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Chronic refractory angina is a disabling condition affecting patients with coronary artery disease who continue to experience angina symptoms despite optimal pharmacotherapy and are not eligible for future revascularization. Coronary sinus reducer (CSR) implantation is a novel therapeutic option that targets this unmet clinical need by modulating the coronary venous outflow. Notwithstanding the growing evidence of CSR efficacy, data derived from routine clinical practice focusing on patient‑reported quality of life remain relatively scarce. This study provides valuable insights into the findings of 1‑year implementation of CSR in routine practice. The most significant improvement in symptom control was noted during the initial 3–6 months following implantation, with flattening of the benefits curve in longer follow‑up. There was no evidence of any deleterious long‑term effects. Moreover, the presented data suggest that CSR may have an impact on microcirculation, which might be a potential additional mechanism of angina control. Further studies are necessary to comprehensively evaluate this finding.

Introduction

Persistence of chronic refractory angina (RA) despite the implementation of optimal medical and interventional therapies represents a significant challenge. RA remains an important disabling condition in individuals with chronic coronary syndrome, significantly affecting their quality of life (QoL).¹ The chronic nature of this condition, which results in multiple exacerbations necessitating rehospitalization, places a considerable burden on the limited resources of the public health care system.² Moreover, RA is associated not only with obstructive coronary artery disease (CAD), but also multiple additional clinical conditions, including microvascular disease, various forms of cardiomyopathy, and left ventricular diastolic dysfunction.^3-5 Given the relatively long life expectancy of individuals with RA (on average, 4% mortality per year),⁶ permanent improvement in symptom control remains a key medical objective. Previous studies^7-10 indicate that the coronary sinus reducer (CSR; ShockWave Medical, Santa Clara, California, United States), an hourglass‑shaped stent made of stainless steel, designed for permanent narrowing of the CS, may enhance short- and mid‑term symptom control in patients with RA. Still, data from routine clinical practice observation are scarce.^11,12 Therefore, we collected real‑life 12‑month data from the single‑center observational Lower Silesia Sinus Reducer Registry to fully assess the efficacy of CSR implantation in routine clinical practice.

Patients and methods

Study device and implantation procedure

CSR, which is an hourglass‑shaped stainless steel stent, is delivered into the CS using a standard over‑the‑wire balloon catheter system. The device delivery system has 3 radiopaque markers: 2 situated on the distal edges of the scaffold, and a third one located proximally to the balloon. This marker is used to determine the precise position of the device during the implantation procedure (Figure 1).

The vascular access site (using a 9‑French [F] introducer sheath) for CSR implantation is primarily the internal jugular vein; however, in selected cases, a femoral approach is employed to deliver the device. Subsequently, upon reaching the central vein system with a standard 0.035‑inch wire, the multipurpose diagnostic catheter is advanced into the right atrium to measure the arterial pressure, with a target mean pressure value below 15 mm Hg. Next, diagnostic catheter venography is performed to identify the optimal implantation site, which should have a diameter between 10 and 14 millimeters, and no side branches or vascular anomalies. Following the transition to a 9‑F guiding catheter, the CSR is implanted (4–6 atm) with a maximum device oversize of up to 20%, as compared with the CS size. Each patient was administered a standard dose of unfractionated heparin (100 UI/kg) during the procedure. Additionally, dual antiplatelet therapy was implemented at the day of implantation for up to 3 months.

Results

The study population comprised 67 consecutive patients who underwent implantation of the CSR between July 2022 and July 2023 and completed the 1‑year postimplantation clinical follow‑up. General characteristics of the study group are presented in Table 1. A majority of the patients were men (n = 55 [82.1%]), and the mean (SD) patient age was 72.9 (6.9) years. The study population was characterized by a high prevalence of cardiovascular risk factors, including hypertension (100%), dyslipidemia (91%), and glucose tolerance disorders (67.1%).

Before the CSR implantation, all patients were diagnosed with various forms of CAD. A total of 56 participants (83.6%) underwent percutaneous revascularization. Nearly half of the patients (n = 32) underwent both CABG and percutaneous coronary intervention (PCI), while 10.4% (n = 7) received isolated CABG, and 35.8% (n = 24) were revascularized only with PCI. An overwhelming majority of patients presented with advanced obstructive CAD (91%); however, 6 individuals (9%) underwent CSR implantation due to severe, nonobstructive CAD with confirmed advanced coronary microcirculation dysfunction (Table 2).

