prognosis", section on 'Management of antithrombotic therapy'.) SOCIETY GUIDELINE LINKS Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Anticoagulation" and "Society guideline links: Stroke in adults" and "Society guideline links: COVID-19 Anticoagulation" and "Society guideline links: COVID-19 Index of guideline topics".) SUMMARY AND RECOMMENDATIONS Urgent evaluation We perform a rapid clinical assessment to identify important features of the history and neuroimaging to distinguish hemorrhage from ischemia. Lumbar puncture (LP) is generally required when there is strong suspicion for subarachnoid hemorrhage (SAH) despite a normal head computed tomography (CT). All patients should have a complete blood count (CBC) with platelet count, prothrombin time (PT) with international normalized ratio (INR), and activated partial thromboplastin https://www.uptodate.com/contents/reversal-of-anticoagulation-in-intracranial-hemorrhage/print 24/47 7/5/23, 12:24 PM Reversal of anticoagulation in intracranial hemorrhage - UpToDate time (aPTT). Liver function tests and a metabolic panel may also be appropriate. (See 'Urgent evaluation' above.) Additional laboratory evaluation varies by anticoagulant: Dabigatran Thrombin time (TT), creatinine determination, and calculation of the creatinine clearance Factor Xa inhibitors (apixaban, edoxaban, rivaroxaban, low molecular weight [LMW] heparin) Anti-factor Xa activity calibrated to the drug, creatinine, and calculated creatinine clearance TT and anti-factor Xa activity may not be immediately available. General measures for all patients General measures for anticoagulant-associated intracranial hemorrhage (ICH) include discontinuation of all antithrombotic agents, admission with intensive monitoring, and blood pressure control. Other interventions may be needed to treat severe thrombocytopenia, anemia, and metabolic abnormalities. (See 'General measures for all anticoagulants' above.) Indications for anticoagulant reversal Reversal of the anticoagulant effect is indicated in virtually all cases of documented acute ICH and in patients requiring an urgent LP to exclude SAH or infection. A rare exception is an individual for whom the risk of thrombosis is clinically more serious than the risk of hematoma expansion (eg, individual with a mechanical heart valve and a small, stable subdural hematoma). (See 'Indications for reversal and goals of treatment' above.) Specific reversal strategies Reversal should be done as rapidly as possible to limit hemorrhage enlargement, which can be fatal. Warfarin For warfarin-associated ICH, we recommend reversal with 4-factor prothrombin complex concentrate (4-factor PCC) rather than plasma (Grade 1B). PCC is typically given as a fixed dose of 1500 to 2000 international units at a rate of 100 units/minute ( table 7). (See 'Prothrombin complex concentrate' above.) Options if 4-factor PCC is unavailable include 3-factor PCC supplemented with a source of factor VII or a plasma product such as Fresh Frozen Plasma or Thawed Plasma. Use of plasma may delay warfarin reversal, leading to a greater risk of complications of hematoma expansion, and may cause a transfusion reaction. https://www.uptodate.com/contents/reversal-of-anticoagulation-in-intracranial-hemorrhage/print 25/47 7/5/23, 12:24 PM Reversal of anticoagulation in intracranial hemorrhage - UpToDate Vitamin K is also given to all patients because PCC and plasma act transiently. The dose is 10 mg intravenously (which acts within several hours). Repeat vitamin K dosing may be appropriate if the PT or INR remains elevated. (See 'Intravenous vitamin K' above.) Dabigatran For dabigatran-associated ICH, we suggest idarucizumab (Grade 2C). The dose is 5 g (two 2.5 g vials). If idarucizumab is not available, activated PCC (aPCC; factor eight inhibitor bypassing activity [FEIBA]) may be used. Oral activated charcoal may be given if the patient can take oral medications and the last dose of dabigatran was within the prior two hours. Dabigatran may also be removed by hemodialysis. (See 'Dabigatran' above.) Direct factor Xa inhibitors (eg, apixaban, edoxaban, rivaroxaban) For direct factor Xa inhibitor-associated ICH, we suggest andexanet alfa rather than 4-factor PCC (Grade 2C). 