Top

Published in:

Open Access 01-12-2024 | Anticoagulant | Review

Reversal and resumption of anticoagulants in patients with anticoagulant-associated intracerebral hemorrhage

Authors: Jingfei Yang, Jie Jing, Shiling Chen, Xia Liu, Jiahui Wang, Chao Pan, Zhouping Tang

Published in: European Journal of Medical Research | Issue 1/2024

Abstract

The use of anticoagulants has become more frequent due to the progressive aging population and increased thromboembolic events. Consequently, the proportion of anticoagulant-associated intracerebral hemorrhage (AAICH) in stroke patients is gradually increasing. Compared with intracerebral hemorrhage (ICH) patients without coagulopathy, patients with AAICH may have larger hematomas, worse prognoses, and higher mortality. Given the need for anticoagulant reversal and resumption, the management of AAICH differs from that of conventional medical or surgical treatments for ICH, and it is more specific. Understanding the pharmacology of anticoagulants and identifying agents that can reverse their effects in the early stages are crucial for treating life-threatening AAICH. When patients transition beyond the acute phase and their vital signs stabilize, it is important to consider resuming anticoagulants at the right time to prevent the occurrence of further thromboembolism. However, the timing and strategy for reversing and resuming anticoagulants are still in a dilemma. Herein, we summarize the important clinical studies, reviews, and related guidelines published in the past few years that focus on the reversal and resumption of anticoagulants in AAICH patients to help implement decisive diagnosis and treatment strategies in the clinical setting.

Milling TJ Jr, Ziebell CM. A review of oral anticoagulants, old and new, in major bleeding and the need for urgent surgery. Trends Cardiovasc Med. 2020;30(2):86–90. https://doi.org/10.1016/j.tcm.2019.03.004.CrossRefPubMed

Flaherty ML, Kissela B, Woo D, et al. The increasing incidence of anticoagulant-associated intracerebral hemorrhage. Neurology. 2007;68(2):116–21. https://doi.org/10.1212/01.wnl.0000250340.05202.8b.CrossRefPubMed

Raval AN, Cigarroa JE, Chung MK, et al. Management of patients on non-vitamin K antagonist oral anticoagulants in the acute care and periprocedural setting: a scientific statement from the American heart association. Circulation. 2017;135(10):e604–33. https://doi.org/10.1161/cir.0000000000000477.CrossRefPubMedPubMedCentral

Sweidan AJ, Singh NK, Conovaloff JL, et al. Coagulopathy reversal in intracerebral haemorrhage. Stroke Vasc Neurol. 2020;5(1):29–33. https://doi.org/10.1136/svn-2019-000274.CrossRefPubMedPubMedCentral

Veltkamp R, Rizos T, Horstmann S. Intracerebral bleeding in patients on antithrombotic agents. Semin Thromb Hemost. 2013;39(8):963–71. https://doi.org/10.1055/s-0033-1357506.CrossRefPubMed

Feigin VL, Lawes CM, Bennett DA, et al. Worldwide stroke incidence and early case fatality reported in 56 population-based studies: a systematic review. Lancet Neurol. 2009;8(4):355–69. https://doi.org/10.1016/s1474-4422(09)70025-0.CrossRefPubMed

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(7):e282–361. https://doi.org/10.1161/str.0000000000000407.CrossRefPubMed

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(1):6–46. https://doi.org/10.1007/s12028-015-0222-x.CrossRefPubMed

Seiffge DJ, Goeldlin MB, Tatlisumak T, et al. Meta-analysis of haematoma volume, haematoma expansion and mortality in intracerebral haemorrhage associated with oral anticoagulant use. J Neurol. 2019;266(12):3126–35. https://doi.org/10.1007/s00415-019-09536-1.CrossRefPubMedPubMedCentral

10.

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(8):824–36. https://doi.org/10.1001/jama.2015.0846.CrossRefPubMed

11.

Flaherty ML, Haverbusch M, Sekar P, et al. Location and outcome of anticoagulant-associated intracerebral hemorrhage. Neurocrit Care. 2006;5(3):197–201. https://doi.org/10.1385/ncc:5:3:197.CrossRefPubMed

12.

