Clinical trial NCT02557672
Conditions: Bleeding Blood Loss, Surgical Cardiovascular Surgical Procedures Prothrombin Complex Concentrates Fresh Frozen Plasma
Sponsor: Mayo Clinic
Start date: 2016-08-01; Completion date: 2022-01-01
Enrollment: 106 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This will be the first prospective randomized controlled clinical trial directly comparing Prothrombin Complex Concentrate (PCC) Compared to Fresh Frozen Plasma (FFP) for post cardiopulmonary bypass microvascular bleeding and factor-mediated coagulopathy. Is there a difference in bleeding and transfusion requirements in patients received PCC versus FFP?

Detailed description:

Arms: arm 1: After cardiopulmonary bypass, patients will receive protamine at dose 0.01 mg/unit of heparin given with target activated clotting time (ACT) within 10% of baseline value. After protamine administration the ACT, complete blood count (CBC), prothrombin time (PT)/ international normalized ratio (INR), activated partial thromboplastin time (APTT), and fibrinogen, will be collected via preexisting arterial access. If ACT \>10% baseline additional protamine will be given at the anesthesiologists discretion. Evaluation and determination of excessive microvascular bleeding in the surgical field will occur 10 minutes after return of ACT to within 10% of baseline. Patients with clinical evidence of excessive microvascular bleeding in the surgical field as determined by the surgical team, along with a PT \>16.6 sec/ INR \>1.6 sec will receive fresh frozen plasma as this is standard therapy per our institutional algorithm at a dose of 10-15 mL/kg rounded up to the nearest unit. arm 2: After cardiopulmonary bypass, patients will receive protamine at dose 0.01 mg/unit of heparin given with target ACT within 10% of baseline value. After protamine administration the ACT, CBC, PT/ INR, APTT, and fibrinogen, will be collected via preexisting arterial access. If ACT \>10% baseline additional protamine will be given at the anesthesiologists discretion. Evaluation and determination of excessive microvascular bleeding in the surgical field will occur 10 minutes after return of ACT to within 10% of baseline. Patients with clinical evidence of excessive microvascular bleeding in the surgical field as determined by the surgical team, along with a PT \>16.6 sec/ INR \>1.6 sec will receive Prothrombin complex concentrate (Human) 15 units/kg.
Interventions: intervention 1: Prothrombin complex concentrate (Human) intervention 2: Fresh frozen plasma (FFP)
Intervention descriptions: intervention 1: PCC (Kcentra) intervention 2: FFP

Protocol documents:
Prot_SAP_000.pdf: 
 
 
Prothrombin complex concentrate 
compared to fresh frozen plasma for 
post-cardiopulmonary bypass 
coagulopathy and bleeding, a 
prospective randomized trial at large US 
medical center 
 
 
NCT02557672 
 
11/2/2020 


 
1
November 2, 2020,  protocol version 7.6 
 
 
Prothrombin complex concentrate compared to fresh frozen plasma for post-
cardiopulmonary bypass coagulopathy and bleeding, a prospective 
randomized trial at large US medical center. 
 
 
Principal Investigators: Gregory. A. Nuttall M.D1, Mark M. Smith, M.D. 1 
Co-investigators: 
  
 
 
 
 
1Department of Anesthesiology 
2Division of Cardiovascular Surgery 
 
 
 


 
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Abstract 
 
Background:  
 
Post-cardiopulmonary bypass coagulopathy and bleeding represents one of the largest areas of 
blood product transfusion in surgical practices today. Abnormal bleeding after cardiopulmonary 
bypass has been shown to be present in about 11% patients.1 Current literature shows lower 
transfusion rate and blood loss in patients receiving prothrombin complex concentrate (PCC) 
when compared to fresh frozen plasma (FFP) after cardiac surgery.2  
 
Specific Aim: 
 
Determine best practice in management of postcardiopulmonary bypass coagulopathy and 
bleeding. Our aim is to compare administration of PCC (Kcentra) to FFP for patients with post 
bypass factor mediated coagulopathy and clinically significant microvascular bleeding. Primary 
endpoints for the study will be allogenic blood product transfusion rate and 24 hour 
postoperative blood loss. 
 
 
Hypothesis: 
 
 Patients receiving PCC (Kcentra) will have same or decreased allogenic blood product 
transfusion rate and blood loss after cardiac surgery compared to patients receiving fresh frozen 
plasma.  
 
Significance: 
 
This will be the first prospective randomized controlled clinical trial directly comparing PCC to 
FFP for post cardiopulmonary bypass microvascular bleeding and factor-mediated coagulopathy. 
 
