FFP Versus PCC in Intracranial Hemorrhage

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

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.

Study Overview

• Status: Withdrawn
• Conditions: Intracranial Hemorrhage, Traumatic; Intracranial Hemorrhage, Spontaneous
• Intervention / Treatment: Biological: Fresh Frozen Plasma; Drug: Four Factor Prothrombin Complex Concentrate

Detailed Description

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.

• Study Type: Interventional
• Phase: Not Applicable

Contacts and Locations

Study Locations

• United States
  • Utah
    • Salt Lake City, Utah, United States, 84132
      • University of Utah Medical Center

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

• 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

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Fresh Frozen Plasma; 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; A pooled collection of plasma from donors
Experimental: Four Factor Prothrombin Complex Concentrate; 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; A purified, non-activated prothrombin complex concentrate containing factors II, VII, IX and X and proteins C & S; Other Names: Kcentra

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: University of Utah

Study record dates

Study Major Dates

• Study Start: April 1, 2015
• Primary Completion (Actual): March 1, 2016
• Study Completion (Actual): March 1, 2016

Study Registration Dates

• First Submitted: April 21, 2015
• First Submitted That Met QC Criteria: April 23, 2015
• First Posted (Estimate): April 29, 2015

Study Record Updates

• Last Update Posted (Estimate): November 16, 2016
• Last Update Submitted That Met QC Criteria: November 15, 2016
• Last Verified: November 1, 2016

More Information

Terms related to this study

• Keywords: Warfarin; fresh frozen plasma; prothrombin complex concentrate; Traumatic intracranial hemorrhage; Spontaneous intracranial hemorrhage
• Additional Relevant MeSH Terms: Pathologic Processes; Cardiovascular Diseases; Vascular Diseases; Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Wounds and Injuries; Craniocerebral Trauma; Trauma, Nervous System; Hemorrhage; Intracranial Hemorrhages; Intracranial Hemorrhage, Traumatic; Hemostatics; Coagulants; Thrombin
• Other Study ID Numbers: IRB_00078143