Kuramatsu JB, Sembill JA, Huttner HB. Reversal of oral anticoagulation in patients with acute intracerebral hemorrhage. Crit Care. 2019;23(1):206. https://doi.org/10.1186/s13054-019-2492-8.CrossRefPubMedPubMedCentral

13.

Poli D, Antonucci E, Vignini E, et al. Anticoagulation resumption after intracranial hemorrhage in patients treated with VKA and DOACs. Eur J Intern Med. 2020;80:73–7. https://doi.org/10.1016/j.ejim.2020.05.020.CrossRefPubMed

14.

Korompoki E, Filippidis FT, Nielsen PB, et al. Long-term antithrombotic treatment in intracranial hemorrhage survivors with atrial fibrillation. Neurology. 2017;89(7):687–96. https://doi.org/10.1212/wnl.0000000000004235.CrossRefPubMedPubMedCentral

15.

Flaherty ML, Tao H, Haverbusch M, et al. Warfarin use leads to larger intracerebral hematomas. Neurology. 2008;71(14):1084–9. https://doi.org/10.1212/01.wnl.0000326895.58992.27.CrossRefPubMedPubMedCentral

16.

Larsen KT, Sandset EC, Selseth MN, et al. Antithrombotic treatment, prehospital blood pressure, and outcomes in spontaneous intracerebral hemorrhage. J Am Heart Assoc. 2023;12(5): e028336. https://doi.org/10.1161/jaha.122.028336.CrossRefPubMedPubMedCentral

17.

Inohara T, Xian Y, Liang L, et al. Association of intracerebral hemorrhage among patients taking non-vitamin K antagonist vs vitamin K antagonist oral anticoagulants with in-hospital mortality. JAMA. 2018;319(5):463–73. https://doi.org/10.1001/jama.2017.21917.CrossRefPubMedPubMedCentral

18.

Schrag M, Kirshner H. Management of intracerebral hemorrhage: JACC focus seminar. J Am Coll Cardiol. 2020;75(15):1819–31. https://doi.org/10.1016/j.jacc.2019.10.066.CrossRefPubMed

19.

Das AS, Gökçal E, Regenhardt RW, et al. Clinical and neuroimaging risk factors associated with the development of intracerebral hemorrhage while taking direct oral anticoagulants. J Neurol. 2022;269(12):6589–96. https://doi.org/10.1007/s00415-022-11333-2.CrossRefPubMedPubMedCentral

20.

Lin SY, Chen YF, Chen CH, et al. Impact of cerebral small vessel disease burden and drug level at admission on direct oral anticoagulant associated intracerebral hemorrhage. Eur Stroke J. 2023. https://doi.org/10.1177/23969873231205673.CrossRefPubMedPubMedCentral

21.

Ballestri S, Romagnoli E, Arioli D, et al. Risk and management of bleeding complications with direct oral anticoagulants in patients with atrial fibrillation and venous thromboembolism: a narrative review. Adv Ther. 2023;40(1):41–66. https://doi.org/10.1007/s12325-022-02333-9.CrossRefPubMed

22.

van Es N, Coppens M, Schulman S, et al. Direct oral anticoagulants compared with vitamin K antagonists for acute venous thromboembolism: evidence from phase 3 trials. Blood. 2014;124(12):1968–75. https://doi.org/10.1182/blood-2014-04-571232.CrossRefPubMed

23.

Ruff CT, Giugliano RP, Braunwald E, et al. Comparison of the efficacy and safety of new oral anticoagulants with warfarin in patients with atrial fibrillation: a meta-analysis of randomised trials. Lancet. 2014;383(9921):955–62. https://doi.org/10.1016/s0140-6736(13)62343-0.CrossRefPubMed

24.

Oral anticoagulants for prevention of stroke in atrial fibrillation: systematic review, network meta-analysis, and cost effectiveness analysis. Bmj. 2017; 359:j5631.https://doi.org/10.1136/bmj.j5631.

25.

Ntaios G, Papavasileiou V, Makaritsis K, et al. Real-World Setting comparison of nonvitamin-k antagonist oral anticoagulants versus vitamin-K antagonists for stroke prevention in atrial fibrillation: a systematic review and meta-analysis. Stroke. 2017;48(9):2494–503. https://doi.org/10.1161/strokeaha.117.017549.CrossRefPubMed

26.