 


 
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1. Background and Significance: 
 
Post-cardiopulmonary bypass coagulopathy and bleeding represents one of the largest areas of 
blood product transfusion in surgical practices today. Abnormal bleeding necessitating blood 
product transfusion occurs in about 11% of cardiac surgical patients.1 Bleeding after 
cardiopulmonary bypass is multifactorial and related largely to blood exposure to bypass circuit 
components. Consequential coagulation aberrations include thrombocytopenia, platelet 
dysfunction, clotting factor consumption and dilution, hyper-fibrinolysis, and 
hypofibrinogenemia.3 Surgical field and bypass circuit blood which is processed through cell 
salvage processing and then transfused to the patient is devoid of remaining coagulation 
factors.4,5  Standardized transfusion algorithms for patients with post-cardiopulmonary bypass 
bleeding are not utilized across all healthcare institutions; however, algorithm based transfusion 
is standard practice at our institution.1 Currently, patients with factor mediated coagulopathy and 
bleeding after cardiopulmonary bypass at our institution receive transfusion of fresh frozen 
plasma.1 Factor concentrations within FFP are variable, and large volumes of transfused product 
are often necessary to correct factor deficiencies. In addition FFP transfusion carries the risk of 
transfusion related lung injury, transfusion related circulatory overload, infectious and allergic 
complications among others.6  
 
Prothrombin complex concentrate use in hemophiliac patients dates back several decades, and 
has recently become the treatment of choice for management of bleeding in patients taking 
vitamin K antagonists (warfarin).7-9 Current formulations of inactivated PCC available in the 
United States include Bebulin (Baxter) which contains factors 2, 9, 10, and Kcentra (CSL 
Behring) which contains factors 2, 7, 9, 10. PCC administration in the perioperative setting 
including post-cardiopulmonary bypass coagulopathy and bleeding is common in European 
countries. Studies evaluating the efficacy of PCC’s in this patient population have demonstrated 
faster normalization of INR, lower blood loss, and lower transfusion requirements.2,10,11 
Historically, PCC use in the perioperative setting has been limited due to fear of thrombotic 
complications. Newer formulations of PCC’s include a variety of anti-coagulants such as 
heparin, protein C & S, and anti-thrombin 3. Such additives are felt to reduce thrombotic risk 
when compared to PCC formulations void of these additives.12 Thromboembolic events remain a 
concern when using any procoagulant including PCC’s, especially formulations with activated 
factors such as FEIBA (Baxter), which contains activated factor 7. Inactivated PCC use has not 
been directly linked to significantly higher rates of adverse outcomes or thrombotic 
complications when compared to conventional therapies in surgical patients.2,10,13 Large 
prospective randomized trials comparing PCC and FFP in cardiac surgical patients to assess 
clinical outcomes and safety have not been performed. Distinct advantages to PCC 
administration compared with FFP include higher factor concentration despite significantly less 
infusate volume, ambient storage with rapid reconstitution, unnecessary blood group 
compatibility, lower risk of transfusion related complications such as acute lung injury and 
infection, along with potential cost savings.14 Current transfusion practices in European countries 
involve use of inactivated PCC in lieu of FFP. 
 
The significance of this study is related to the potential for reduction in allogenic transfusion 
requirements and hence associated transfusion related complications. Transfusion reduction 
would also lead to institutional cost savings which in busy cardiac surgical practices could be 


 
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substantial. In addition, massive bleeding after cardiac surgery is associated with higher rates of 
reoperation, morbidity, and mortality.3 Current practice per our institutional transfusion 
algorithm is to use fresh frozen plasma as first line therapy for factor mediated coagulopathy and 
bleeding after cardiopulmonary bypass.  
 
Large prospective randomized studies directly comparing PCC to FFP in the setting of factor-
mediated bleeding after cardiac surgery have not been conducted.  
We hypothesize that PCC use will show a reduction in allogenic transfusion requirements in 
cardiac surgical patients with factor mediated postcardiopulmonary bypass bleeding. 
 
2. Specific Aims:  
 
Our aim is to conduct a prospective randomized controlled trial of patients undergoing elective 
cardiac surgery. We plan to preoperatively consent and enroll sufficient patients to reach a goal 
of 200 randomized patients (100 patients per arm) that demonstrate clinically significant 
microvascular bleeding and factor mediated coagulopathy after cardiopulmonary bypass. 
Randomized patients with clinically significant factor mediated bleeding will receive transfusion 
of PCC (Kcentra) (100 patients) or fresh frozen plasma (100 patients). Factor mediated 
coagulopathy will be defined per our current transfusion algorithm as PT >16.6 sec/ INR >1.6 
sec. Primary outcome measures for efficacy will be total units of allogenic blood product 
transfused, and 24 hour postoperative blood loss. Outcome measure for safety will be rate of 
serious adverse outcomes. Analysis of coagulation factor levels will also be conducted prior to 
cardiopulmonary bypass, post cardiopulmonary bypass, and after product administration (PCC or 
FFP). 
 
 
Hypothesis: 
 
 PCC arm will have same or decreased allogenic blood product transfusion rate and blood loss 
after cardiac surgery compared to patients receiving fresh frozen plasma. 
 
