Refractory angina is a chronic condition (lasting for ≥3 months) defined as recurrent angina episodes in individuals with proven myocardial ischemia who receive optimal medical treatment and are not eligible for any further revascularization options.¹ Patients with refractory angina are typically men over 60 years of age, who have already undergone either percutaneous or surgical revascularization but continue to present with angina due to residual obstructive coronary artery disease characterized by diffuse atherosclerosis and / or chronic total occlusion (CTO) of the coronary arteries. Alternatively, angina can be a result of microvascular disease with no angiographic signs of obstructive coronary artery disease; in such a case, it is referred to as angina with nonobstructive coronary arteries (ANOCA).²

Coronary sinus reducer (CSR; Neovasc Reducer, Shockwave Medical, Santa Clara, California, United States) is an hourglass‑shaped mesh that is implanted into the distal coronary sinus through the left jugular vein.³ After an endothelization period, it creates an iatrogenic narrowing, which is believed to alter the perfusion of ischemic myocardial segments through increased backward pressure propagated from the coronary sinus to the capillary bed.⁴ This alleviation of ischemia may manifest in improved subjective perception of angina, which, ideally, should be followed by objective improvement of the patient’s functional capacity.

In this issue of Polish Archives of Internal Medicine, Włodarczak et al⁵ report on 1‑year outcomes of 67 patients treated with CSR implantation who were prospectively included in the Lower Silesia Sinus Reducer Registry. After the procedure, 86.6% of the patients experienced an improvement by at least 1 Canadian Cardiovascular Society (CCS) functional class. It was accompanied by objective improvement in the 6‑minute walking distance (6MWD) and quality of life. The authors also reported excellent procedural statistics, with only 1 patient necessitating an additional implantation procedure due to CSR embolization in the pulmonary artery. Except for 6 conservatively managed access site hematomas, there were no periprocedural complications. These findings further confirm the safety of CSR implantation and its effect on angina improvement. The latter is in line with a previously published meta‑analysis including 846 patients, which demonstrated an improvement by at least 1 CCS functional class in 76% of the patients.⁶ The main novelty of the present analysis is the chronological presentation of patient status at 1, 3, 6, and 12 months postprocedure, which showed persistent improvement of functional class; nonetheless, there was a trend toward mitigation of the improvement in 6MWD.

To date, only 3 studies explored the effect of CSR treatment using a randomized, double‑blind sham‑controlled study protocol—the COSIRA (Coronary Sinus Reducer for Treatment of Refractory Angina) trial,⁷ the CROSSROAD (Effect of Coronary Sinus Reducer Implantation for Ischemia Reduction) study,⁸ and the ORBITA‑COSMIC (Coronary Sinus Reducer Objective Impact on Symptoms, MRI Ischaemia and Microvascular Resistance) trial.⁹ The COSIRA trial⁷ equally randomized 104 patients to CSR implantation and a sham control procedure. After 6 months, the CCS functional score improved by 1 class in 71% of the patients in the CSR group, and 42% of the patients in the control group (P = 0.003). In contrast, there was no difference in the duration of the exercise stress test and most of the Seattle Angina Questionnaire (SAQ) domains, except for the quality of life domain (P = 0.048).⁷ The CROSSROAD study⁸ randomized 25 patients in a manner similar to that adopted in the COSIRA trial. The main findings were increased maximal oxygen consumption, exercise time, and maximal workload in the patients undergoing CSR implantation. This was contrasted with no observable difference in subjective measures of functional class and SAQ domains, pointing toward a pronounced placebo effect in the sham control group.⁸ The ORBITA‑COSMIC trial⁹ enrolled 50 patients. The study failed to achieve its primary end point, that is, increased perfusion of ischemic segments measured with quantitative magnetic resonance imaging (MRI). The authors observed a reduction in the number of daily reported angina episodes. However, this outcome was not supported by power calculations and did not manifest in improved angina frequency reported by patients as part of the SAQ.⁹

In the 2024 European Society of Cardiology guidelines,¹⁰ CSR treatment is a level 2b recommendation; the level of recommendation has not changed since the previous chronic coronary syndrome guidelines published in 2019. In 2020, the Food and Drug Administration Circulatory Systems Devices panel voted in favor of the method’s safety but against its effectiveness.¹¹ To reduce the evidence gap, future properly powered and sham‑controlled studies should aim to unequivocally demonstrate CSR effectiveness in objective outcomes and further explore its mechanism of action. As already noted, Włodarczak et al⁵ reported a high rate of improvement by at least 1 functional class (86.6%). This should be, however, contrasted with a 42% improvement rate in the sham control group of the COSIRA trial.⁷ The placebo effect, frequently encountered in patients undergoing pain management therapies, may be even more pronounced, if the method in question is an invasive procedure.¹² As elegantly demonstrated by Baldetti et al,¹³ an important feature of the placebo effect might be its alleviation over time. This might also explain mitigation of the 6MWD in the study by Włodarczak et al.⁵

The main difference between a subjective and objective outcome is a measurable threshold for the occurrence of angina and total functional capacity if the objective outcome is used. Both the COSIRA and ORBITA‑COSMIC trials were neutral regarding the change in treadmill exercise time.^7,9 The strength of the CROSSROAD study was its individually adjusted ramp protocol with measurement of oxygen consumption, which allowed for detecting smaller, yet demonstrable increments in exercise capacity. The study, however, was hampered by the small number of enrolled patients.⁸

As a secondary end point, the MRI analysis in the ORBITA‑COSMIC trial showed signs of improved subendocardial‑to‑subepicardial perfusion ratio inside individual ischemic segments.⁹ This is in contrast to some preclinical animal studies, which showed increased perfusion of ischemic segments, even as a result of increased collateral circulation. In the context of CSR treatment, the individual variability in epicardial coronary disease is further complicated by the complexity of the venous drainage system. Clear understanding of the underlying mechanism would not only strengthen the rationale for its utilization but also help us with the optimal selection of patients to reduce the 20%–30% share of nonresponders. This lack of response could be partly explained by suboptimal endothelization, ischemia location, and anatomy of the drainage system including the Thebesian veins. Furthermore, clarification of the mechanism would provide the basis for implementation of this treatment option in patients with CTO of the right coronary artery or ANOCA.^14,15

To conclude, CSR implantation constitutes a promising treatment option for patients with refractory angina, which is already used in clinical practice in many European centers. The paper by Włodarczak et al⁵ offers additional information about the high success rate and low number of complications. However, to univocally determine its effectiveness, further randomized, placebo‑controlled studies with objective outcomes are needed.