Patel MR, Mahaffey KW, Garg J, et al. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med. 2011;365(10):883–91. https://doi.org/10.1056/NEJMoa1009638.CrossRefPubMed

27.

Giugliano RP, Ruff CT, Braunwald E, et al. Edoxaban versus warfarin in patients with atrial fibrillation. N Engl J Med. 2013;369(22):2093–104. https://doi.org/10.1056/NEJMoa1310907.CrossRefPubMed

28.

Granger CB, Alexander JH, McMurray JJ, et al. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med. 2011;365(11):981–92. https://doi.org/10.1056/NEJMoa1107039.CrossRefPubMed

29.

Santing JAL, Lee YX, van der Naalt J, et al. Mild traumatic brain injury in elderly patients receiving direct oral anticoagulants: a systematic review and meta-analysis. J Neurotrauma. 2022;39(7–8):458–72. https://doi.org/10.1089/neu.2021.0435.CrossRefPubMed

30.

Lv M, Wu T, Jiang S, et al. Risk of intracranial hemorrhage caused by direct oral anticoagulants for stroke prevention in patients with atrial fibrillation (from a network meta-analysis of randomized controlled trials). Am J Cardiol. 2022;162:92–9. https://doi.org/10.1016/j.amjcard.2021.09.011.CrossRefPubMed

31.

Wu T, Lv C, Wu L, et al. Risk of intracranial hemorrhage with direct oral anticoagulants: a systematic review and meta-analysis of randomized controlled trials. J Neurol. 2022;269(2):664–75. https://doi.org/10.1007/s00415-021-10448-2.CrossRefPubMed

32.

Polymeris AA, Macha K, Paciaroni M, et al. Oral anticoagulants in the oldest old with recent stroke and atrial fibrillation. Ann Neurol. 2022;91(1):78–88. https://doi.org/10.1002/ana.26267.CrossRefPubMed

33.

Kurogi R, Nishimura K, Nakai M, et al. Comparing intracerebral hemorrhages associated with direct oral anticoagulants or warfarin. Neurology. 2018;90(13):e1143–9. https://doi.org/10.1212/wnl.0000000000005207.CrossRefPubMedPubMedCentral

34.

Wilson D, Seiffge DJ, Traenka C, et al. Outcome of intracerebral hemorrhage associated with different oral anticoagulants. Neurology. 2017;88(18):1693–700. https://doi.org/10.1212/wnl.0000000000003886.CrossRefPubMedPubMedCentral

35.

Gerner ST, Kuramatsu JB, Sembill JA, et al. Characteristics in non-vitamin k antagonist oral anticoagulant-related intracerebral hemorrhage. Stroke. 2019;50(6):1392–402. https://doi.org/10.1161/strokeaha.118.023492.CrossRefPubMed

36.

Kuramatsu JB, Sembill JA, Gerner ST, et al. Management of therapeutic anticoagulation in patients with intracerebral haemorrhage and mechanical heart valves. Eur Heart J. 2018;39(19):1709–23. https://doi.org/10.1093/eurheartj/ehy056.CrossRefPubMedPubMedCentral

37.

Hemphill JC 3rd, Greenberg SM, Anderson CS, et al. Guidelines for the management of spontaneous intracerebral hemorrhage: a guideline for healthcare professionals from the American heart association/american stroke association. Stroke. 2015;46(7):2032–60. https://doi.org/10.1161/str.0000000000000069.CrossRefPubMed

38.

Sahai T, Tavares MF, Sweeney JD. Rapid response to intravenous vitamin K may obviate the need to transfuse prothrombin complex concentrates. Transfusion. 2017;57(8):1885–90. https://doi.org/10.1111/trf.14166.CrossRefPubMed

39.

Bower MM, Sweidan AJ, Shafie M, et al. Contemporary reversal of oral anticoagulation in intracerebral hemorrhage. Stroke. 2019;50(2):529–36. https://doi.org/10.1161/strokeaha.118.023840.CrossRefPubMed

40.

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(3):397–406. https://doi.org/10.1007/s12028-014-9972-0.CrossRefPubMed

41.

