Executive Summary (English version

potenzialmente portare ad un aumento della qualità della vita nei pazienti affetti da angina refrattaria. I maggiori costi iniziali correlati alla procedura sono ampiamente compensati nel breve periodo dai migliori risultati clinici ottenibili (ospedalizzazioni, visite, accessi al pronto soccorso, coronarografie), con conseguenti risparmi a partire dal quarto anno nell'analisi di impatto sul budget ed un rapporto di dominanza nell'analisi di costo-utilità. Ulteriori analisi alla luce di nuove evidenze dovranno essere condotte e sviluppate per stabilire in modo ancora più robusto la sostenibilità economica del dispositivo nel contesto del Servizio Sanitario Nazionale, soprattutto sulla sua efficacia nel medio-lungo termine.

Impatto organizzativo: Secondo le linee guida ESC 2019, i pazienti con angina refrattaria dovrebbero essere trattati in cliniche specializzate con l'aiuto di team multidisciplinari esperti nel selezionare l'approccio terapeutico più adatto al singolo paziente sulla base di una diagnosi accurata dei meccanismi della sindrome e del dolore che ne deriva. In Germania, l'Institut für das Entgeltsystem im Krankenhaus, (l'istituto tedesco per il sistema di remunerazione degli ospedali), ha assegnato a Neovasc Reducer la denominazione NUB Status 1 anche per il 2020. Questo status (NUB) permette ai nuovi farmaci o dispositivi di essere utilizzati dagli ospedali prima di raggiungere la piena idoneità al rimborso. Inoltre, il Reducer ha recentemente ottenuto il rimborso nazionale in Inghilterra a seguito dell'inclusione nel catalogo nazionale degli High Cost Tariff Excluded Devices (HCTED). Infine, recentemente il Reducer ha ottenuto il rimborso del “Prise en Charge Transitoire” (“PECT”) in Francia, dall’autorità sanitaria nazionale (Haute Autorité de Santé – HAS). Il processo “prise en charge transitoire” (PECT) è progettato per consentire ai pazienti con malattie significative e senza altre opzioni terapeutiche di beneficiare di nuove terapie per indicazioni selezionate.

Executive Summary (English version)

Literature review: In order to achieve the aim of this research, a systematic review of the scientific literature was conducted. The results of this research will be enriched with grey literature sources and input provided by key opinion leaders during an Advisory Board. Our search strategy produced the following results. After deleting 2 duplicates, 85 studies were identified. Of these 31 records were excluded based on title / abstract for reporting an irrelevant study design (19), for reporting on a different technology (10), for reporting on another condition (1), for reporting of insufficient information (1), as it is neither in English nor in Italian (0). Other records were identified through a manual search.

Health Problem and Current Management: Treatments for coronary heart disease patients have had major developments in recent decades, both in the pharmacological and interventional fields, and this has helped to prolong the survival of these patients. However, the growing number of patients who show persistent and disabling symptoms of angina proves that at the same time their quality of life has not been equally improved. Consequently, the treatment of refractory angina remains a challenge for today's medicine. Refractory angina is defined as a chronic clinical condition, Canadian Cardiovascular Society (CCS) class III or IV, characterized by the presence of debilitating anginal symptoms due to severe and / or widespread obstructive coronary artery disease, in which it has been clinically established the presence of myocardial ischemia as a cause of symptoms. The Coronary Sinus Reducer System (CSRS) is the latest line of therapy for patients with coronary artery disease (CAD) who are ineligible for

revascularization, demonstrate reversible ischaemia, and have refractory angina pectoris (AP) despite optimal standard medical therapy. CAD is a pathological process characterized by the accumulation of atherosclerotic plaques in the epicardial arteries, both obstructive and non-obstructive (Knuuti J. et Al., 2019). A number of clinical symptoms of CAD are chronic coronary syndromes to which refractory AP also belongs. Currently there are not yet very detailed epidemiological data regarding refractory angina pectoris, but according to some studies in Italy the prevalence in the age group between 35 and 75 years of chronic ischemic heart disease and stable angina is about 30,000 cases per million inhabitants (3.3% in men and 3.9% in women). Considering the increase in the elderly population, it is estimated that in Italy there are about 5 million coronary heart disease patients, of which 1.5 million with stable angina. The annual incidence of hospitalizations for acute myocardial infarction is about 100,000 cases in Italy, while the annual incidence of new cases of angina pectoris is about 1% per year in the male population aged 45 to 65 years with a slightly greater in women (Report by the national coordinator of Cardiac Surgery of GVM Care & Research). About 5-10% of patients with chronic ischemic heart disease, who are already taking adequate medical therapy, and who undergo coronary angiography for angina, are not treatable by revascularization and constitute the population affected by refractory angina.