4-factor PCC is a reasonable alternative if andexanet is unavailable. (See 'Apixaban, edoxaban, and rivaroxaban' above.) There are two dose levels for andexanet; the choice between them depends on the anticoagulant being reversed, how much was taken, and the timing of the most recent dose. (See 'Andexanet alfa' above.) The higher dose level uses a bolus of 800 mg at 30 mg/minute followed by an infusion of 960 mg at 8 mg/minute. The lower dose level uses a bolus of 400 mg at 30 mg/minute followed by an infusion of 480 mg at 4 mg/minute. Oral activated charcoal may be given if the patient can take oral medications and the last dose of the anticoagulant was recent (edoxaban within two hours; apixaban within six hours; rivaroxaban within eight hours). The direct factor Xa inhibitors cannot be dialyzed. (See 'Apixaban, edoxaban, and rivaroxaban' above.) UFH Unfractionated heparin (UFH)-associated ICH is treated with protamine sulfate (protamine). The dose is 1 mg protamine per 100 units of heparin; if rapid calculation is not possible, a single intravenous dose of 25 or 50 mg can be given by slow infusion over at least 20 or 30 minutes. Protamine can cause allergic reactions, particularly in individuals previously exposed to protamine sulfate, protamine-containing insulin, or those with a fish allergy. (See 'Unfractionated heparin' above.) LMW heparin (enoxaparin, dalteparin, tinzaparin) For LMW heparin-associated ICH, we suggest andexanet alfa rather than protamine (Grade 2C). The higher dose level (800 mg at 30 mg/minute followed by an infusion of 960 mg at 8 mg/minute) is https://www.uptodate.com/contents/reversal-of-anticoagulation-in-intracranial-hemorrhage/print 26/47 7/5/23, 12:24 PM Reversal of anticoagulation in intracranial hemorrhage - UpToDate appropriate. Protamine sulfate is a reasonable alternative if andexanet is unavailable. (See 'LMW heparin' above.) Fondaparinux Treatment of fondaparinux-associated ICH is individualized. Andexanet alfa at the higher dose level is a reasonable option. (See 'Fondaparinux' above and "Fondaparinux: Dosing and adverse effects", section on 'Bleeding/emergency surgery'.) ACKNOWLEDGMENT The UpToDate editorial staff acknowledges Maria I Aguilar, MD, who contributed to earlier versions of this topic review. Use of UpToDate is subject to the Terms of Use. REFERENCES 1. Rosand J, Eckman MH, Knudsen KA, et al. The effect of warfarin and intensity of anticoagulation on outcome of intracerebral hemorrhage. Arch Intern Med 2004; 164:880. 2. Flaherty ML, Tao H, Haverbusch M, et al. Warfarin use leads to larger intracerebral hematomas. Neurology 2008; 71:1084. 3. Berwaerts J, Dijkhuizen RS, Robb OJ, Webster J. Prediction of functional outcome and in- hospital mortality after admission with oral anticoagulant-related intracerebral hemorrhage. Stroke 2000; 31:2558. 4. Yasaka M, Minematsu K, Naritomi H, et al. Predisposing factors for enlargement of intracerebral hemorrhage in patients treated with warfarin. Thromb Haemost 2003; 89:278. 5. Cucchiara B, Messe S, Sansing L, et al. Hematoma growth in oral anticoagulant related intracerebral hemorrhage. Stroke 2008; 39:2993. 6. Flibotte JJ, Hagan N, O'Donnell J, et al. Warfarin, hematoma expansion, and outcome of intracerebral hemorrhage. Neurology 2004; 63:1059. 7. Punthakee X, Doobay J, Anand SS. Oral-anticoagulant-related intracerebral hemorrhage. Thromb Res 2002; 108:31. 8. Sj blom L, H rdemark HG, Lindgren A, et al. Management and prognostic features of intracerebral hemorrhage during anticoagulant therapy: a Swedish multicenter study. Stroke 2001; 32:2567. 9. Neau JP, Couderq C, Ingrand P, et al. Intracranial hemorrhage and oral anticoagulant treatment. Cerebrovasc Dis 2001; 11:195. https://www.uptodate.com/contents/reversal-of-anticoagulation-in-intracranial-hemorrhage/print 27/47 7/5/23, 12:24 PM Reversal of anticoagulation in intracranial hemorrhage - UpToDate 10. Hylek EM, Go AS, Chang Y, et al. Effect of intensity of oral anticoagulation on stroke severity and mortality in atrial fibrillation. N Engl J Med 2003; 349:1019. 11. Yasaka M, Sakata T, Minematsu K, Naritomi H. Correction of INR by prothrombin complex concentrate and vitamin K in patients with warfarin related hemorrhagic complication. Thromb Res 2002; 108:25. 12. Bower MM, Sweidan AJ, Shafie M, et al. Contemporary Reversal of Oral Anticoagulation in Intracerebral Hemorrhage. Stroke 2019; 50:529. 13. Kuramatsu JB, Gerner ST, Schellinger PD, et al. Anticoagulant reversal, blood pressure levels, and anticoagulant resumption in patients with anticoagulation-related intracerebral hemorrhage. JAMA 2015; 313:824. 14. Frontera JA, Lewin JJ 3rd, Rabinstein AA, et al. 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; 24:6. 15. Steiner T, Al-Shahi Salman R, Beer R, et al. European Stroke Organisation (ESO) guidelines for the management of spontaneous intracerebral hemorrhage. Int J Stroke 2014; 9:840. 16. Ageno W, Gallus AS, Wittkowsky A, et al. Oral anticoagulant therapy: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence- Based Clinical Practice Guidelines. Chest 2012; 141:e44S. 17. National Institute for Health and Clinical Excellence. Stroke and transient ischaemic attack in over 16s: diagnosis and initial management. Available at: https://www.nice.org.uk/guidanc e/cg68/chapter/1-Guidance#pharmacological-treatments-for-people-with-acute-stroke (Acc essed on January 11, 2019). 