Tomaselli GF, Mahaffey KW, Cuker A, et al. 2020 ACC expert consensus decision pathway on management of bleeding in patients on oral anticoagulants: a report of the American college of cardiology solution set oversight committee. J Am Coll Cardiol. 2020;76(5):594–622. https://doi.org/10.1016/j.jacc.2020.04.053.CrossRefPubMed

42.

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(2 Suppl):e152S-e184S. https://doi.org/10.1378/chest.11-2295.CrossRefPubMedPubMedCentral

43.

Imberti D, Barillari G, Biasioli C, et al. Prothrombin complex concentrates for urgent anticoagulation reversal in patients with intracranial haemorrhage. Pathophysiol Haemost Thromb. 2008;36(5):259–65. https://doi.org/10.1159/000252822.CrossRefPubMed

44.

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(11):1234–43. https://doi.org/10.1161/circulationaha.113.002283.CrossRefPubMedPubMedCentral

45.

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(6):566–73. https://doi.org/10.1016/s1474-4422(16)00110-1.CrossRefPubMed

46.

Hill R, Han TS, Lubomirova I, et al. Prothrombin complex concentrates are superior to fresh frozen plasma for emergency reversal of vitamin K antagonists: a meta-analysis in 2606 subjects. Drugs. 2019;79(14):1557–65. https://doi.org/10.1007/s40265-019-01179-w.CrossRefPubMed

47.

Dowlatshahi D, Butcher KS, Asdaghi N, et al. Poor prognosis in warfarin-associated intracranial hemorrhage despite anticoagulation reversal. Stroke. 2012;43(7):1812–7. https://doi.org/10.1161/strokeaha.112.652065.CrossRefPubMed

48.

Laible M, Jenetzky E, Beynon C, et al. Adverse events following international normalized ratio reversal in intracerebral hemorrhage. Cerebrovasc Dis. 2016;42(5–6):446–54. https://doi.org/10.1159/000448815.CrossRefPubMed

49.

Skolnick BE, Mathews DR, Khutoryansky NM, et al. Exploratory study on the reversal of warfarin with rFVIIa in healthy subjects. Blood. 2010;116(5):693–701. https://doi.org/10.1182/blood-2009-11-253492.CrossRefPubMed

50.

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(20):2127–37. https://doi.org/10.1056/NEJMoa0707534.CrossRefPubMed

51.

Diringer MN, Skolnick BE, Mayer SA, et al. Thromboembolic events with recombinant activated factor VII in spontaneous intracerebral hemorrhage: results from the factor seven for acute hemorrhagic stroke (FAST) trial. Stroke. 2010;41(1):48–53. https://doi.org/10.1161/strokeaha.109.561712.CrossRefPubMed

52.

Gladstone DJ, Aviv RI, Demchuk AM, et al. Effect of recombinant activated coagulation factor VII on hemorrhage expansion among patients with spot sign-positive acute intracerebral hemorrhage: the spotlight and STOP-IT randomized clinical trials. JAMA Neurol. 2019;76(12):1493–501. https://doi.org/10.1001/jamaneurol.2019.2636.CrossRefPubMedPubMedCentral

53.

Mega JL, Simon T. Pharmacology of antithrombotic drugs: an assessment of oral antiplatelet and anticoagulant treatments. Lancet. 2015;386(9990):281–91. https://doi.org/10.1016/s0140-6736(15)60243-4.CrossRefPubMed

54.

Wienen W, Stassen JM, Priepke H, et al. In-vitro profile and ex-vivo anticoagulant activity of the direct thrombin inhibitor dabigatran and its orally active prodrug, dabigatran etexilate. Thromb Haemost. 2007;98(1):155–62.PubMed

55.

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(2 Suppl):e44S-e88S. https://doi.org/10.1378/chest.11-2292.CrossRefPubMedPubMedCentral

56.

Levy JH, Douketis J, Weitz JI. Reversal agents for non-vitamin K antagonist oral anticoagulants. Nat Rev Cardiol. 2018;15(5):273–81. https://doi.org/10.1038/nrcardio.2017.223.CrossRefPubMed

57.

