Clinical trial NCT01623531
Conditions: Cardiac Complication During Procedure
Keywords: Fibrinogen cardiac surgery high risk cardiopulmonary bypass bleeding blood transfusion
Sponsor: Nova Scotia Health Authority
Start date: 2014-02-01; Completion date: 2019-06-30
Enrollment: 62 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

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.

Arms: arm 1: Intravenous fibrinogen(RiaSTAP) will be administered according to FIBTEM based calculation formula arm 2: Intravenous saline (placebo) will be calculated according to FIBTEM based calculation formula
Interventions: intervention 1: Fibrinogen
Intervention descriptions: intervention 1: Intravenous concentrated fibrinogen will be infused according to a hemostatic algorithm based on ROTEM (FIBTEM)

Protocol documents:
Prot_SAP_000.pdf: 
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THE USE OF FIBRINOGEN CONCENTRATE IN HIGH-RISK CARDIAC SURGERY:  
A PROSPECTIVE DOUBLE BLIND RANDOMIZED CONTROLLED STUDY 
 
 
 
 
SPONSOR AND 
AUTHORIZING SIGNATORY 
FOR PROTOCOL AND 
AMENDMENTS: 
Myron Kwapisz, MD 
Capital District Health Authority 
Staff Anesthesiologist,  
Queen Elizabeth II Health Sciences 
Centre 
10 West Victoria, 1278 South Park 
Street  
Halifax, Nova Scotia, B3H 2Y9 
Phone: (902) 473 7736 
Fax: (902) 473 3820 
 
QUALIFIED PRINCIPAL 
INVESTIGATOR: 
Same as Sponsor 
 
SUB-INVESTIGATOR: 
Dr. Blaine Kent, MD 
Staff Anesthesiologist,  
Queen Elizabeth II Health Sciences 
Centre 
10 West Victoria, 1278 South Park 
Street 
Halifax, Nova Scotia, B3H 2Y9 
 
MEDICAL ADVISOR: 
Dr. Jean-Francois Legare, MD 
Staff Cardiac Surgeon  
Department of Cardiovascular Surgery
 
 
 
Halifax Infirmary,  
Halifax, Nova Scotia B3H 3A7 
 
 


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TABLE OF CONTENTS 
 
BACKGROUND INFORMATION......................................... 4 
Name and description of the investigational product ................ 5 
RELEVANT SYSTEMATIC REVIEWS AND PUBLISHED TRIALS............... 5 
Evidence supporting need for a trial ............................... 6 
How will the results impact clinical practice? ..................... 7 
RISKS AND BENEFITS TO HUMAN SUBJECTS........................... 8 
Risks .............................................................. 8 
Benefits ........................................................... 8 
ROUTE OF ADMINISTRATION, DOSAGE, DOSAGE REGIMEN, AND TREATMENT 
PERIOD........................................................ 11 
STUDY POPULATION.............................................. 11 
REFERENCES.................................................... 12 
TRIAL OBJECTIVES AND PURPOSE.................................. 16 
Research question ................................................. 16 
TRIAL DESIGN.................................................. 18 
Primary and secondary outcomes .................................... 18 
METHODOLOGY................................................... 18 
Intervention ...................................................... 18 
RANDOMIZATION METHOD.......................................... 20 
Randomization process ............................................. 20 
Dosage and Dosage Regimen ......................................... 20 
Reconstitution .................................................... 22 
PLANNED FREQUENCY AND DURATION OF FOLLOW-UP................... 22 
In-Hospital Follow-Up ............................................. 22 
After Discharge Follow-up ......................................... 22 
Proposed frequency of analysis .................................... 23 
SELECTION AND WITHDRAWAL OF SUBJECTS.......................... 23 
Inclusion criteria ................................................ 23 
Subject exclusion criteria ........................................ 24 
Subject withdrawal criteria ....................................... 24 
TREATMENT OF SUBJECTS......................................... 25 
Anaesthesia management ............................................ 26 
Surgical technique ................................................ 27 
Post-operative management ......................................... 27 
ASSESSMENT OF SAFETY.......................................... 27 
Adverse Events .................................................... 28 
Unblinding ........................................................ 28 
STATISTICS.................................................... 29 
Sample size ....................................................... 29 


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Details of the planned analysis ................................... 29 
Estimated Recruitment Rate ........................................ 31 
DATA HANDLING AND RECORD KEEPING.............................. 31 
QUALITY CONTROL AND QUALITY ASSURANCE PROCEDURES.............. 32 
Monitoring ........................................................ 32 
Data Storage ...................................................... 32 
 
Figure 1.  ROTEM® Parameters.................................. 34 
Figure 2.  FIBTEM® Test Specificities......................... 35 
Figure 3. Treatment Algorithm................................. 36 
Table 1.  Sample Size Calculation............................. 37 
Table 2.  Schedule of Assessments............................. 38 


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BACKGROUND INFORMATION 
 
Complex cardiac surgery (time-consuming surgeries, e.g. aortic 
root/arch repair or combined procedures, e.g. aortic valve 
replacement and coronary artery bypass grafting) is often 
accompanied by excessive perioperative bleeding. Contributing 
factors are hemodilution, platelet dysfunction and low levels of 
coagulation factors caused by prolonged cardiopulmonary bypass 
(CPB) time. Fibrinogen has a key role in maintaining and 
restoring hemostasis after long and complex cardiovascular 
surgery. One molecule of thrombin can activate 1680 molecules of 
fibrinogen1. A large amount of fibrinogen is captured by a few 
platelets via the abundant GPIIb/IIIa receptors (40,000-50,000 
copies per platelet). 2 Clinical and in vitro data from Lang and 
coworkers demonstrates that even in the presence of reduced 
platelet count and thrombin levels (e.g. after extensive 
cardiopulmonary bypass) administration of fibrinogen increases 
clot strength. 3 Unfortunately the concentration of fibrinogen in 
fresh frozen plasma (FFP) is not high enough to treat 
hemorrhagic complications efficiently after complex cardiac 
surgery. 4 The average concentration of fibrinogen in FFP is 2.0 
g/L. 
5 The fibrinogen concentration can vary significantly 
between units. For the clinician it is difficult to predict the 
increase in patient plasma fibrinogen concentration after 
administration of FFP. 6 Chowdhury et al. measured a median 
increase of 1.0 g/L of fibrinogen after transfusion with 30ml/kg 
of FFP (2.4 L for 80 kg patient) in critical ill patients. 4 
Those large volumes of FFP could be harmful (volume overload, 
hemodilution) for cardiac surgery patients who often suffer from 
myocardial dysfunction after complex and high-risk procedures.  
 