18. Witt DM, Nieuwlaat R, Clark NP, et al. American Society of Hematology 2018 guidelines for management of venous thromboembolism: optimal management of anticoagulation therapy. Blood Adv 2018; 2:3257. 19. Greenberg SM, Ziai WC, Cordonnier C, et al. 2022 Guideline for the Management of Patients With Spontaneous Intracerebral Hemorrhage: A Guideline From the American Heart Association/American Stroke Association. Stroke 2022; 53:e282. 20. Hellstern P, Halbmayer WM, K hler M, et al. Prothrombin complex concentrates: indications, contraindications, and risks: a task force summary. Thromb Res 1999; 95:S3. 21. Pabinger I, Brenner B, Kalina U, et al. Prothrombin complex concentrate (Beriplex P/N) for emergency anticoagulation reversal: a prospective multinational clinical trial. J Thromb Haemost 2008; 6:622. https://www.uptodate.com/contents/reversal-of-anticoagulation-in-intracranial-hemorrhage/print 28/47 7/5/23, 12:24 PM Reversal of anticoagulation in intracranial hemorrhage - UpToDate 22. Evans SJ, Biss TT, Wells RH, Hanley JP. Emergency warfarin reversal with prothrombin complex concentrates: UK wide study. Br J Haematol 2008; 141:268. 23. S rensen B, Johansen P, Nielsen GL, et al. Reversal of the International Normalized Ratio with recombinant activated factor VII in central nervous system bleeding during warfarin thromboprophylaxis: clinical and biochemical aspects. Blood Coagul Fibrinolysis 2003; 14:469. 24. Freeman WD, Brott TG, Barrett KM, et al. Recombinant factor VIIa for rapid reversal of warfarin anticoagulation in acute intracranial hemorrhage. Mayo Clin Proc 2004; 79:1495. 25. Sarode R, Milling TJ Jr, Refaai MA, et al. Efficacy and safety of a 4-factor prothrombin complex concentrate in patients on vitamin K antagonists presenting with major bleeding: a randomized, plasma-controlled, phase IIIb study. Circulation 2013; 128:1234. 26. Abdoellakhan RA, Khorsand N, Ter Avest E, et al. Fixed Versus Variable Dosing of Prothrombin Complex Concentrate for Bleeding Complications of Vitamin K Antagonists-The PROPER3 Randomized Clinical Trial. Ann Emerg Med 2022; 79:20. 27. Mayer SA, Brun NC, Begtrup K, et al. Efficacy and safety of recombinant activated factor VII for acute intracerebral hemorrhage. N Engl J Med 2008; 358:2127. 28. Yin EB, Tan B, Nguyen T, et al. Safety and Effectiveness of Factor VIII Inhibitor Bypassing Activity (FEIBA) and Fresh Frozen Plasma in Oral Anticoagulant-Associated Intracranial Hemorrhage: A Retrospective Analysis. Neurocrit Care 2017; 27:51. 29. Lee SB, Manno EM, Layton KF, Wijdicks EF. Progression of warfarin-associated intracerebral hemorrhage after INR normalization with FFP. Neurology 2006; 67:1272. 30. Makris M, Greaves M, Phillips WS, et al. Emergency oral anticoagulant reversal: the relative efficacy of infusions of fresh frozen plasma and clotting factor concentrate on correction of the coagulopathy. Thromb Haemost 1997; 77:477. 31. Fredriksson K, Norrving B, Str mblad LG. Emergency reversal of anticoagulation after intracerebral hemorrhage. Stroke 1992; 23:972. 32. Cartmill M, Dolan G, Byrne JL, Byrne PO. Prothrombin complex concentrate for oral anticoagulant reversal in neurosurgical emergencies. Br J Neurosurg 2000; 14:458. 33. Bershad EM, Suarez JI. Prothrombin complex concentrates for oral anticoagulant therapy- related intracranial hemorrhage: a review of the literature. Neurocrit Care 2010; 12:403. 34. Steiner T, Poli S, Griebe M, et al. Fresh frozen plasma versus prothrombin complex concentrate in patients with intracranial haemorrhage related to vitamin K antagonists (INCH): a randomised trial. Lancet Neurol 2016; 15:566. https://www.uptodate.com/contents/reversal-of-anticoagulation-in-intracranial-hemorrhage/print 29/47 7/5/23, 12:24 PM Reversal of anticoagulation in intracranial hemorrhage - UpToDate 35. Frontera JA, Gordon E, Zach V, et al. Reversal of coagulopathy using prothrombin complex concentrates is associated with improved outcome compared to fresh frozen plasma in warfarin-associated intracranial hemorrhage. Neurocrit Care 2014; 21:397. 36. Hickey M, Gatien M, Taljaard M, et al. Outcomes of urgent warfarin reversal with frozen plasma versus prothrombin complex concentrate in the emergency department. Circulation 2013; 128:360. 37. Hanger HC, Geddes JA, Wilkinson TJ, et al. Warfarin-related intracerebral haemorrhage: better outcomes when reversal includes prothrombin complex concentrates. Intern Med J 2013; 43:308. 38. Huttner HB, Schellinger PD, Hartmann M, et al. Hematoma growth and outcome in treated neurocritical care patients with intracerebral hemorrhage related to oral anticoagulant therapy: comparison of acute treatment strategies using vitamin K, fresh frozen plasma, and prothrombin complex concentrates. Stroke 2006; 37:1465. 