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Original research
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
  1. E Marc Jolicoeur1,
  2. Stefan Verheye2,
  3. Timothy D Henry3,
  4. Lawrence Joseph4,
  5. Serge Doucet1,
  6. Christopher J White5,
  7. Elazer Edelman6,7,
  8. Shmuel Banai8
  1. 1Department of Medicine, Interventional Cardiology, Montreal Heart Institute, Montreal, Quebec, Canada
  2. 2Antwerp Cardiovascular Institute, ZNA Middelheim Hospital, Antwerpen, Belgium
  3. 3The Carl and Edyth Lindner Center for Research and Education, The Christ Hospital, Cincinnati, Ohio, United States
  4. 4Department of Epidemiology and Biostatistics, McGill University, Montreal, Quebec, Canada
  5. 5The John Ochsner Heart & Vascular Institute, Ochsner Clinical School, University of Queensland, New Orleans, Louisiana, USA
  6. 6Institute for Medical Engineering and Science, Cambridge, Massachusetts, USA
  7. 7Cardiovascular Division, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, USA
  8. 8The Tel Aviv Medical Center, The Tel Aviv University Medical School, Tel Aviv, Israel
  1. Correspondence to Dr E Marc Jolicoeur, Department of Medicine, Interventional Cardiology, Montreal Heart Institute, Montreal H1T 1C8, Quebec, Canada; marc.jolicoeur{at}icm-mhi.org

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.

  • cardiac catheterisation and angiography
  • interventional cardiology and endovascular procedures
  • percutaneous coronary intervention
  • coronary artery disease
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Footnotes

  • Contributors The following authors have contributed to the planning (EMJ, SV, TDH, LJ, SB), conduct (EMJ, LJ) and reporting (EMJ, SV, TDH, LJ, SD, CJW, EE, SB) of this manuscript. The corresponding author EMJ is responsible for the overall content as guarantor(s).

  • Funding The trial was sponsored and funded by Neovasc (British Columbia, Canada) which participated in the design of the protocol and management of sites but was not involved in the writing of the drafts of the manuscript or in the management or analysis of the data. EMJ is supported by research grants from les Fonds la Recherche du Québec en santé, the Canadian Institutes for Health Research. EE is supported by grants from the US National Institutes of Health including R01 GM49039.

  • Competing interests None declared.

  • Patient and public involvement Patients and/or the public were not involved in the design, conduct, reporting or dissemination plans of this research.

  • Patient consent for publication Not required.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Data availability statement Data are available on reasonable request. The data are available from the corresponding author EMJ.

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