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Protocol for a phase III, non-inferiority, randomised comparison of a new fibrinogen concentrate versus cryoprecipitate for treating acquired hypofibrinogenaemia in bleeding cardiac surgical patients: the FIBRES trial
  1. Keyvan Karkouti1,2,
  2. Jeannie Callum3,4,
  3. Vivek Rao2,5,
  4. Nancy Heddle6,
  5. Michael E Farkouh7,
  6. Mark A Crowther8,
  7. Damon C Scales9,10
  1. 1 Department of Anesthesia and Institute of Health Policy, Management, and Evaluation, University of Toronto, Toronto, Ontario, Canada
  2. 2 Peter Munk Cardiac Centre and Toronto General Research Institute, Toronto General Hospital, University Health Network, University of Toronto, Toronto, Ontario, Canada
  3. 3 Department of Clinical Pathology, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, Ontario, Canada
  4. 4 Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada
  5. 5 Division of Cardiovascular Surgery, University of Toronto, Toronto, Ontario, Canada
  6. 6 Department of Medicine, Faculty of Health Sciences, McMaster University, Hamilton, Ontario, Canada
  7. 7 Peter Munk Cardiac Centre and Heart and Stroke Richard Lewar Centre, University of Toronto, Toronto, Ontario, Canada
  8. 8 Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario, Canada
  9. 9 Department of Critical Care Medicine, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, Ontario, Canada
  10. 10 Interdepartmental Division of Critical Care and Department of Medicine, University of Toronto, Toronto, Ontario, Canada
  1. Correspondence to Dr Keyvan Karkouti; keyvan.karkouti{at}uhn.ca

Abstract

Introduction Coagulopathic bleeding is a serious complication of cardiac surgery to which an important contributor is acquired hypofibrinogenaemia (plasma fibrinogen <1.5–2.0 g/L). The standard intervention for acquired hypofibrinogenaemia is cryoprecipitate, but purified fibrinogen concentrates are also available. There is little comparative data between the two therapies and randomised trials are needed.

Methods and analysis FIBrinogen REplenishment in Surgery (FIBRES) is a multicentre, randomised (1:1), active-control, single-blinded, phase III trial in adult cardiac surgical patients experiencing clinically significant bleeding related to acquired hypofibrinogenaemia. The primary objective is to demonstrate that fibrinogen concentrate (Octafibrin/Fibryga; Octapharma) is non-inferior to cryoprecipitate. All patients for whom fibrinogen supplementation is ordered by the clinical team within 24 hours of cardiopulmonary bypass will receive 4 g of fibrinogen concentrate or 10 units of cryoprecipitate (dose-equivalent to 4 g), based on random allocation and deferred consent. The primary outcome is total red cell, platelet and plasma transfusions administered within 24 hours of bypass. Secondary outcomes include major bleeding, fibrinogen levels and adverse events within 28 days. Enrolment of 1200 patients will provide >90% power to demonstrate non-inferiority. One preplanned interim analysis will include 600 patients. The pragmatic design and treatment algorithm align with standard practice, aiding adherence and generalisability.

Ethics and dissemination The study is approved by the local research ethics board and will be conducted in accordance with the Declaration of Helsinki, Good Clinical Practice guidelines and regulatory requirements. Patient consent prior to treatment is waived, as per criteria in the Tri-Council Policy Statement. Results will be published in the scientific/medical literature, and at international congresses. Non-inferiority of purified fibrinogen concentrate would support its use in acquired hypofibrinogenaemia. The results are likely to improve care for cardiac surgical patients experiencing significant bleeding, an understudied yet high-risk population.

Trial registration number NCT03037424; Pre-results.

  • bleeding disorders and coagulopathies
  • cardiac surgery
  • clinical trials
  • adult surgery
  • blood bank & transfusion medicine
  • haematology

This is an Open Access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/

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Footnotes

  • Contributors Conception and design: KK, JC. Preparation of the first draft of the manuscript: KK. Critical revision of the manuscript for important intellectual content: KK, JC, VR, NH, MEF, MAC, DCS. Read and approved the final version of the manuscript to be published: KK, JC, VR, NH, MAF, MAC, DCS.

  • Funding This work was supported by Octapharma AG through an unrestricted grant for study conduct and the provision of fibrinogen concentrate. Cryoprecipitate was provided by Canadian Blood Services.

  • Competing interests KK has received support for research and/or honoraria from Octapharma. JC has received support for research through peer-reviewed grants from Canadian Blood Services. NH is the Research Director for the McMaster Centre for Transfusion Research, which receives funding support from Canadian Blood Services and Health Canada. The remaining authors have no competing interests or conflicts to declare.

  • Patient consent Not required.

  • Ethics approval UHN.

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

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