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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.
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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Fresh Frozen Plasma | Active Comparator | 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+ |
|
| Four Factor Prothrombin Complex Concentrate | Experimental | 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 |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Four Factor Prothrombin Complex Concentrate | Drug | A purified, non-activated prothrombin complex concentrate containing factors II, VII, IX and X and proteins C & S |
|
| 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 |
| 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 |
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Exclusion Criteria:
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| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| University of Utah Medical Center | Salt Lake City | Utah | 84132 | United States |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 37870112 | Derived | Eilertsen H, Menon CS, Law ZK, Chen C, Bath PM, Steiner T, Desborough MJ, Sandset EC, Sprigg N, Al-Shahi Salman R. Haemostatic therapies for stroke due to acute, spontaneous intracerebral haemorrhage. Cochrane Database Syst Rev. 2023 Oct 23;10(10):CD005951. doi: 10.1002/14651858.CD005951.pub5. |
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| ID | Term |
|---|---|
| D020198 | Intracranial Hemorrhage, Traumatic |
| D020300 | Intracranial Hemorrhages |
| D002836 | Hemophilia B |
| ID | Term |
|---|---|
| D002561 | Cerebrovascular Disorders |
| D001927 | Brain Diseases |
| D002493 | Central Nervous System Diseases |
| D009422 | Nervous System Diseases |
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|
| Fresh Frozen Plasma | Biological | A pooled collection of plasma from donors |
|
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 |
| D006259 | Craniocerebral Trauma |
| D020196 | Trauma, Nervous System |
| D014652 | Vascular Diseases |
| D002318 | Cardiovascular Diseases |
| D014947 | Wounds and Injuries |
| D006470 | Hemorrhage |
| D010335 | Pathologic Processes |
| D013568 | Pathological Conditions, Signs and Symptoms |
| D025861 | Blood Coagulation Disorders, Inherited |
| D001778 | Blood Coagulation Disorders |
| D006402 | Hematologic Diseases |
| D006425 | Hemic and Lymphatic Diseases |
| D020147 | Coagulation Protein Disorders |
| D006474 | Hemorrhagic Disorders |
| D030342 | Genetic Diseases, Inborn |
| D009358 | Congenital, Hereditary, and Neonatal Diseases and Abnormalities |
| D040181 | Genetic Diseases, X-Linked |