3. Research Design and Methods: 
 
A. Study Overview 
 
All patients enrolled in the study will have a perioperative anesthetic care plan standardized as 
much as possible conforming to the current institutional protocol utilized for intraoperative 
medication administration. Patients will be anticoagulated according to institutional practice with 
heparin 400 units/kg with goal ACT >400 prior to initiation of cardiopulmonary bypass. After 
cardiopulmonary bypass, patients will receive protamine at dose 0.01 mg/unit of heparin given 
with target ACT within 10% of baseline value. If ACT >10% baseline additional protamine will 
be given at the anesthesiologists discretion. Evaluation and determination of excessive 
microvascular bleeding in the surgical field will occur 10 minutes after return of ACT to within 
10% of baseline. Determination for treatment with PCC or FFP will be based off of the current 
algorithm used at our institution.1  Specifically this study will focus on patients with a PT >16.6 
sec/ INR >1.6 sec, or aPTT > 57 sec with clinical evidence of excessive microvascular bleeding 


 
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in the surgical field as determined by the surgical team. All other coagulopathies will be treated 
as per the current institutional transfusion protocol. 
 
 
B. Study Population 
 
Consecutive adult patients undergoing cardiac surgery at St. Marys Hospital will be potentially 
eligible for the study.  All of the cardiac surgeons at Mayo Clinic Rochester will be asked to 
participate in the study. 
 
 
Inclusion Criteria 
All subjects eligible for enrollment must: 
 
1. Be ≥ 18 years of age 
2. Be undergoing a cardiac surgical procedure utilizing cardiopulmonary bypass 
3. Have an INR ≤ 1.3 if warfarin was not held for 5 days 
Exclusion Criteria 
All subjects with one of the following are not eligible for enrollment: 
 
1. Are unable to grant informed consent or comply with study procedure 
2. History of hypercoagulable condition (e.g. Factor V Leiden, AT-3 deficiency, 
Prothrombin gene mutation, Anti-phospholipid antibody syndrome, etc.) or previous 
unprovoked thromboembolic complications 
3. Coagulopathic conditions such as factor deficiencies, factor inhibitors, heparin induced 
thrombocytopenia, or use of intravenous anticoagulants other than heparin at the time of 
cardiovascular surgery 
4. Thromboembolic event with past 3 months 
5. Received oral therapy with ELIQUIS (apixaban) or Xarelto (rivaroxaban) within 3 days 
prior to planned surgical procedure 
6. Received oral therapy with clopidogrel,  prasugrel, or dabigatran within 5 days prior to 
planned surgical procedure 
7. Are undergoing emergency open heart-surgery 
8. Cardiopulmonary bypass time is expected to be <30 minutes 
9. Are pregnant 
10. Heparin allergy 
11. ECMO post op 
12. Life threatening bleeding necessitating transfusion of hemostatic products (FFP or PCC)  
prior to the study intervention time point 
13. Circumstances for which the safety of the patient could be jeopardized by continued 
adherence to the study protocol 


 
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Enrolled subjects must meet additional criteria in order to receive study treatment: 
Inclusion Criteria 
 
1. Have evidence of excessive microvascular bleeding in the surgical field as determined by 
the surgical team 
2. PT >16.6 sec/ INR >1.6 sec, or aPTT > 57 sec. on initial post cardiopulmonary bypass 
labs  
 
Exclusion Criteria 
1. Fibrinogen < 144 mg/dL on initial post cardiopulmonary bypass labs 
 
 C. Enrollment 
 
Subjects will be enrolled at the time of pre-operative visit with cardiothoracic surgery if they 
meet the eligibility criteria. Informed written consent will be obtained and randomization 
performed to one of the two study arms. 
 
We estimate approximately 1000 subjects will be need to consented with intent of having 100 
patients receive treatment (50 patients in each treatment arm). This study will terminate once 50 
patients in each study arm have received treatment. Our data and safety monitoring board 
(DSMB) will provide oversight and monitoring to the study to ensure the safety of participants 
and validity and intensity of data. The DSMB will consist of 2 physicians and a statistician not 
affiliated with study. They will review data from the study and meet at the 50% and 75% 
enrollment milestones or every 6 months from previous meeting date whichever comes first. The 
DSMB will provide aggregated data summaries to the Mayo IRB with explanations of 
seriousness and relatedness of adverse events to the study.  In addition to the above, the authors 
will inform the National Institute of Health (NIH) of any actions taken by the IRB as a result of 
its continuing review. 
 
The primary adverse event of concern in this study would be thromboembolic events. DSMB 
(anesthesiologist, hematologist, and statistician) will meet quarterly, and review all data from 
each study arm. Thromboembolic complications will be reviewed and clinical judgment will 
used to determine necessity of study termination. No formal stopping rules are feasible given the 
study size and low incidence of TEE. 
   
 
Early termination of the study will ensue if adverse events in either study arm exceed acceptable 
level. 
 
D. Randomization and Blinding 
 
Upon consent for study participation enrolled patients will be randomized via computer-
generated blocks and with stratification according to the surgical procedure to either receive PCC 
or FFP during cardiac surgery should they develop excessive microvascular bleeding in the 


 
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surgical field as determined by the surgical team in addition to a PT >16.6 sec/ INR >1.6 sec 
after cardiopulmonary bypass. The randomization assignments will be concealed in opaque 
envelopes and disclosed to the anesthesiologist caring for the patient. The surgical and intensive 
care personnel will not be blinded to the treatment arm, as transparency of transfusion product is 
necessary to prevent overdosage of PCC and potential thrombotic complications. 
 