The concentration of fibrinogen in cryoprecipitates (Cryo) is 
much higher compared to FFP. According to Canadian Blood 
Services each unit of Cryo is supposed to have between 150 - 450 
mg of fibrinogen (7.5 g/L - 22.5 g/L). Canadian Blood Services 
guaranties this concentration in 75% of the provided units. 7 
Thus, Cryo has the same problem as FFP the concentrations of 
fibrinogen do differ between units. Additionally Cryo can't be 
virus-inactivated. Because of the risk of transmission of 


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infectious agents most European countries have stopped using 
Cryo. 8 
 
RiaSTAPTM (CLS Behring, Marburg, Germany) is a new alternative 
source of fibrinogen. It provides purified, virus-inactivated, 
standardized concentration of fibrinogen.  It is reconstituted 
with low volume of sterile water (1 g/50ml, 20 g/L). Although 
much anecdotal evidence exists there are few studies that 
provide evidence supporting its superiority to conventional 
treatment using FFP and Cryo. Current indication for fibrinogen 
concentrate 
has 
been 
replacement 
therapy 
in 
congenital 
fibrinogen deficiency.   
 
Name and description of the investigational product 
 
RiaSTAPTM (Fibrinogen concentrate (Human), FCH) is a pasteurized, 
preservative free, lyophilized human fibrinogen concentrate. It 
is derived from human plasma and presented as a white powder for 
reconstitution with sterile water for injection (not provided 
with the product) and infusion. RiaSTAPTM is to be intravenously 
(i.v.) administered.  
 
 
RELEVANT SYSTEMATIC REVIEWS AND PUBLISHED TRIALS 
 
There have been several articles in a cardiovascular setting. 
One study was comparing retrospective and prospective data in 
patients having aortic valve operation and ascending aorta 
replacement. Most patients (80%) of the prospective group who 
received concentrated fibrinogen did not need any allogeneic 
blood products. In the retrospective group without concentrated 
fibrinogen treatment almost everyone required blood products (41 
of 42 patients). 9 A follow up study with small numbers (n=6) 
investigated patients with thoracoabdominal aortic aneurysm 
repair. Rahe-Meyer and co-workers found a significant reduction 
of 
transfusion 
of 
allogeneic 
blood 
products 
in 
patients 
receiving concentrated fibrinogen. 10  
 
A review article from Sørensen et al. gives a very detailed and 
critical evaluation of Cryo for replacement of fibrinogen. This 


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article discusses the problems of pathogen transmission, immune-
mediated 
complications 
and 
timing 
issues 
(thawing, 
transportation) 
with 
the 
usage 
of 
Cryo 
in 
perioperative 
bleeding. 8 A recently (February 2012) published review article 
by Levy and co-workers points out that "fibrinogen is critical 
for effective clot formation, and its monitoring and guided 
supplementation 
in 
the 
treatment 
of 
major 
bleeding 
is 
increasingly 
recognized... 
further 
prospective, 
randomized 
controlled studies on the use of fibrinogen concentrate are 
essential to help define the breadth of clinical settings in 
which fibrinogen supplementation may be beneficial".11  
 
Evidence supporting need for a trial 
 
Several studies have demonstrated that the fibrinogen level is 
the 
limiting 
factor 
for 
postoperative 
hemostasis. 
9,12-
14 Conventional treatment of excessive perioperative bleeding 
after complex cardiac surgery consists of administration of FFP, 
platelets and Cryo. This empirical approach needs to be 
evaluated in view of reported unfavourable outcomes (e.g. lung 
injury, myocardial infarction, right-ventricular dysfunction, 
stroke, arrhythmia, infection) associated with FFP and platelet 
transfusion. 14,15 Cryo has several disadvantages compared to 
concentrated 
fibrinogen: 
risk 
of 
ABO 
incompatibility, 
no 
standardized 
concentration, 
no 
viral 
inactivation, 
higher 
thrombotic activity, more expensive, must first be thawed, and 
delayed administration (45 min.). 8,16 
 
There is evidence that side effects associated with the use of 
packed red cells, platelets, FFP, and Cryo significantly 
increases the risk of complications after surgery. The most 
significant evidence linking transfusion and the development of 
ALI/ARDS comes from the Canadian Critical Care Trial.  Hebert et 
al. randomized 838 critically ill patients to either a liberal 
transfusion regime or a restrictive transfusion regime. 17 The 
liberal transfusion regime was associated with a higher rate of 
ALI/ARDS and a higher mortality. Gong and coworkers demonstrated 
significantly higher odds of the development of ALI/ARDS in 
patients treated with a blood transfusion. 18  Croce at al. 
showed in a retrospective analysis of 5260 trauma patients a 
much higher risk of ALI/ARDS in those patients who had received 


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any transfusion. 19 An investigation conducted by Silverboard and 
coworkers demonstrated a dose-dependent relationship between the 
number of units of blood products and the development of an 
acute lung injury. The risk was significantly increased after 5 
units. 20 Another contributing factor for postoperative morbidity 
and mortality is nosocomial infections. In a prospective 
observational study by Taylor and coworkers the number of 
transfused RBC units was an independent risk factor for 
nosocomial infections. Mortality and length of stay (ICU and 
hospital) were significantly higher in transfused patients. 21 
 
How will the results impact clinical practice?  
 
With 
the 
expected 
positive 
results, 
we 
hypothesize 
that 
concentrated fibrinogen will be used as first line therapy in 
perioperative management of bleeding during and after major 
surgery. With an overall blood transfusion rate of 38% (all 
cardiac cases, last 5 years, n=5100) and a blood transfusion 
rate of higher risk cases of 60% (aortic valve replacement (AVR) 
+ coronary artery bypass grafting (CABG), n=386); the primary 
use of blood components like packed red blood cells (RBCs), 
platelets, FFP, and Cryo will be reduced.  
 


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RISKS AND BENEFITS TO HUMAN SUBJECTS 
Risks 
 
There are no studies published to date that clearly address the 
risk associated purely to fibrinogen supplementation. Based on 
the available literature the risk of any adverse event directly 
related appears to be < 1/10000 patient. The following outlines 
the state of knowledge regarding the use of fibrinogen products. 
 
