Randomized trials are also essential for device therapy: reply

We welcome Rück and Sylvén's comments as they highlight some important points on the treatment of refractory angina. The examples they quote demonstrate that clinicians have yet to identify a satisfactory treatment strategy for this group of patients and that limited data are available on the incidence, prevalence and natural history of refractory angina [1]. Clearly, the scientific evaluation of enhanced external counterpulsation (EECP) is still in its infancy and like many other technologies such as defibrillators or angioplasty will take decades to demonstrate its strengths and failings. As stated in our original manuscript, we also believe that randomized controlled trials (RCT) are essential and that ‘an important placebo effect associated with device therapy may also contribute to patients’ improvement’. That is why we have participated in multi-centre studies of EECP whenever possible [2] and are currently conducting single-site randomized trials. Although we agree with the premise that RCT is the gold standard design (the success of the Cochrane collaboration is testament to this), it is not ‘the only way to prove efficacy’ as the authors state. For example, for rare diseases the RCT may not be practical. It did not take an RCT to witness the devastating effects of thalidomide in pregnancy, the aftermath of which is still seen today. Where it is not possible to carry out RCT, evidence has shown that cross-sectional studies provide valid results [3] and play a critical role in providing evidence for practice [4]. A nontreatment arm is not the same as a placebo but identifying an appropriate ‘placebo’ for EECP is problematic. Low-pressure sham-placebo control was adopted by the multi-centre randomized control trial, MUST-EECP [5]. However, some central haemodynamic effects can be observed in the coronary artery using invasive measurement even at a low cuff inflation pressure of 100 mmHg [6]. Although this may be avoided by even lower cuff inflation pressure, it is unclear whether such a strategy has an exercise training effect or a haemodynamic effect on the peripheral vascular system. If the intervention that is assumed to be a placebo is in fact therapeutic, treatment effects may be underestimated. The lowest cuff inflation pressure that can be achieved by newer generation of treatment console (MC-3 model) is 80 mmHg and patients notice the difference, creating uncertainty about robustness of the ‘placebo’. Both the suggested duration and number of EECP sessions needed to achieve a therapeutic effect are largely based on experience rather than on data. Regulatory authorities indicate that demonstration of a dose–response is supportive evidence of therapeutic effect. Accordingly, comparisons between the number or duration of treatment sessions may be a better approach. However, treatment as short as 5 min can cause peripheral vasodilatation and therefore this cannot be considered a no-effect dose [7]. The MUST-EECP study showed improvements in total exercise time in both the active treatment and low-pressure sham-placebo groups. However, an increase in the time to 1-mm ST-segment depression was only observed in the active treatment group. Some of the possible explanations had been discussed by the authors. However, refractory angina was not one of the entry criteria for this study. Over 75% of the patients suffered from Canadian Cardiovascular Society (CCS) Class I and II angina and the mean exercise treadmill time (Standard or Modified Bruce) at baseline was over 7 min. A greater treatment effect may be observed in patients with more severe angina. The American-based observational multi-centre radionuclide study using symptom-limited quantitative gated technetium Tc 99 m sestamibi single photon emission computed tomography (SPECT) in 34 patients treated with EECP was not available when our manuscript was submitted [8]. As there was an increase in exercise time without any improvement in the SPECT, the authors suggested that exercise-training effect might be one of the possible mechanisms of action for EECP. However, a previous but larger retrospective international multi-centre radionuclide study on 175 patients has shown an improvement in exercise time and radionuclide scan within 6 months after a course of EECP treatment [9]. Sample size, patient population and methodology may partly explain the difference in the outcome of both studies. One of the main reasons why there are so few RCTs of patients with truly refractory angina is that the patient has proved unresponsive to all available conventional measures. As no intervention has yet worked, even though all interventions have a placebo effect, why should a new ‘placebo’ work? If EECP is a placebo, then it seems a highly effective, relatively low cost and with little associated morbidity. Compared with many other interventions that are advocated in such patients, including high-risk revascularization, transplantation, spinal stimulation and transmyocardial laser revascularization, EECP is an attractive option from a patient's and health service perspective and should be tried before such procedures are contemplated. Any effort to identify the most appropriate treatment strategy for these patients would be welcomed. Perhaps the most appropriate way forward is to use EECP as the first-line treatment for angina refractory to pharmacological therapy and conventional revascularization, due to its low cost and low morbidity, and then to determine which intervention can displace it on the basis of cost or efficacy in RCTs. No conflict of interest was declared.

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