A vast majority of patients (88.1%; P <⁠0.001) exhibited an improvement by at least 1 CCS class 1 month following CSR implantation, relative to the baseline. This positive effect was sustained (86.6%; P <⁠0.001) for up to 12 months (Figure 2). All changes in the CCS angina class during the observation period are pooled in Figure 3.

In terms of the safety outcomes, all patients underwent successful device deployment with negligible frequency of site complications, including 6 cases (8.9%) of hematoma at the vascular access site not requiring significant medical intervention. As previously reported,¹⁶ a single case of migration of the CSR into the pulmonary artery was observed in the study cohort. The device was retrieved using percutaneous loops, and the patient underwent a second successful attempt at CSR implantation during the index procedure.

In terms of the secondary end points, favorable outcomes of implantation were confirmed by a significant improvement in 12‑month angina control, as assessed by the total SAQ‑7 score (mean [SD], 39.9 [15.2] vs 54.6 [19.7]; P <⁠0.001; Figure 4). The initial poor exercise tolerance (mean [SD] 6MWD of 234.9 [109.1] m) also improved postimplantation, reaching the highest value at the 3‑month follow‑up (310.6 [120.1] m; P <⁠0.001). One year after the CSR implantation, a slight reduction in exercise tolerance was observed in the study cohort, although a significant improvement was still found, as compared with the baseline (mean [SD] 6MWD, 265.9 [136.9] m vs 234.9 [109.1] m; P = 0.03; Figure 5). Of note, the time‑period landmark analysis demonstrated that the most pronounced clinical response (measured by the capacity to undertake exercise—6MWD) occurred during the initial 3‑month period postimplantation. This was followed by an absence of significant clinical gains in the subsequent follow‑up period (Table 3).

In terms of the quality of life, the patients reported a significant improvement in this regard throughout the entire 12‑month follow‑up period. The EQ‑5D‑5L, EQ‑VAS, and SF‑36 results are summarized in Supplementary material, Figure S1.

The antianginal pharmacotherapy remained unchanged (median [IQR] number of drugs used, 4 [3.5–5.5] vs 3.9 [3.4–5.5]; P = 0.88) throughout the observation period. A complete overview of patient therapeutic data is presented in Supplementary material, Figure S2). At the end of follow‑up, CAD progression necessitating hospital readmission was observed in 8 participants (11.9%); of those, 4 individuals (5.9%) underwent a subsequent PCI.

Discussion

The objective of this study was to evaluate 12‑month outcomes of CSR implantation in a real‑world population of patients with RA. The primary findings of this study are as follows: 1) The clinical benefit observed following CSR implantation was maintained over a long‑term period, with a reduction in angina severity observed despite the use of intensive antianginal medication. The most significant improvement in symptom control was noted during the initial 3–6 months following implantation. After this critical period, a flattening of the benefits curve was observed, accompanied by a lack of notable clinical gains in the longer follow‑up. 2) CSR implantation is a safe procedure with a low rate of device‑oriented unfavorable clinical events.

The concept of angina symptom alleviation resulting from CS narrowing was first articulated before the introduction of CABG to clinical practice,¹⁷ and was initially linked with potential improvement in perfusion of the ischemic myocardial regions.¹⁸ However, due to the continued evolution of techniques in the field of cardiac revascularization, for an extended period, these procedures remained limited to animal models and preclinical studies. Over 5 decades elapsed before this concept was incorporated into clinical practice. Preliminary findings indicate that CSR is a safe and efficacious therapy for patients with RA who were previously deemed unsuitable for any revascularization procedures.^19,20 Recently published collective data²¹ suggest that CSR markedly alleviated angina symptoms, and improved health‑related quality of life measures. These findings are supported by significant improvements in patient self‑reported angina features, the CCS classification, and SAQ scores. Although the efficacy of symptom control has been well documented in short‑term follow‑up studies,^9,10,22-25 data on long‑term impact remain limited.^26-28 Nevertheless, CSR has been introduced to clinical guidelines as an optional therapy for patients with advanced CAD.²⁹ The data on self‑reported angina symptom control obtained from our cohort indicate a notable improvement (by at least 1 CCS class) in a significant proportion of patients (88.1%) at the initial follow‑up (1 month), which persisted at the 1‑year mark (86.6%). This finding is consistent with the collective data from previous studies conducted over an analogous timeframe (12 months), which suggest improvement in 76% of patients.²¹ With respect to the QoL, similar correlations were identified between our cohort and other studies, particularly concerning real‑world data.^21,30 Although both QoL and symptom control are subjective measures, it is important to remember that they have been postulated to be associated with mortality, myocardial infarction, and the need for coronary revascularization.³¹ We also noted a significant improvement in exercise capacity, which is generally in line with a majority of published studies.^20,21 However, it is important to note that not all previous reports have yielded results that confirm this favorable effect of CSR implantation. The ORBITA‑COSMIC (Coronary Sinus Reducer Objective Impact on Symptoms, MRI Ischaemia and Microvascular Resistance) trial³² demonstrated no significant improvement in exercise capacity. This finding is not only inconsistent with the results of our study but also with the outcomes of other randomized trials.³³