E. Interventions 
 
Patients will be consented and enrolled in the study until 50 patients have received treatment in 
each arm of the study. Patients will be anticoagulated according to institutional practice with 
heparin 400 units/kg with goal ACT >400 prior to initiation of cardiopulmonary bypass. After 
cardiopulmonary bypass, patients will receive protamine at dose 0.01 mg/unit of heparin given 
with target ACT within 10% of baseline value. After protamine administration the ACT, CBC, 
PT/ INR, and fibrinogen, will be collected via preexisting arterial access. If ACT >10% baseline 
additional protamine will be given at the anesthesiologists discretion. Evaluation and 
determination of excessive microvascular bleeding in the surgical field will occur 10 minutes 
after return of ACT to within 10% of baseline. Patients with clinical evidence of excessive 
microvascular bleeding in the surgical field as determined by the surgical team, along with a PT 
>16.6 sec/ INR >1.6 sec will receive randomized treatment with either PCC or FFP.  
 
 
PCC (Kcentra) Dosage: Patients randomized to the PCC arm with evidence of microvascular 
bleeding and PT >16.6 sec/ INR >1.6 sec will have Kcentra 15 units/kg prepared from pharmacy. 
 
Patients who have received PCC and continue to demonstrate microvascular bleeding 10 
minutes after the full PCC dose has been administered will undergo repeat laboratory evaluation 
of PT/INR +/- CBC, and fibrinogen depending on previous lab results and product 
administration other than PCC. Therapy will ensue following our institutions current transfusion 
algorithm. Patients who received full dose PCC and continue to have microvascular bleeding in 
addition to a PT >16.6 sec/ INR >1.6 sec will receive FFP at a dose of 10-15 mL/kg rounded up 
to the nearest unit.  
 
FFP dosage: Patients randomized to the FFP arm will continue with standard therapy per our 
institutional algorithm at a dose of 10-15 mL/kg rounded up to the nearest unit. Patients who 
have received FFP by randomization per the above dosage protocol and continue to demonstrate 
microvascular bleeding 10 minutes after product administration will undergo repeat laboratory 
evaluation of PT/INR +/- CBC, APTT, and fibrinogen depending on previous lab results and 
product administration other than FFP.  Therapy will ensue following our institutions current 
transfusion algorithm. Patients who receive FFP per randomization and continue to have 
microvascular bleeding 10 minutes after product administration in addition to a PT >16.6 sec/ 
INR >1.6 sec, or aPTT > 57 sec will receive additional FFP. 
 


 
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Transfusion of coagulation products other than PCC or FFP (e.g. platelets and cryoprecipitate) 
will be determined by laboratory abnormalities requiring treatment within our institutions current 
algorithm in the presence of excessive microvascular bleeding.  
 
Resolution of microvascular bleeding within the surgical field as determined by the surgical team 
is the endpoint for necessitation of transfusion, not normalization of coagulation testing. 
Examples of this are as follows: 
1. A patient with an INR of 1.9 and evidence of microvascular bleeding who receives either 
PCC or FFP, for which the microvascular bleeding resolves but the INR remains elevated 
at 1.7 would not receive additional transfusion.  
2. In the absence of laboratory deviations, continued bleeding is most commonly secondary 
to surgically related issues. The extremely rare instance that bleeding persists despite 
normalization of laboratory indices and there is no identifiable surgical cause for bleeding 
(thus presumed to be continued microvascular bleeding), the decision to transfuse blood 
component products, PCC, or potentially salvage therapy with activated PCC will be left 
to the discretion of the anesthesiologist and surgeon caring for the particular patient.  
 
 
Red blood cell transfusion (PRBC) threshold will be a hemoglobin concentration of 8g/dL (Hct 
24%) for patients enrolled in this study, as this threshold was not inferior to a threshold of 10 
g/dL (Hct 30%) in the TRACS trial.15  PRBC transfusion threshold deviations from this 
recommendation may occur at the discretion of the anesthesiologist caring for the patient in rare 
instances (e.g. severe surgical bleeding). Transfusion of PRBC in intensive care setting will also 
target a hemoglobin transfusion threshold of > 8 g/dL. Resolution of microvascular bleeding is 
the endpoint for necessitation of transfusion, not normalization of coagulation testing.  
 
Thrombin generation testing 
A blood sample will be collected to analyze thrombin generation prior to cardiopulmonary 
bypass, post-cardiopulmonary bypass after protamine administration, after transfusion of product 
(either FFP or PCC), 24 hours postoperative, 3 days postoperative, and 5 days postoperative or 
day of discharge . This sample will be collected in conjunction with other standard laboratory 
tests. Thrombin generation testing is not performed at Mayo Clinic. These samples will be stored 
at -20 degrees Celsius and sent batched to a specialized laboratory for testing. All samples will 
be deidentified and contain no PHI. Study participants will not be charged for this testing. No 
genetic analysis or testing other than AT-3 and Thrombin generation testing will occur with these 
samples. 
 
