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 |
|
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
- Akwaa, F., & Spyropoulos, A. (2013). Treatment of Bleeding Complications When Using Oral Anticoagulants for Prevention of Strokes. Current Treatment Options In Cardiovascular Medicine, 15(3), 288-298. doi:10.1007/s11936-013-0238-5
- Awad, N., & Cocchio, C. (2013). Activated Prothrombin Complex Concentrates for the Reversal of Anticoagulant-Associated Coagulopathy. Pharmacy And Therapeutics, 38(11), 696.
- 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
- Davis, P., Musunuru, H., Walsh, M., Mitra, R., Ploplis, V., & Castellino, F. (2012). The ex vivo reversibility of dabigatran-induced whole-blood coagulopathy as monitored by thromboelastography: Mechanistic implications for clinical medicine. Thromb Haemost, 108(3), 586-588. doi:10.1160/th12-04-0222
- Ebright, J., & Mousa, S. (2014). Oral Anticoagulants and Status of Antidotes for the Reversal of Bleeding Risk. Clinical And Applied Thrombosis/Hemostasis. doi:10.1177/1076029614545211
- Eerenberg, E., Kamphuisen, P., Sijpkens, M., Meijers, J., Buller, H., & Levi, M. (2011). Reversal of Rivaroxaban and Dabigatran by Prothrombin Complex Concentrate: A Randomized, Placebo-Controlled, Crossover Study in Healthy Subjects. Circulation, 124(14), 1573-1579. doi:10.1161/circulationaha.111.029017
- Fawole, A., Daw, H., & Crowther, M. (2013). Practical management of bleeding due to the anticoagulants dabigatran, rivaroxaban, and apixaban. Cleveland Clinic Journal Of Medicine, 80(7), 443-451. doi:10.3949/ccjm.80a.13025
- Ferrandis, R., Castillo, J., de Andrés, J., Gomar, C., Gómez-Luque, A., & Hidalgo, F. et al. (2013). The perioperative management of new direct oral anticoagulants: a question without answers. Thromb Haemost, 110(3), 515-522. doi:10.1160/th12-11-0868
- Gordon, J., Fabian, T., Lee, M., & Dugdale, M. (2013). Anticoagulant and antiplatelet medications encountered in emergency surgery patients. Journal Of Trauma And Acute Care Surgery, 75(3), 475-486. doi:10.1097/ta.0b013e3182a07391
- Hankey, G., & Eikelboom, J. (2011). Dabigatran Etexilate: A New Oral Thrombin Inhibitor. Circulation, 123(13), 1436-1450. doi:10.1161/circulationaha.110.004424
- Herrmann, R., Thom, J., Wood, A., Phillips, M., Muhammad, S., & Baker, R. (2013). Thrombin generation using the calibrated automated thrombinoscope to assess reversibility of dabigatran and rivaroxaban. Thromb Haemost, 111(5), 989-995. doi:10.1160/th13-07-0607
- James, R., Palys, V., Lomboy, J., Lamm, J., & Simon, S. (2013). The role of anticoagulants, antiplatelet agents, and their reversal strategies in the management of intracerebral hemorrhage. Neurosurgical Focus, 34(5), E6. doi:10.3171/2013.2.focus1328
- Kaatz, S., & Crowther, M. (2013). Reversal of target-specific oral anticoagulants. J Thromb Thrombolysis, 36(2), 195-202. doi:10.1007/s11239-013-0923-y
- Kasliwal, M., Panos, N., Munoz, L., Moftakhar, R., Lopes, D., & Byrne, R. (2014). Outcome following intracranial hemorrhage associated with novel oral anticoagulants. Journal Of Clinical Neuroscience. doi:10.1016/j.jocn.2014.04.025
- Khoo, T., Weatherburn, C., Kershaw, G., Reddel, C., Curnow, J., & Dunkley, S. (2012). The use of FEIBA® in the correction of coagulation abnormalities induced by dabigatran. International Journal Of Laboratory Hematology, 35(2), 222-224. doi:10.1111/ijlh.12005
- Lai, A., Davidson, N., Galloway, S., & Thachil, J. (2014). Perioperative management of patients on new oral anticoagulants. British Journal Of Surgery, 101(7), 742-749. doi:10.1002/bjs.9485
- Lambe, S. (2013). Reversing the New Anticoagulants. Retrieved 7 September 2014, from http://www.ucsfcme.com/2014/MEM14001/slides/24LambeTheNewAnticoagulants.pdf
- Lazo-Langner, A., Lang, E., & Douketis, J. (2013). Clinical review: Clinical management of new oral anticoagulants: a structured review with emphasis on the reversal of bleeding complications. Critical Care, 17(3), 230. doi:10.1186/cc12592
- Levine, M., & Goldstein, J. (2014). Emergency Reversal of Anticoagulation: Novel Agents. Current Neurology And Neuroscience Reports, 14(8). doi:10.1007/s11910-014-0471-7
- Luddington, R., & Baglin, T. (2004). Clinical measurement of thrombin generation by calibrated automated thrombography requires contact factor inhibition. Journal Of Thrombosis And Haemostasis, 2(11), 1954--1959.