39. Boulis NM, Bobek MP, Schmaier A, Hoff JT. Use of factor IX complex in warfarin-related intracranial hemorrhage. Neurosurgery 1999; 45:1113. 40. Dowlatshahi D, Butcher KS, Asdaghi N, et al. Poor prognosis in warfarin-associated intracranial hemorrhage despite anticoagulation reversal. Stroke 2012; 43:1812. 41. Robinson MT, Rabinstein AA, Meschia JF, Freeman WD. Safety of recombinant activated factor VII in patients with warfarin-associated hemorrhages of the central nervous system. Stroke 2010; 41:1459. 42. Peksa GD, Mokszycki RK, Rech MA, et al. Reversal of Warfarin-Associated Major Hemorrhage: Activated Prothrombin Complex Concentrate versus 4-Factor Prothrombin Complex Concentrate. Thromb Haemost 2020; 120:207. 43. Bertram M, Bonsanto M, Hacke W, Schwab S. Managing the therapeutic dilemma: patients with spontaneous intracerebral hemorrhage and urgent need for anticoagulation. J Neurol 2000; 247:209. 44. Hellstern P. Production and composition of prothrombin complex concentrates: correlation between composition and therapeutic efficiency. Thromb Res 1999; 95:S7. 45. Toth P, van Veen JJ, Robinson K, et al. Real world usage of PCC to "rapidly" correct warfarin induced coagulopathy. Blood Transfus 2013; 11:500. 46. Cabral KP, Fraser GL, Duprey J, et al. Prothrombin complex concentrates to reverse warfarin- induced coagulopathy in patients with intracranial bleeding. Clin Neurol Neurosurg 2013; 115:770. https://www.uptodate.com/contents/reversal-of-anticoagulation-in-intracranial-hemorrhage/print 30/47 7/5/23, 12:24 PM Reversal of anticoagulation in intracranial hemorrhage - UpToDate 47. Ansell J, Hirsh J, Hylek E, et al. Pharmacology and management of the vitamin K antagonists: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest 2008; 133:160S. 48. Demchuk AM, Yue P, Zotova E, et al. Hemostatic Efficacy and Anti-FXa (Factor Xa) Reversal With Andexanet Alfa in Intracranial Hemorrhage: ANNEXA-4 Substudy. Stroke 2021; 52:2096. 49. Cohen AT, Lewis M, Connor A, et al. Thirty-day mortality with andexanet alfa compared with prothrombin complex concentrate therapy for life-threatening direct oral anticoagulant- related bleeding. J Am Coll Emerg Physicians Open 2022; 3:e12655. 50. Pham H, Medford WG, Horst S, et al. Andexanet alfa versus four-factor prothrombin complex concentrate for the reversal of apixaban- or rivaroxaban-associated intracranial hemorrhages. Am J Emerg Med 2022; 55:38. 51. https://clinicaltrials.gov/ct2/show/NCT03661528 (Accessed on November 18, 2021). 52. Bourdin M, Perrotin D, Mathieu O, et al. Measuring residual anti-Xa activity of direct factor Xa inhibitors after reversal with andexanet alfa. Int J Lab Hematol 2021; 43:795. 53. Panos NG, Cook AM, John S, et al. Factor Xa Inhibitor-Related Intracranial Hemorrhage: Results From a Multicenter, Observational Cohort Receiving Prothrombin Complex Concentrates. Circulation 2020; 141:1681. 54. 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; 380:1326. Topic 1325 Version 51.0 https://www.uptodate.com/contents/reversal-of-anticoagulation-in-intracranial-hemorrhage/print 31/47 7/5/23, 12:24 PM Reversal of anticoagulation in intracranial hemorrhage - UpToDate GRAPHICS Medications that interfere with the effect of warfarin May increase INR May decrease INR Acetaminophen Antibiotics Dicloxacillin Allopurinol Griseofulvin Amiodarone Nafcillin Androgens Rifampin Methyltestosterone Azathioprine Oxandrolone Cholestyramine Testosterone Enzyme-inducing antiseizure medications Antibiotics Carbamazepine Cephalosporins Phenobarbital Doxycycline Phenytoin (mixed effects described) Fluoroquinolones Ciprofloxacin Ritonavir Levofloxacin Saint John's wort Moxifloxacin Sucralfate Norfloxacin Vitamin K Macrolides Azithromycin Clarithromycin Erythromycin Metronidazole Penicillins (exceptions: dicloxacillin and nafcillin may decrease the INR) Amoxicillin Amoxicillin-clavulanate Trimethoprim-sulfamethoxazole Azole antifungals* Fluconazole Miconazole (oral) Voriconazole Cancer therapies Capecitabine Fluorouracil (5-FU) Imatinib https://www.uptodate.com/contents/reversal-of-anticoagulation-in-intracranial-hemorrhage/print 32/47 7/5/23, 12:24 PM Reversal of anticoagulation in intracranial hemorrhage - UpToDate Tamoxifen Cholesterol-lowering agents (exception: cholestyramine may decrease the INR) Fenofibrate Fluvastatin Gemfibrozil Lovastatin Rosuvastatin Simvastatin Cimetidine Glucocorticoids Methylprednisolone Prednisone Omeprazole (case reports with other proton pump inhibitors) Serotonin reuptake inhibitors Duloxetine Fluoxetine Fluvoxamine Venlafaxine Sitaxentan (not available in United States) Tramadol This is a partial list of medications that may increase or decrease warfarin effect on the INR. The patient's medications should