Prospective Double Blinded Randomized Control Study of the Use of Fibrinogen in High-Risk Cardiac Surgery

The Use of Fibrinogen Concentrate in High-Risk Cardiac Surgery. A Prospective, Double-blinded, Randomized, Controlled Study

The aim of the study is to show that first line treatment with concentrated fibrinogen has superiority over the conventional therapy with fresh frozen plasma (FFP), platelets, and cryoprecipitate in perioperative management of bleeding after complex cardiac surgery.

Study Overview

• Status: Completed
• Conditions: Cardiac Complication During Procedure
• Intervention / Treatment: Drug: Fibrinogen

Detailed Description

All patients will be recruited from the Queen Elizabeth II (QEII) Health Sciences Center, Halifax, Nova Scotia, which is the sole tertiary cardiac surgical referral center in Nova Scotia that performs approximately 1000 open heart surgical procedures yearly, including more than 700 isolated coronary artery bypass graft (CABG) procedures.

Inclusion criteria: All patients who are scheduled for elective complex cardiac surgical procedures including, double procedures (aortic valve replacement+coronary artery bypass graft , mitral valve replacement+coronary artery bypass graft , aortic valve replacement+mitral valve replacement), redo-sternotomies, and aortic root repair +/-aortic valve replacement.

Exclusion criteria: Any known congenital or preexisting bleeding disorder, preexisting clinically significant abnormal fibrinogen level, severe liver disease (alanine aminotransferase or aspartate aminotransferase > 150 U/l), inability of providing informed consent, emergency surgery, pregnancy or nursing, age under 18 years, intake of anti-platelet drugs within the last 2- 5 days before surgery (low dose aspirin is allowed) allergy to concentrated fibrinogen or other components in the product, anemia (Hb < 110), diagnosed deep venous thrombosis, pulmonary embolism, acute stroke or acute myocardial infarction.

The primary outcome: Cumulative perioperative amount (number of units and total volume) of blood components used between the start of surgery and 24 hours after administration of the study drug or placebo. 'Blood Components' are defined as all fresh components of blood (RBCs, plasma, platelets, and Cryo).

The secondary outcomes: Fibrinogen levels, hematocrit, prothrombin time (PT), partial prothrombin time (PTT), INR, platelet count, Hemoglobin (Hb), Thromboelastometry (ROTEM®, clotting time (CT), clot formation time (CFT), Angle, maximum clot firmness (MCF), Cardiovascular intensive care unit (CVICU-stay), Hospital-stay, In-Hospital Mortality, Hemoglobin, adverse events (anaphylaxis, stroke, myocardial infarction, pulmonary embolism, and deep vein thromboembolism) and usage of factor VII concentrate and human prothrombin complex (factors II, VII,IX, X), total avoidance of transfusion after cardiopulmonary bypass (CPB) 24h after administration of study drug or placebo.

• Study Type: Interventional
• Enrollment (Actual): 62
• Phase: Phase 3

Contacts and Locations

Study Locations

• Canada
  • Nova Scotia
    • Halifax, Nova Scotia, Canada, B3H3A7
      • CapitalDHACanada

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

All patients who are scheduled for elective complex cardiac surgical procedures including

• double procedures (aortic valve replacement (AVR)+CABG, mitral valve repair/replacement (MVR)+CABG, AVR+MVR)
• Redo-sternotomies
• Aortic root repair +/- AVR

Exclusion Criteria:

• Any known congenital or pre-existing bleeding disorder
• pre-existing clinically significant abnormal fibrinogen level (normal: 2.5-4.79g/l)
• severe liver disease (alanine aminotransferase or aspartate aminotransferase > 150 U/l)
• inability to provide informed consent
• emergency surgery
• pregnancy or nursing
• age under 18 years
• intake of anti-platelet drugs within2- 5 days preoperatively (low dose ASA is allowed)
• allergy to concentrated fibrinogen or other components in the product
• anemia (Hgb < 110)
• diagnosed deep vein thrombosis (DVT)
• pulmonary embolism
• acute stroke
• acute myocardial infarction

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: TRIPLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: RiaSTAP; Intravenous fibrinogen(RiaSTAP) will be administered according to FIBTEM based calculation formula	Drug: Fibrinogen; Intravenous concentrated fibrinogen will be infused according to a hemostatic algorithm based on ROTEM (FIBTEM); Other Names: RiaSTAP or Haemocomplettan P
Placebo Comparator: Intravenous saline; Intravenous saline (placebo) will be calculated according to FIBTEM based calculation formula	Drug: Fibrinogen; Intravenous concentrated fibrinogen will be infused according to a hemostatic algorithm based on ROTEM (FIBTEM); Other Names: RiaSTAP or Haemocomplettan P

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Cumulative Transfusion Units	Including packed red cells, frozen plasma, platelets, cryoprecipitates	24 hours after administration of study drug

