FFP Versus PCC in Intracranial Hemorrhage

Study Overview
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Brief Summary
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The goal of this study will be to determine whether PCC confers any benefits over FFP in traumatic and spontaneous intracranial hemorrhage with respect to multiple factors including time to correction, absolute international normalized ratio correction amount, cost, need for surgical intervention, and radiographic bleed expansion through a prospective, randomized control trial.

Detailed Description
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Vitamin K antagonists in general and Coumadin in particular remains the most common form of outpatient anticoagulation in patients today. Despite the therapeutic benefits of these agents, bleeding in general and intracranial bleeding in particular are significant risks associated with these medications. Intracranial bleeding on oral anticoagulation agents are associated with a 20% increase in 30 day mortality versus non-anticoagulated controls, and rapid reversal of vitamin K antagonists in this population has been shown to have survival benefits. Historically, vitamin K antagonists have been reversed using fresh frozen plasma (FFP) transfusions which, though effective, often incur delays due to the time required to obtain a type & screen, thaw the product, and administer the product to the patient. In 2013, the FDA approved 4-factor prothrombin complex (PCC), a concentrate of factors II, VII, IX, X, protein C and protein S for use as a method for correcting vitamin K antagonist related coagulopathy. Though large, prospective randomized control trials have demonstrated efficacy and safety in a general population of all-comers bleeding, there is very little literature regarding the benefits of PCC versus FFP in the traumatic and spontaneous intracranial hemorrhage population. Current standard of care in patients with traumatic and spontaneous intracranial hemorrhage who are on vitamin K antagonists is to reverse the effect of these agents with FFP or PCC. The choice of which agent to use is currently determined by both availability of each agent and surgeon preference. For this study, there will be an equal likelihood of either treatment being given. The goal of this study will be to determine whether PCC confers any benefits over FFP in traumatic and spontaneous intracranial hemorrhage with respect to multiple factors including time to correction, absolute international normalized ratio correction amount, cost, need for surgical intervention, and radiographic bleed expansion through a prospective, randomized control trial.

Official Title
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Fresh Frozen Plasma Versus Four Factor Prothrombin Complex Concentrate for Reversal of Vitamin K Antagonists in Intracranial Hemorrhage

Conditions
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Intracranial Hemorrhage, Traumatic, Intracranial Hemorrhage, Spontaneous

Intervention / Treatment
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* Drug: Four Factor Prothrombin Complex Concentrate
* Biological: Fresh Frozen Plasma


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Coumadin use INR of 2.0 or higher on arrival at the study center Evidence on cranial imaging of spontaneous intracranial hemorrhage, subdural hematoma, epidural hematoma, cerebral contusion, traumatic subarachnoid hemorrhage, or traumatic intraparenchymal hemorrhage Exclusion Criteria: Unable to obtain consent Estimated survival <24 hours Hypersensitivity to 4 factor prothrombin complex concentrate Concomitant use of novel vitamin K antagonists Religious/social prohibition to receiving blood products Need for emergent, non-neurosurgical operative intervention Mechanical heart valves

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Fresh Frozen Plasma<br>Administration of a single dose of fresh frozen plasma based on INR per the following regimen: 2U for INR of 2-2.5; 3U for INR of 2.5-3; 4U for INR of 3-3.5; 5U for INR of 3.5-4; 6U for INR of 4+ | Biological: Fresh Frozen Plasma<br>* A pooled collection of plasma from donors<br>|
| Experimental: Four Factor Prothrombin Complex Concentrate<br>Administration of a single dose of four factor prothrombin complex concentrate per the following dosing regimen: 25 U/kg for INR of 2-4; 35 U/kg for INR of 4-6; 50 U/kg for INR of 6+; maximum dosing weight of 100kg, patients may be dispensed +/- 10% of ordered dose | Drug: Four Factor Prothrombin Complex Concentrate<br>* A purified, non-activated prothrombin complex concentrate containing factors II, VII, IX and X and proteins C & S<br>* Other names: Kcentra;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Rapid reversal of warfarin as measured by international normalized ratio (INR) drawn at 30 minutes after transfusion | INR level 30 minutes after transfusion completion of FFP or 4 factor prothrombin complex concentrate | 30 minutes after transfusion completion | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Radiographic expansion of traumatic intracerebral hemorrhage as measured by CT scan within 24 hours of presentation | Expansion of blood on repeat CT scan of >10% | 24 hours after presentation | 
| Timing of reversal of warfarin as measured by INR drawn at 3 hours, 8 hours and 24 hours after transfusion | INR level at 3 hours, 8 hours and 24 hours after transfusion completion of FFP or prothrombin complex concentrate | 3-24 hours after completion of FFP or 4 factor prothrombin complex concentrate transfusion | 
| Thromboelastography response as measured by results of ROTEM analysis at 30 minutes and 24 hours after transfusion | Results of ROTEM analysis at 30 minutes and 24 hours after transfusion | 30 minutes and 24 hours after completion of FFP or 4 factor prothrombin complex concentrate transfusion | 
| Absolute INR reversal as measured by INR drawn 24 hours after transfusion | Difference between initial INR and INR 24 hours after completion of transfusion | 24 hours after completion of FFP or 4 factor prothrombin complex concentrate transfusion | 
| Need for operative intervention as measured by need for neurosurgical procedure during the hospitalization | Need for operative intervention during hospitalization related to initial trauma | During duration of hospital stay, an expected average of 1 week | 
| Estimated blood loss during any neurosurgical procedure | Estimated blood loss during any neurosurgical interventions during the hospitalization | During duration of hospital stay, an expected average of 1 week | 
| Further transfusion needs as measured by number of units of blood/platelet/plasma products transfused during the hospitalization | Need for blood product transfusions during hospitalization | During duration of hospital stay, an expected average of 1 week | 
| In hospital mortality | Mortality during hospital stay | During duration of hospital stay, an expected average of 1 week | 
| Total hospital cost | Total cost of hospital stay based on hospital charges | During duration of hospital stay, an expected average of 1 week | 
| 30 day outcome as measured by the Glasgow outcome score | Glasgow outcome score 30 days after discharge | 30 days after discharge | 
| Complications as measured by development of deep vein thrombosis, pulmonary embolism, myocardial infarction, stroke, unanticipated intubation, heart failure, or need for aggressive diuresis during the hospitalization | Development of deep vein thrombosis, pulmonary embolism, myocardial infarction, stroke, unanticipated intubation, heart failure, or need for aggressive diuresis | During duration of hospital stay, an expected average of 1 week | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Warfarin, Traumatic intracranial hemorrhage, prothrombin complex concentrate, fresh frozen plasma, Spontaneous intracranial hemorrhage