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Fixed Versus Variable Dosing of 4-factor Prothrombin Complex Concentrate for Emergent Warfarin Reversal (kcentra)

Primary Purpose

Acute Bleeding on Long-Term Anticoagulation Therapy, Hemorrhage, Significant Bleeding in Patients With a Coagulopathy (Prolonged Thrombin Time)

Status
Completed
Phase
Phase 4
Locations
United States
Study Type
Interventional
Intervention
4-factor prothrombin complex concentrate (4FPCC)
Sponsored by
HealthPartners Institute
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Acute Bleeding on Long-Term Anticoagulation Therapy

Eligibility Criteria

18 Years - 125 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  • Chronic anticoagulation with warfarin and initial INR ≥2
  • Emergent bleeding (i.e. intracranial hemorrhage, gastrointestinal hemorrhage, urgent invasive procedures, etc.) or urgent surgery requiring reversal of INR to ≤1.5

Exclusion Criteria:

  • Younger than 18 years of age
  • History of heparin-induced thrombocytopenia (HIT)
  • Patients without initial or post-administration INR readings
  • Patients with an initial INR <2
  • Pregnant patients
  • Prisoners

Sites / Locations

  • Regions Hospital

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Active Comparator

Arm Label

Fixed dose 4FPCC

Variable dose 4FPCC

Arm Description

Incorporating a fixed dose of 1500 IU. If the patient receiving the 1500 IU fixed dose remains in a bleeding state and the INR remains above goal, an additional 500 IU may be administered at the physician's discretion to minimize bleeding and attempt to achieve hemostasis.

The FDA-approved variable dosing algorithm is as follows: initial INR 2-3.9: 25 IU/kg (maximum dose 2500 IU), initial INR 4-6: 35 IU/kg (maximum dose 3500 IU), and initial INR >6: 50 IU/kg (maximum dose 5000 IU). The patient weight will be obtained using a scale and documented by the treating registered nurse

Outcomes

Primary Outcome Measures

Number of Participants Who Demonstrated Significant Reversal of INR Within 15 Minutes
To evaluate whether fixed dose 4FPCC is acceptably comparable to variable dosing with respect to anticoagulation reversal, as defined by a targeted INR of ≤1.5

Secondary Outcome Measures

Number of Participants With a Thromboembolic Event
Study patients will be followed post-administration of 4FPCC for thromboembolic events such as deep vein thrombosis, pulmonary embolism, ischemic stroke or transient ischemic event, or myocardial infarction.
Total Cost of Dosing Strategy
Cost outcomes will be assessed for all study patients and compared by dosing assignment. Cost of treatment was assessed based on the amount of 4FPCC doses administered during admission, using the study-contemporary rate of $1.57/unit

Full Information

First Posted
February 16, 2017
Last Updated
September 1, 2023
Sponsor
HealthPartners Institute
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1. Study Identification

Unique Protocol Identification Number
NCT03064035
Brief Title
Fixed Versus Variable Dosing of 4-factor Prothrombin Complex Concentrate for Emergent Warfarin Reversal
Acronym
kcentra
Official Title
A Prospective, Randomized Study of Fixed Versus Variable Dosing of 4-factor Prothrombin Complex Concentrate for Emergent Warfarin Reversal at a Large Tertiary Care Medical Center
Study Type
Interventional

2. Study Status

Record Verification Date
June 2019
Overall Recruitment Status
Completed
Study Start Date
April 5, 2017 (Actual)
Primary Completion Date
April 17, 2019 (Actual)
Study Completion Date
April 24, 2019 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
HealthPartners Institute

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Product Manufactured in and Exported from the U.S.
Yes
Data Monitoring Committee
No

5. Study Description

Brief Summary
The goal of this study is to determine if a fixed dose of 4-factor prothrombin complex concentrate (4FPCC) is as effective as the current standard of care. 4FPCC is used to reverse the effects of warfarin when a patient has emergent bleeding. The investigators hope that this study will help doctors treat patients quicker in the future. In addition, it may be cheaper for patients and hospitals. This is the same medication the doctor would use to reverse warfarin's effects, but at a lower dose. Hypothesis: A fixed dose of 4FPCC will be comparable to FDA-approved variable dosing for reversal of warfarin-induced anticoagulation (defined as an international normalized ratio [INR] ≤ 1.5) in patients with an INR ≥2 experiencing an emergent bleed or requiring emergent surgery.
Detailed Description
Warfarin is a common oral anticoagulant utilized in the United States for the treatment and prevention of thromboembolic events and conditions. Although effective, the major complication associated with warfarin is the risk of major bleeding events. Incidence of major bleeding events in long-term warfarin users is 1.5% to 5.2% per year, with mortality exceeding 13%. Among patients with an intracranial bleed, the mortality rate increases to 46%-55%. In these situations, it is imperative to reverse the pharmacologic effects of warfarin quickly in order to minimize bleeding and reduce the risk of death. Warfarin inhibits formation of vitamin K-dependent clotting factors II, VII, IX, X, and proteins C and S. An international normalized ratio (INR) is a commonly utilized laboratory test to measure the amount of anticoagulation provided by warfarin and is monitored throughout therapy. The INR is a standardized ratio utilizing prothrombin time to prevent variation between institutional laboratories. Prothrombin time is defined as the time required for plasma to clot after addition of clotting factor. A normal INR in a healthy adult can range from 0.8-1.2. The majority of patients on chronic warfarin therapy will have a target INR of 2-3. The optimal dose of 4FPCC is currently unknown despite multiple studies evaluating different dosing regimens. The FDA-approved dosing is 25 to 50 IU factor IX per kilogram of body weight, depending on INR. It is dosed to a maximum of 100 kilograms of body weight. The FDA-approved variable dosing algorithm is as follows: initial INR 2-3.9: 25 IU/kg (maximum dose 2500 IU), initial INR 4-6: 35 IU/kg (maximum dose 3500 IU), and initial INR >6: 50 IU/kg (maximum dose 5000 IU). Exact doses of 4FPCC administered may vary slightly from the calculated doses as the amount of 4FPCC differs based on the vials utilized. By incorporating a fixed dose of 1500 IU, presenting INR and body weight may not need to be determined prior to administration. This may allow for early administration and prevent delay for warfarin reversal in patients with emergent bleeding. This research may determine whether a fixed dose is effective for reversing warfarin to a target INR less than 1.5 compared to FDA-approved variable dosing. In addition, the lower fixed-dose will significantly reduce costs to the institution. Hypothesis: A fixed dose of 4FPCC will be comparable to FDA-approved variable dosing for reversal of warfarin-induced anticoagulation (defined as an international normalized ratio [INR] ≤ 1.5) in patients with an INR ≥2 experiencing an emergent bleed or requiring emergent surgery.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Acute Bleeding on Long-Term Anticoagulation Therapy, Hemorrhage, Significant Bleeding in Patients With a Coagulopathy (Prolonged Thrombin Time), Urgent Reversal of Vitamin K Antagonist (VKA) Anticoagulation