A review article by Dickneite et al. analyzed an extensive 
pharmacosurveillance database of more than 250000 treatment 
episodes with fibrinogen concentrate. They found an incidence of 
thrombotic 
events 
possibly 
related 
to 
fibrinogen 
of 
approximately 3.5 per 100,000 treatment episodes. 22 
 
Kreuz et al. analyzed 151 fibrinogen infusions in 12 patients 
with congenital fibrinogen deficiency (median dosage range 
63.5mg/kg body weight to 105.6mg/kg body weight). One patient 
experienced an anaphylactic reaction after the 56th infusion. 
Another patient developed deep vein thrombosis and non-fatal 
pulmonary embolism after complex orthopedic surgery. Fibrinogen 
treatment could not be excluded as a contributing factor in this 
high-risk patient. 23 
 
The current indication for fibrinogen concentrate has been 
replacement therapy in congenital fibrinogen deficiency. Two 
studies with patients who suffered from congenital fibrinogen 
deficiency also showed a good clinical efficacy and a favourable 
safety profile. 23,24 Manco-Johnson et al. assessed the safety of 
fibrinogen concentrate in 15 patients with afibrinogenemia. They 
concluded that fibrinogen concentrate has a good safety profile 
with 
no 
evidence 
of 
serious 
adverse 
events 
(e.g. 
viral 
transmission, thromboembolism nor vital sign changes). Four 
patients experienced minor symptoms during the study (headache, 
pain, GERD and epistaxis) and were not related to the study 
drug. 24 
Benefits 
 
The available evidence suggests that fibrinogen concentrate 
rapidly 
and 
safely 
restore 
hemostasis 
in 
patients 
with 


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congenital fibrinogen deficiency. 
24 Perioperative fibrinogen 
concentrate 
infusion 
reduced 
bleeding 
after 
CABG 
without 
evidence of postoperative hypercoagulability in a prospective 
randomized pilot study by Karlsson et al. 25 
 
Depending on the results of our proposed study, concentrated 
fibrinogen will be used as first line therapy in perioperative 
management of bleeding during and after major surgery. The 
expected outcome is that primary use of blood products like 
packed red cells, platelets, FFP, and cryo will be reduced. The 
potential overall reduction of the use of blood products (RBC, 
platelets, and FFP) due to fibrinogen will possibly improve 
significantly patient's outcome after complex cardiac surgery. 
Blood transfusions have long been implicated as a risk factor 
for severe complications like acute lung injury (ALI), acute 
respiratory distress syndrome (ARDS) and nosocomial infections. 
Probably the most significant evidence of the link between 
transfusion and the development of ALI/ARDS has come from the 
Canadian Critical Care Trial.  
 
The studies available to date that have used concentrated 
fibrinogen in cardiac surgery showed a very low risk of 
thrombosis. Karlsson et al. demonstrated the preoperative 
infusion 
of 
concentrated 
fibrinogen 
reduced 
significantly 
bleeding in patients (n=20) after coronary artery bypass 
grafting (CABG). No adverse thrombotic events were recorded. 25 
Rahe-Meyer 
and 
coworkers 
showed 
that 
intraoperative 
administration of concentrated fibrinogen reduced transfusion 
requirements and postoperative bleeding (n=42). 9 In a study of 
Solomon et al. with patients who had diffuse bleeding after 
cardiac 
surgery 
fibrinogen 
concentrate 
was 
effective 
in 
increasing plasma fibrinogen levels and contributed to the 
correction of bleeding after cardiac surgery (n=39).26 In a 
retrospective 
study 
from 
Thorarinsdottir 
and 
coworkers 
concentrated 
fibrinogen 
administration 
improved 
coagulation 
parameters and reduced transfusion requirements.  Most of the 
investigate patients had open heart surgery (n=30). 27 All those 
studies reported no thromboembolic complications associated to 
administration of concentrated fibrinogen. Other investigations 
demonstrated the efficacy of intravenous fibrinogen in various 
clinical 
hemorrhage 
scenarios 
(orthopedic 
procedures, 
GI 


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bleeding, sepsis, liver dysfunction, trauma). 28-31 In all the 
studies the administration of fibrinogen was well-tolerated. No 
severe adverse events attributable to fibrinogen concentrate 
were recorded.  
 
Although 
the 
current 
literature 
shows 
that 
concentrated 
fibrinogen has a good safety profile the above authors have the 
opinion that there is a strong need for better studies because 
the evidence is restricted to case studies and retrospective 
analyses.  
 
The expected outcome is that primary use of blood products 
(packed red cells, platelets, FFP, and Cryo) will be reduced. 
This overall reduction due to the use of fibrinogen concentrate 
will also reduce the side effects associated with the use of 
packed 
red 
cells, 
platelets, 
FFP, 
and 
Cryo 
and 
will 
significantly benefit patients.  
 


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ROUTE OF ADMINISTRATION, DOSAGE, DOSAGE REGIMEN, AND TREATMENT 
PERIOD 
 
Fibrinogen dosing will be based on the results of the FIBTEM® 
analysis.  The amount of fibrinogen concentrate corresponds to 
approximately 0.5 g of fibrinogen concentrate needed to raise 
MCF by 1 mm in a 70 kg patient. 9,10,26  The maximum amount of 
fibrinogen concentrate used in this study will be 10 g in any 
participant. In the placebo group, the standard hemostatic 
algorithm involving the use of plasma, Cryo and platelets 
(Figure 1), will be used as per the standard of care currently 
in place at CDHA. 
 
Once randomized to treatment, the test compound will be 
administered through the central line (usually internal jugular 
vein catheter) by the anesthesiologist within 10 minutes (25-50 
ml/minute).  Since high doses of anticoagulants are used in this 
surgical population while on cardiopulmonary bypass it is 
important that the test compound is administered in a relatively 
short period of time to boost the fibrinogen level.   
 
The trial will be conducted in compliance with the protocol, GCP 
and the applicable regulatory requirements. 
 
STUDY POPULATION 
 
All patients will be recruited from the Queen Elizabeth II 
Health Sciences Center (QEIIHSC), Halifax, Nova Scotia, which is 
the sole tertiary cardiac surgery referral center in Nova 
Scotia. There are approximately 1000 open heart surgical 
procedures performed yearly, including more than 700 isolated 
CABG procedures.  
 
 


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of injury. The Journal of trauma 2005; 59(1): 19-23; discussion 
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deficiency and active or in high-risk severe bleeding. Vox 
sanguinis 2008; 94(3): 221-6. 
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C, 
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101(6): 769-73. 
30. Mittermayr M, Streif W, Haas T, et al. Hemostatic changes 
after crystalloid or colloid fluid administration during major 
orthopedic surgery: the role of fibrinogen administration. 
Anesthesia 
and 
analgesia 
2007; 
105(4): 
905-17, 
table 
of 
contents. 
31. Weinkove R, Rangarajan S. Fibrinogen concentrate for 
acquired hypofibrinogenaemic states. Transfusion medicine 2008; 
18(3): 151-7. 
 


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TRIAL OBJECTIVES AND PURPOSE 
 
Research question 
 
Hypothesis:  The aim of the study is to show that prophylactic 
first line treatment with concentrated fibrinogen prior to 
conventional therapy with FFP, platelets, Cryo, and other blood 
products such as factor VII concentrate and human prothrombin 
complex 
(factors 
II, 
VII, 
IX, 
X) 
has 
superiority 
over 
conventional therapy alone (“wait and see”) in perioperative 
management 
of 
bleeding 
patients 
with 
low 
or 
low 
normal 
fibrinogen levels (≤3.8g/l) after complex cardiac surgery. 
 
Primary objective:  To determine the cumulative perioperative 
amount (number of units) 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 (PRBCs, plasma, platelets, and Cryo).   
 