be analyzed closely for drug interactions with warfarin, especially when initiating or altering therapy. The effect of a drug interaction can be unpredictable; thus, individuals receiving interacting medications are likely to require increased INR monitoring. Additional medications may increase bleeding risk independent of (or in addition to) effects on the INR (eg, NSAIDs, antiplatelet medications). Refer to UpToDate for additional details. Drug interactions may be evaluated using the Lexi-interact program included with UpToDate. INR: international normalized ratio; NSAIDs: nonsteroidal anti-inflammatory drugs. A more moderate effect on INR control may also be seen with posaconazole and itraconazole. In addition to potentially increasing the INR, serotonin reuptake inhibitors may also increase bleeding risk by inhibiting platelet reuptake of serotonin. References: 1. Greenblatt DJ, von Moltke L. Interaction of warfarin with drugs, natural substances, and foods. J Clin Pharmacol 2005; 45:127. https://www.uptodate.com/contents/reversal-of-anticoagulation-in-intracranial-hemorrhage/print 33/47 7/5/23, 12:24 PM Reversal of anticoagulation in intracranial hemorrhage - UpToDate 2. Holbrook A, Schulman S, Witt D, et al. Evidenced-based management of anticoagulant therapy: Antithrombotic therapy and prevention of thrombosis, 9th ed. Chest 2012; 141:e152S. 3. Hazlewood KA, Fugate SE, Harrison DL. E ect of oral corticosteroids on chronic warfarin therapy. Ann Pharmacother 2006; 40:2101. 4. Lexi-Interact. Copyright 1978-2023 Lexicomp, Inc. All Rights Reserved. Graphic 62697 Version 15.0 https://www.uptodate.com/contents/reversal-of-anticoagulation-in-intracranial-hemorrhage/print 34/47 7/5/23, 12:24 PM Reversal of anticoagulation in intracranial hemorrhage - UpToDate Pharmacokinetics and drug interactions of direct oral anticoagulants Potential for Metabolism pharmacokinetic drug interactions* Anticoagulant Bioavailability and clearance* Half-life Dabigatran (Pradaxa) 3 to 7% bioavailable Over 80% cleared by the 12 to 17 hours P-gp inhibitors can increase kidney dabigatran effect Unaffected by food Prolonged with kidney P-gp P-gp inducers can substrate* impairment and in older decrease dabigatran Capsule must be taken intact adults effect and requires gastric acidity Avoidance of for absorption some combinations or dose adjustment may be needed Apixaban 50% 27% cleared 12 hours Strong dual (Eliquis) bioavailable by the kidney CYP3A4 and P-gp inhibitors can Prolonged in older adults Unaffected by Metabolized, increase food primarily by CYP3A4 apixaban effect Strong CYP3A4 P-gp substrate* inducers and/or P-gp inducers can decrease apixaban effect Avoidance of some combinations or dose adjustment may be needed Edoxaban (Savaysa, Lixiana) 62% bioavailable 50% cleared by the kidney 10 to 14 hours P-gp inhibitors can increase edoxaban effect Unaffected by food Reduced efficacy in Prolonged in renal P-gp inducers can patients with nonvalvular impairment decrease edoxaban effect atrial fibrillation Avoidance of some combinations or https://www.uptodate.com/contents/reversal-of-anticoagulation-in-intracranial-hemorrhage/print 35/47 7/5/23, 12:24 PM Reversal of anticoagulation in intracranial hemorrhage - UpToDate and CrCl >95 mL/minute dose adjustment may be needed Undergoes minimal CYP metabolism P-gp substrate* Rivaroxaban (Xarelto) 10 mg dose: 36% cleared by the kidney 5 to 9 hours Strong dual CYP3A4 and P-gp 80 to 100% Prolonged to inhibitors can increase bioavailable Metabolized, primarily by 11 to 13 hours in Unaffected rivaroxaban CYP3A4 older adults by food effect P-gp 20 mg dose: Strong CYP3A4 substrate* 66% inducers and/or P-gp inducers can bioavailable if taken when decrease rivaroxaban fasting; increased if effect Avoidance of taken with food some combinations or dose adjustment may be needed Refer to UpToDate for dosing in specific clinical settings, including nonvalvular AF, VTE treatment, and VTE prophylaxis. Data on clearance may help assess the potential for accumulation in patients with kidney impairment. Data on metabolism may help assess potential drug interactions through alteration of CYP3A4 metabolism and/or P-gp-mediated drug efflux. Refer to Lexi-Interact, the drug interactions tool included with UpToDate, for specific drug interactions. Tables of P-gp inhibitors and inducers and CYP3A4 inhibitors and inducers are available separately in UpToDate. P-gp: P-glycoprotein drug efflux pump; CYP3A4: cytochrome p450 3A4 isoform; CrCl: creatinine clearance estimated by the Cockcroft-Gault equation; AF: atrial fibrillation; VTE: venous thromboembolism, includes deep vein thrombosis and pulmonary embolism; DOAC: direct oral anticoagulant. Examples of P-gp inhibitors that reduce metabolism of DOACs, leading to increased DOAC