The Coronary Sinus Reducer; 5-year Dutch experience

Refractory angina (RA) is a growing and major health-care problem affecting millions of patients with coronary artery disease (CAD) worldwide [1]. RA is defined as long-lasting (for ≥3 months) symptoms that are caused by established myocardial ischaemia in the presence of obstructive CAD, without further pharmacological or revascularisation options [2]. It is estimated that up to 10% of patients with CAD have RA, and the incidence is expected to grow due to an ageing population and the increasing prevalence of severe and advanced CAD [3].

The quality of life of patients with RA is reduced significantly with debilitating symptoms and increasing hospitalisations. Additionally, RA is leading to an increase in related health-care costs [4, 5]. The number of potential therapeutic options that aim to improve symptoms and quality of life is rising, but large and thorough studies evaluating their efficacy and safety are limited [6, 7].

Currently, the European Society of Cardiology acknowledges that there are three non-pharmacological options to be considered for symptom relief in patients with debilitating RA despite optimal medical and revascularisation strategies: enhanced external counter pulsation, spinal cord stimulation and the Coronary Sinus Reducer (CSR) [2].

The CSR is an hourglass-shaped device that can be placed in the coronary sinus. The presumed mechanism of action is based on an increased venous pressure as a consequence of the CSR placement, which results in a dilatation of arterioles and reduced vascular resistance in the sub-endocardium. Consequently, the coronary blood flow is redistributed from the epicardium to the ischaemic subendocardial territory, leading to reduction of ischaemia and symptoms [8].

The first-in-men procedure was performed in 2005 and multiple studies have been published since then, showing that about 70–85% of patients receiving a CSR experience an improvement in symptoms [9‐12]. The majority of these results are applicable to patients with an ejection fraction above 30% and objective evidence of reversible ischaemia affecting the left coronary territory, although some studies also mention positive effects on the right coronary territory [13]. Its efficacy is currently under study for several other indications, for example in patients without obstructive CAD, or with microvascular dysfunction. Additionally, growing evidence about the efficacy is collected from several multicentre, multinational registries [14‐16]. Furthermore, recently the CSR was shown to decrease the health-care burden and related costs of patients with RA and it also appears to be cost-effective according to the Dutch societal willingness to pay threshold [17].

We aim to provide an overview of the safety and efficacy of the CSR in a real-world Dutch population. We will therefore present the results of the 5‑year Dutch experience regarding CSR implantation and provide recommendations on how to proceed with further research.

A total of 132 patients were eligible for CSR implantation. The baseline characteristics for all patients and stratified on response are shown in Tab. 1. Mean age was 66 years, 75.8% of all patients were male and an average BMI of 29 was observed. A history of coronary revascularisation was present in most patients (83.3% previous PCI and 76.5% CABG). The most frequently used antianginal agents were beta blockers and nitrates (both 77.3%). One hundred and eleven patients (84.1%) used 2 or more antianginal drugs and 58 (43.9%) used 3 or more. Stratified results revealed a higher number of current smokers among the responders (22.4% vs 2.6%, P = 0.006) and showed a higher percentage of patients using nitrates (84.7% vs 63.4%, P = 0.007). No differences were found with regard to age, sex or other traditional risk factors for CAD. Tab. 2 gives an overview of the type of disease among the patients. Up to 20% of patients had diffuse vessel disease, often indicating multiple affected coronary arteries without clear culprit lesions. Almost half of the patients had a chronic total occlusion (50% concerning the right coronary artery). The stratified analysis did not show any difference in disease characteristics between responders and non-responders. Procedural details are summarised in Tab. 3. In one case no CSR was placed due to the patient’s coronary sinus anatomy (too small) leading to successful placement in 99% of the patients. Mean procedure time was 37 (±22) minutes. Complications were seen in 6 cases. Most complications were dislocation of the device before it reached the target area. In all cases this could be solved, resulting in successful placement. In one patient multiple complications occurred (access site complication, wire perforation and dislocation of the device), but all complications were solved and the CSR was placed. None of the patients died during implantation or because of the procedural complications.

Follow-up details were available in 127 patients. Treatment with the CSR resulted in a significantly lower CCS class after 6 months (2.12 ± 1.07 vs 3.17 ± 0.61, P < 0.001, Fig. 1). In total 67.5% of all patients improved at least one CCS class after implantation of the CSR (Fig. 2). Additionally, approximately one third of the patients improved 2 or more CCS classes and 7.1% 3 or more. Distribution of CCS class among patients is shown in Fig. 3. Before CSR implantation 90% of patients suffered from CCS class III and IV, after implantation this was reduced to 34.6%, corresponding to a reduction of 62%. Two patients received coronary revascularisation within 6 months after implantation (data not shown). Additional clinical follow-up details are summarised in Supplementary Tab. 1. Implantation of the CSR resulted in a significant reduction of hospitalisations as a result of anginal complaints (34.4% vs 11.7%, P < 0.001). The same was seen for visits at the emergency department (28% vs 15.8%, P = 0.009). No differences in blood pressure and heart rate were found during the 6 months before and after CSR (Supplementary Table 1).

