Fixed-dose Activated Versus Variable-dose Inactivated Prothrombin Complex Concentrate for Warfarin-associated Major Bleed

Study Overview
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Brief Summary
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This study aims to assess a fixed-dose regimen of activated prothrombin complex concentrate (FEIBA VH, Baxter) versus the variable, manufacturer recommended, dose regimen of inactivated prothrombin complex concentrate (Kcentra, CSL Behring) for reversal of warfarin-associated major hemorrhage.

Detailed Description
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Warfarin, a vitamin K antagonist (VKA), is the most frequently prescribed oral anticoagulant. Warfarin-associated major hemorrhage occurs at a rate of 1.7% to 3.4% in routine clinical practice and warrants rapid reversal of anticoagulation by correcting supratherapeutic international normalized ratio (INR) values. Warfarin inhibits synthesis of vitamin K dependent coagulation factors II, VII, IX, and X, and strategies for reversal of warfarin-associated coagulopathy are aimed at restoring deficient factors. Four-factor prothrombin complex concentrates (PCCs) contain the coagulation factors which warfarin inhibits and are an attractive option for rapid reversal due to ease of reconstitution and no requirement for blood-type matching. Manufacturer dosing recommendations exist for PCCs based on patient weight, baseline INR, and target INR, but studies have suggested fixed dosing strategies in an effort to determine the most efficacious dose for VKA-reversal while sparing adverse events. These studies have also utilized different PCC formulations, with some studies utilizing 4-factor activated PCC (aPCC), which denotes product containment of factor VII in an activated state. In the United States, product availability is limited to a single 4-factor aPCC (FEIBA VH, Baxter) indicated for hemophilia patients with inhibitors and a single 4-factor inactivated PCC (Kcentra, CSL Behring) approved for VKA-reversal. Various institutions choose to utilize off-label fixed dosing strategies of 4-factor aPCC in an effort to administer the lowest possible dose to reverse VKAs, while others utilize manufacturer recommended dosing of 4-factor inactivated PCC.

Official Title
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Reversal of Warfarin-associated Major Hemorrhage: a Multicenter, Retrospective Cohort Study of Fixed-dose Activated (FEIBA VH) Versus Variable-dose Inactivated (Kcentra) Prothrombin Complex Concentrate

Conditions
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Hemorrhage

Intervention / Treatment
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* Drug: fixed-dose activated prothrombin complex concentrate
* Drug: variable-dose inactivated prothrombin complex concentrate


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Pre-treatment INR lab value greater than 1.5 Receipt of treatment with a 4-factor PCC for INR normalization due to warfarin-associated major hemorrhage Exclusion Criteria: Patients treated with a PCC for an urgent invasive procedure without active hemorrhage Patients treated with PCC not taking a VKA Unavailable pre- or post-treatment INR lab values Pregnant patients

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| fixed-dose aPCC<br>Patients receiving fixed-dose activated prothrombin complex concentrate (FEIBA VH) for reversal of warfarin-associated major hemorrhage. | Drug: fixed-dose activated prothrombin complex concentrate<br>* FEIBA VH 500 units IV one time for INR less than 5. FEIBA VH 1000 units IV one time for INR greater than 5. Check INR after infusion and may repeat dose if INR still elevated<br>* Other names: FEIBA VH;|
| variable-dose PCC<br>Patients receiving vairable-dose inactivated prothrombin complex concentrate (Kcentra) for reversal of warfarin-associated major hemorrhage. | Drug: variable-dose inactivated prothrombin complex concentrate<br>* Kcentra 25 units/kg IV one time for INR less than 4. Kcentra 35 units/kg IV one-time for INR 4 to 6. Kcentra 50 units/kg IV one-time for INR greater than 6. Check INR after infusion and may repeat dose if INR still elevated.<br>* Other names: Kcentra;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Achievement of INR less than or equal to 1.5 | The number of patients achieving a goal INR of less than or equal to 1.5 within 60 minutes following administration of 4-factor fixed-dose aPCC (FEIBA VH) versus variable-dose inactivated PCC (Kcentra) for reversal of warfarin-associated major hemorrhage. | 60 minutes | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of mortality or thrombotic events | Incidence of mortality, deep vein thrombosis, pulmonary embolism, myocardial infarction, and ischemic cerebrovascular events within 30 days following administration of 4-factor fixed-dose aPCC (FEIBA VH) or variable-dose inactivated PCC (Kcentra) for reversal of warfarin-associated major hemorrhage. | 30 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Vitamin K 1, prothrombin complex concentrates, warfarin