levels, include clarithromycin, ombitasvir- or ritonavir-containing combinations, and verapamil. Examples of P-gp inducers that increase DOAC metabolism, leading to lower DOAC levels, include phenytoin, rifampin, and St. John's wort. Refer to list available as a separate table in UpToDate. Examples of strong CYP3A4 inhibitors that reduce metabolism of some DOACs, leading to increased DOAC levels, include clarithromycin and ombitasvir- or ritonavir-containing combinations. Examples of strong CYP3A4 inducers that increase metabolism of some DOACs, leading to lower https://www.uptodate.com/contents/reversal-of-anticoagulation-in-intracranial-hemorrhage/print 36/47 7/5/23, 12:24 PM Reversal of anticoagulation in intracranial hemorrhage - UpToDate DOAC levels, include carbamazepine, phenytoin, and rifampin. Refer to list available as a separate table in UpToDate. In patients with AF, combined use of levetiracetam or valproate with dabigatran, apixaban, or rivaroxaban was associated with an increased risk of ischemic stroke or systemic embolism. The [1] mechanism of this interaction is unknown. Inhibition of CYP3A4 (ie, without P-gp inhibition) may also increase apixaban and rivaroxaban effect, but to a lesser extent than dual inhibition of CYP3A4 and P-gp. Examples of CYP3A4 inhibitors that do not also inhibit P-gp include diltiazem, fluconazole, and voriconazole. Increased monitoring is advised. Blood levels of edoxaban were reduced and a higher rate of ischemic stroke was observed in patients with AF and CrCl >95 mL/minute who were treated with edoxaban compared with those receiving warfarin. Refer to the UpToDate topic on anticoagulation in AF for additional information. Reference: 1. Gronich N, Stein N, Muszkat M. Association between use of pharmacokinetic-interacting drugs and e ectiveness and safety of direct acting oral anticoagulants: Nested case-control study. Clin Pharmacol Ther 2021; 110:1526. Prepared with data from: 1. Lexicomp Online. Copyright 1978-2023 Lexicomp, Inc. All Rights Reserved. 2. Drugs@FDA: FDA-Approved Drugs. U.S. Food and Drug Administration. Available at: https://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm (Accessed on December 9, 2021). Graphic 112756 Version 19.0 https://www.uptodate.com/contents/reversal-of-anticoagulation-in-intracranial-hemorrhage/print 37/47 7/5/23, 12:24 PM Reversal of anticoagulation in intracranial hemorrhage - UpToDate Expected effects of anticoagulant drugs on commonly used coagulation tests Brand Anti-factor Drug class Drug PT aPTT name(s) Xa activity / * Vitamin K Warfarin Jantoven antagonists / * Acenocoumarol Sintrom Heparins Unfractionated heparin / LMW heparins Enoxaparin Lovenox Dalteparin Fragmin Nadroparin Fraxiparine / Fondaparinux Arixtra Direct Argatroban Acova thrombin inhibitors / Dabigatran Pradaxa / / Direct factor Rivaroxaban Xarelto Xa inhibitors / / Apixaban Eliquis Edoxaban Lixiana, Savaysa PT and aPTT are measured in seconds; anti-factor Xa activity is measured in units/mL. Upward arrow ( ) signifies an increase above normal due to the anticoagulant (prolongation of PT or aPTT; increase in anti-factor Xa activity). The effect magnitude will vary depending on the reagent formulation and instrument used. Dash ( ) signifies no appreciable effect. Normal ranges for the PT, aPTT, and anti-factor Xa activity vary among laboratories and should be reported from the testing laboratory along with the patient result. Refer to the UpToDate topic on coagulation testing for details. PT: prothrombin time; aPTT: activated partial thromboplastin time; LMW heparin: low molecular weight heparin. Warfarin has a weak effect on most aPTT reagents. However, warfarin use will increase the sensitivity of the aPTT to heparin effect. While heparin, LMW heparin, and fondaparinux should, in theory, prolong the PT as indirect thrombin inhibitors, in practice most PT reagents contain heparin-binding chemicals that block any heparin effect below a concentration of 1 unit/mL. Above concentrations of 1 unit/mL, heparin effect on the PT may be observed. https://www.uptodate.com/contents/reversal-of-anticoagulation-in-intracranial-hemorrhage/print 38/47 7/5/23, 12:24 PM Reversal of anticoagulation in intracranial hemorrhage - UpToDate Anti-factor Xa activity testing must be calibrated for the specific anticoagulant; this information should be verified with the clinical laboratory. Some of the data are from: Samuelson BT, Cuker A, Crowther M, Garcia DA. Laboratory assessment of the anticoagulant activity of direct oral anticoagulants: A systematic review. Chest 2017; 151:127. Graphic 91267 Version 9.0 https://www.uptodate.com/contents/reversal-of-anticoagulation-in-intracranial-hemorrhage/print 39/47 7/5/23, 12:24 PM Reversal of anticoagulation in intracranial hemorrhage - UpToDate Guideline recommendations for management of warfarin-associated bleeding and/or high INR Clinical setting 2018 ASH guideline 2012 ACCP guideline Serious or life-threatening 4-factor PCC 4-factor PCC* bleeding Vitamin K (intravenous) Vitamin K (intravenous) Any INR Hold warfarin Hold warfarin (No recommendations given) No bleeding Vitamin K (oral) INR >10 Hold warfarin No bleeding Hold warfarin Hold warfarin INR 4.5 to 10 No vitamin K Vitamin K (low dose, oral) is optional Clinical judgment is required to assess the severity of bleeding, urgency of warfarin reversal, and need for other interventions. Refer to UpToDate for details and additional advice such as the duration of warfarin interruption and repeat INR testing. INR: international normalized ratio; ASH: American Society of Hematology; ACCP: American College of Chest Physicians; PCC: prothrombin complex concentrate; FFP: fresh frozen plasma. A plasma product such as thawed plasma or FFP (approximately 10 mL/kg, depending on INR) can be used as an alternative if PCC is not available. References: 1. Witt DM, Nieuwlaat R, Clark NP, et al. American Society of Hematology 2018 guidelines for management of venous thromboembolism: Optimal management of anticoagulation therapy. Blood Adv 2018; 2:3257. 2. Holbrook A, Schulman S, Witt DM, et al. Evidence-based management of anticoagulant therapy: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012; 141:e152S. Graphic 119954 Version 2.0 https://www.uptodate.com/contents/reversal-of-anticoagulation-in-intracranial-hemorrhage/print 40/47 7/5/23, 12:24 PM Reversal of anticoagulation in intracranial hemorrhage - UpToDate Reversing anticoagulation in warfarin-associated bleeding Management option Time to anticoagulation reversal Comments and cautions Discontinuing warfarin therapy 5 to 14 days Five days is typical for patients with an INR in the therapeutic range Vitamin K* 6 to 24 hours to correct the INR, longer Recovery of factors X and II to fully reverse anticoagulation (prothrombin) takes longer than 24 hours Risk of anaphylaxis with intravenous injection Impaired response to warfarin lasting up to one week may occur after large doses (ie, >5 mg) Fresh frozen Depends on the time it takes to Effect is transient and concomitant plasma complete the infusion; typically 12 to 32 hours for complete reversal vitamin K must be administered Potential for volume overload (2 to 4 L to normalize INR) Potential for TRALI Potential for viral transmission Prothrombin 15 minutes after 10-minute to 1-hour Effect is transient, and concomitant complex infusion vitamin K must be administered; concentrate limited availability Cost Variable factor VII content depending on the product: a 4-factor PCC is preferred Potentially prothrombotic Recombinant factor VIIa 15 minutes after bolus infusion Effect is transient, and concomitant vitamin K must be administered Cost Potentially prothrombotic Please refer to the UpToDate topic on warfarin reversal in intracerebral hemorrhage for further details of management. INR: international normalized ratio; TRALI: transfusion-related acute lung injury; PCC: prothrombin complex concentrate. https://www.uptodate.com/contents/reversal-of-anticoagulation-in-intracranial-hemorrhage/print 41/47 7/5/23, 12:24 PM Reversal of anticoagulation in intracranial hemorrhage - UpToDate A total of 10 mg intravenously by slow infusion given over 10 minutes. Adapted with permission from: Aguilar MI, Hart RG, Kase CS, et al. Treatment of warfarin-associated intercerebral hemorrhage: Literature review and expert opinion. Mayo Clin Proc 2007; 82:82. Copyright 2007 Dowden Health Media. Graphic 79151 Version 16.0 https://www.uptodate.com/contents/reversal-of-anticoagulation-in-intracranial-hemorrhage/print 42/47 7/5/23, 12:24 PM Reversal of anticoagulation in intracranial hemorrhage - UpToDate PCC products available in the United States* Unactivated prothrombin complex concentrates (PCCs) 4 factor: Contains inactive forms of 4 factors: Factors II, VII, IX, and X Kcentra Also contains heparin 3 factor: Contains inactive forms of 3 factors: Factors II, IX, and X Profilnine Contains little or no factor VII Does not contain heparin Activated prothrombin complex concentrate (aPCC) 4 factor: Contains 4 factors: Factors II, VII, IX, and X. Of these, only factor VII is mostly the activated form FEIBA Does not contain heparin The table lists 4-factor and 3-factor PCC products available in the United States. Kcentra is available as Beriplex in Canada. Bebulin (a 3-factor PCC) was discontinued in 2018 due to decreased demand for the product. Potency is determined differently for different products; refer to product information. All PCCs are plasma derived and contain other proteins, including anticoagulant proteins (proteins C