In 2003, (before the establishment of the Ontario Health Technology Advisory Committee), the Medical Advisory Secretariat conducted a health technology policy assessment on enhanced external counterpulsation (EECP). The goal of treatment with EECP is to decrease the frequency and severity of angina symptoms and increase angina-free exercise duration. The Medical Advisory Secretariat concluded that there was insufficient evidence to support the use of EECP for : 1) patients with refractory stable Canadian Cardiovascular Society (CCS) class III/IV angina; or 2) patients with heart failure (HF).

Accordingly, as part of an annual review and publication of more recent articles, the Medical Advisory Secretariat updated its health technology policy assessment of EECP.

Angina is a clinical syndrome characterized by discomfort in the chest, jaw, shoulder, back or arm. Angina usually occurs in patients with coronary artery disease (CAD) involving ≥1 large epicardial artery. However it can also occur in people with valvular heart disease, hypertrophic cardiomyopathy, and uncontrolled hypertension.

Conventional approaches to restoring the balance between oxygen supply and demand focus on the disruption of the underlying disease through: drug therapy (β blockers, calcium channel blockers, nitrates, antiplatelet agents, ACE inhibitors, statins); life-style modifications (smoking cessation, weight loss); or revascularization techniques such as coronary artery bypass graft surgery (CABG) or percutaneous coronary interventions (PCI). Limitations of each of these approaches include: adverse drug effects, procedure-related mortality and morbidity, restenosis after PCI, and time dependent graft attrition after CABG. Furthermore, an increasing number of patients are not appropriate candidates for standard revascularization options, due to co-morbid conditions (HF, peripheral vascular disease), poor distal coronary artery targets, and patient preference. The morbidity and mortality associated with repeat surgical revascularization procedures are significantly higher, and often excludes these patients from consideration for further revascularizations.

Patients with CAD who have chronic ischemic symptoms that are unresponsive to both conventional medical therapy and revascularization techniques have refractory angina pectoris. It has been estimated that greater than 100,000 patients each year in the US may be diagnosed as having this condition. Patients with refractory angina have marked limitation of ordinary physical activity or are unable to perform any ordinary physical activity without discomfort (CCS functional class III/IV). Also, there must be some objective evidence of ischemia as demonstrated by exercise treadmill testing, stress imaging studies or coronary physiologic studies.

Dejongste et al. estimated that the prevalence of chronic refractory angina is about 100,000 patients in the United States. This would correspond to approximately 3,800 (100,000 x 3.8% [Ontario is approximately 3.8% of the population of the United States]) patients in Ontario having chronic refractory angina.

Heart failure results from any structural or functional cardiac disorder that impairs the ability of the heart to act as a pump.

A recent study revealed 28,702 patients were hospitalized for first-time HF in Ontario between April 1994 and March 1997. Women comprised 51% of the cohort. Eighty-five percent were aged 65 years or older, and 58% were aged 75 years or older.

Patients with chronic HF experience shortness of breath, a limited capacity for exercise, high rates of hospitalization and rehospitalization, and die prematurely. The New York Heart Association (NYHA) has provided a commonly used functional classification for the severity of HF:

• Class I : No limitation of physical activity. No symptoms with ordinary exertion.
• Class II : Slight limitations of physical activity. Ordinary activity causes symptoms.
• Class III : Marked limitation of physical activity. Less than ordinary activity causes symptoms. Asymptomatic at rest.
• Class IV : Inability to carry out any physical activity without discomfort. Symptoms at rest.

The National Heart, Lung, and Blood Institute estimates that 35% of patients with HF are in functional NYHA class I; 35% are in class II; 25%, class III; and 5%, class IV. Surveys suggest that from 5% to 15% of patients with HF have persistent severe symptoms, and that the remainder of patients with HF is evenly divided between those with mild and moderately severe symptoms.

To date, the diagnosis and management of chronic HF has concentrated on patients with the clinical syndrome of HF accompanied by severe left ventricular systolic dysfunction. Major changes in treatment have resulted from a better understanding of the pathophysiology of HF and the results of large clinical trials. Treatment for chronic HF includes lifestyle management, drugs, cardiac surgery, or implantable pacemakers and defibrillators. Despite pharmacologic advances, which include diuretics, angiotensin-converting enzyme inhibitors, beta-blockers, spironolactone, and digoxin, many patients remain symptomatic on maximally tolerated doses.

Patients are typically treated by a trained technician in a medically supervised environment for 1 hour daily for a total of 35 hours over 7 weeks. The procedure involves sequential inflation and deflation of compressible cuffs wrapped around the patient's calves, lower thighs and upper thighs. In addition to 3 sets of cuffs, the patient has finger plethysmogram and electrocardiogram (ECG) attachments that are connected to a control and display console.

External counterpulsation was used in the United States to treat cardiogenic shock after acute myocardial infarction. More recently, an enhanced version namely "enhanced external counterpulsation" (EECP) was introduced as a noninvasive procedure for outpatient treatment of patients with severe, uncontrollable cardiac ischemia. EECP is said to increase coronary perfusion pressure and reduce the myocardial oxygen demand. Currently, EECP is not applicable for all patients with refractory angina pectoris. For example, many patients are considered ineligible for therapy due to co-morbidities, including those with severe pulmonary vascular disease, deep vein thrombosis, phlebitis and irregular heart rhythms, and heart failure.

Very recently, investigation began into EECP as an adjunctive treatment for patients with HF. Anecdotal reports suggested that EECP may benefit patients with coronary disease and left ventricular dysfunction. The safety and effectiveness of EECP in patients with symptomatic heart failure and coronary disease and its role in patients with nonischemic heart failure secondary to LV dysfunction is unclear. Furthermore, the safety and effectiveness of EECP in the different stages of HF and whether it is only for patients who are refractive to pharmacotherapy is unknown.