Antithrombin III Level 
AT-3 levels will be drawn at time periods that mirror thrombin generation testing below: prior to 
cardiopulmonary bypass, post-cardiopulmonary bypass after protamine administration, after 


 
9
transfusion of product (either FFP or PCC), 24 hours postoperative, 3 days postoperative, and  5 
days postoperative or day of discharge . Patients will not be charged for this testing. AT-3 levels 
will be collected in the same sample tube as Thrombin generation testing and shipped to a 
facility capable of performing such testing. All samples will be deidentified and contain no PHI. 
No genetic analysis or testing other than AT-3 and Thrombin generation testing will occur with 
these samples. 
 
Coagulation Factor Levels 
A blood sample will be collected to analyze coagulation factors 1-12 and protein C & S levels 
prior to cardiopulmonary bypass, post-cardiopulmonary bypass after protamine administration, 
and after transfusion of product (either FFP or PCC). This blood sample will be collected 
through an arterial catheter which is routinely placed as standard practice for cardiovascular 
operations. The collected coagulation factor level results will not be available to alter treatment 
in either study arm. Analysis of coagulation factor levels will focus on changes in factor levels 
resultant of cardiopulmonary bypass, and changes in factor levels resultant of product 
administration (either FFP or PCC). Study participants will not be charged for coagulation factor 
laboratory analysis.  These samples will be batch shipped to CSL Behring’s central laboratory in 
Germany for testing.  All samples will de-identified and contain no PHI (Protected Health 
Information).  No genetic analysis or testing other than the factor levels will occur on these 
samples. 
 
 
Current intraoperative transfusion algorithm 
 




 
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patients will be at a nasopharyngeal temperature of >36°C prior to discontinuation of CPB.  
Anticoagulation will be reversed with protamine as previously described. The patient will be 
transported intubated on a monitored cart to the cardiac surgical ICU.   
 
 
 
  
Postoperative ICU transfusion  
Current postoperative ICU transfusion requirements will follow the institutional algorithm (see 
ICU transfusion algorithm below). Deviation from the protocol in rare circumstances is left to 
the discretion of the ICU consultant and Surgeon. Transfusion of PRBC in intensive care setting 
will aim for a hemoglobin transfusion threshold of > 8 g/dL.   
 
 




 
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Respiratory rate ≤ 25/min 
 
Discharge from the intensive care unit and hospital criteria 
Current conventional discharge from the intensive care unit criteria and hospital will be used.  
 
ICU discharge time will be recorded and traditionally assumes following criteria: 
Alert and cooperative 
No inotropic support 
No hemodynamically unstable dysrhythmia 
Adequate respiratory status 
Minimal chest tube drainage 
Urine output ≥ 0.5 ml/kg/hr 
 
Discharge from the hospital will be recorded and traditionally assumes following criteria: 
Hemodynamically stable 
Stable cardiac rhythm 
Noninfected incisions 
Afebrile 
Ability to void and bowel movements 
Independent ambulation and feeding. 
 
 
G. Data Collection 
 
The following variables will be entered into a database: 
1. Demographic:  
a. Age 
b. Sex 
c. Society of Thoracic Surgeons (STS) risk score (where applicable) 
 
2. Comorbidities:  
a. History of cerebrovascular accident  
b. History of vascular thromboembolic disease (arterial or venous thrombosis, organ 
ischemia secondary to thromboembolic phenomenon). 
c. Coronary artery disease  
d. History of atrial fibrillation 
e. GFR < 60 mL/min/1.73 m2 
 
3. Preoperative laboratory variables: 
a. CBC, and the following if available preoperatively PT/ INR, APTT, Fibrinogen 
 
4. Preoperative medications: 
a. Anticoagulant medications 
 
5. Intraoperative variables: 
a. Procedure performed 


 
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b. Initial or Redo-Sternotomy 
c. Cardiopulmonary bypass time 
d. Aortic cross clamp time (if applicable)? 
e. Presence and (if present) duration of deep hypothermic circulatory arrest 
f. Allogenic blood product utilization after cardiopulmonary bypass 
g. Laboratory variables (CBC, PT/ INR, APTT, and Fibrinogen) 
h. Anticoagulant (Heparin +/- other) and anti-fibrinolytic use (aminocaproic acid or 
tranexamic acid) 
i. Direct transfusion related complications/reactions  
1. TRALI (Transfusion related acute lung injury) by standard definition16 
2. ABO/Non-ABO hemolytic reaction 
3. Anaphylactic or Allergic reaction 
 
