Factor VII, Prothrombin Complex Concentrate, and Fresh Frozen Plasma in Warfarin-Related Intracranial Hemorrhage

This study has been terminated.
(poor enrollment)
Sponsor:
Collaborator:
Sheila B. Terry Memorial Research Fund
Information provided by:
University of Utah
ClinicalTrials.gov Identifier:
NCT00770718
First received: October 9, 2008
Last updated: November 22, 2011
Last verified: November 2011
  Purpose

The purpose of this dose-ranging pilot study is to compare Recombinant Activated Factor VII, Prothrombin Complex Concentrate and Fresh Frozen Plasma (each starting at low doses with escalation if necessary) for the reversal of warfarin in the setting of acute intracranial hemorrhage.


Condition Intervention Phase
Intracranial Hemorrhage
Drug: Recombinant Activated Factor VII (rFVIIa)
Drug: Prothrombin Complex Concentrate
Biological: Fresh Frozen Plasma
Phase 1

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Comparison of Recombinant Activated Factor VII, Prothrombin Complex Concentrate, and Fresh Frozen Plasma for Anticoagulation Reversal in Warfarin-Associated Acute Intracranial Hemorrhage: A Dose Ranging Pilot Study

Resource links provided by NLM:


Further study details as provided by University of Utah:

Primary Outcome Measures:
  • Normalization of INR (<1.4) [ Time Frame: 20min, 2hrs, 4hrs, 6hrs, 24hrs ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • Hematoma progression [ Time Frame: 24hrs ] [ Designated as safety issue: No ]
  • Neurological status [ Time Frame: 24hrs & 1month ] [ Designated as safety issue: No ]
  • Timing of intervention completion [ Time Frame: 24hrs ] [ Designated as safety issue: No ]
  • Dosing of intervention required [ Time Frame: 24hrs ] [ Designated as safety issue: No ]
  • Medical complications during hospitalization [ Time Frame: days ] [ Designated as safety issue: Yes ]

Enrollment: 2
Study Start Date: April 2008
Study Completion Date: April 2010
Primary Completion Date: April 2010 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Recombinant Activated Factor VII
The first five patients who meet the selection criteria will be administered an intravenous dose of rFVIIa 1mg upon arrival. INR will be drawn at 20 minutes post-rFVIIa administration. If normalized (≤1.3), then repeat INR with be drawn every 2 hours thereafter for 6 hours total, and again at 24 hours after initial administration. If at any time, the INR is >1.3, then rFVIIa 1mg will be readministered and the INR will again be checked 20 minutes after administration and every 2 hours for 6 hours total and again at 24 hours post-administration. This may be repeated until a total dose of 80mcg/kg has been given. If a maximum total of 80mcg/kg has been administered without successful correction of INR, then FFP infusions will be utilized to complete correction.
Drug: Recombinant Activated Factor VII (rFVIIa)
Five patients who meet the selection criteria will be administered an intravenous dose of rFVIIa 1mg upon arrival. INR will be drawn at 20 minutes post-rFVIIa administration. If normalized (≤1.3), then repeat INR with be drawn every 2 hours thereafter for 6 hours total, and again at 24 hours after initial administration. If at any time, the INR is >1.3, then rFVIIa 1mg will be readministered and the INR will again be checked 20 minutes after administration and every 2 hours for 6 hours total and again at 24 hours post-administration. This may be repeated until a total dose of 80mcg/kg has been given.
Other Name: Novoseven®
Experimental: Prothrombin Complex Concentrate (PCC)
5 patients will receive PCC based on ideal body weight. Each patient will receive 30 i.u./kg ideal body weight as is rounded to the nearest dispensed vial size. Vials are dispensed as 5mL (500 i.u.), 10mL (1000 i.u.), or 10mL (1500i.u.). INR will be drawn at 20 minutes post-administration and, if normalized (≤1.3), 2 hours post-administration and every 2 hours for 6 hours total. The INR will also be checked 24 hours post-administration. If at any time, the INR is >1.3, then PCC will be readministered at the same dose and the INR will again be checked 20 minutes after administration and every 2 hours for 6 hours total and again at 24 hours post-administration. A maximum total of 60 iu/kg can be administered before FFP will be used to complete the correction.
Drug: Prothrombin Complex Concentrate
5 patients will receive PCC based on ideal body weight. Each patient will receive 30 i.u./kg ideal body weight as is rounded to the nearest dispensed vial size. Vials are dispensed as 5mL (500 i.u.), 10mL (1000 i.u.), or 10mL (1500i.u.). INR will be drawn at 20 minutes post-administration and, if normalized (≤1.3), 2 hours post-administration and every 2 hours for 6 hours total. The INR will also be checked 24 hours post-administration. If at any time, the INR is >1.3, then PCC will be readministered at the same dose and the INR will again be checked 20 minutes after administration and every 2 hours for 6 hours total and again at 24 hours post-administration. A maximum total of 60 iu/kg can be administered.
Other Name: Profilnine®
Active Comparator: Fresh Frozen Plasma (FFP)
The last five patients will receive transfusions of FFP to normalize INR. If the initial INR is between 2-4, then 2 units of FFP (Round 1) will be administered emergently. If the initial INR is >4, then 4 units of FFP will be administered (Round 1). The INR will be checked after each round of FFP infusion completed. Once INR ≤1.3, then the INR will be again checked every 2 hours after normalization for 6 hours total and then 24 hours post-initial infusion. If the INR should ever return to >1.3, then repeat infusions of FFP will begin as outlined above and the INR will be checked serially as defined above.
Biological: Fresh Frozen Plasma
Five patients will receive transfusions of FFP to normalize INR. If the initial INR is between 2-4, then 2 units of FFP (Round 1) will be administered emergently. If the initial INR is >4, then 4 units of FFP will be administered (Round 1). The INR will be checked after each round of FFP infusion completed. Once INR ≤1.3, then the INR will be again checked every 2 hours after normalization for 6 hours total and then 24 hours post-initial infusion. If the INR should ever return to >1.3, then repeat infusions of FFP will begin as outlined above and the INR will be checked serially as defined above.
Other Name: FFP