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 4
Interventional Study Model
Parallel Assignment
Model Description
For adults on long-term warfarin therapy who present to the ED with emergent bleeding, or who are in need of urgent invasive surgical procedures: the exposure of interest will be fixed vs. variable dose 4FPCC, to which eligible patients will be randomly assigned in a 1:1 ratio.
Masking
None (Open Label)
Allocation
Randomized
Enrollment
79 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Fixed dose 4FPCC
Arm Type
Experimental
Arm Description
Incorporating a fixed dose of 1500 IU. If the patient receiving the 1500 IU fixed dose remains in a bleeding state and the INR remains above goal, an additional 500 IU may be administered at the physician's discretion to minimize bleeding and attempt to achieve hemostasis.
Arm Title
Variable dose 4FPCC
Arm Type
Active Comparator
Arm Description
The FDA-approved variable dosing algorithm is as follows: initial INR 2-3.9: 25 IU/kg (maximum dose 2500 IU), initial INR 4-6: 35 IU/kg (maximum dose 3500 IU), and initial INR >6: 50 IU/kg (maximum dose 5000 IU). The patient weight will be obtained using a scale and documented by the treating registered nurse
Intervention Type
Drug
Intervention Name(s)
4-factor prothrombin complex concentrate (4FPCC)
Intervention Description
4-factor prothrombin complex concentrate (4FPCC) contains all of the vitamin K-dependent clotting factors inhibited by warfarin, making it desirable for use in warfarin reversal for emergent bleeds. Multiple guidelines currently recommend 4FPCC for warfarin reversal in vitamin K-dependent major bleeding or intracranial hemorrhage. 4FPCC has a fast onset of action and has demonstrated significant reversal of INR within 10 minutes. Its duration of action is up to 8 hours, and for this reason it should be given concurrently with vitamin K. Vitamin K has a delayed onset of action due to its need to stimulate the synthesis of clotting factors so its effects begin as the effects of 4FPCC diminish. 4FPCC is the standard of care treatment for this clinical population in the Regions Hospital Emergency Department.
Primary Outcome Measure Information:
Title
Number of Participants Who Demonstrated Significant Reversal of INR Within 15 Minutes
Description
To evaluate whether fixed dose 4FPCC is acceptably comparable to variable dosing with respect to anticoagulation reversal, as defined by a targeted INR of ≤1.5
Time Frame
15 minutes
Secondary Outcome Measure Information:
Title
Number of Participants With a Thromboembolic Event
Description
Study patients will be followed post-administration of 4FPCC for thromboembolic events such as deep vein thrombosis, pulmonary embolism, ischemic stroke or transient ischemic event, or myocardial infarction.
Time Frame
up to 7 days post administration of 4FPCC
Title
Total Cost of Dosing Strategy
Description
Cost outcomes will be assessed for all study patients and compared by dosing assignment. Cost of treatment was assessed based on the amount of 4FPCC doses administered during admission, using the study-contemporary rate of $1.57/unit
Time Frame
Hospital Stay, Up to 6 months

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
125 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Chronic anticoagulation with warfarin and initial INR ≥2 Emergent bleeding (i.e. intracranial hemorrhage, gastrointestinal hemorrhage, urgent invasive procedures, etc.) or urgent surgery requiring reversal of INR to ≤1.5 Exclusion Criteria: Younger than 18 years of age History of heparin-induced thrombocytopenia (HIT) Patients without initial or post-administration INR readings Patients with an initial INR <2 Pregnant patients Prisoners
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Zachary Stoecker, PharmD
Organizational Affiliation
Regions Hospital
Official's Role
Principal Investigator
Facility Information:
Facility Name
Regions Hospital
City
Saint Paul
State/Province
Minnesota
ZIP/Postal Code
55101
Country
United States

12. IPD Sharing Statement

Plan to Share IPD
No

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Fixed Versus Variable Dosing of 4-factor Prothrombin Complex Concentrate for Emergent Warfarin Reversal

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