his associates looked at the effect of EECP on functional class, treadmill time, and nuclear scan findings in 175 angina patients undergoing EECP at 7 centers in the US, Europe, and Asia. At 4 centers, pre- and post-EECP nuclear scans were carried out at the same treadmill exercise level (apples to apples comparison), while in 3 centers the scans were recorded at the maximally tolerated exercise level.
At the 4 centers where same distance nuclear scans were
carried out, the scans improved in 81 of 97 patients, 83%, and in the other 16 patients
there was no change. The scan did not worsen in any. At the 3
centers comparing the scans at the maximal tolerated exercise level, treadmill
time was found to increase on average by 48 seconds (397 pre- to 445 seconds
post-EECP). In these patients, where we are looking at the adequacy of
coronary blood flow at a heightened demand (no longer an apples to apples
comparison),
the scans improved in 42 of 78 patients, or 54%. In 4% the scans worsened
while in 42% no significant change was noted. Clinically the patients did
well. 85% improved by at least 1 functional class and 15% improved by 2
(see graphic). This study fits with what we already know. We know
that nearly every patient improves clinically with EECP. EECP doesn't open
up blocked arteries, so we're not distressed with only a 54% scan improvement at
a greater exercise level. We expect EECP to improve endothelial tone,
increase Nitric Oxide elaboration, and improve collateral flow, so we expect the
83% improvement in the same-distance scans. A same-distance improved scan is something
that we like to see, as article 4 showed us that an improved same distance
perfusion scan correlated with a good 5-year post-EECP outcome.
15. The Improvements in Exercise Tolerance Post Enhanced External Counterpulsation in patients with Chronic Refractory Angina are related to Diastolic Augmentation. Brown, A, et al. Heart 2001;85(Suppl I): page 41, Abstract 125.
When our kids were younger, my family participated in Project Children; every summer we would host a child from Northern Ireland in our home. Some of the kids had health problems, so we needed to make contact with their physicians at home. We made a lot of friends and contacts, and while our kids are now in high school and college, we have maintained our Irish connections. One thing led to another; my wife has continued her education through Trinity College in Dublin, achieving her Masters degree in Law, and my daughter is an undergraduate at the same institution, so I was delighted to see that EECP is now available in Ireland (another reason to visit my daughter).
In the communication abstracted below, Brown and colleagues report treatment outcome in 40 inoperable, refractory angina patients who received 35 hours of EECP. Treadmill time, functional class, and quality of life parameters were recorded pre- and post-EECP. Dr. Brown also looked at the level of diastolic augmentation achieved (reflecting the technical ability of EECP to increase aortic and coronary artery diastolic pressure) at the first session.
|
|
Pre-EECP |
Post-EECP |
| Exercise Time | 6:18 | 8:11 |
| Class 3-4 Status |
54% |
13% |
| Class 1-2 Status | 46% | 87% |
| Peak Augmentation | .96 | 1.65 |
| Hospital Days per Year | 14.5 | 7.8 |
Treadmill time increased by just under two minutes, and post-EECP, nearly all of the patients were in Functional Class 1or 2, just as we have seen in the Chinese, Indonesian, and American studies. Peak augmentation reflects the elasticity of our great vessels, and it is interesting to see that this parameter improves with EECP treatment. Utilizing the SF-36 Quality of Life and the Seattle Angina Questionnaires, significant post-EECP improvements were noted in physical functioning, general health, energy, emotional health, and social functioning. EECP certainly cut down their need for in-hospital care, with a nearly 50% reduction in hospital days per year, pre-EECP vs. post-EECP. This saves the Irish health care system a lot of pence and pounds, but it may or not be a good thing for the patients involved, because if you are hospitalized in Ireland, every day at 3 PM a nurse with green eyes and red hair comes by and gives you a large glass of Guinness. On the other hand, most inoperable and previously refractory angina patients would prefer to enjoy their Guinness at home, and not in the hospital.
SECTION TWO: CLINICAL STUDIES - HEART ATTACK
1. Clinical Assessment of External Pressure Circulatory Assistance in Acute Myocardial Infarction
. Amsterdam EA, et al. American Journal of Cardiology 1980; 45: 349-562. Management of Cardiogenic Shock.
Soroff HS, et al. Journal of the American Medical Association; 229:1441-503. New Sequential External Counterpulsation for the Treatment of Acute Myocardial Infarction. Zheng-sheng Zheng et al Thoracic Artificial Organs 8(4): 470-77, Raven Press, New York 1984 International Society of Artificial Organs
4. Comparison of Hemodynamic Effects of Enhanced
External Counterpulsation and Intra-Aortic Balloon Pumping in Patients With
Acute Myocardial Infarction. Taguchi,
I, et al The American Journal of Cardiology
2000;86:1139-41
5. External Counterpulsation increases capillary density during experimental myocardial infarction. Huang, W, et al Journal of the European Society of Cardiology 1999;20(Abstract Supplement):168
6. Effect
of enhanced external counterpulsation on circulating and tissue Angiotensin II
in experimental myocardial infarction.
