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

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.

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