A 68-year-old man presents to the emergency department with new onset unilateral weakness, altered LOC, and dysphagia. A stat head CT reveals a large right temporal intracranial hemorrhage (ICH). The patient is unable to provide you with a history, but his daughter tells you that he takes apixaban for his atrial fibrillation.
Direct oral anticoagulation drugs (DOACs), including the direct thrombin inhibitor dabigatran, and factor Xa inhibitors apixaban, rivaroxaban, and edoxaban, are now commonly prescribed for treatment of venous thromboembolism (VTE) and prevention of stroke in patients with non-valvular atrial fibrillation. Urgent reversal of these drugs is often necessary to prevent worsened mortality and morbidity in patients who suffer from acute intracranial hemorrhages (ICH). Unlike with warfarin, FFP will not reverse DOAC drugs.
Idarucizimab is a monoclonal antibody that binds to dabigatran, inactivating it and preventing it from binding thrombin. The affinity between dabigatran and idarucizimab is 350x greater than the affinity between dabigatran and thrombin so it forces bound drug to release thrombin. Idarucizimab is administered as a 5g IV bolus and has been shown to be effective at rapid and complete reversal of anticoagulant effects without significant prothrombotic complications. If idarucizimab is not available, 50 units/kg of 4-factor prothrombin complex concentrate (4F-PCC) may be used, although there is increased prothrombotic effect with 4F-PCC.
Factor Xa Inhibitors
Andexanet is a recombinant, modified factor Xa-like protein that acts as a “decoy molecule,” binding and reversing apixaban or rivaroxaban (there is insufficient data for edoxaban reversal). While this a welcome addition to the tool kit, there are a number of problems with andexanet; dosing is complicated (see table) and the cost ($22,120/patient) has kept many hospitals from stocking it.
Beyond the issues of complex dosing and cost, there is some question as to andexanet’s effectiveness. Unlike idarucizimab, andexanet does not clear the DOAC, but rather temporarily inactivates it during and for about one hour following the infusion. After that, depending on the timing of the last dose, a rebound anticoagulation effect may occur. There is no data or recommendation on redosing should this occur. The original study was a single arm study which showed improved factor Xa levels and hemostasis in patients with ICH; however, with no control arm, we don’t really know if this is any better than placebo. In fact, a recent study in Neurocritical Care showed no difference in outcomes between patients receiving andexanet and those receiving 4F-PCC. We know that 4F-PCC is safe and effective in this cohort. For now, reversal of factor Xa inhibitors is probably best achieved with 4F-PCC administration. Although data is still somewhat inconclusive, multiple guidelines recommend at least considering its use. 4F-PCC dosing is 25-50IU/kg, not to exceed 5000 units and repeat dosing not recommended due to potential prothrombotic effects.
Ciraparantag is an investigational drug that was designed to bind to heparin, but has been shown to also prevent all the DOAC drugs from binding to their respective targets. If approved, it could represent a “one-size-fits-all” reversal strategy for anticoagulation.
- DOAC drugs may need emergent reversal in patients with serious or life-threatening ICH
- Dabigatran should be reversed with idarucizamab, if available; 4F-PCC if not
- The factor Xa inhibitors have a reversal drug, andexanet, but it has issues related to cost and efficacy; for now, 4F-PCC is the best reversal agent
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