Gottlieb M, Khishfe B. Idarucizumab for the reversal of dabigatran. Ann Emerg Med. 2017;69(5):554–8. https://doi.org/10.1016/j.annemergmed.2016.11.025.CrossRefPubMed

58.

Glund S, Stangier J, van Ryn J, et al. Effect of age and renal function on idarucizumab pharmacokinetics and idarucizumab-mediated reversal of dabigatran anticoagulant activity in a randomized, double-blind. Crossover Phase Ib Study Clin Pharmacokinet. 2017;56(1):41–54. https://doi.org/10.1007/s40262-016-0417-0.CrossRefPubMed

59.

Pollack CV Jr, Reilly PA, Eikelboom J, et al. Idarucizumab for dabigatran reversal. N Engl J Med. 2015;373(6):511–20. https://doi.org/10.1056/NEJMoa1502000.CrossRefPubMed

60.

Pollack CV Jr, Reilly PA, van Ryn J, et al. Idarucizumab for dabigatran reversal—full cohort analysis. N Engl J Med. 2017;377(5):431–41. https://doi.org/10.1056/NEJMoa1707278.CrossRefPubMed

61.

Kermer P, Eschenfelder CC, Diener HC, et al. Antagonizing dabigatran by idarucizumab in cases of ischemic stroke or intracranial hemorrhage in Germany-updated series of 120 cases. Int J Stroke. 2020;15(6):609–18. https://doi.org/10.1177/1747493019895654.CrossRefPubMed

62.

Claisse G, Delavenne X, Masson I, et al. Venovenous haemodiafiltration for the management of dabigatran overdose in intensive care unit. Clin Kidney J. 2015;8(2):199–201. https://doi.org/10.1093/ckj/sfv001.CrossRefPubMedPubMedCentral

63.

Chen BC, Sheth NR, Dadzie KA, et al. Hemodialysis for the treatment of pulmonary hemorrhage from dabigatran overdose. Am J Kidney Dis. 2013;62(3):591–4. https://doi.org/10.1053/j.ajkd.2013.02.361.CrossRefPubMed

64.

Chai-Adisaksopha C, Hillis C, Lim W, et al. Hemodialysis for the treatment of dabigatran-associated bleeding: a case report and systematic review. J Thromb Haemost. 2015;13(10):1790–8. https://doi.org/10.1111/jth.13117.CrossRefPubMed

65.

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(14):1326–35. https://doi.org/10.1056/NEJMoa1814051.CrossRefPubMedPubMedCentral

66.

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(6):2096–105. https://doi.org/10.1161/strokeaha.120.030565.CrossRefPubMedPubMedCentral

67.

Lu G, Pine P, Leeds JM, et al. Andexanet alfa effectively reverses edoxaban anticoagulation effects and associated bleeding in a rabbit acute hemorrhage model. PLoS ONE. 2018;13(3): e0195122. https://doi.org/10.1371/journal.pone.0195122.CrossRefPubMedPubMedCentral

68.

Huttner HB, Gerner ST, Kuramatsu JB, et al. Hematoma expansion and clinical outcomes in patients with factor-Xa inhibitor-related atraumatic intracerebral hemorrhage treated within the ANNEXA-4 trial versus real-world usual care. Stroke. 2022;53(2):532–43. https://doi.org/10.1161/strokeaha.121.034572.CrossRefPubMed

69.

Barra ME, Das AS, Hayes BD, et al. Evaluation of andexanet alfa and four-factor prothrombin complex concentrate (4F-PCC) for reversal of rivaroxaban- and apixaban-associated intracranial hemorrhages. J Thromb Haemost. 2020;18(7):1637–47. https://doi.org/10.1111/jth.14838.CrossRefPubMed

70.

Chan NC, Weitz JI. Ciraparantag as a potential universal anticoagulant reversal agent. Eur Heart J. 2022;43(10):993–5. https://doi.org/10.1093/eurheartj/ehab706.CrossRefPubMed

71.

Ansell J, Laulicht BE, Bakhru SH, et al. Ciraparantag, an anticoagulant reversal drug: mechanism of action, pharmacokinetics, and reversal of anticoagulants. Blood. 2021;137(1):115–25. https://doi.org/10.1182/blood.2020007116.CrossRefPubMed

72.

