Dataset Information

A novel method to interpret early phase trials shows how the narrowing of the coronary sinus concordantly improves symptoms, functional status and quality of life in refractory angina.

ABSTRACT:

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 (Coronary Sinus Reducer for Treatment of Refractory Angina) 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.

SUBMITTER: Jolicoeur EM

PROVIDER: S-EPMC8641517 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundMany 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.MethodsWe 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.ResultsA 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.ConclusionsIn 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.).

Project description:AimTo summarize the evidence on the clinical effectiveness and safety of coronary sinus reducing stent (CSRS) therapy in refractory angina pectoris (AP) patients.MethodsWe performed a systematic literature search in common databases (n=4). The evidence obtained was summarized according to GRADE methodology. A health technology assessment (HTA) was conducted using the HTA Core Model® for Rapid Relative Effectiveness Assessment. Primary outcomes for the clinical effectiveness domain were the proportion of patients with improvement in two or more Canadian Cardiovascular Society (CCS) angina score classes, overall mean reduction of CCS class, and Seattle Angina Questionnaire (SAQ) quality of life (QoL) score improvement. Outcomes for the safety domain were adverse device effects (ADEs) and serious adverse device effects (SADEs).ResultsOne randomized controlled trial (RCT) was identified. Outcomes that showed statistically significant differences between CSRS and sham treatment (in favor of CSRS) were CCS angina score improvement of one or two classes, overall mean reduction of CCS class, and SAQ QoL score improvement. Concerning safety, the sham-controlled trial data indicate that there were fewer SADEs in the intervention group (19%) than in the control group (46%). SADEs reported in observation studies ranged from none to 30%. The most frequently reported SADEs were death and stable angina. In the RCT, the only case of death occurred in the control group. Concerning clinical effectiveness, the risk of bias (RoB) was rated to be low, and concerning safety, the RoB was rated to range from low to moderate. As assessed by GRADE, the overall strength of evidence for effectiveness and safety was moderate. Internal and external validity of the evidence base were low.ConclusionEven though the current evidence indicates that the assessed technology, CSRS, is potentially more effective than sham intervention for refractory AP patients, the lack of internal validity of the studies undermines the partially positive results.

Project description: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.