Clinical trial NCT05780125: Effectiveness of Different Fibrinogen Preparations in Restoring Clot Firmness
Official title: Effectiveness of Different Fibrinogen Preparations in Restoring Clot Firmness
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Hypofibrinogenemia
Surgical Blood Loss
Bleeding
Cardiac Disease
Surgery
Keywords: hypofibrinogenemia
cardiac surgery
postoperative bleeding
Lead sponsor: IRCCS Policlinico S. Donato
Sponsor class: OTHER
First posted: 2023-03-22
Enrollment: 40
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Prospective, double-blind, randomized
Primary purpose: DIAGNOSTIC

Brief summary: Fibrinogen concentrate is produced by different manufacturers using different purification technologies. The products available in Italy are three: RiaSTAP (CSL Behring), FIBRYGA (Octapharma), and FibCLOT (LFB). RiaSTAP and FIBRYGA are sold in 1-gram vials, and FibCLOT - in 1.5-gram vials. A recent in vitro study assessed how these products affected the clot firmness measured by the ROTEM FIBTEM maximum clot firmness (MCF) parameter. In vitro conditions, FibCLOT was verified to be the most efficient in increasing clot firmness.

The present study is aimed to assess, in a series of patients undergoing cardiac surgery with cardiopulmonary bypass, the hypothesis that the FibCLOT fibrinogen is superior to the RiaSTAP fibrinogen in increasing the FIBTEM MCF parameter in a clinical model of bleeding (postoperative bleeding after complex cardiac surgery).

Detailed description: The Effectiveness of DIfferent fibrinogen PreparatiOns in Restoring clot firmness (EDIPO RE) is a pragmatic, double-blinded, randomized controlled trial testing the hypothesis that FibCLOT is superior to RiaSTAP in restoring fibrinogen-dependent clot firmness in cardiac surgery acquired hypofibrinogenemia.

A randomization sequence was generated by a computerized system, and then sealed envelopes containing the drug assigned were prepared. The randomization ratio of the treatment arms was 1:1. An unblinded biologist was in charge of running the ROTEM® tests, randomization, drug preparation, and masking, and its delivery to the operating room. The attending anesthesiologist, the surgical staff, and the medical staff in the ICU and ward were blinded.

After protamine administration, if microvascular bleeding was observed or suspected, POC testing, including ROTEM® EXTEM and FIBTEM, was run. If FIBTEM MCF was lower than 10 mm, the patient was randomly allocated to receive a dose of RiaSTAP® or FibCLOT® of 30 mg/kg, approximated to the closest between 2 or 3 grams. If no sign of ongoing bleeding was present, or FIBTEM MCF was 10 mm or higher the patient was considered screen failure and excluded from further observation.

Forty patients were randomized to receive the assigned treatment.

Fibrinogen was administrated intravenously by infusion at a rate of approximately 20 ml/min. Ten minutes after fibrinogen administration a second test was performed with ROTEM® EXTEM and FIBTEM tests to record the change of the parameters due to fibrinogen supplementation. No other hemostatic drugs nor transfusions, outside the study drug, were administered between the first and the second testing. In case of ongoing intra- or postoperative bleeding, after the second testing, all the hemostatic corrections were allowed and guaranteed by our institutional protocol for postoperative bleeding management, which includes the following step-by-step interventions:

* 30-50 mg of additional protamine for the correction of residual heparin, if the CT at INTEM exceeded 20% of the CT at HEPTEM;
* Additional fibrinogen concentrate, if FIBTEM MCF \< 10 mm or Clauss fibrinogen \< 150 mg dL-1;
* Platelet concentrates if P2Y12 receptor inhibitors were discontinued not later than 7 days, a postoperative ADP test at Multiplate® aggregometry \< 12 U, or a postoperative platelet count measured or presumed from preoperative count \<100,000 cells/µL;
* 4-factors prothrombin complex concentrate (PCC, Pronativ, Octapharma, Lachen, Switzerland) 20 IU kg-1 if EXTEM CT \> 100 s (after correction of fibrinogen and platelet values) or INR \> 1,5.