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Fibrinogen Plasma Concentration (g/L)		24h after infusion of study drug
Hematocrit (%)		24h after infusion of study drug
Hemoglobin Concentration (g/L)		24h after infusion of study drug
Platelet Count (10^3/μL)		24h after infusion of study drug
Partial Thromboplastin Time (s)		24h after infusion of study drug
International Normalized Ratio	International normalized ratio (INR) is calculated based on the prothrombin time (PT) test results.The PT is usually measured in seconds and is compared to a normal range that reflects PT values in healthy individuals. Because the reagents used to perform the PT test vary from one laboratory to another and even within the same laboratory over time, the normal ranges also will fluctuate. To standardize results across different laboratories in the world, a World Health Organization (WHO) committee developed and recommended the use of the Internationalized Normalized Ratio (INR). The INR is calculated with the ratio of the patient's prothrombin time (PT test) to a normal prothrombin time (control) sample (PT normal): INR=PT test:PT normal. The normal range is from 0.9 to 1.2. The higher the value the more is the patient anticoagulated. This means the patient's blood is thinner with a lower concentration of coagulation factors.	24h after infusion of study drug
Prothrombin Time (s)	The prothrombin time (PT) test evaluates how well all of the coagulation factors in the extrinsic and common pathways of the coagulation cascade work together. Included are: factors I (Fibrinogen), II (Prothrombin), V, VII and X.	24h after infusion of study drug
EXTEM Clotting Time (s)	EXTEM = rotational thrombelastometry (measurement of extrinsic coagulation pathway); clotting time: time from start of the measurement until initiation of clotting (thrombin formation, start of clot polymerisation).	24h after infusion of study drug
EXTEM Maximum Clot Firmness (mm)	EXTEM = rotational thrombelastometry (measurement of extrinsic coagulation pathway); maximum clot firmness: increasing stabilisation of the clot by the polymerised fibrin, platelets as well as factor XIII.	24h after infusion of study drug
INTEM Clotting Time (s)	INTEM = rotational thrombelastometry (measurement of intrinsic coagulation pathway); clotting time: time from start of the measurement until initiation of clotting (thrombin formation, start of clot polymerisation).	24h after infusion of study drug
INTEM Maximum Clot Firmness (mm)	INTEM = rotational thrombelastometry (measurement of intrinsic coagulation pathway); maximum clot firmness: increasing stabilisation of the clot by the polymerised fibrin, platelets as well as factor XIII.	24h after infusion of study drug
FIBTEM Clotting Time (s)	FIBTEM = rotational thrombelastometry (measurement of functional fibrinogen); clotting time: time from start of the measurement until initiation of clotting (thrombin formation, start of clot polymerisation).	24h after infusion of study drug
FIBTEM MCF (Maximum Clot Firmness)	Rotational thrombelastometry (measurement of functional fibrinogen). Rotational thrombelastometry (ROTEM) is a point-of-care viscoelastic coagulation test. The device provides four channels for simultaneous assays. With the so called "FIBTEM" assay coagulation is activated by a small amount of tissue thromboplastin (tissue factor) and platelets are blocked with cytochalasin D. The resulting clot is therefore only depending on fibrin formation and fibrin polymerisation. The maximum clot firmness (MCF) is the amplitude in mm on the result graph representing the increasing stabilisation of the clot.	24 hours after study drug administration
HEPTEM Clotting Time (s)	HEPTEM = rotational thrombelastometry (measurement of INTEM with heparinase);clotting time: time from start of the measurement until initiation of clotting (thrombin formation, start of clot polymerisation).	24h after infusion of study drug
HEPTEM Maximum Clot Firmness (mm)	HEPTEM = rotational thrombelastometry (measurement of INTEM with heparinase); maximum clot firmness: increasing stabilisation of the clot by the polymerised fibrin, platelets as well as factor XIII.	24h after infusion of study drug
Total Avoidance of Transfusions	Total avoidance of any transfusion after cardiopulmonary bypass (CPB) 24h after administration of study drug or placebo.	24h after infusion of study drug

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall Numbers of Patients Receiving Blood Products	Including Packed Red Cells, Fresh Frozen Plasma, Platelets, Cryoprecipitate and coagulation factor concentrates. The study was not sufficiently powered to test differences between this outcome.	24 hours after administration of study drug

Collaborators and Investigators

• Sponsor: Nova Scotia Health Authority
• Investigators: Principal Investigator: Myron Kwapisz, MD, Nova Scotia Health Authority

Publications and helpful links

General Publications

• Kwapisz MM, Kent B, DiQuinzio C, LeGare JF, Garnett S, Swyer W, Whynot S, Mingo H, Scheffler M. The prophylactic use of fibrinogen concentrate in high-risk cardiac surgery. Acta Anaesthesiol Scand. 2020 May;64(5):602-612. doi: 10.1111/aas.13540. Epub 2020 Jan 17.

Study record dates

Study Major Dates

• Study Start: February 1, 2014
• Primary Completion (Actual): March 31, 2019
• Study Completion (Actual): June 30, 2019

Study Registration Dates

• First Submitted: June 18, 2012
• First Submitted That Met QC Criteria: June 18, 2012
• First Posted (Estimate): June 20, 2012

Study Record Updates

• Last Update Posted (Actual): May 22, 2020
• Last Update Submitted That Met QC Criteria: May 18, 2020
• Last Verified: May 1, 2020

More Information

Terms related to this study

• Keywords: cardiac surgery; bleeding; cardiopulmonary bypass; blood transfusion; high risk; Fibrinogen
• Other Study ID Numbers: Fibrinogenstudy0911