 
6. Postoperative variables: 
a. Allogenic blood product transfusion 
b. Mediastinal and chest tube output for 24 hours after chest closure 
c. Serious Adverse Events occurring within 30 days of operation: 
i. Thromboembolic events (new DVT or arterial thrombosis diagnosed by 
Doppler ultrasound, cerebrovascular accident or transient ischemic attack, 
new 
myocardial 
infarction, 
end 
organ 
ischemia 
secondary 
to 
thromboembolic phenomenon, all-cause mortality) 
1. The concern for thromboembolic complications is certainly 
present, and will be monitored closely as an adverse event in both 
treatment 
arms. 
The 
presence 
of 
clinically 
significant 
thromboembolic complications will be diagnosed as per current 
clinical practice in this patient population. It is assumed that 
clinical symptomatology or suspicion to such diagnoses will 
trigger diagnostic testing when deemed appropriate, and any 
confirmed diagnoses of thromboembolic complications will be 
noted. No specific screening tests will occur in patients enrolled 
for this study. 
ii. Renal 
failure 
necessitating 
unplanned 
initiation 
of 
dialysis 
or 
hemofiltration 
iii. Acute Respiratory Distress Syndrome (ARDS) by Berlin definition17 
iv. Direct transfusion related complications/reactions  
1. TRALI (Transfusion related acute lung injury) by standard 
definition16 
2. ABO/Non-ABO hemolytic reaction 
3. Anaphylactic or Allergic reaction 
d. Length of stay (ICU and total hospital stay) 
 
 
H. Outcomes  
 
All suspected outcome events will be evaluated in a standardized way by an adjudication panel 
that will be unaware of the patients’ assignments.  


 
15
 
In the study, outcome measures for efficacy will be total allogenic blood products transfused and 
24 hour postoperative blood loss.  Outcome measure for safety will be rate of serious adverse 
events. 
 
Length of stay in the ICU and hospital will also be recorded in both groups. 
 
 
 
 
I. Follow-Up 
 
A telephonic assessment will be made by a study nurse at 30 days + 7 days.  A standardized 
phone survey will be used to obtain information for assessing events of interest (Attached 
below).    
 
J. Statistics/Power Analysis 
 
Power Analysis was determined from a study by Arnekian et al that retrospectively presented a 
reduction in blood loss in patients receiving PCC over those receiving FFP.2 In that study, the 
distribution of 24-hr chest tube drainage was highly skewed, but the observed difference between 
the two groups was at least 0.65 standard deviation units. Using a non-parametric test, a sample-
size of N=50 per group should provide statistical power of >85% to detect a difference of 
this magnitude. Therefore we suggest a sample-size of at least 50 per group. In the paper, 
they also found a dramatic difference in ICU red cell transfusions. If the true difference is as 
large as they observed a sample-size of N=50 per group would also provide adequate statistical 
power for this endpoint.2 
 
Primary endpoints in this study will be units of allogenic blood product administration, and 24 
hour postoperative blood loss. Exploratory endpoints will include rate of serious adverse 
outcomes. 
 
Baseline patient characteristics, including demographics, comorbidities, preoperative laboratory 
values, and cardiovascular variables will be reported and compared across treatment groups. 
Categorical variables will be reported as counts and percentages, and compared across groups 
using chi-square or Fisher’s exact tests.  Continuous variables will be reported as median and 
interquartile ranges, and compared across groups using Wilcoxon rank sum tests.   
 
 
K. Feasibility and Time Frame 
 
This study with the combined collaboration of divisions of anesthesiology and cardiovascular 
surgery is quite feasible. Approximately 2200-2500 cardiopulmonary bypass procedures are 
done annually at St. Mary’s Hospital.  Making the conservative estimate that 50% will consent 
1000 patients should be consented within 1 year. Given that approximately 11% of patients 


 
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receive transfusion; this would result in approximately 100-110 patients to be treated within 12 
months. We expect to get IRB approval within the next one month.  The study and data 
collection will take about 1 year with approximately two months for data analysis. 
 
L. Strengths and Limitations 
 
Strengths: This will be the first prospective randomized controlled trial in the United States 
directly assessing the effect of PCC compared to FFP in the setting of postcardiac surgery 
coagulopathy and bleeding in patients undergoing elective cardiac surgery. 
 
Limitations: If the study demonstrates lower transfusion requirements and blood loss in the PCC 
arm, further studies will need to address optimal dosing requirements. Current PCC dosing is 
based on INR and weight for patients on warfarin therapy. Should no difference be found 
between groups, or lower transfusion rate and/or postsurgical blood loss is found in the FFP arm, 
the question as to whether this represents a superior result of FFP or underdosing of the PCC arm 
will remain. 
 
 
M. Anticipated Results  
 
a. PCC administration will reduce the amount of allogenic blood product transfused and 
amount of postoperative bleeding in patients undergoing cardiac surgery. 
 
b. Adverse event rate will be similar between the 2 treatment arms, representing the 
known risk associated with cardiovascular surgery. 
 
c. Perioperative transfusion related costs will be similar or lower in patients receiving 
PCC compared with FFP 
 
N. Estimated Costs 
 
Kcentra will be supplied and funded by CSL Behring (Melbourne, Australia). FFP if 
administered will be covered by the patient/payer as this treatment is the current practice 
standard. All laboratory testing not routine to this patient population will be funded by CSL 
Behring and is outline within the budget. 
 
O.  Research Materials 
  
All data forms will be stored in individual patients study folders and handled securely for patient 
confidentiality. This data will be entered into an access database that is password protected.  
 
