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

Phase 4

Completed

• Conditions: Acute Bleeding on Long-Term Anticoagulation Therapy; Hemorrhage; Urgent Reversal of Vitamin K Antagonist (VKA) Anticoagulation; Significant Bleeding in Patients With a Coagulopathy (Prolonged Thrombin Time)
• Interventions: Drug: 4-factor prothrombin complex concentrate (4FPCC)

• Registration Number: NCT03064035
• Lead Sponsor: HealthPartners Institute

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.

Study Timeline

• Study First Submitted: 2017-02-16
• Study First Submitted QC: 2017-02-21
• Study First Posted: 2017-02-24
• Study Start: 2017-04-05
• Primary Completion: 2019-04-17
• Study Completion: 2019-04-24
• Status Verified: 2019-06
• Results First Submitted: 2023-01-12
• Results First Submitted QC: 2023-06-19
• Results First Posted: 2023-07-11
• Last Update Submitted: 2023-09-01
• Last Update Posted: 2023-09-14

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 79

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

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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

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Fixed dose 4FPCC	4-factor prothrombin complex concentrate (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.
Variable dose 4FPCC	4-factor prothrombin complex concentrate (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

Primary Outcome Measures

Name	Time	Method
Number of Participants Who Demonstrated Significant Reversal of INR Within 15 Minutes	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

Name	Time	Method
Number of Participants With a Thromboembolic Event	up to 7 days post administration of 4FPCC	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	Hospital Stay, Up to 6 months	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

Trial Locations

Locations (1)

Regions Hospital; 🇺🇸 Saint Paul, Minnesota, United States