Secondary objective:  To determine the effect of RiaSTAPTM on 
fibrinogen levels, hematocrit, prothrombin time (PT), partial 
thromboplastin time (PTT), international normalized ratio (INR), 
platelet count, hemoglobin, thromboelastometry* (ROTEM®, EXTEM, 
INTEM, HEPTEM, FIBTEM test, Clotting Time, Clot Formation Time, 
Angle, Maximum Clot Firmness), CVICU-stay, Hospital-stay, In-
Hospital 
Mortality, 
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 CPB (24h after administration of study drug or 
placebo).  
 
*Thromboelastometry (ROTEM®; Pentapharm GmbH, Munich, Germany) is 
a bedside qualitative test of whole blood coagulation (Figure 
1). The Clotting Time (CT) represents the time required for 
initial fibrin formation. Both Clot Formation Time (CFT) and 
angle represent the rate of clot formation, fibrin cross-
linking, and platelet-fibrin interaction. Maximum Clot Firmness 
(MCF) 
represents 
the 
overall 
clot 
quality 
determined 
by 


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polymerised fibrin, platelets and factor XIII. The ROTEM® system 
provides several tests, one of them is the FIBTEM® test. The 
FIBTEM® test shows the isolated fibrinogen contribution to the 
clot firmness (Figure 2). 
 


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TRIAL DESIGN 
 
Primary and secondary outcomes 
 
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).    
 
Secondary outcomes: To determine the effect of RiaSTAPTM on 
fibrinogen levels, hematocrit, PT, PTT, INR, platelet count, 
Hemoglobin (Hb), Thromboelastometry (ROTEM®, CT, CFT, Angle, 
MCF), 
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 CPB (24h after administration of study drug or placebo). 
 
 
METHODOLOGY 
 
The proposed trial will be a prospective, single-centre, double 
blind, randomized, controlled trial comparing blood product 
utilization between patients receiving saline therapy (PLACEBO) 
compared 
to 
fibrinogen 
therapy 
(FIB) 
in 
the 
setting 
of 
perioperative surgical bleeding blood management in patients 
with low or low normal fibrinogen levels after complex cardiac 
surgery. Blood products refer to any manufactured product 
derived from blood or plasma (albumin, fibrinogen, rFVIIa, human 
prothrombin complex, etc.).   
 
Intervention 
 
Prospective, randomized controlled study involving two groups: 
fibrinogen group (FIB) and saline group (PLACEBO), with a 
standardized 
anaesthesia 
protocol. Anesthesia 
management, 
surgical technique, post-operative management and follow-up will 
be as per the standard of care for this surgical population.  


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In-Hospital 
Follow-up: 
 All 
postoperative 
cardiac 
surgery 
patients will be followed for the duration of their hospital 
stay. Blood work and amount of blood components and products 
will be assessed at the end of surgery, 12hr, and 24hr after 
delivery of the study medication. The study endpoint for the 
primary outcome parameter (amount of blood components) will be 
24h after administration of the study medication. 
 
Other outcomes assessed include Thromboelastometry (ROTEM®, 
EXTEM, INTEM, HEPTEM, FIBTEM, CT, CFT, Angle, MCF), CVICU-stay, 
Hospital-stay, In-Hospital Mortality, Hemoglobin, and adverse 
events.  
 
Any patients with evidence of study drug related adverse events 
at follow-up will be reviewed by the Data and Safety Monitoring 
Committee (DSMC) to review all the supporting evidence. The 
(DSMC) will consist of at least one anesthesiologist, one 
surgeon and a statistician not otherwise associated with the 
trial. Their role will be to review the available evidence 
provided by the research coordinator for the follow-up of all 
patients including in-hospital and follow-up study drug related 
adverse events. The outcomes of interest are listed above and 
will follow-strict study definitions as outlined. All outcomes 
will be based on consensus of the DSMC. 
 
There will be an interim analysis performed by the Data and 
Safety Monitoring Committee. This analysis will be conducted 
when half of the patients have been enrolled. The final analysis 
will be conducted once all enrolled patients have reached their 
follow-up date. All final analysis will take into consideration 
that an interim analysis was conducted.  
 
In case the study is terminated prematurely, the REB will be 
notified within 14 days in writing including the reason for the 
termination. If the termination is related to an emergent safety 
issue, the notification will be faxed to the REB office or 
preceded by a telephone call to the Chair or REB Coordinator. 
The study will be unblinded and all patients having received 
fibrinogen concentrate will be notified in writing and by direct 
contact via a telephone call of the study termination as well as 


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the reason for termination. Patients will also be informed of 
any emergent safety issues or adverse outcomes. Patients will be 
instructed on how to proceed in terms of medical care and follow 
up investigations. 
 
 
RANDOMIZATION METHOD 
 
Informed consent will be obtained from the patient prior to the 
operation either in the same-day surgery clinic or at the 
bedside if the patient has already been admitted to hospital 
pre-operatively. The randomization process will be performed 
with the help of software (G*Power version 3.1.2). Treatment 
allocation cards will be provided by the study Sponsor and 
placed in sealed, opaque envelopes for safe storage in a secure 
location to preserve the integrity of the blinding. The study 
drug 
designate 
will 
withdraw 
the 
envelope 
directing 
the 
patient's randomization to the FIB group or the PLACEBO group. 
Both the surgeon and anaesthesiologist will be blinded to 
patient randomization.   
 
Randomization process 
 
After eligibility and written informed consent is confirmed 
patients will be randomized on the day of surgery after arrival 
at the OR to receive either fibrinogen concentrate or placebo 
after heparin reversal as indicated in the algorithm (Figure 3).  
If the patient has a diffuse medical bleed then the research 
coordinator will be called to inform The research coordinator 
study drug designate will call the study drug designate to 
randomize the patient and a sequential envelope will be opened 
by them in the blood bank. The drug/placebo will be prepared in 
the Blood Transfusion Services at the Infirmary site. The 
drug/placebo will be transported to the OR by the study drug 
designate. 
 
Dosage and Dosage Regimen  
 
The dose of fibrinogen concentrate will be calculated based on 
the point of care measurement of n maximum clot firmness (MCF) 


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in the FIBTEM® test performed on CPB (aortic cross clamp off)10. 
According to the available literature we will use the following 
formula to achieve the preoperative (baseline) FIBTEM MCF (mm): 
 
Fibrinogen dosage (g) = [Preop FIBTEM MCF (mm) - FIBTEM MCF 
(mm)] x bodyweight (kg) x c 
        
 
 
C =            0.5 g              . 
                                                       1(mm) X 
70 
 
The formula can be simplified to: 
(Preop FIBTEM MCF – FIBTEM MCF) x bodyweight/140. 
 