Detailed Description:

Both recombinant activated Factor VIIa (rFVIIa) as well as Prothrombin Complex Concentrate (PCC) are labeled for the treatment of bleeding episodes in patients with hemophilia. Many hospitals are also using each for the following unlabeled indications: bleeding rescue in surgical patients, severe multiple trauma with ongoing bleeding, intracranial bleeding < 4 hours since symptom onset, traumatic head injury with evidence of expanding bleed, retroperitoneal bleed, and life-threatening bleeding due to idiopathic coagulopathy. To our knowledge, these two products have never been clinically compared head to head for the reversal of warfarin in the setting of intracranial hemorrhage.

The rFVIIa (Novoseven) guidelines are based off of national data and utilize a dose range of 40-90 mcg/kg of ideal body weight (2.8-6.3 mg for a 70 kg. patient) with an additional dose if needed. The dose cited in the literature for the management of intracerebral bleeds ranges from 10 to 120 mcg/kg (0.7 - 8.4 mg for a 70 kg. patient,) with higher doses associated with increased risk of thromboembolic events.

The recommended dosing of PCC is 30-50 i.u. per kilogram of ideal body weight with additional dosing if needed. PCC (Profilnine®SD) is a mixture of the following vitamin K-dependent clotting factors: II (prothrombin), VII (proconvertin), IX (plasma thromboplastin component; PTC; Christmas factor), and X (Stuart-Prower factor). These factors are required for the conversion of prothrombin to thrombin and thus adequate hemostasis, and are synthesized in the liver.

Currently at the most hospitals around the country, fresh frozen plasma (FFP) is the mainstay for reversal of warfarin-related coagulopathy in intracranial hemorrhage at the discretion of the treating attending physician. We propose to study all the current reversal practices in the intracranial hemorrhage population here at the University of Utah as part of a quality improvement project for both patient safety and cost.

We will perform a safety and feasibility study comparing dosage regimens of rFVIIa, FIXa and fresh frozen plasma (FFP) infusion in the normalization of coagulopathy in the context of warfarin-related intracerebral hemorrhage. Our primary outcome is time to INR normalization defined as INR≤ 1.3 on two consecutive readings separated by 2 hours.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

  • Non-traumatic intracranial hemorrhage (subdural or intraparenchymal)
  • Known warfarin ingestion
  • INR ≥2.0
  • GCS <13

Exclusion Criteria:

  • Pregnancy
  • History of venous thrombosis or pulmonary embolus
  • Acute myocardial infarction
  • Acute stroke
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

No Contacts or Locations Provided
  More Information

No publications provided

Responsible Party: Bradley Duhon, M.D./Resident, Department of Neurosurgery, University of Utah Department of Neurosurgery
ClinicalTrials.gov Identifier: NCT00770718     History of Changes
Other Study ID Numbers: 21152
Study First Received: October 9, 2008
Last Updated: November 22, 2011
Health Authority: United States: Institutional Review Board

Keywords provided by University of Utah:
intracranial hemorrhage
warfarin
anticoagulant
Factor VII
Prothrombin

Additional relevant MeSH terms:
Hemorrhage
Intracranial Hemorrhages
Pathologic Processes
Cerebrovascular Disorders
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Vascular Diseases
Cardiovascular Diseases
Warfarin
Thrombin
Anticoagulants
Hematologic Agents
Therapeutic Uses
Pharmacologic Actions
Hemostatics
Coagulants

ClinicalTrials.gov processed this record on September 18, 2014