Preoperative, and perioperative data and details of postoperative outcomes were retrieved from our institutional database and patients' medical charts, including demographics, preoperative risk factors, procedure details, postoperative bleeding and transfusions, intensive care unit (ICU), and hospital stay duration. For the study, the following additional data have been collected: preoperative fibrinogen, platelet count, coagulation parameters (prothrombin time, PT; international normalized ratio, INR; activated partial thromboplastin time, aPTT), post protamine EXTEM CT and MCF and FIBTEM MCF; post-fibrinogen supplementation EXTEM CT and MCF and FIBTEM MCF; fibrinogen, platelet count and coagulation at the ICU arrival.

Eligibility criteria: Inclusion Criteria:

* elective cardiac surgery with cardiopulmonary bypass;
* complex cardiac surgery (coronary artery bypass graft + valve repair/replacement; double/triple valve repair/replacement; ascendant aorta surgery);
* written consent to participate;

Exclusion Criteria:

* urgent or emergent cardiac surgery;
* known hypersensitivity to the active principle or to one of the excipients of the study drugs;
* coagulation disorders, known or presumable from anamnesis;
* known hepatopathy;
* known risk of thrombosis or disseminated intravascular coagulation;
* participation in another clinical study where an experimental product has been administered within 30 days from the day of the inclusion in the study;
* whatever clinical condition that, in the opinion of the investigator, makes the patients not suitable to the experimentation.

Primary outcomes:
measure: FIBTEM MCF (mm)
timeFrame: Within 10 minutes after protamine administration
measure: FIBTEM CT and CFT (sec)
timeFrame: Within 10 minutes after protamine administration
measure: EXTEM CT and CFT (sec)
timeFrame: Within 10 minutes after protamine administration
Secondary outcomes:
measure: Postoperative bleeding
timeFrame: 12 and 24 hours after surgery
measure: Incidence of moderate/severe bleeding
timeFrame: 12 hours after surgery
measure: Incidence of transfusion
timeFrame: 12 and 24 hours after surgery
Other outcomes:
Locations:
city: San Donato Milanese
country: Italy
facility: IRCCS Policlinico San Donato
state: MI
Study officials:
affiliation: IRCCS Policlinico S. Donato
name: Marco Ranucci, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Ranucci M, Baryshnikova E. Fibrinogen supplementation after cardiac surgery: insights from the Zero-Plasma trial (ZEPLAST). Br J Anaesth. 2016 May;116(5):618-23. doi: 10.1093/bja/aev539. Epub 2016 Feb 17.
citation: Stolt H, Shams Hakimi C, Singh S, Jeppsson A, Karlsson M. A comparison of the in vitro effects of three fibrinogen concentrates on clot strength in blood samples from cardiac surgery patients. Acta Anaesthesiol Scand. 2021 Nov;65(10):1439-1446. doi: 10.1111/aas.13967. Epub 2021 Sep 1.
citation: Scolletta S, Simioni P, Campagnolo V, Celiento M, Fontanari P, Guadagnucci A, Guarracino F, Haxhiademi D, Paniccia R, Simeone F, Ranucci M; Granducato Research Group. Patient blood management in cardiac surgery: The "Granducato algorithm". Int J Cardiol. 2019 Aug 15;289:37-42. doi: 10.1016/j.ijcard.2019.01.025. Epub 2019 Jan 11.
citation: Tibi P, McClure RS, Huang J, Baker RA, Fitzgerald D, Mazer CD, Stone M, Chu D, Stammers AH, Dickinson T, Shore-Lesserson L, Ferraris V, Firestone S, Kissoon K, Moffatt-Bruce S. STS/SCA/AmSECT/SABM Update to the Clinical Practice Guidelines on Patient Blood Management. J Cardiothorac Vasc Anesth. 2021 Sep;35(9):2569-2591. doi: 10.1053/j.jvca.2021.03.011. Epub 2021 Jun 30. No abstract available.
citation: Dyke C, Aronson S, Dietrich W, Hofmann A, Karkouti K, Levi M, Murphy GJ, Sellke FW, Shore-Lesserson L, von Heymann C, Ranucci M. Universal definition of perioperative bleeding in adult cardiac surgery. J Thorac Cardiovasc Surg. 2014 May;147(5):1458-1463.e1. doi: 10.1016/j.jtcvs.2013.10.070. Epub 2013 Dec 9.