Calculation example: A patient's bodyweight is 75kg. The 
baseline FIBTEM MCF showed 22mm. The FIBTEM test on CPB shows a 
MCF of 10 mm. The overall dose of concentrated fibrinogen to 
achieve the baseline MCF of 22 mm would be: 
 
Fibrinogen dosage (g) = (22 - 10) x 75/140 = 12 x 75/140 = 6.4 
 
Fibrinogen dosing will be based on the results of the FIBTEM® 
analysis. The amount of fibrinogen concentrate corresponds to 
approximately 0.5 g of fibrinogen concentrate needed to raise 
MCF by 1 mm in a 70 kg patient 9,10,26 The maximum fibrinogen 
concentrate dose used in this study will be 10 g. If the 
baseline FIBTEM® is ≤ 12 mm the fibrinogen dosage will be 
calculated from a minimum baseline value of 15 mm to achieve a 
more effective fibrinogen dosage. In the placebo group, the 
standard hemostatic algorithm involving the use of plasma, Cryo 
and platelets (Figure 3), will be used as per the standard of 
care currently in place at CDHA. 
 
The test compound will be administered through the central line 
(usually internal jugular vein catheter) within 10 minutes (25-
50 ml/minute) by the anesthesiologist. Since high doses of 
anticoagulants are used in this surgical population while on 
cardiopulmonary bypass it is important that the test compound is 
administered in a relatively short period of time to boost the 
fibrinogen level. Two studies in cardiac surgery used an 
infusion rate of 20ml/minute and 150ml/minute without any 
adverse events. 25,26 


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This bolus approach interrupts the circle of hemodilution and 
ongoing bleeding produced from cardiopulmonary bypass. This is 
the practice at CDHA in the cardiovascular anesthesia group.  
This technique has not produced any thromboembolic complications 
or severe side effects in the 25+ patients that have received 
this product in our health centre. 
Reconstitution 
 
The RiaSTAP, and placebo, are labelled as per Health Canada 
regulations. The reconstituted RiaSTAP or placebo will be 
transported by the the Research Coordinator Study drug designate 
to the OR and the Blood Transfusion requisition will be signed 
and 
completed 
by 
the 
anesthesiologist 
and 
the 
Research 
Coordinator Study drug designate once the medication has been 
given. 
 
 
PLANNED FREQUENCY AND DURATION OF FOLLOW-UP  
In-Hospital Follow-Up 
 
All postoperative cardiac surgery patients will be followed for 
the duration of their hospital stay. Blood work and amount of 
blood components and products will be assessed at end of 
surgery, 12hr and 24hr after administration of study medication 
or placebo. The study endpoint for the primary outcome parameter 
(amount of blood components) will be 24h after administration of 
study medication or placebo. 
 
Other outcomes assessed include Thromboelastometry (ROTEM®, CT, 
CFT, 
Angle, 
MCF), 
CVICU-stay, 
Hospital-stay, 
In-Hospital 
Mortality, Hemoglobin, and adverse events.  
After Discharge Follow-up 
 
After discharge from hospital all patients, including those 
involuntarily withdrawn from the study by a member of the 
research team, are followed-up in clinic six weeks postsurgery. 
This is currently the standard of care for patients post CABG 
surgery. If the patient a study participant does not return to 


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clinic at the time window of six weeks +/- 1 week, a phone visit 
will occur by the research coordinator. Additionally all 
patients will be contacted by a research coordinator at three 
and six months. The focus of the interviews will be to determine 
anginal symptoms, and need for if readmission to hospital for 
acute myocardial infarction (AMI), acute coronary syndrome (ACS) 
or congestive heart failure (CHF) occurred. Events of interest 
include: 
incisional 
wound 
infection, 
thrombosis, 
recurrent 
angina, 
myocardial 
infarction, 
angiography, 
percutaneous 
coronary intervention (PCI), repeat cardiac surgery, stroke and 
cardiac related mortality. Any patients with evidence of adverse 
study drug related events at follow-up will be investigated 
further by the Data and Safety Monitoring Committee to review 
all the supporting evidence.  
 
Proposed frequency of analysis  
 
As previously stated there will be an interim analysis performed 
by the data and safety monitoring committee. This analysis will 
be conducted when half of the patients have been enrolled. The 
final analysis will be conducted once all enrolled patients have 
reached their follow-up date. All final analysis will take into 
consideration that an interim analysis was conducted.  
 
 
SELECTION AND WITHDRAWAL OF SUBJECTS 
Inclusion criteria 
 
Participants will be eligible to participate in this trial if 
they: 
 are  scheduled for elective complex cardiac surgical 
procedures including: 
o double 
procedures 
(aortic 
valve 
replacement 
(AVR)+CABG, 
mitral 
valve 
repair/replacement 
(MVR)+CABG, AVR+MVR),  
o redo-sternotomies, and  
o Aortic root repair +/-AVR.  
 have a preoperative fibrinogen level of ≤ 3.8 g/l 


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Subject exclusion criteria 
 
Participants will be excluded if they have: 
 Any known congenital or pre-existing bleeding disorder,  
 pre-existing clinically significant abnormal fibrinogen 
levels 
 pre-existing clinically significant abnormal fibrinogen 
levels 
 pre-existing clinically significant abnormal FIBTEM MCF 
tests  
 Preoperative fibrinogen level of < 1.0 g/l  
 Preoperative FIBTEM® of < 5 mm 
 Preoperative fibrinogen level of > 3.8 g/l 
 severe liver disease (alanine aminotransferase or aspartate 
aminotransferase > 150 U/l),  
 inability to provide informed consent,  
 emergency surgery, 
 self-report pregnancy or nursing,  
 age under 18 years,  
 intake 
of 
anti-clotting 
drugs 
within 
2-5 
days 
preoperatively (low dose ASA is allowed) based on the 
drug’s half life or pharmacokinetic profile,  
 allergy to concentrated fibrinogen or other components in 
the product,  
 anemia (Hb < 110),  
 diagnosed deep vein thrombosis (DVT),  
 pulmonary embolism,  
 acute stroke (within the last 3 months), 
 acute myocardial infarction (within the last 3 months), 
 any unstable medical condition as determined by the 
Principal Investigator  
 within the past 30 days, participated in or currently 
enrolled in a clinical trial. 
 
Subject withdrawal criteria  
 


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As 
per 
the 
intraoperative 
algorithm 
(Figure 
3) 
the 
Anesthesiologist and the Surgeon complete a bleeding assessment 
ten minutes after the protamine is given. If the patient is not 
having a diffuse medical bleed they will not be randomized and 
will be considered a screen failure.  Patients who are 
experiencing surgical bleeding after weaning from CPB and 
protamine administration with requirement of a second pump run 
are withdrawn from the study. In case of an ongoing bleeding 
after step 3 of the study algorithm (Figure 3) an immediate and 
blinded FIBTEM is performed in order to prevent an overdosing of 
fibrinogen. If the FIBTEM shows an amplitude > 20 mm the patient 
will be unblinded and drop out of the study for safety reasons. 
This way it is ensured that a patient who received concentrated 
fibrinogen is not getting Cryoprecipitate (step 4 of study 
algorithm; Figure 3) leading to supraphysiologic levels of 
fibrinogen. Patients who have extremely rare complications like 
air embolism, heart perforation or heart lung machine failure 
will be excluded withdrawn from the study. 
 
