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Original Investigation
October 21, 2019

Effect of Fibrinogen Concentrate vs Cryoprecipitate on Blood Component Transfusion After Cardiac Surgery: The FIBRES Randomized Clinical Trial

Author Affiliations
  • 1Department of Laboratory Medicine and Molecular Diagnostics, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada
  • 2Laboratory Medicine Program, University Health Network, Toronto, Ontario, Canada
  • 3Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada
  • 4Peter Munk Cardiac Centre, University Health Network, Toronto, Ontario, Canada
  • 5Heart and Stroke Richard Lewar Centre, University of Toronto, Toronto, Ontario, Canada
  • 6Interdepartmental Division of Critical Care, Department of Medicine, University of Toronto, Toronto, Ontario, Canada
  • 7Sunnybrook Research Institute, Department of Critical Care Medicine, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada
  • 8Faculty of Health Sciences, McMaster University, Hamilton, Ontario, Canada
  • 9Department of Medicine, McMaster University, Hamilton, Ontario, Canada
  • 10University Health Network, Division of Cardiovascular Surgery, Toronto General Hospital, Toronto, Ontario, Canada
  • 11University of Toronto, Toronto, Ontario, Canada
  • 12Department of Biostatistics, ERGOMED CDS GmbH, Cologne, Germany
  • 13Department of Anesthesia and Pain Management, Sinai Health System, Women’s College Hospital, University Health Network, Toronto, Ontario, Canada
  • 14Department of Anesthesiology, Pharmacology and Therapeutics; University of British Columbia, Vancouver, Canada
  • 15Royal Columbian Hospital, Vancouver, British Columbia, Canada
  • 16Anesthesiology Department, Institut universitaire de cardiologie et de pneumologie de Québec-Université Laval, Québec City, Québec, Canada
  • 17Departments of Anesthesiology, Perioperative and Pain Medicine, and Surgery, University of Manitoba, Winnipeg, Canada
  • 18Department of Anesthesia and Perioperative Medicine, Western University, London, Ontario, Canada
  • 19St Michael’s Hospital, Division of Transfusion Medicine, Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada
  • 20Department of Anesthesiology, Montréal Heart Institute, Université de Montréal, Montréal, Québec, Canada
  • 21Department of Anesthesiology and Perioperative Medicine; Kingston General Hospital, Queen’s University, Kingston, Ontario, Canada
  • 22Department of Pathology and Molecular Medicine, Kingston Health Science Center, Queen’s University, Kingston, Ontario, Canada
  • 23Department of Anesthesiology; Hamilton Health Sciences Corporation, McMaster University, Hamilton, Ontario, Canada
  • 24University of Ottawa Heart Institute, Division of Cardiac Anesthesiology and Critical Care, Department of Anesthesia and Pain Medicine, University of Ottawa School of Epidemiology and Public Health, Ottawa, Ontario, Canada
  • 25Cardiac Surgery, Royal Columbian Hospital, University of British Columbia, Vancouver, Canada
  • 26McMaster Centre for Transfusion Research, Department of Medicine, McMaster University, Hamilton, Ontario, Canada
  • 27Department of Anesthesia and Institute of Health Policy, Management, and Evaluation, University of Toronto, Toronto, Ontario, Canada
JAMA. 2019;322(20):1966-1976. doi:10.1001/jama.2019.17312
Key Points

Question  Is fibrinogen concentrate noninferior to cryoprecipitate for treatment of bleeding related to acquired hypofibrinogenemia in cardiac surgery?

Findings  In this randomized trial of 735 adult patients who underwent cardiac surgery and developed clinically significant bleeding and hypofibrinogenemia post cardiopulmonary bypass, the mean number of blood components transfused within 24 hours post bypass was 16.3 units in the fibrinogen concentrate group and 17.0 units in the cryoprecipitate group; ratio of the mean number of units transfused was 0.96, which met the prespecified noninferiority margin ratio of less than 1.2.

Meaning  For management of cardiac surgery–associated bleeding related to acquired hypofibrinogenemia, fibrinogen concentrate may be considered for fibrinogen replacement.

Abstract

Importance  Excessive bleeding is a common complication of cardiac surgery. An important cause of bleeding is acquired hypofibrinogenemia (fibrinogen level <1.5-2.0 g/L), for which guidelines recommend fibrinogen replacement with cryoprecipitate or fibrinogen concentrate. The 2 products have important differences, but comparative clinical data are lacking.

Objective  To determine if fibrinogen concentrate is noninferior to cryoprecipitate for treatment of bleeding related to hypofibrinogenemia after cardiac surgery.

Design, Setting, and Participants  Randomized clinical trial at 11 Canadian hospitals enrolling adult patients experiencing clinically significant bleeding and hypofibrinogenemia after cardiac surgery (from February 10, 2017, to November 1, 2018). Final 28-day follow-up visit was completed on November 28, 2018.

Interventions  Fibrinogen concentrate (4 g; n = 415) or cryoprecipitate (10 units; n = 412) for each ordered dose within 24 hours after cardiopulmonary bypass.

Main Outcomes and Measures  Primary outcome was blood components (red blood cells, platelets, plasma) administered during 24 hours post bypass. A 2-sample, 1-sided test for the ratio of the mean number of units was conducted to evaluate noninferiority (threshold for noninferiority ratio, <1.2).

Results  Of 827 randomized patients, 735 (372 fibrinogen concentrate, 363 cryoprecipitate) were treated and included in the primary analysis (median age, 64 [interquartile range, 53-72] years; 30% women; 72% underwent complex operations; 95% moderate to severe bleeding; and pretreatment fibrinogen level, 1.6 [interquartile range, 1.3-1.9] g/L). The trial met the a priori stopping criterion for noninferiority at the interim analysis after 827 of planned 1200 patients were randomized. Mean 24-hour postbypass allogeneic transfusions were 16.3 (95% CI, 14.9 to 17.8) units in the fibrinogen concentrate group and 17.0 (95% CI, 15.6 to 18.6) units in the cryoprecipitate group (ratio, 0.96 [1-sided 97.5% CI, −∞ to 1.09; P < .001 for noninferiority] [2-sided 95% CI, 0.84 to 1.09; P = .50 for superiority]). Thromboembolic events occurred in 26 patients (7.0%) in the fibrinogen concentrate group and 35 patients (9.6%) in the cryoprecipitate group.

Conclusions and Relevance  In patients undergoing cardiac surgery who develop clinically significant bleeding and hypofibrinogenemia after cardiopulmonary bypass, fibrinogen concentrate is noninferior to cryoprecipitate with regard to number of blood components transfused in a 24-hour period post bypass. Use of fibrinogen concentrate may be considered for management of bleeding in patients with acquired hypofibrinogenemia in cardiac surgery.

Trial Registration  ClinicalTrials.gov Identifier: NCT03037424

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