Notably, the 6MWD demonstrated fluctuations throughout the follow‑up period. The initial improvement was observed for up to 3 months, after which a gradual decline ensued. Nevertheless, this decline did not reach significance, as compared with the baseline value. Several important factors may be potentially involved. Firstly, the natural, slow progression of CAD^34,35 may overwhelm the positive effect of CSR implantation. Secondly, the placebo effect of the procedure may be a significant favorable factor, and further follow‑up may reveal a gradual alleviation of this effect manifested by a shorter 6MWD. Lastly, changes in the alternative venous drainage system (increased activity) may occur following CSR implantation. Some data suggest that this factor may impact the 6MWD results after the procedure.³⁶

Concerns have emerged regarding the long‑term cost‑effectiveness of CSR implantation, particularly in the context of the nonresponder populations.³⁷ In our real‑life cohort, we observed 9 nonresponders (13.4%) to CSR therapy. A high‑volume cost‑effectiveness analysis of the procedure has yet to be conducted, largely due to the novelty of this therapy. However, preliminary data for Western European countries suggest that the device is feasible in this field.³⁸ Although the results of the preceding study, together with our present findings, indicated a notable long‑term reduction in the rate of rehospitalizations for angina exacerbations, it is important not to overlook the fact that we observed no reduction in antianginal drug use, which is generally in line with previous evidence.³⁹ Evaluation of these parameters under local health system conditions remains an important issue, as it could establish a new range of cost‑effectiveness thresholds and influence a national reimbursement policy in the future.

Experimental animal models suggested that a potential mechanism of action of the CSR in patients with RA might have been an improvement in perfusion of ischemic myocardial segments.¹⁸ The initial data derived from human models seem to be in line with this finding—Giannini et al⁴⁰ postulated that CSR implantation may provide greater benefit in ischemic regions of the myocardium supplied by the left coronary artery, as compared with other regions. However, a recent study focused on cardiac magnetic resonance perfusion assessment has challenged this finding, suggesting that the improvement is more likely related to the redistribution of perfusion from the subepicardial to subendocardial myocardium in ischemic regions.⁴¹ This finding appears to be consistent with the results of the randomized ORBITA‑COSMIC trial,³² which, apart from a clinical evaluation of CSR, investigated the potential mechanisms of action of CSR on stress magnetic resonance imaging. The results appear to contradict the theory of perfusion transfer (from nonischemic to ischemic regions) as a potential mechanism of CSR action. Nevertheless, they suggest that potential redistribution of perfusion within the ischemic segments may be a contributing factor to the observed favorable clinical effect.

We did not investigate the potential mechanism of action of CSR; however, a relevant finding is that all patients with nonobstructive CAD and no microvascular dysfunction showed significant improvement in angina control (by at least 1 CCS class). This observation is in line with initial reports^42,43 indicating that coronary microvascular function improves (as reflected by a reduction in the index of microcirculatory resistance and an increase in coronary flow reserve values) subsequent to CSR implantation. This may form a basis for the novel potential mechanism of action of the device that we intend to investigate further in separate studies.

The limitations of the present study are primarily attributable to its observational, nonrandomized design. Due to an absence of a control group, it was not possible to definitively exclude a possibility that outcomes were related to the potential placebo effect. Furthermore, the study protocol did not include objective imaging studies to measure the reduction of myocardial ischemia following the CSR implantation. The study cohort was relatively heterogeneous, comprising individuals with obstructive and nonobstructive CAD. Also, it must be highlighted again that we did not investigate the potential mechanisms of action of CSR. Consequently, the analysis of changes in clinical outcomes during the study period was significantly hindered.