 
TREATMENT OF SUBJECTS 
 
After weaning from cardiopulmonary bypass (CPB), completion of 
heparin reversal with protamine and surgical hemostasis either 
concentrated fibrinogen or saline will be given intravenously. 
The surgeon and anaesthesiologist will the amount of blood loss 
that is considered diffuse (non-surgical) bleeding.  determine 
when surgical hemostasis is completed. After agreement on 
completion of surgical hemostasis and defined intraoperative 
conditions a transfusion algorithm is initiated (Figure 3). After 
the surgeon and anesthesiologist have agreed on diffuse bleeding 
then the patients are randomized FIB patients are treated with 
concentrated fibrinogen based on maximum clot firmness (MCF) in 
the FIBTEM test (Figures 1 and 2) performed on CPB (aortic cross 
clamp off).  
 
Defined Intraoperative Conditions – Standard of Care Assessments 
 
As per the usual standard of care/clinical assessment to treat, 
the 
following 
criteria 
must 
be 
met 
prior 
to 
Fibrinogen 
administration: 


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 ACT less than 150s, 
 body temperature higher than  36 35.5°C, 
 pH more than 7.3, 
 hemoglobin level higher than 70g/l, 
 calcium level higher than 1 mmol/l (ionized) ) and 
 no blood products given before or during CPB (Defined 
intraoperative conditions).  
 
Anaesthesia management 
 
As per the standard of care in this surgical population, all 
patients will undergo general anaesthesia and will be induced 
with 
midazolam, 
fentanyl 
or 
sufentanil, 
propofol 
and 
rocuronium. General 
anaesthesia 
will 
be 
maintained 
with 
sevoflurane titrated to maintain an end-tidal concentration of 
1-2% and boluses of fentanyl or sufentanil, until initiation of 
cardiopulmonary bypass.   
 
Tranexamic acid (Sandoz Canada Inc.) will be infused at a rate 
of 2mg/kg/hr following an initial bolus of 1000-2000mg. During 
the cardiopulmonary bypass run, propofol will be infused with 
subsequent 
boluses 
of 
fentanyl 
or 
sufentanil. Prior 
to 
cardiopulmonary bypass, patients will be given unfractionated 
heparin (500 units/kg; PPC, Pharmaceuticals Partners of Canada 
Inc.) to maintain an activated clotting time (ACT) > 480 
seconds.  The cardiopulmonary bypass circuit includes a membrane 
oxygenator 
and 
roller 
pumps 
to 
maintain 
a 
non-pulsatile 
perfusion technique. Depending on the procedure, deep or 
moderate hypothermia (nasopharyngeal temperature of 18 or 32 to 
34oC) will be utilized and cardioprotection will be maintained 
using antegrade and retrograde cold blood cardioplegia when 
possible. Separation 
from 
cardiopulmonary 
bypass 
will 
be 
achieved once the patient is re-warmed to a nasopharyngeal 
temperature of 36.5oC. Following separation from cardiopulmonary 
bypass, 
heparin 
will 
be 
reversed 
with 
protamine 
(1mg 
protamine/100units heparin; protamine sulphate, Sandoz Canada 
Inc.). A hemoglobin concentration below 70 g/l will be treated 
with PRBCs to maintain a hemoglobin of 70 g/l or greater 
throughout the procedure.  


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Surgical technique  
 
As per standard of care in this surgical population and 
depending on the procedure, a median sternotomy or lateral 
thoracotomy will be performed in all patients. Surgery will be 
performed in a standardized fashion with CPB. During CPB, the 
mean arterial pressure target will be 60-70 mmHg and the body 
temperature will be allowed to drift to approximately 320C or 
lower. Intermittent cold blood cardioplegia (1:4 blood to 
crystalloid with maximal K+ concentration 22 meq/L) will be 
delivered antegrade via the aortic root unless otherwise 
indicated. No special blood conservation technique will be 
utilized other than: non-hemic prime, retransfusion of all 
contents of the oxygenator at the end of CPB, and acceptance of 
normovolemic anemia. Post-operatively non-hemic volume expanders 
are utilized routinely (Voluven®, Kabi Fresenius Inc., Germany). 
Post-operative management 
 
As per the standard of care in this surgical population, all 
post-operative 
cardiac 
surgery 
patients 
will 
be 
taken 
immediately to a dedicated cardiovascular intensive care unit 
(CVICU).  All patients will receive respiratory and hemodynamic 
support as needed. Each patient will be required to meet 
standard hospital criteria both prior to extubation and prior to 
transfer 
to 
the 
intermediate-care 
unit 
(IMCU). Discharged 
patients will be transferred to an intermediate-care unit or 
general-care ward under the care of the same cardiac surgical 
team. All patients will be monitored continuously for a minimum 
of 24 hours. In case of a post-operative bleeding in CVICU the 
same algorithm (Figure 3) like in the OR will be used. In case 
of surgical bleeding a re-sternotomy will be performed. Diffuse 
bleeding will be treated with blood components (step 2 -5, 
Figure 3). Patients having a valve replaced with a mechanical 
valve will receive heparin or warfarin 48 hours after surgery. 
All other patients will get ASA (acetylsalicylic acid, Aspirin®, 
Bayer Canada) on the first postoperative day (anticoagulation 
protocol, Division of Cardiac Surgery, QEII, Halifax, Canada).   
 
 
ASSESSMENT OF SAFETY 


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Adverse Events 
 
The following treatment-emergent and adverse effects will be 
captured during this study from the date  the consent was signed 
of randomization to the 6 month follow-up:  
 
Treatment-emergent adverse events 
 Pleural effusion 
 Atrial fibrillation 
 Postoperative Delirium 
 Reoperation because of surgical bleeding and 
unknown bleeding 
 Air embolism 
 
Adverse events (A/E) and Serious adverse events (SAE)  
 Anaphylaxis 
 Stroke 
 Myocardial infarction 
 Pulmonary embolism 
 Deep vein thromboembolism 
 Sternal wound infection 
 Recurrent angina 
 Angiography 
 Percutaneous coronary intervention (PCT) 
 Repeated cardiac surgery 
 Cardiorespiratory arrest 
 Cerebral hemorrhage 
 Death 
  
All serious unexpected adverse drug reactions will be reported 
to Health Canada as per ICH/GCP guidelines. 
Unblinding 
 
Unblinding for this study will occur when:  
1. Clinical treatment decisions need to be made and when an 
unexpected 
serious 
adverse 
event 
occurs 
and 
the 
intervention must be made known. 
2. At the request of the Data Safety Monitoring Committee. 


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3. After 110 participants have reached the primary endpoint 
for interim analysis. 
4. At the conclusion of the study to determine the effect of 
the intervention. 
 