Lu,
L, et al
Journal of Cardiac Failure
2001, Suppl. 2, Vol. 7, No. 3,
Abstract 123
Based on the studies reviewed in section one, FDA clearance (technically referred to as 510-K clearance) was granted in 1995 for the use of EECP in angina pectoris and refractory angina. EECP was also cleared for the treatment of acute myocardial infarction (heart attack) and cardiogenic shock. EECP is not available at any of our area hospitals or emergency rooms, and we have other techniques for treating heart attack patients, but reviewing these articles and the Chinese experience with EECP in heart attack (article 3) will give us a better understanding of the power and versatility of EECP to improve coronary artery blood flow.
In the first paper, Amsterdam and associates describe the effect of EECP on patient outcome in heart attack complicated by congestive heart failure. 258 patients presenting to emergency rooms at 25 different US medical centers were randomly divided into a control group, receiving standard medical therapy, and a treatment group. The treatment group received the same standard medical therapy plus 3 hours of external counterpulsation on their first hospital day. This study was carried out in 1980, using one of the earlier external counterpulsation devices, not the sequential inflation, enhanced external counterpulsation device that we use today. In all 258 patients, the heart attack was complicated by mild congestive heart failure. In a heart attack, some heart muscle dies; if enough muscle is lost the heart will begin to fail as a pump. Blood will back up behind the heart into the lungs, producing shortness of breath and an abnormal X-Ray; we refer to this as congestive heart failure.
So what effect, if any, did EECP have on patient outcome? In patients 45 years of age or younger, overall mortality was low, and EECP had no effect on survival. In patients 46 years of age and older, hospital mortality was 17.5% in the standard therapy control group and 8.3% in the standard therapy plus external counterpulsation treatment group. Complications were fewer and less severe in the treatment group. Which group would you want to be in? If I had a heart attack, I would want the emergency room physician and cardiologist to treat me with the best of modern day medicine, including blood thinners, clot dissolving drugs, and if needed, urgent angioplasty, but if I couldn’t be treated with these techniques, I would sure like to receive three hours of EECP. Some day, after more hospitals and physicians learn about the efficacy and cost-effectiveness of EECP, we will begin to see EECP machines in emergency rooms (and maybe ambulances), to be used in conjunction with the best of standard cardiology.
In a large heart attack, involving ³ 40% of the heart muscle, the heart will begin to fail completely as a pump, producing a condition known as cardiogenic shock. The lungs fill with fluid, producing marked respiratory distress. Blood flow to the kidneys, brain, and other vital organs is compromised, as the weakened heart just can’t generate enough blood pressure. This is a disastrous heart attack, and hospital mortality is typically 85%. To treat cardiogenic shock and other pump related complications of heart attack, we often place an IntraAortic Balloon Pump (IABP). This is a large bore catheter with a large balloon at its tip. (A catheter is essentially a hollow tube, inserted into the femoral artery in the groin, and advanced under X-ray guidance into the heart. Through the tube we can inject x-ray dye into the three arteries which serve the heart, to determine the extent of the blockage present, or measure the blood pressure within the heart, which tells us how well the heart is functioning as a pump.) The IABP is advanced into the aorta, just inches away from the heart itself. The patients blood pressure wave form is recorded through the IABP; this physiologic information and the patient's EKG is fed into the computer that controls the IABP. During diastole, when the heart muscle is relaxing and able to receive blood through the coronary arteries that serve it, the balloon is inflated, forcing oxygenated blood into the coronary arteries, providing immediate relief to the oxygen starved heart muscle. The pressure applied also begins to recruit and force open collateral vessels, hopefully to produce a sustained improvement in cardiac blood supply. This is a powerful tool. No matter how sick the patient is, they nearly always benefit from the IABP. The problem is that the IABP is a fairly large catheter, which in a smaller patient may compromise blood flow to the patient's leg. Also, the IABP can provide only temporary support. If we leave it in beyond two to three days, we begin to get into problems with balloon failure, clot formation and infection. The idea is to provide short term support, allowing time for the heart to recover. Appreciation of the benefits, and knowledge of the limitations of the IABP led researchers at Harvard to develop the initial external counterpulsation machines 25 years ago.
In the second study, Soroff treated 20 cardiogenic shock patients with standard therapy and external counterpulsation, to see if the addition of external counterpulsation could improve upon the expected 85% mortality rate. Patients received 3 to 5 hours of external counterpulsation on their first hospital day; the average delay from diagnosis to the initiation of counterpulsation was nine hours. Hospital survival was 45%, nothing stellar, but certainly an improvement from the 85% mortality typically associated with this condition. This study was carried out in 1974. In 1998 we treat cardiogenic shock with an IABP combined with clot busting drugs and urgent balloon angioplasty, but if these techniques are not possible or not available (i.e. a small hospital without a cardiac catheterization lab), then EECP might be a useful tool.
