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December 2019

Fibrinogen Replacement for Bleeding After Cardiac Surgery: The Results 0f the Canadian FIBRES Trial

Author: J. Callum1 , MD and K. Karkouti2 , MD on behalf of the FIBRES Research Group

1 Department of Laboratory Medicine and Molecular Diagnostics, Sunnybrook Health Sciences Centre and Department of Laboratory Medicine and Molecular Diagnostics, University of Toronto, Ontario

2 Department of Anesthesia and Pain Management, Sinai Health System, Women’s College Hospital, University Health Network, Toronto, Ontario; Department of Anesthesia and Institute of Health Policy, Management, and Evaluation, University of Toronto, Ontario; Peter Munk Cardiac Centre, University Health Network, Toronto, Ontario

Hemorrhage is a common complication after cardiac surgery and accounts for a large proportion of the blood products transfused across Ontario. An important cause of bleeding is hypofibrinogenemia (fibrinogen <1.5-2.0 g/L), for which international guidelines recommend fibrinogen replacement with cryoprecipitate or fibrinogen concentrate. The two products have important differences, but comparative clinical data is limited and large randomized trials have not been carried out. Cryoprecipitate is the most common product used in Ontario but it is not used in many other jurisdictions (e.g., European countries) due to the concerns regarding the risk of future emerging pathogens with a non-pathogen reduced product. Due to the lack of definitive clinical trials, the following are unknown: (1) the preferred product for fibrinogen replacement; (2) the optimal dose of the preferred product; and, (3) the right threshold for administration of fibrinogen when faced with a bleeding patient. The objective of the FIBRES study was to answer the first question and determine if fibrinogen concentrate is non-inferior to cryoprecipitate for the treatment of bleeding related to hypofibrinogenemia after cardiac surgery.

The study randomized patients at 11 Canadian hospitals. The study included adult patients experiencing clinically significant bleeding and low fibrinogen levels after cardiac surgery (the patients underwent surgery between February 10, 2017 and November 1, 2018). The patients were randomized to fibrinogen concentrate 4 g (N=415) or cryoprecipitate 10 units (N=412) for each ordered dose within 24-hours after cardiopulmonary bypass. Quality control data from Canadian Blood Services showed that 4 grams was the closest dose to the standard 10 U pooled cryoprecipitate dose. The fibrinogen concentrate was Fibryga provided by Octapharma (room temperature storage product with rapid reconstitution in <5 minutes and rapid infusion (4 grams over 5-10 minutes)). No other aspect of their care was modified. The primary outcome was blood components (red cells, platelets, plasma) administered during the 24-hours after bypass. A two-sample, one-sided test for the ratio of the mean number of units was conducted to evaluate non-inferiority (threshold for non-inferiority <1.2).

Overall, 735 patients (372 fibrinogen concentrate, 363 cryoprecipitate) were treated and included in the primary analysis. The patients represented approximately 6% of all patients undergoing cardiac surgery at these centres and therefore represent unusual patients with significant hemorrhage. The median (IQR) age was 64 (53–72) years, 30% were women, 71% underwent complex surgeries, 92% had moderate to severe post-operative bleeding, and pre-treatment fibrinogen level was 1.6 (1.3–1.9) g/L. The mean (95% CI) 24-hour post-bypass allogeneic transfusions were 16.3 (14.9 to 17.8) and 17.0 (15.6 to 18.6) units in the fibrinogen concentrate and cryoprecipitate groups, respectively (ratio 0.96; 1-sided 97.5% CI, -∞ to 1.09; p-value for non-inferiority <0.001; superiority 2-sided 95% CI, 0.84 to 1.09; p-value for superiority =0.5). Thromboembolic events occurred in 26 (7.0%) and 35 (9.6%) of patients in the fibrinogen concentrate and cryoprecipitate groups, respectively. No other outcomes differences for secondary outcomes or safety concerns were identified. The full trial results and supplementary appendix can be found at this link: https://jamanetwork.com/journals/jama/fullarticle/2753529

In conclusion, in the FIBRES study fibrinogen concentrate was found to be non-inferior to cryoprecipitate with regard to number of blood components transfused in a 24-hour period post-bypass. Use of fibrinogen concentrate should be considered for management of bleeding in patients with acquired hypofibrinogenemia after cardiac surgery to mitigate the risk of emerging pathogens. In addition, fibrinogen concentrates are logistically easier for the technologists to prepare, they are stored at room temperature, are easier to redistribute if not used before the expiration date, can be prepared at the bedside (may reduce wastage), and have no impact on the production of other components (platelets and plasma).

Fibrinogen Concentrate (Human) (Riastap®)– Frequently Asked Questions for Physicians

University Health Network, Version 3: March 7, 2018

1. What are fibrinogen concentrates?

Fibrinogen concentrate is a blood product/ plasma derivative (from pooled human plasma) containing fibrinogen (1 gram per vial).

2. When should this product be used?

This product is indicated for the treatment of congenital fibrinogen deficiency (i.e. congenital afibrinogenemia and hypofibrinogenemia). Off label use may be considered for replacement of fibrinogen in urgent situations (e.g. hemorrhage post CV surgery, severe trauma, postpartum hemorrhage, and tPA-related intracranial hemorrhage)

3. Is it a blood product?

Yes. This product is derived from human plasma. As with blood transfusion, the donors have been screened for viral infections such as Human Immunodeficiency Virus (HIV), Hepatitis C (HCV) and Hepatitis B (HBV). In addition, virus inactivation and virus removal steps which are part of the manufacturing process, are considered effective for enveloped viruses such as HIV, HCV, HBV, and for the non-enveloped Hepatitis A virus (HAV). The measures taken may be of limited value against non-enveloped viruses such as parvovirus B19, and theoretically, Creutzfeldt-Jakob disease (CJD) and variant-CJD.

4. Is consent required?

Yes. Patients should be informed that it is a blood product and that the risk of viral transmission is exceptionally low, but not zero, because the product is derived from blood donors. They should also be informed of the risk of allergic reactions.

5. What Blood Bank testing is required?

None. A group and screen is NOT required before use.

6. Are there patients who should not receive this product?

Exercise caution when administering to patients with a history of deep vein thrombosis, pulmonary embolism, arterial thrombosis or liver disease as there is a risk of thrombosis

For complete information please refer to the product monograph.

7. What are the common side effects that my patient could experience?

Hives, generalized urticaria, tightness of the chest, wheezing, hypotension, and anaphylaxis.

8. What is the typical adult emergency dose?

4grams of Fibrinogen concentrate is equivalent to 1 adult pool of cryoprecipitate (~10U)

9. What do I do if the patient refuses fibrinogen concentrate?

Some Jehovah’s Witness patients may decline the use of fibrinogen concentrate – this should be discussed with the patient on a case by case basis.

Document in the patient’s chart and communicate the reason to the Blood Bank so we can put a comment in the electronic blood bank record.

The form Transfusion and Alternative Options as Selected by Patient, available from Blood Bank, should be used to document the patient’s wishes.

References 1. Riastap® product monograph