The Blood Transfusion Services are able to unblind for the 
clinical treatment of a patient. Please refer to the site 
Standard operating procedure for more details of this process. 
If a patients treatment is unblinded before the 24 hour primary 
end point their data will not be used in the analysis.  
 
STATISTICS 
 
Sample size  
 
The primary outcome of interest will be overall need for blood 
transfusion at 24hr after surgery (including all used blood 
components from the start of surgery). For the sample size 
calculations G*Power version 3.1.2 was used.   
 
Based on the available literature 
9,10,12, the investigator 
hypothesized a 70-90% reduction in total units of blood products 
in the group receiving fibrinogen compared with the group 
receiving conventional therapy. An estimate of blood product 
requirement in the group receiving conventional therapy is mean 
3.4 units (standard deviation 5.9) based on our data from 2005 
to 2007 for AVR+CABG, MVR+CABG, AVR+MVR, and Aortic root repair 
+/-AVR. Standard deviation 5.9 was used for both groups. Blood 
product requirement in the two groups will be compared using the 
Mann-Whitney U test for two independent samples. The sample size 
calculation was based on a two-tailed test with α = 0.05, for β = 
0.2, 0.1, and 0.05. The sample sizes shown Table 1 represent the 
number of patients required in each group. 
 
Details of the planned analysis  
 
Individual case forms will be completed by the research 
coordinator for individual patients.  The research coordinator 
will complete individual case forms for individual patients. 
These forms will be detailing demographic characteristics, 


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intra-operative, post-operative and follow-up outcomes. Outcome 
data and blood samples will be collected according a lab/data 
schedule (Table 2). All data will be reviewed by the appropriate 
clinical outcomes committee. The Sponsor will review all data. 
Once 
reviewed 
all 
data 
will 
entered 
and 
maintained 
electronically.   
 
Primary outcome: Blood component requirement in the two groups 
will be compared using the Mann-Whitney U test for two 
independent samples.  
 
Secondary outcomes: Univariate comparisons between patients 
randomized to FIB and patients randomized to PLACEBO group will 
be carried out based on pre-, intra-, and post-operative 
variables using Chi-square tests for dichotomous variables, two-
tailed t-tests for continuous variables and Wilcoxon rank sum 
tests for nominal variables.  
 
All statistical analyses will be performed at the QEII Health 
Sciences Center using SAS version 9.2 (Cary, North Carolina). 
Data validation will be an integral part of this protocol and 
will be carried out using already established clinical and 
administrative patient databases available through the Division 
of Cardiac Surgery at the QEIIHSC. This will ensure 100% follow-
up of all patients and data accuracy.  All discrepancy will be 
investigated by the clinical outcomes committee.  The Data and 
Safety Monitoring Committee will investigate all discrepancies. 
The Maritime Heart Center (MHC) cardiac surgery database is a 
prospectively 
collected, 
clinical 
database 
that 
captures 
detailed information on a wide range of pre-operative, intra-
operative, and in-hospital post-operative variables including 
post-operative complications and in-hospital mortality for all 
patients undergoing cardiac surgery at the QE II Health Sciences 
Center.  It is audited on an annual basis to ensure reliability 
of data capture.  The MHC cardiac surgery database will be 
linked to the Canadian Institute for Health Information (CIHI) 
Discharge Abstract Database and the Nova Scotia Vital Statistics 
database through the Population Health Research Unit (PHRU) at 
Dalhousie University. The CIHI Discharge Abstract Database is a 
national administrative database that contains extensive data on 
all admissions to hospital and enables us to track all 


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readmissions to hospital.  The Nova Scotia Vital Statistics 
database collects information on all deaths occurring within the 
province of Nova Scotia and enables us to track all-cause 
mortality following discharge from hospital. The following data 
will be obtained from the MHC-PHRU data link after 6-months 
follow-up for all patients:  
 
i) 
Cardiac related mortality   
ii) 
Readmission to hospital for acute myocardial infarction 
(AMI), acute coronary syndrome (ACS), or congestive heart 
failure  (CHF) 
iii) Re-intervention including CABG and/or PCI  
 
Estimated Recruitment Rate 
 
Approximately 200 complex cardiac procedures are performed 
annually in Halifax by nine cardiac surgeons. Of these patients, 
conflicting studies and patients being disqualified on the basis 
of exclusion criteria will result in a maximal annual number of 
eligible patients of 100 per year. We would plan to recruit 222 
patients for this study.  With a length of follow up of 6 months 
and using administrative data of an already well established 
data base we are expecting a rate of loss under 5%. 
 
 
DATA HANDLING AND RECORD KEEPING 
 
Data will be collected from patient charts and health records, 
the anesthetic record as well as the Maritime heart center 
cardiac surgery database. A data collection sheet will be filled 
out by the study nurse for patients included in the study. 
Follow-up data will be collected from patients themselves. In 
cases where patients have adverse outcomes, this information 
will be obtained from hospital records and the patient. 
 
A data collection form will be used to collect study information 
and will be completed by the designated study personnel for 
participants. 
These 
forms 
will 
be 
detailing 
demographic 
characteristics, intra-operative, postoperative and follow-up 
outcomes. Individual data forms will record: the perioperative 
amount of blood products used (packed red cells, FFP, platelets, 


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Cryo). Also fibrinogen levels, hematocrit, PTT, INR, platelet 
count, Hemoglobin, Thromboelastometry (ROTEM®, CT, CFT, Angle, 
MCF), 
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 will be collected for study purposes. All data will be 
reviewed by the appropriate outcome committee. Once reviewed all 
data will entered and maintained electronically on a designated 
CDHA computer. 
 
Data will also be collected using the Maritime Heart Center 
(MHC) cardiac surgery database. This database is a prospectively 
collected, clinical database that captures detailed information 
on a wide range of pre-operative, intra-operative, and in-
hospital 
postoperative 
variables 
including 
post-operative 
complications 
and 
in-hospital 
mortality 
for 
all 
patients 
undergoing cardiac surgery at the QE II Health Sciences Center.  
 
 
QUALITY CONTROL AND QUALITY ASSURANCE PROCEDURES 
 
Data validation will be an integral part of this protocol and 
will be carried out using already established clinical and 
administrative patient databases available through the Division 
of Cardiac Surgery at the QEIIHSC. This will ensure 100% follow-
up of all patients and data accuracy. The Data and Safety 
Monitoring Committee will investigate all discrepancies. 
 
Monitoring 
 
The 
study 
will 
be 
monitored 
in 
accordance 
with 
ICH-GCP 
guidelines that require a minimum of three visits, before the 
trial starts, once during the trial, and after the trial is 
completed. 
 