P.  Human Subjects 
 
We will obtain informed consent from all participants prior to initiation of the study.  Informed 
consent will meet the requirements of the code of federal regulations 21CFR 50.25 (elements of 
informed consent) and the IRB of this center.  During informed consent for the study cardiac 


 
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surgical patients will be told that the chance of needing a transfusion in the perioperative period 
is around 11%. Should they meet criteria by our current transfusion algorithm to receive FFP, 
they would have been randomized to receive either FFP or the study PCC infusion. A copy of the 
consent form will be placed in the patient’s medical records. The study will be stopped when 50 
patients have received treatment in each study arm. Efficacy will be defined as either a 
statistically significant reduction in transfusion of allogenic blood products or 24 hour 
postoperative blood loss.  Safety will be defined as similar rate of serious adverse outcomes in 
the PCC study drug arm to the standard therapy FFP arm.   
 
The trial will be conducted in accordance with the Declaration of Helsinki.   
 
 
Q.  Institutional IRB training Narrative 
 
The institution has established a formal program entitled the Mayo Investigator Training 
Program or MITP.  The MITP is a web based educational course designed to provide all 
personnel involved in human subject research with training about human subject protection.  All 
Mayo personnel engaged in human subject research are required to complete the course.  The 
primary objectives of the course are to provide the historical framework for current human 
subject protection regulations and to explore the evolving issues related to human subject 
research.   The course is divided into four sections: 
 
• Course introduction and general overview 
• History section which explores examples of unethical behavior in human subject research 
• Review of major human subject protection issues 
• Discussion of the various roles and responsibilities of individuals involved in human subject 
research 
• At the conclusion of the instruction, individuals are required to complete a thirty-question 
assessment. 
 
 
R.  Confidentiality 
 
Every effort will be made to ensure strict patient confidentiality.  Research records are stored 
securely and are separate from hospital records.  No patient identifier will be used in any 
publication resulting from this study. 
 
S.  Recruitment 
 
Volunteers will be recruited by study personnel during their preoperative medical evaluation. 
The investigators will review the purpose, the procedures risks and discomforts, benefits 
alternatives, costs, participation and termination, treatment for research related injury and 
confidentiality issues of the study in person with all potential volunteers.  Before participation, 
all volunteers are given adequate time to read the consent form before written informed consent 
is obtained.  The original consent form is placed in the subject’s study file.  A copy is provided 
to the participant and sent to HIM scanning to include in the electronic medical record. 
 
T.  Gender/Minority Mix 
 


 
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We expect an equal distribution of male and female study participants. The study population will 
comprise patients mainly from Olmsted County, MN and a few referred patients from throughout 
the country. We expect the racial/ethnic characteristics of the group to reflect the communities in 
Olmsted County, MN and are anticipated to be 95% white, 3% Asian and 2% other minorities. 
No efforts will be made to alter these characteristics, as there are no data that suggest differences 
in outcomes that we are studying in different genders or ethnic groups. 
 