Technical Features: The idea of considering the coronary sinus as a potential target for the treatment of ischemic heart disease dates back more than 60 years. In 1955, cardiac surgeon Claude Beck demonstrated in an animal model how the surgical reduction of the diameter of the coronary sinus was associated with a reduction of the infarct area (from coronary occlusion). This experiment suggested that the narrowing of the coronary sinus could favour the flow of oxygenated blood in the most ischemic myocardial areas, thus reducing the extension of the infarct area. Coronary sinus plastic surgery, to determine a residual diameter of 3 mm, was associated, in patients with severe angina, with a reduction of anginal symptoms, an improvement in exercise tolerance and reduced mortality at 5 years. The Coronary Sinus Reducer or "Reducer" is a medical device for the treatment of patients with severe angina symptoms who are unresponsive to optimal medical therapy and who are not suitable for further revascularization. Indeed, in the absence of effective alternative treatment options for patients with refractory angina, the coronary sinus reduction stent (CSRS) aims to reduce the extent and severity of ischemia, improving perfusion in the ischemic areas of the myocardium, and through this mechanism of action improve the quality of life and alleviate the symptoms of angina in patients with obstructive coronary artery disease (CAD) who are not candidates for revascularization. The Neovasc Reducer System device received the CE mark in 2011 for the treatment of refractory angina and its use is foreseen by the ESC (European Society of Cardiology) 2019 guidelines for the diagnosis and management of coronary syndromes (Diagnostic and Interventional Cardiology , 2011).

Efficacy & Safety: Several studies in the literature have shown that the device is related to an increase in quality of life and an improvement in symptoms of refractory angina. However, concerning efficacy, limitations on problems with the mechanism of action, the placebo effect, the sample size, and the randomization procedure in the identified studies should be taken into account. First, the mechanism of action of the device is unclear. Although the Reducer is hypothesized to be able to relieve symptoms by improving perfusion in ischemic myocardial territories, no studies have evaluated its effect on myocardial perfusion with clear evidence of its mechanism of action. Still regarding the mechanism of action, it is not clear why there is still a 15-30% non-response rate. One line

of interpretation suggests that individual anatomical variants of the cardiac venous system may lead to insufficient generation of the pressure gradient across the device. Another line of interpretation assumes that the lack of endothelialization may be the cause - that is, in some patients, the surface of the device does not get to be completely covered by the endothelium (the inner lining of the vein) - and therefore the pressure gradient is not created. Second, the clinical benefit of the Reducer could potentially be overestimated due to the sample size. For this reason, further studies will be needed to confirm the effectiveness of the device.

Regarding the interpretation of safety results, approximately 20% of patients with refractory angina are ineligible to receive CSRS implantation due to the high variability in anatomy and CS size, but also other relevant considerations. Thus, anatomical features of the patient should be evaluated during the procedure. Considerations include the close proximity of the circumflex coronary artery which, if accidentally damaged, causes an acute myocardial infarction. In addition, device migration EDS poses a potential problem as cases of migration of the Reducer into the right atrium have been reported.

Economic Impact: The budget impact analysis and the cost-effectiveness model show how the Reducer device, despite an increase in the resources absorbed in the first years of implementation and use, can potentially lead to an increase in the quality of life in patients suffering from refractory angina. These costs are amply compensated in the short term by the best clinical outcomes achievable, resulting in savings from the fourth year onwards in the budget impact analysis and a dominance profile in the cost-utility analysis. Further analyzes in the light of new evidence will have to be conducted and developed to establish even more robustly the economic sustainability of the device in the context of the National Health Service, especially on its effectiveness in the medium to long term.

Organizational impact: According to the ESC guidelines 2019, patients with refractory angina are best treated in specialized clinics with the help of multidisciplinary teams experienced in selecting the most suitable therapeutic approach for the individual patient based on an accurate diagnosis of the mechanisms of the syndrome and the resulting pain. Neovasc Reducer is currently CE marked and is only available in the EU. In Germany, the Institut für das Entgeltsystem im Krankenhaus, (the German institute for hospital remuneration system), has awarded the Neovasc Reducer a NUB Status 1 designation again for 2020. This status (NUB) allows new drugs or devices to be used by hospitals before reaching full reimbursement eligibility. In addition, the Reducer has recently been granted national reimbursement in England following the inclusion in the national catalogue of high cost excluded devices (HCTED). Furthermore, Reducer recently obtained reimbursement of the "Prise en Charge Transitoire" ("PECT") in France, from the national health authority (Haute Autorité de Santé - HAS). The new PECT process is designed to allow patients with significant disease and no other treatment options to benefit from novel therapies for selected indications.