Critical care nurse practitioner and assistant program director of the Critical Care APP Fellowship at the University of Kentucky. Co-host of the podcast Critical Care Scenarios (www.icuscenarios.con). Can be found in the ICU with coffee in one and and the US probe in the other.
The Case:
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.
Prebrief:
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.
Dabigatran
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.
The Future
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.
The Debrief
- 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
References
- Pollack CV Jr, Reilly PA, van Ryn J, Eikelboom JW, Glund S, Bernstein RA, Dubiel R, Huisman MV, Hylek EM, Kam CW, Kamphuisen PW, Kreuzer J, Levy JH, Royle G, Sellke FW, Stangier J, Steiner T, Verhamme P, Wang B, Young L, Weitz JI. Idarucizumab for Dabigatran Reversal – Full Cohort Analysis. N Engl J Med. 2017 Aug 3;377(5):431-441. doi: 10.1056/NEJMoa1707278. Epub 2017 Jul 11. PMID: 28693366.
- Frontera JA, Lewin JJ 3rd, Rabinstein AA, Aisiku IP, Alexandrov AW, Cook AM, del Zoppo GJ, Kumar MA, Peerschke EI, Stiefel MF, Teitelbaum JS, Wartenberg KE, Zerfoss CL. Guideline for Reversal of Antithrombotics in Intracranial Hemorrhage: A Statement for Healthcare Professionals from the Neurocritical Care Society and Society of Critical Care Medicine. Neurocrit Care. 2016 Feb;24(1):6-46. doi: 10.1007/s12028-015-0222-x. PMID: 26714677.
- Kipp K. I Have Andexxa Issues. EM:CRIT. June 19, 2018. Accessed October 24, 2020. https://emcrit.org/emcrit/issues-andexanet/
- Frontera JA, Bhatt P, Lalchan R, Yaghi S, Ahuja T, Papadopoulos J, Joset D. Cost comparison of andexanet versus prothrombin complex concentrates for direct factor Xa inhibitor reversal after hemorrhage. J Thromb Thrombolysis. 2020 Jan;49(1):121-131. doi: 10.1007/s11239-019-01973-z. PMID: 31664662.
- Andexxa. Package insert. Portola Pharmaceuticals, Inc. 2018.
- Nasrazadani Z. I Have Andexxa Issues, 2: A Formulary Toolkit. EM PharmD. April 9, 2019. Accessed October 24, 2020. https://empharmd.com/2019/04/09/i-have-andexanet-issues-2-a-formulary-toolkit/
- Connolly SJ, Crowther M, Eikelboom JW, Gibson CM, Curnutte JT, Lawrence JH, Yue P, Bronson MD, Lu G, Conley PB, Verhamme P, Schmidt J, Middeldorp S, Cohen AT, Beyer-Westendorf J, Albaladejo P, Lopez-Sendon J, Demchuk AM, Pallin DJ, Concha M, Goodman S, Leeds J, Souza S, Siegal DM, Zotova E, Meeks B, Ahmad S, Nakamya J, Milling TJ Jr; ANNEXA-4 Investigators. Full Study Report of Andexanet Alfa for Bleeding Associated with Factor Xa Inhibitors. N Engl J Med. 2019 Apr 4;380(14):1326-1335. doi: 10.1056/NEJMoa1814051. Epub 2019 Feb 7. PMID: 30730782; PMCID: PMC6699827.
- Ammar AA, Ammar MA, Owusu KA, Brown SC, Kaddouh F, Elsamadicy AA, Acosta JN, Falcone GJ. Andexanet Alfa Versus 4-Factor Prothrombin Complex Concentrate for Reversal of Factor Xa Inhibitors in Intracranial Hemorrhage. Neurocrit Care. 2021 Jan 6. doi: 10.1007/s12028-020-01161-5. Epub ahead of print. PMID: 33403588.
- Panos NG, Cook AM, John S, Jones GM; Neurocritical Care Society (NCS) Pharmacy Study Group. Factor Xa Inhibitor-Related Intracranial Hemorrhage: Results From a Multicenter, Observational Cohort Receiving Prothrombin Complex Concentrates. Circulation. 2020 May 26;141(21):1681-1689. doi: 10.1161/CIRCULATIONAHA.120.045769. Epub 2020 Apr 8. PMID: 32264698.
- Baumann Kreuziger LM, Keenan JC, Morton CT, Dries DJ. Management of the bleeding patient receiving new oral anticoagulants: a role for prothrombin complex concentrates. Biomed Res Int. 2014;2014:583794. doi: 10.1155/2014/583794. Epub 2014 Jul 20. PMID: 25136597; PMCID: PMC4127295.
- Ansell J, Laulicht BE, Bakhru SH, Burnett A, Jiang X, Chen L, Baker C, Villano S, Steiner S. Ciraparantag, an anticoagulant reversal drug: mechanism of action, pharmacokinetics, and reversal of anticoagulants. Blood. 2021 Jan 7;137(1):115-125. doi: 10.1182/blood.2020007116. PMID: 33205809.