In the current study, we show the 5-year experience regarding CSR implantation in a large, real-world Dutch cohort of RA patients. Within a time frame of 5 years, a total of 132 patients were included. A CSR was successfully implanted in 99% of patients and only minor complications during implantation were reported, which could be solved immediately. Furthermore, no long-term complications related to the device were observed.

CSR implantation significantly reduced the mean CCS class (3.17 before vs 2.15 after, P < 0.001) and an improvement of at least one CCS class at 6 months was seen in 67.5% of patients. Furthermore, we showed that at baseline a total of 90% of patients had complaints of debilitating angina at rest or with only mild exertion (CCS class III or IV). After implantation, this percentage decreased with 62% to only 34.6%, meaning more than half of the patients no longer suffered from severe complaints of angina. Additional analysis revealed a significant reduction in hospital admissions (34.4% vs 11.7%, P < 0.001) and visits to the emergency department (28.0% vs 11.7%, P = 0.009), which is in line with a recent study that reported decreased health-care resource use and related costs following CSR implantation [17]. Although medication changes after CSR implantation were allowed, these were very rare. No differences were found with regard to blood pressure and heart rate before and after the procedure, further indicating that the beneficial effects are indeed attributable to the CSR and not to changes in medical treatment.

The efficacy of the CSR is slightly lower than previously reported (70–85% compared with 68%), which could be explained by several reasons. Most importantly, we included patients with less robust inclusion criteria compared with the strict protocols that were used in previous studies. Another important difference with the existing RCT and registries is the lack of a uniform protocol. For example, we have included patients with an ejection fraction below 30% and patients with chronic renal failure. Careful evaluation before implantation is necessary in all patients and even more pivotal in patients with severe systolic heart failure that may need future cardiac resynchronisation therapy (CRT). Therefore, at this stage, CSR implantation is not advisable in patients with systolic heart failure with an ejection fraction <30%. However, two recent case reports suggest that CRT is still possible after the CSR is implanted, but further evaluation is needed [18, 19]. Moreover, we have also treated a few “no-option” patients with significant right-sided CAD and patients with significant CAD without objective ischaemia on SPECT or MRI. This could have affected our outcomes. However, we do believe that CSR treatment should be considered in all patients with RA not amenable to revascularisation and medication as currently stated in the ESC guidelines [2]. Furthermore, most patients in our study are patients referred for second or even third opinion, leading to re-evaluation of existing angiographic data and information regarding ischaemia. This automatically leads to a much more heterogeneous population compared with the previously performed RCT and registry studies in which patients were recruited by the treating physician [11, 12].

A clear explanation for non-response to this treatment is lacking, however, some explanations have been proposed. Firstly, the presumed mechanism of action is based on an increased venous pressure in the coronary sinus resulting in better oxygen supply of the ischaemic myocardium. This is based on the idea that in most patients the drainage system is relatively comparable. However, patients with an accessory venous drainage system could, therefore, benefit less from its working mechanism. A proposed measurement to evaluate the accessory venous drainage system is the differential pressure between baseline right atrial pressure and coronary sinus systolic pressuring during balloon occlusion of the CSR, with a low differential pressure indicating alternative drainage and thus potential non-response. Baldetti et al. showed a comparison of one patient with a high differential pressure and one patient without, which supported this hypothesis [20]. Other factors that have been proposed to play a causative role for non-responders are the presence of epicardial and/or microvascular spasm, symptoms unrelated to myocardial ischaemia (e.g. heart failure), incomplete endothelialisation of the CSR and inadequate pressure gradient across the device. However, robust data on these suggestions do not (yet) exist [8, 21, 22]. The lack of clear predictors for response and non-response is consistent with our findings as no differences were observed between baseline or disease characteristics, and treatment response.

In this real-world, multicentre 5‑year Dutch experience, implantation of the CSR was shown to be a safe and effective treatment for the majority of patients with refractory angina. A clear explanation for the non-response in about thirty percent of the patients is still lacking. Our results support the need for further research investigating the determinants of effectiveness, ineffectiveness and long-term follow-up. In conclusion, a CSR is a simple and safe option for reducing symptoms in patients with RA in the Netherlands.