The MAS health technology assessment (originally published in February 2003) reported on the effectiveness of EECP for patients with angina and HF. The report concluded that there was insufficient evidence to support the use of EECP in patients with refractory stable CCS III/IV angina as well as insufficient evidence to support the use of EECP in patients with HF.

The aim of this literature review was to assess the effectiveness, safety, and cost effectiveness of EECP for the treatment of refractory stable CCS III/IV angina or HF.

The standard search strategy used by the Medical Advisory Secretariat was used. This included a search of all international health technology assessments as well as a search of the medical literature from December 2002 to March 2006.

A modification of the GRADE approach was used to make judgments about the quality of evidence and strength of recommendations systematically and explicitly. GRADE provides a framework for structured reflection and can help to ensure that appropriate judgments are made. GRADE takes into account a study's design, quality, consistency, and directness in judging the quality of evidence for each outcome. The balance between benefits and harms, quality of evidence, applicability, and the certainty of the baseline risks are considered in judgments about the strength of recommendations.

The Cochrane and INAHTA databases yielded 3 HTAs or systematic reviews on EECP treatment (Blue Cross Blue Shield Technology Evaluation Center [BCBS TEC], ECRI, and the Centers for Medicare and Medicaid Services [CMS]). A search of Medline and Embase December 2005 - March 2006 (after the literature search cutoff from the most recent HTA) was conducted using key words enhanced external counterpulsation, EECP, angina, myocardial ischemia, congestive heart failure. This search produced 1 study which met the inclusion criteria. This level 4a study was inferior in quality to the RCT which formed the basis of the 2003 MAS recommendation.

BCBS reviewed the evidence through November 2005 to determine if EECP improves health outcomes for refractory chronic stable angina pectoris or chronic stable HF. BCBS concluded that the available evidence is not sufficient to permit conclusions of the effect of EECP on health outcomes. Both controlled trials had methodologic flaws (MUST EECP and MUST EECP quality of life studies). The case series and observational studies for both indications while suggestive of a treatment benefit from EECP have shortcomings as well.

On March 20 2006, CMS posted their proposed coverage decision memorandum for external counterpulsation therapy. Overall, CMS stated that the evidence is not adequate to conclude that external counterpulsation therapy is reasonable and necessary for:

• Canadian Cardiovascular Society Classification (CCSC) II angina
• Heart failure
• NYHA class II/III stable HF symptoms with an EF≤35%
• NYHA class II/III stable HF symptoms with an EF≤40%
• NYHA class IV HF
• Acute HF
• Cardiogenic shock
• Acute MI

In January 2005, ECRI stated that there was insufficient evidence available to draw conclusions about the long-term effectiveness of EECP, with respect to morbidity, survival, or quality of life, for any coronary indication (refractory angina, congestive heart failure, cardiogenic shock and acute MI).

According to the GRADE Working Group criteria, the quality of the trials was examined (Table 1).

Quality refers to the criteria such as the adequacy of allocation concealment, blinding and follow-up.

Consistency refers to the similarity of estimates of effect across studies. If there is important unexplained inconsistency in the results, our confidence in the estimate of effect for that outcome decreases. Differences in the direction of effect, the size of the differences in effect and the significance of the differences guide the decision about whether important inconsistency exists.

Directness refers to the extent to which the people interventions and outcome measures are similar to those of interest. For example, there may be uncertainty about the directness of the evidence if the people of interest are older, sicker or have more comorbidity than those in the studies.

As stated by the GRADE Working Group, the following definitions were used in grading the quality of the evidence.

No economic analysis of EECP was identified in the published literature.

3,800 patients with chronic refractory angina :

The number of patients with chronic refractory angina in the US is estimated to be approximately 100,000. This corresponds to about 3,800 patients in Ontario (3.8% x 100,000) with refractory angina.

3,800 patients x $7,000 Cdn (approximate cost for a full course of therapy) ~ $26.6M Cdn.

23,700 patients EF ≤ 0.35 :

This estimate is from an expert (personal communication) at the Institute for Clinical Evaluative Sciences (ICES), where they examined a sample of echocardiography studies drawn from a diagnostic lab in 2001. They found that the prevalence of EF ≤ 0.35 was 8.3%, and if generalized to all patients undergoing echocardiography, there would be 23,700 patients.

23,700 patients with EF ≤35% x $7,000 Cdn ~ $166 M Cdn.

There is insufficient evidence to support the effectiveness and safety of EECP treatment for patients with refractory stable CCS III-IV angina or HF.

As per the GRADE Working Group, overall recommendations consider 4 main factors :

• The tradeoffs, taking into account the estimated size of the effect for the main outcome, the confidence limits around those estimates and the relative value placed on the outcome.
• The quality of the evidence.
• Translation of the evidence into practice in a specific setting, taking into consideration important factors that could be expected to modify the size of the expected effects such as proximity to a hospital or availability of necessary expertise.
• Uncertainty about the baseline risk for the population of interest.

The GRADE Working Group also recommends that incremental costs of healthcare alternatives should be considered explicitly alongside the expected health benefits and harms. Recommendations rely on judgments about the value of the incremental health benefits in relation to the incremental costs. The last column in Table 2 is the overall trade-off between benefits and harms and incorporates any risk/uncertainty.

• For angina and heart failure, the overall GRADE and strength of the recommendations is "weak" - the quality of the evidence is "low" (uncertainties due to methodological limitations in the study design in terms of study quality and directness), and the corresponding risk/uncertainty is increased due to a budget impact of approximately $26.6 M Cdn or $166 M Cdn respectively while the cost-effectiveness of EECP is unknown and difficult to estimate considering that there are no high quality studies of effectiveness.