Rivaroxaban reversal

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Background

  • Millions of people in the United States are on at least one type of anticoagulant medication, for a number of medical conditions including atrial fibrillation, placement of cardiac stents, stroke prevention, deep vein thrombosis/pulmonary embolism, and prevention of acute coronary syndromes.
  • In the past several years, there have been numerous new anticoagulant medications that have entered the market, with claims of easier dosing and need for less monitoring compared to older generation medications.
  • However, with use of these new medications in increasing numbers by the public, and uncertainty regarding the best mechanisms of reversal, this can lead to a difficult situation for the emergency physician when a patient on one of these medications presents with a catastrophic intracranial or gastrointestinal bleed.
  • Since the introduction of the direct thrombin inhibitor (DTI) dabigatran (Pradaxa) and the Factor Xa inhibitors rivaroxaban (Xarelto) and epixiban (Eliquis), there have been multiple studies that have attempted to determine 1) which test(s) could be used to assess whether a patient has supratherapeutic drug levels, and 2) the best way to reverse anticoagulation in patients on these medications who have a life-threatening bleed.
  • However, the available studies are lacking in that none of these studies are assessing human subjects taking these medicaitions who are potentially supratherapeutic and symptomatic.

Clinical Features

  • Patient taking rivaroxaban with a life-threatening bleeding event (GI, ICH, etc.)

Differential Diagnosis

  • bleeding secondary to other coagulopathy
  • spontaneous bleeding

Diagnosis

  • clinical manifestation of GI bleeding
  • low H&H
  • non contrast head CT showing ICH
  • Factor Xa inhibiting agents affect the PT, however the degree of PT elevation does not directly correlate with that produced by warfarin and is not reliable in assessing level of anticoagulation with rivaroxaban or epixaban.
  • Antifactor Xa assays can be performed but the test needs to be calibrated specifically for these drugs, rather than using the calibration scale for LMWH, in order for the results to be reliable. However, Antifactor Xa assays measure drug levels and not degree of coagulopathy.
  • One test that has shown promise in determining level of coagulopathy and reversal of coagulopathy with both DTIs and Xa inhibitors is the Calibrated Automated Thrombogram (CAT) test, as shown with in vitro studies on reversal of dabigatran and rivaroxaban. CAT measures coagulability by measuring the thrombin concentration of a sample. It is a fluorogenic assay that compares the concentration of thrombin in clotting plasma with a constant known thrombin activity in a parallel non-clotting sample. This test could potentially be a global test of coagulation state and is therefore potentially very useful in the clinical setting to assess patients with any possible coagulopathy.

Management

  • IV/O2/Monitor, ABCs
  • standard resuscitation with IVF; PRBCs if needed
  • If ICH, treat for increased ICP
  • Currently published manuscripts and protocols is that either PCC or aPCC is recommended as a reversal agent for DTIs and FXa inhibitors, with no clear data as to which is superior.
  • Consider Tranexamic acid

Factor Xa Inhibitor Reversal

Anticoagulant Half-life Removed by HD Strategies to reverse or minimize anticoagulant effects
Apixaban[1] (Eliquis®) 8-15 hrs (longer in renal impairment) No
  • If ingested within 2 hours, administer activated charcoal
  • 4-factor PCC (Kcentra™)^
    • 25units/kg—max 2500 units for treatment of documented intracranial hemorrhage
    • 50 units/kg—max 5000 units for all other life-threatening bleeds
Edoxaban[2] (Savaysa®) 10-14 hrs (longer in renal impairment) ~ 25% As above
Rivaroxaban[3] (Xarelto®) 9-13 hrs (longer in renal impairment) No As above
Fondaparinux (Arixtra®) 17-21 hrs (significantly longer in renal impairment) No 4-factor PCC (Kcentra™)^ 50 units/kg—max 5000 units

^Off-label

Andexanet alfa

FDA approved in May 2018, limited availability June 2018

  • Cost is $20,000 to $55,000 per dose
  • Trial that led to FDA approval does not have the most sound evidence behind it [4]:
    • Prospective single center single group study of 352 patients receiving a Factor Xa Inhibitor (apixaban, rivaroxaban, edoxaban, enoxaparin) with life threatening bleed (those with expected survival <1 month were excluded).
    • Anti-Factor Xa activity was decreased in all groups. 82% were judged to have excellent hemostatic control. 14% mortality rate at 30 days.
    • No comparison group available. It is unlikely that following anti-Factor Xa activity as a lab value is clinically important. High mortality rate even after excluding sick patients.


Low Dose

400 mg IV bolus at rate of ~30 mg/minute, followed 2 minutes later by 4 mg/minute for up to 120 minutes

High Dose

800 mg IV bolus at rate of ~30 mg/minute, followed 2 minutes later by 8 mg/minute for up to 120 minutes

Disposition

  • admission to a monitored setting

See Also

External Links

References

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  2. Awad, N., & Cocchio, C. (2013). Activated Prothrombin Complex Concentrates for the Reversal of Anticoagulant-Associated Coagulopathy. Pharmacy And Therapeutics, 38(11), 696.
  3. Babilonia, K., & Trujillo, T. (2014). The role of prothrombin complex concentrates in reversal of target specific anticoagulants. Thrombosis Journal, 12(1), 8. doi:10.1186/1477-9560-12-8
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  1. ↑ Eliquis prescribing information. Princeton, NJ: Bristol Myers Squibb; December 2012.
  2. ↑ Savaysa prescribing information. Parsippany, NJ: Daiichi Sankyo, Inc.; November 2015.
  3. ↑ Xarelto prescribing information. Titusville, NJ: Janssen Pharmaceuticals, Inc.; December 2014.
  4. ↑ Connolly SJ, Crowther M, Eikelboom JW, et al. Full Study Report of Andexanet Alfa for Bleeding Associated with Factor Xa Inhibitors. N Engl J Med. 2019
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