- Majeed, A., & Schulman, S. (2013). Bleeding and antidotes in new oral anticoagulants. Best Practice & Research Clinical Haematology, 26(2), 191-202. doi:10.1016/j.beha.2013.07.001
- Mancl, E., Crawford, A., & Voils, S. (2012). Contemporary Anticoagulation Reversal: Focus on Direct Thrombin Inhibitors and Factor Xa Inhibitors. Journal Of Pharmacy Practice, 26(1), 43-51. doi:10.1177/0897190012465989
- Miller, M., Trujillo, T., & Nordenholz, K. (2014). Practical considerations in emergency management of bleeding in the setting of target-specific oral anticoagulants. The American Journal Of Emergency Medicine, 32(4), 375-382. doi:10.1016/j.ajem.2013.11.044
- Mittal, M., & Rabinstein, A. (2012). Anticoagulation-Related Intracranial Hemorrhages. Current Atherosclerosis Reports, 14(4), 351-359. doi:10.1007/s11883-012-0258-8
- Nitzki-George, D., Wozniak, I., & Caprini, J. (2013). Current State of Knowledge on Oral Anticoagulant Reversal Using Procoagulant Factors. Annals Of Pharmacotherapy, 47(6), 841-855. doi:10.1345/aph.1r724
- Peacock, W., Gearhart, M., & Mills, R. (2012). Emergency Management of Bleeding Associated With Old and New Oral Anticoagulants. Clin Cardiol, 35(12), 730-737. doi:10.1002/clc.22037
- Pernod, G., Albaladejo, P., Godier, A., Samama, C., Susen, S., & Gruel, Y. et al. (2013). Management of major bleeding complications and emergency surgery in patients on long-term treatment with direct oral anticoagulants, thrombin or factor-Xa inhibitors: Proposals of the Working Group on Perioperative Haemostasis (GIHP) – March 2013. Archives Of Cardiovascular Diseases, 106(6-7), 382-393. doi:10.1016/j.acvd.2013.04.009
- Perzborn, E., Heitmeier, S., Laux, V., & Buchmüller, A. (2014). Reversal of rivaroxaban-induced anticoagulation with prothrombin complex concentrate, activated prothrombin complex concentrate and recombinant activated factor VII in vitro. Thrombosis Research, 133(4), 671-681. doi:10.1016/j.thromres.2014.01.017
- Pollack, C. (2013). Managing Bleeding in Anticoagulated Patients in the Emergency Care Setting. The Journal Of Emergency Medicine, 45(3), 467-477. doi:10.1016/j.jemermed.2013.03.016
- Siegal, D., Garcia, D., & Crowther, M. (2014). How I treat target-specific oral anticoagulant-associated bleeding. Blood, 123(8), 1152-1158. doi:10.1182/blood-2013-09-529784
- Yates, S., & Sarode, R. (2013). Novel thrombin and factor Xa inhibitors. Current Opinion In Hematology, 20(6), 552-557. doi:10.1097/moh.0b013e328365a164
- Zumberg, M., Rajasekhar, A., Lawson, M., & Khanna, A. (2013). . Retrieved 7 September 2014, from https://com-dom-hemonc.sites.medinfo.ufl.edu/files/2012/02/Anticoag-reversal-in-ICH-2013-2.pdf
- ↑ Eliquis prescribing information. Princeton, NJ: Bristol Myers Squibb; December 2012.
- ↑ Savaysa prescribing information. Parsippany, NJ: Daiichi Sankyo, Inc.; November 2015.
- ↑ Xarelto prescribing information. Titusville, NJ: Janssen Pharmaceuticals, Inc.; December 2014.
- ↑ 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