Data Storage 
 


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During the study data will be stored in a filing cabinet in a 
designated office for the study nurse as well as a CDHA 
computer, as a data file. All other data will be stored on the 
CDHA network. Once the study is complete, data will be stored in 
a filing cabinet in the Principal investigator's office under 
lock and key. All other data will be stored as per current 
standard of practice for elective cardiac surgery patients; on 
the CDHA network and in the Maritime Heart Center (MHC) cardiac 
surgery database. De-identified information will be available to 
the sponsor after study completion. In case of adverse outcomes, 
the study will be unblinded and may be reviewed by regulatory 
agencies through CDHA. The research team also intends to publish 
de-identified in a research journal that will be available to 
the study participants and to the public.  
 
Prior to data transfer to CSL Behring, study participant 
information will be de-identified using a serial number system. 
This unique number will be assigned to each study participant 
and will be stored on paper in a filing cabinet in a designated, 
secure office in the Department of Anesthesia.  The study 
research data will be archived for a minimum of 25 years 
according to the current Capital Health policy. Once the 
information requires destruction, paper data will be shredded 
through the hospital confidential waste disposal. Electronic 
data will be deleted from the designated CDHA computer. Data 
stored independently on the CDHA hospital network and the 
Maritime Heart Center database will be disposed of by the 
regulations governing those networks or databases. 
 


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Figure 1.  ROTEM® Parameters 
 
 
 


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Figure 2.  FIBTEM® Test Specificities 


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Figure 3. Treatment Algorithm  


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Table 1.  Sample Size Calculation 
 
 
 
 
Relative Risk Reduction in Mean Number of Units 
Transfused 
 
 
 
 
Power = 1-
beta 
 
30% 
∆ = 1.0 
units 
(3.4 to 2.4) 
 
 
50% 
∆ = 1.7 
units 
(3.4 to 
1.7) 
 
 
70% 
∆ = 2.4 
units 
(3.4 to 
1.0) 
 
90% 
∆ = 3.1 
units 
(3.4 to 
0.3) 
 
80% 
 
634 
 
220 
 
111 
 
69 
 
 
90% 
 
848 
 
295 
 
149 
 
 
92 
 
 
95% 
 
1049 
 
364 
 
183 
 
113 
 
 
 
 
 


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Table 2.  Schedule of Assessments 
 
Preop 
I+II 
Intraop I 
Intraop II 
Intraop III 
Postop I 
Postop II 
Postop III 
Postop IV 
Time 
intervals 
Baseline 
 
On Bypass 
Aortic  
Clamp Off 
 
Off Bypass  
After Heparin 
reversal 
(5-15 minutes 
post 
protamine) 
10 minutes 
after 
administratio
n 
(+5 minutes) 
End of 
Surgery 
(+10 minutes) 
Blood Draw  
12 Hours  
(+60 minutes) 
Blood Draw  
24 Hours 
(+60 minutes) 
Discharge 
Primary Outcome 
 
 
 
 
Total Blood 
Components 
Used 
Total Blood 
Components 
Used 
Total Blood 
Components 
Used 
Total Blood 
Components Used 
Cryo Used 
Cryo Used 
Cryo Used 
Cryo Used 
FFP Used 
FFP Used 
FFP Used 
FFP Used 
Packed Red   
Cells Used 
Packed Red   
Cells Used 
Packed Red   
Cells Used 
Packed Red 
Cells Used 
Platelets 
Used 
Platelets 
Used 
Platelets 
Used 
Platelets Used 
Secondary Outcomes 
Fibrinoge
n Levels 
 
Fibrinogen 
Levels 
Fibrinogen 
Levels 
Fibrinogen 
Levels 
Fibrinogen 
Levels 
Fibrinogen 
Levels 
Adverse 
Effects: 
Hematocri
t 
 
Hematocrit 
Hematocrit 
Hematocrit 
Hematocrit 
Hematocrit 
Anaphylaxis 
Hemoglobi
n 
ABG/ 
Hemoglobin 
ABG/ 
Hemoglobin 
ABG/ 
Hemoglobin 
ABG/ 
Hemoglobin 
 
Hemoglobin 
Hemoglobin 
CVICU LOS 
INR/PT 
 
INR/PT 
INR/PT 
INR/PT 
INR/PT 
INR/PT 
Deep Vein 
Thromboembolism 
Platelet 
Count 
 
Platelet 
Count 
Platelet 
Count 
Platelet 
Count 
Platelet 
Count 
Platelet 
Count 
Hospital LOS 
PTT 
 
PTT 
PTT 
PTT 
PTT 
PTT 
 
*ACT 
ACT 
ACT 
ACT 
ACT 
 
Blood 
Drainage 
In Hospital 
Mortality 
*EXTEM 
EXTEM 
EXTEM 
EXTEM 
EXTEM 
EXTEM 
EXTEM 
Myocardial 
Infarction 
*INTEM 
 
INTEM 
INTEM 
INTEM 
INTEM 
INTEM 
Pulmonary 
Embolism 
*FIBTEM 
FIBTEM 
FIBTEM 
FIBTEM 
FIBTEM 
FIBTEM 
FIBTEM 
Stroke 
 
 
HEPTEM 
HEPTEM 
HEPTEM 
HEPTEM 
HEPTEM 
 
AT III 
 
Usage of  
Factor VII a 
Usage of    
Factor VII a 
Usage of    
Factor VII a 
Usage of    
Factor VII a 
Usage of    
Factor VII a 
Usage of  
Factor VII a 
*ABG 
 
Usage of 
human 
prothrombin 
complex 
Usage of 
human 
prothrombin 
complex 
Usage of 
human 
prothrombin 
complex 
Usage of 
human 
prothrombin 
complex 
Usage of 
human 
prothrombin 
complex 
Usage of human 
prothrombin 
complex 
Please Note:  24 hour blood draw = primary endpoint highlighted in green, assessments highlighted in peach are outside 


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Table 2.  Schedule of Assessments (continued) 
Time 
intervals 
6 week post operative 
clinic visit 
(+1week) 
(phone visit may occur if 
patient is not brought in 
within window) 
3 month phone visit 
(+1week) 
6 month phone visit 
(+1week) 
Secondary Outcomes 
 Angina 
 Re-admission (CHF, AMI, 
ACS) 
 Incisional wound 
infection 
 Thrombosis 
 MI 
 Angiography 
 PCI (percutaneous 
conronary intervention) 
 Repeat cardiac surgery 
 Cardiac Mortality 
 
 Angina 
 Re-admission (CHF, AMI, 
ACS) 
 Incisional wound 
infection 
 Thrombosis 
 MI 
 Angiography 
 PCI (percutaneous 
conronary intervention) 
 Repeat cardiac surgery 
 Cardiac Mortality 
 
 Angina 
 Re-admission (CHF, AMI, 
ACS) 
 Incisional wound 
infection 
 Thrombosis 
 MI 
 Angiography 
 PCI (percutaneous 
conronary intervention) 
 Repeat cardiac surgery 
 Cardiac Mortality 
 
 
 
 
the standard of care , 
Preoperative 1- assessments done in Same day admission or on the floor the day prior to OR 
*Only these values will be done on the Preoperative II time point. Preoperative II (window is +10 minutes post art line 
insertion)