and S). Unactivated factors are proenzymes (inactive precursor proteins). Activated factors have higher enzymatic activity. Refer to UpToDate topics for use of these products. US: United States; PCC: prothrombin complex concentrate; FEIBA: factor eight inhibitor bypassing activity. Other 4-factor PCCs available outside the US include Octaplex and Cofact Proplex. Single-factor recombinant activated factor VII (rFVIIa) products are also available. Graphic 94210 Version 8.0 https://www.uptodate.com/contents/reversal-of-anticoagulation-in-intracranial-hemorrhage/print 43/47 7/5/23, 12:24 PM Reversal of anticoagulation in intracranial hemorrhage - UpToDate Emergency reversal of anticoagulation from warfarin for life-threatening hemorrhage in adults: Suggested approaches based upon available resources A. If 4-factor prothrombin complex concentrate (4F PCC) is available (preferred approach): 1. Give 4F PCC* 1500 to 2000 units IV over 10 minutes. Check INR 15 minutes after completion of the infusion. If INR is not 1.5, give additional 4F PCC (refer to topic or drug reference for details). 2. Give vitamin K 10 mg IV over 10 to 20 minutes. B. If 3-factor prothrombin complex concentrate (3F PCC) is available but 4F PCC is not available: 1. Give 3F PCC* 1500 to 2000 units IV over 10 minutes. Check INR 15 minutes after completion of the infusion. If INR is not 1.5, give additional 3F PCC (refer to topic or drug reference for details). 2. Give Factor VIIa 20 mcg/kg IV OR give FFP 2 units IV by rapid infusion. Factor VIIa may be preferred if volume overload is a concern. 3. Give vitamin K 10 mg IV over 10 to 20 minutes. C. If neither 3F PCC nor 4F PCC is available: 1. Give FFP 2 units IV by rapid infusion. Check INR 15 minutes after completion of infusion. If INR 1.5, administer 2 additional units of FFP IV rapid infusion. Repeat process until INR 1.5. May wish to administer loop diuretic between FFP infusions if volume overload is a concern. 2. Give vitamin K 10 mg IV over 10 to 20 minutes. These products and doses are for use in life-threatening bleeding only. Evidence of life-threatening bleeding and over-anticoagulation with a vitamin K antagonist (eg, warfarin) are required. Anaphylaxis and transfusion reactions can occur. It may be reasonable to thaw 4 units of FFP while awaiting the PT/INR. The transfusion service may substitute other plasma products for FFP (eg, Plasma Frozen Within 24 Hours After Phlebotomy [PF24]); these products are considered clinically interchangeable. PCC will reverse anticoagulation within minutes of administration; FFP administration can take hours due to the volume required; vitamin K effect takes 12 to 24 hours, but administration of vitamin K is needed to counteract the long half-life of warfarin. Subsequent monitoring of the PT/INR is needed to guide further therapy. Refer to topics on warfarin reversal in individual situations for further management. PCC: unactivated prothrombin complex concentrate; 4F PCC: PCC containing coagulation factors II, VII, IX, X, protein S and protein C; 3F PCC: PCC containing factors II, IX, and X and only trace factor VII; FFP: fresh frozen plasma; PT: prothrombin time; INR: international normalized ratio; FEIBA: factor eight inhibitor bypassing agent. Before use, check product label to confirm factor types (3 versus 4 factor) and concentration. Activated complexes and single-factor IX products (ie, FEIBA, AlphaNine, Mononine, Immunine, BeneFix) are NOT used for warfarin reversal. https://www.uptodate.com/contents/reversal-of-anticoagulation-in-intracranial-hemorrhage/print 44/47 7/5/23, 12:24 PM Reversal of anticoagulation in intracranial hemorrhage - UpToDate PCC doses shown are those suggested for initial treatment of emergency conditions. Subsequent treatment is based on INR and patient weight if available. Refer to topic and Lexicomp drug reference included with UpToDate for INR-based dosing. Graphic 89478 Version 10.0 https://www.uptodate.com/contents/reversal-of-anticoagulation-in-intracranial-hemorrhage/print 45/47 7/5/23, 12:24 PM Reversal of anticoagulation in intracranial hemorrhage - UpToDate Direct oral anticoagulant reversal agents for life-threatening bleeding (imminent risk of death from bleeding) Reversal agent (all are given intravenously) Anticoagulant Dabigatran (Pradaxa; oral thrombin inhibitor) Idarucizumab (Praxbind). Dose: 5 grams* Oral factor Xa inhibitors: Andexanet alfa (AndexXa). Dosing for the Apixaban (Eliquis) initial bolus and subsequent infusion depend on the dose level of the factor Xa inhibitor and Edoxaban (Lixiana, Savaysa) the interval since it was last taken. Rivaroxaban (Xarelto) OR- 4-factor PCC (Kcentra, Beriplex P/N, Octaplex). Dosing can be done with a fixed dose of 2000 units OR a weight-based dose of 25 to 50 units per kg.