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

Phase 3

Completed

Conditions: Cardiac Complication During Procedure

Interventions: Drug: Fibrinogen

Registration Number: NCT01623531

Lead Sponsor: Nova Scotia Health Authority

Brief Summary: 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.

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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 62

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 & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Intravenous saline	Fibrinogen	Intravenous saline (placebo) will be calculated according to FIBTEM based calculation formula
RiaSTAP	Fibrinogen	Intravenous fibrinogen(RiaSTAP) will be administered according to FIBTEM based calculation formula

Primary Outcome Measures

Name	Time	Method
Cumulative Transfusion Units	24 hours after administration of study drug	Including packed red cells, frozen plasma, platelets, cryoprecipitates

Secondary Outcome Measures

Name	Time	Method
Hemoglobin Concentration (g/L)	24h after infusion of study drug
INTEM Maximum Clot Firmness (mm)	24h after infusion of study drug	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.
Platelet Count (10^3/μL)	24h after infusion of study drug
Fibrinogen Plasma Concentration (g/L)	24h after infusion of study drug
FIBTEM Clotting Time (s)	24h after infusion of study drug	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).
Hematocrit (%)	24h after infusion of study drug
Partial Thromboplastin Time (s)	24h after infusion of study drug
EXTEM Maximum Clot Firmness (mm)	24h after infusion of study drug	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.
INTEM Clotting Time (s)	24h after infusion of study drug	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).
EXTEM Clotting Time (s)	24h after infusion of study drug	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).
FIBTEM MCF (Maximum Clot Firmness)	24 hours after study drug administration	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.
International Normalized Ratio	24h after infusion of study drug	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.
Prothrombin Time (s)	24h after infusion of study drug	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.
HEPTEM Maximum Clot Firmness (mm)	24h after infusion of study drug	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.
Total Avoidance of Transfusions	24h after infusion of study drug	Total avoidance of any transfusion after cardiopulmonary bypass (CPB) 24h after administration of study drug or placebo.
HEPTEM Clotting Time (s)	24h after infusion of study drug	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).