Fixed Versus Variable Dosing of 4-factor Prothrombin Complex Concentrate for Emergent Warfarin Reversal
Condition: 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
MeSH terms: Hemorrhage
Study type: Interventional
Phase: Phase 4

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.
    

Intervention name(s): 4-factor prothrombin complex concentrate (4FPCC)
Intervention type(s): Drug
Intervention description(s): 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 MeSH terms: Thrombin
Allocation: Randomized
Intervention model: Parallel Assignment
Intervention 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)
Primary purpose: Treatment