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

NCT ID: NCT03064035

Last Updated: 2023-09-14

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE4
• Total Enrollment: 79 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2017-04-05
• Study Completion Date: 2019-04-24

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.

Conditions

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

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Fixed dose 4FPCC

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.

Group Type: EXPERIMENTAL

4-factor prothrombin complex concentrate (4FPCC)

Intervention Type: DRUG

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.

Variable dose 4FPCC

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

Group Type: ACTIVE_COMPARATOR

4-factor prothrombin complex concentrate (4FPCC)

Intervention Type: DRUG

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.

Interventions

4-factor prothrombin complex concentrate (4FPCC)

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.

Intervention Type: DRUG

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

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 125 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

HealthPartners Institute

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Zachary Stoecker, PharmD

Role: PRINCIPAL_INVESTIGATOR

Regions Hospital

Locations

Regions Hospital

Saint Paul, Minnesota, United States

Countries

United States

Provided Documents

Document Type: Study Protocol and Statistical Analysis Plan

View Document

Other Identifiers

A16-732

Identifier Type: -

Identifier Source: org_study_id