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. 2019 Nov 26;322(20):1966-1976.
doi: 10.1001/jama.2019.17312.

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

Jeannie Callum  1   2   3 , Michael E Farkouh  4   5 , Damon C Scales  6   7 , Nancy M Heddle  8   9 , Mark Crowther  9 , Vivek Rao  4   10   11 , Hans-Peter Hucke  12 , Jo Carroll  4   11   13 , Deep Grewal  4   11   13 , Sukhpal Brar  14   15 , Jean Bussières  16 , Hilary Grocott  17 , Christopher Harle  18 , Katerina Pavenski  19 , Antoine Rochon  20 , Tarit Saha  21 , Lois Shepherd  22 , Summer Syed  23 , Diem Tran  24 , Daniel Wong  25 , Michelle Zeller  26 , Keyvan Karkouti  4   6   13   27 ; FIBRES Research Group
Affiliations

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

Jeannie Callum et al. JAMA. .

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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Conflict of interest statement

Conflict of Interest Disclosures: Dr Callum reported receiving grants from Canadian Blood Services, Octapharma, and CSL Behring during the conduct of the study. Dr Farkouh reported receiving grants from Amgen and Novo Nordisk. Dr Scales reported receiving grants from Canadian Institute for Health Research. Dr Heddle reported receiving nonfinancial support from Octapharma during the conduct of the study and receiving grants from Canadian Blood Services. Dr Crowther reported receiving grants or personal fees from Bayer, Pfizer, BMS Canada, CSL Behring, Servier Canada, and Diagnostica Stago. Dr Rao reported receiving grants from Octapharma during the conduct of the study and receiving personal fees from Medtronic and Abbott. Dr Hucke reported receiving grants from Octapharma during the conduct of the study. Dr Pavenski reported serving as a member of the National Advisory Committee on Blood and Blood Products (Canada) and the Ontario Blood Advisory Committee (Ontario). Dr Tran reported receiving grants from Octapharma during the conduct of the study. Dr Zeller reported receiving grants from Canadian Blood Services and receiving personal fees from Pfizer. Dr Karkouti reported receiving grants and personal fees from Octapharma and Instrumentation Laboratory during the conduct of the study. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. Patient Flow in the FIBRES Study of the Effect of Fibrinogen Concentrate vs Cryoprecipitate on Blood Component Transfusion After Cardiac Surgery
CPB indicates cardiopulmonary bypass; IMP, investigational medicinal product.
Figure 2.
Figure 2.. Ratio of Mean Number of Allogeneic Blood Components Transfused in the 24 Hours After Cardiopulmonary Bypass for the Primary Analysis Set, Per-Protocol Analysis Set, and A Priori–Defined Subgroups
All patients in critical state were in the nonelective subgroup. Blue dashed line at x = 1.2 indicates the noninferiority margin.
See this image and copyright information in PMC

Comment in

  • doi: 10.1001/jama.2019.17313

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