HR, a 48-year-old male, was brought into the ED via EMS following a motor-vehicle accident. Head CT showed large right subdural hematoma with a significant midline shift.

PMH: Valvular atrial fibrillation, Hypertension, Hyperlipidemia

Current medications:

Jantoven 5 mg PO QD

Cardizem LA 120 mg PO QD

Livalo 4 mg PO QD

The neurosurgeon wants to perform an emergent craniotomy and is considering agents reverse the Jantoven. Which of the following options can be given for Jantoven reversal? Select all that apply.

A. Phytonadione

B. Andexxa

C. KCentra

D. Praxbind

E. Fresh Frozen Plasma

Answer with Rationale

Anticoagulant reversal can increase a patient’s thrombotic risk due to their own underlying diseases and risk factors. In addition, certain reversal agents, such as Andexxa and KCentra, also carry additional thrombotic risk. As a result, reversal agents should only be considered in severe, life-threatening clinical situations (major bleeding, etc.) where urgent need for anticoagulant reversal outweighs the risk of thrombosis. Subdural hematoma (SDH) is defined as bleeding outside the subarachnoid space directly beneath the dura mater, which can be acute or chronic. The most common cause of SDH is head injury, which often results from car crash, fall, etc. Symptoms include balance/walking problems, confusion, headache, loss of consciousness, seizures, speech problems, weakness/numbness. In chronic situations, these symptoms may develop over time as the hematoma slowly grows. SDH usually requires surgical interventions – craniotomy (cutting a flap of skull open to remove the blood) or burr hole (drilling a small hole in the skull to allow the blood to drain). Jantoven  is better known by its other well known name: Coumadin. Let's examine which options are appropriate to reverse our patient's warfarin. 

Answer A is correct. Phytonadione, or vitamin K, is usually given PO or IV by slow infusion for warfarin reversal. IV push administration should be avoided as it is associated with anaphylaxis.  It works by promoting synthesis of new clotting factors II, VII, IX, and X in the liver. However, the onset is 12-24 hours for PO and 4-12 hours for IV, which is relatively slow. Vitamin K should not be given for warfarin reversal via SQ route due to erratic and unpredictable absorption. IM route should also be avoided due to risk of hematoma formation. 

Answer B is incorrect. Andexxa, or andexanet-alfa, is a recombinant, modified human factor Xa decoy protein that binds to and sequesters factor Xa inhibitors apixaban and rivaroxaban. Currently, there is no FDA-approved indication for edoxaban or enoxaparin reversal with Andexxa.

Answer C is correct. KCentra, or 4-Factor Prothrombin Complex Concentrate (4-Factor PCC), is derived from plasma. It contains factors II, VII, IX, X, protein C and S, as well as small amount of heparin. Therefore, it can be given to reverse warfarin. The onset of action is around 5-15 minutes with duration of 12-24 hours when used in combination with Vitamin K. KCentra is more commonly used in emergent situations due to faster administration and onset. However, it carries a higher thrombosis risk than Fresh Frozen Plasma (FFP).

Answer D is incorrect. Praxbind, or idarucizumab, is a humanized monoclonal antibody fragment that specifically binds to dabigatran and metabolites to neutralize anticoagulation effects and prevent free dabigatran from binding to thrombin and inhibiting thrombin actions. The approved dose for dabigatran reversal is 5g given as a rapid infusion or bolus.

Answer E is correct. Fresh Frozen Plasma, or FFP, contains factors II, VII, IX, X, fibrinogen, protein C, and von Willebrand factor (vWF). Thus, it can be given to reverse warfarin. The onset of action is around 1-4 hours with duration up to 6 hours. Compared to KCentra, it is less concentrated. However, FFP requires blood typing and takes up to 30 minutes to thaw, which can lead to administration delays. Currently, there are no data to support FFP use in reversal of direct oral anticoagulants.

Generic/Brand: Warfarin (Jantoven or Coumadin), Diltiazem (Cardizem), Pitavastatin (Livalo), Phytonadione (Mephyton), Andexanet-alfa (Andexxa), 4-Factor PCC (KCentra), Idarucizumab (Praxbind), Fresh Frozen Plasma

NAPLEX® Core Competencies Covered:

• 1.1 – From instruments, screening tools, laboratory, genomic or genetic information, or diagnostic findings
• 1.2 – From patients: treatment adherence, or medication-taking behavior; chief complaint, medication history, medical history, family history, social history, lifestyle habits, socioeconomic background
• 2.1 – Pharmacology, mechanism of action, or therapeutic class
• 2.2 – Commercial availability; prescription or non-prescription status; brand, generic, or biosimilar names; physical descriptions; or how supplied
• 3.4 – Drug dosing or dosing adjustments; duration of therapy
• 3.5 – Drug route of administration, dosage forms, or delivery systems
• 5.5 – Instructions or techniques for drug administration