 
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References 
 
1. 
Nuttall GA, Oliver WC, Santrach PJ, Bryant S, Dearani JA, Schaff HV, Ereth MH: 
Efficacy of a simple intraoperative transfusion algorithm for nonerythrocyte component 
utilization after cardiopulmonary bypass. Anesthesiology 2001; 94: 773-81; discussion 5A-6A 
2. 
Arnekian V, Camous J, Fattal S, Rezaiguia-Delclaux S, Nottin R, Stephan F: Use of 
prothrombin complex concentrate for excessive bleeding after cardiac surgery. Interactive 
cardiovascular and thoracic surgery 2012; 15: 382-9 
3. 
Thiele RH, Raphael J: A 2014 Update on Coagulation Management for Cardiopulmonary 
Bypass. Seminars in cardiothoracic and vascular anesthesia 2014; 18: 177-189 
4. 
Ballotta A, Saleh HZ, El Baghdady HW, Gomaa M, Belloli F, Kandil H, Balbaa Y, 
Bettini F, Bossone E, Menicanti L, Frigiola A, Bellucci C, Mehta RH: Comparison of early 
platelet activation in patients undergoing on-pump versus off-pump coronary artery bypass 
surgery. Journal of Thoracic and Cardiovascular Surgery 2007; 134: 132-138 
5. 
Woodman RC, Harker LA: Bleeding Complications Associated with Cardiopulmonary 
Bypass. Blood 1990; 76: 1680-1697 
6. 
Pandey S, Vyas GN: Adverse effects of plasma transfusion. Transfusion 2012; 52 Suppl 
1: 65S-79S 
7. 
Holbrook A, Schulman S, Witt DM, Vandvik PO, Fish J, Kovacs MJ, Svensson PJ, 
Veenstra DL, Crowther M, Guyatt GH: Evidence-based management of anticoagulant therapy: 
Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest 
Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012; 141: e152S-84S 
8. 
Kaatz S, Kouides PA, Garcia DA, Spyropolous AC, Crowther M, Douketis JD, Chan AK, 
James A, Moll S, Ortel TL, Van Cott EM, Ansell J: Guidance on the emergent reversal of oral 
thrombin and factor Xa inhibitors. Am J Hematol 2012; 87 Suppl 1: S141-5 
9. 
Levy JH, Faraoni D, Spring JL, Douketis JD, Samama CM: Managing new oral 
anticoagulants in the perioperative and intensive care unit setting. Anesthesiology 2013; 118: 
1466-74 
10. 
Demeyere R, Gillardin S, Arnout J, Strengers PF: Comparison of fresh frozen plasma and 
prothrombin complex concentrate for the reversal of oral anticoagulants in patients undergoing 
cardiopulmonary bypass surgery: a randomized study. Vox Sang 2010; 99: 251-60 
11. 
Gorlinger K, Dirkmann D, Hanke AA, Kamler M, Kottenberg E, Thielmann M, Jakob H, 
Peters J: First-line therapy with coagulation factor concentrates combined with point-of-care 
coagulation testing is associated with decreased allogeneic blood transfusion in cardiovascular 
surgery: a retrospective, single-center cohort study. Anesthesiology 2011; 115: 1179-91 
12. 
Ferreira J, DeLosSantos M: The Clinical Use of Prothrombin Complex Concentrate. 
Journal of Emergency Medicine 2013; 44: 1201-1210 
13. 
Hanke AA, Joch C, Gorlinger K: Long-term safety and efficacy of a pasteurized 
nanofiltrated prothrombin complex concentrate (Beriplex P/N): a pharmacovigilance study. 
British journal of anaesthesia 2013; 110: 764-72 
14. 
Goldberg AD, Kor DJ: State of the art management of transfusion-related acute lung 
injury (TRALI). Current pharmaceutical design 2012; 18: 3273-84 
15. 
Hajjar LA, Vincent JL, Galas FR, Nakamura RE, Silva CM, Santos MH, Fukushima J, 
Kalil Filho R, Sierra DB, Lopes NH, Mauad T, Roquim AC, Sundin MR, Leao WC, Almeida JP, 
Pomerantzeff PM, Dallan LO, Jatene FB, Stolf NA, Auler JO, Jr.: Transfusion requirements after 
cardiac surgery: the TRACS randomized controlled trial. JAMA 2010; 304: 1559-67 


 
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16. 
Toy P, Popovsky MA, Abraham E, Ambruso DR, Holness LG, Kopko PM, McFarland 
JG, Nathens AB, Silliman CC, Stroncek D: Transfusion-related acute lung injury: definition and 
review. Critical care medicine 2005; 33: 721-6 
17. 
Ranieri VM, Rubenfeld GD, Thompson BT, Ferguson ND, Caldwell E, Fan E, 
Camporota L, Slutsky AS: Acute respiratory distress syndrome: the Berlin Definition. JAMA 
2012; 307: 2526-33 
 
 
 
 
 
 
 


 
21
PCC vs. FFP Telephone script  
 
Good morning/afternoon. This is Dr./Ms./Mr. __________ calling from the Mayo Clinic-
Rochester. May I please speak to ___________? (If the participant is there proceed to the 
following; if the participant is not there, see below***)  
 
I am contacting you to ask you some questions in regard to the research study that we are 
doing here at the Mayo Clinic involving people who have had heart surgery. You had 
provided consent to participate in this study prior to your heart surgery. Please understand 
that your current care and future care at the Mayo Clinic will not be affected by whether 
or not you participate. Specifically, your care will not be jeopardized if you choose not to 
answer the questions. Would you be willing to answer some questions regarding your 
surgery?  
If yes: Is now a good time or would you like me to call you back?  
If no: Thank you for your time. 
 
1. Have you seen a doctor for any reason since being discharged from the hospital 
after your surgery? 
If yes: Could you please tell me the reason. 
If no: go to question 2 
_____________________________________________________________________
_____________________________________________________________________ 
 
2. Have there been any changes in your health status since being discharged from 
the hospital after your heart surgery? 
If yes: document 
If no: go to question 3 
_____________________________________________________________________
_____________________________________________________________________ 
 
3. Have you had any problems specifically with blood clots, heart attack, stroke, or 
damage to your kidneys requiring dialysis? 
If yes: document 
_____________________________________________________________________
_____________________________________________________________________ 
 
 
 
***If the participant you wish to speak with is not available, ask: When would it be a 
good time to call to speak with ___________? Thank you, I will return the call at that 
time.  
 
***If there is any indication that the patient is deceased: I’m truly sorry to hear that. 
Mr/Mrs __________________ agreed to participate in a study concerning his/her recent 


 
22
heart surgery. If you are willing to answer some questions, we may be able to collect 
some information that is helpful to the study. Would you be willing to share the 
circumstances of Mr/Mrs _________________ death?  
 
If yes: document. If not stated by call recipient, pose question number three phrased for a 
third party. 
If no: I can certainly understand. Thank you very much for your time. (end call) 
 
Closing: Thank you for participating in our research study. Please understand that your 
answers to the questions will be kept confidential and when the data from this research 
study is reported your data will be included in a summary without your name or any other 
identifying information.