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Background: Reduction of the coronary sinus was shown to improve angina in patients unsuitable for revascularisation. We assessed whether a percutaneous device that reduces the diameter of the coronary sinus improved outcomes across multiple endpoints in a phase II trial., Methods: We conducted a novel analysis performed as a post hoc efficacy analysis of the COSIRA ( Co ronary Si nus R educer for Treatment of Refractory A ngina) trial, which enrolled patients with Canadian Cardiovascular Society (CCS) class 3-4 refractory angina. We used four domains: symptoms (CCS Angina Scale), functionality (total exercise duration), ischaemia (imaging) and health-related quality of life. For all domains, we specified a meaningful threshold for change. The primary endpoint was defined as a probability of ≥80% that the reducer exceeded the meaningful threshold on two or more domains (group-level analysis) or that the average efficacy score in the reducer group exceeded the sham control group by at least two points (patient-level analysis)., Results: We randomised 104 participants to either a device that narrows to coronary sinus (n=52) or a sham implantation (n=52). The reducer group met the prespecified criteria for concordance at the group level and demonstrated improvement in symptoms (0.59 CCS grade, 95% credible interval (CrI)=0.22 to 0.95), total exercise duration (+27.9%, 95% CrI=2.8% to 59.8%) and quality of life (stability +11.2 points, 95% CrI=3.3 to 19.1; perception +11.0, 95% CrI=3.3 to 18.7)., Conclusions: The reducer concordantly improved symptoms, functionality and quality of life compared with a sham intervention in patients with angina unsuitable for coronary revascularisation. Concordant analysis such as this one can help interpret early phase trials and guide the decision to pursue a clinical programme into a larger confirmatory trial., Trail Registration Number: ClinicalTrials.gov identifier: NCT01205893., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. No commercial re-use. See rights and permissions. Published by BMJ.)

Alongside the remarkable advances in medical and invasive therapies for the treatment of ischemic heart disease, an increasing number of patients with advanced coronary artery disease unsuitable for revascularization continue to suffer from angina pectoris despite optimal medical therapy. Patients with chronic angina have poor quality of life and increased levels of anxiety and depression. A considerable number of innovative therapeutic modalities for the treatment of chronic angina have been investigated over the years; however, none of these therapeutic options has become a standard of care, and none are widely utilized. Current treatment options for refractory angina focus on medical therapy and secondary risk factor modification. Interventions to create increased pressure in the coronary sinus may alleviate myocardial ischemia by forcing redistribution of coronary blood flow from the less ischemic subepicardium to the more ischemic subendocardium, thus relieving symptoms of ischemia. Percutaneous, transvenous implantation of a balloon expandable, hourglass-shaped, stainless steel mesh in the coronary sinus to create a fixed focal narrowing and to increase backwards pressure, may serve as a new device-based therapy destined for the treatment of refractory angina pectoris.

Background: Many patients with coronary artery disease who are not candidates for revascularization have refractory angina despite standard medical therapy. The balloon-expandable, stainless steel, hourglass-shaped, coronary-sinus reducing device creates a focal narrowing and increases pressure in the coronary sinus, thus redistributing blood into ischemic myocardium., Methods: We randomly assigned 104 patients with Canadian Cardiovascular Society (CCS) class III or IV angina (on a scale from I to IV, with higher classes indicating greater limitations on physical activity owing to angina) and myocardial ischemia, who were not candidates for revascularization, to implantation of the device (treatment group) or to a sham procedure (control group). The primary end point was the proportion of patients with an improvement of at least two CCS angina classes at 6 months., Results: A total of 35% of the patients in the treatment group (18 of 52 patients), as compared with 15% of those in the control group (8 of 52), had an improvement of at least two CCS angina classes at 6 months (P=0.02). The device was also associated with improvement of at least one CCS angina class in 71% of the patients in the treatment group (37 of 52 patients), as compared with 42% of those in the control group (22 of 52) (P=0.003). Quality of life as assessed with the use of the Seattle Angina Questionnaire was significantly improved in the treatment group, as compared with the control group (improvement on a 100-point scale, 17.6 vs. 7.6 points; P=0.03). There were no significant between-group differences in improvement in exercise time or in the mean change in the wall-motion index as assessed by means of dobutamine echocardiography. At 6 months, 1 patient in the treatment group had had a myocardial infarction; in the control group, 1 patient had died and 3 had had a myocardial infarction., Conclusions: In this small clinical trial, implantation of the coronary-sinus reducing device was associated with significant improvement in symptoms and quality of life in patients with refractory angina who were not candidates for revascularization. (Funded by Neovasc; COSIRA ClinicalTrials.gov number, NCT01205893.).

Background: A growing population of patients lives with severe coronary artery disease not amenable to coronary revascularization and with refractory angina despite optimal medical therapy. Percutaneous reduction of the coronary sinus is an emerging treatment for myocardial ischemia that increases coronary sinus pressure to promote a transcollateral redistribution of coronary artery in-flow from nonischemic to ischemic subendocardial territories. A first-in-man study has demonstrated that the percutaneous reduction of the coronary sinus can be performed safely in such patients. The COSIRA trial seeks to assess whether a percutaneous reduction of the coronary sinus can improve the symptoms of refractory angina in patients with limited revascularization options., Methods/design: The COSIRA trial is a phase II double-blind, sham-controlled, randomized parallel trial comparing the percutaneously implanted coronary sinus Reducer (Neovasc Inc, Richmond, BC, Canada) to a sham implantation in 124 patients enrolled in Canada, Belgium, England, Scotland, Sweden and Denmark. All patients need to have stable Canadian Cardiovascular Society (CCS) class III or IV angina despite optimal medical therapy, with evidence of reversible ischemia related to disease in the left coronary artery, and a left ventricular ejection fraction >25%. Participants experiencing an improvement in their angina ≥2 CCS classes six months after the randomization will meet the primary efficacy endpoint. The secondary objective of this trial is to test whether coronary sinus Reducer implantation will improve left ventricular ischemia, as measured by the improvement in dobutamine echocardiogram wall motion score index and in time to 1 mm ST-segment depression from baseline to six-month post-implantation., Discussion: Based on previous observations, the COSIRA is expected to provide a significant positive result or an informative null result upon which rational development decisions can be based. Patient safety is a central concern and extensive monitoring should allow an appropriate investigation of the safety related to the coronary sinus Reducer., Trial Registration: ClinicalTrials.gov identifier - NCT01205893.