Ansell JE, Bakhru SH, Laulicht BE, et al. Single-dose ciraparantag safely and completely reverses anticoagulant effects of edoxaban. Thromb Haemost. 2017;117(2):238–45. https://doi.org/10.1160/th16-03-0224.CrossRefPubMedPubMedCentral

73.

Ansell J, Bakhru S, Laulicht BE, et al. Ciraparantag reverses the anticoagulant activity of apixaban and rivaroxaban in healthy elderly subjects. Eur Heart J. 2022;43(10):985–92. https://doi.org/10.1093/eurheartj/ehab637.CrossRefPubMed

74.

Eerenberg ES, Kamphuisen PW, Sijpkens MK, et al. Reversal of rivaroxaban and dabigatran by prothrombin complex concentrate: a randomized, placebo-controlled, crossover study in healthy subjects. Circulation. 2011;124(14):1573–9. https://doi.org/10.1161/circulationaha.111.029017.CrossRefPubMed

75.

Zahir H, Brown KS, Vandell AG, et al. Edoxaban effects on bleeding following punch biopsy and reversal by a 4-factor prothrombin complex concentrate. Circulation. 2015;131(1):82–90. https://doi.org/10.1161/circulationaha.114.013445.CrossRefPubMed

76.

Barco S, Whitney Cheung Y, Coppens M, et al. In vivo reversal of the anticoagulant effect of rivaroxaban with four-factor prothrombin complex concentrate. Br J Haematol. 2016;172(2):255–61. https://doi.org/10.1111/bjh.13821.CrossRefPubMed

77.

Piran S, Schulman S. Treatment of bleeding complications in patients on anticoagulant therapy. Blood. 2019;133(5):425–35. https://doi.org/10.1182/blood-2018-06-820746.CrossRefPubMed

78.

Levi M, Moore KT, Castillejos CF, et al. Comparison of three-factor and four-factor prothrombin complex concentrates regarding reversal of the anticoagulant effects of rivaroxaban in healthy volunteers. J Thromb Haemost. 2014;12(9):1428–36. https://doi.org/10.1111/jth.12599.CrossRefPubMed

79.

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(21):1681–9. https://doi.org/10.1161/circulationaha.120.045769.CrossRefPubMed

80.

Cheung YW, Barco S, Hutten BA, et al. In vivo increase in thrombin generation by four-factor prothrombin complex concentrate in apixaban-treated healthy volunteers. J Thromb Haemost. 2015;13(10):1799–805. https://doi.org/10.1111/jth.13115.CrossRefPubMed

81.

Majeed A, Ågren A, Holmström M, et al. Management of rivaroxaban—or apixaban-associated major bleeding with prothrombin complex concentrates: a cohort study. Blood. 2017;130(15):1706–12. https://doi.org/10.1182/blood-2017-05-782060.CrossRefPubMed

82.

Schulman S, Ritchie B, Nahirniak S, et al. Reversal of dabigatran-associated major bleeding with activated prothrombin concentrate: a prospective cohort study. Thromb Res. 2017;152:44–8. https://doi.org/10.1016/j.thromres.2017.02.010.CrossRefPubMed

83.

Hoffman M, Volovyk Z, Monroe DM. Reversal of dabigatran effects in models of thrombin generation and hemostasis by factor VIIa and prothrombin complex concentrate. Anesthesiology. 2015;122(2):353–62. https://doi.org/10.1097/aln.0000000000000540.CrossRefPubMed

84.

Chaudhary R, Singh A, Chaudhary R, et al. Evaluation of direct oral anticoagulant reversal agents in intracranial hemorrhage: a systematic review and meta-analysis. JAMA Netw Open. 2022;5(11): e2240145. https://doi.org/10.1001/jamanetworkopen.2022.40145.CrossRefPubMedPubMedCentral

85.

Castillo R, Chan A, Atallah S, et al. Treatment of adults with intracranial hemorrhage on apixaban or rivaroxaban with prothrombin complex concentrate products. J Thromb Thrombolysis. 2021;51(1):151–8. https://doi.org/10.1007/s11239-020-02154-z.CrossRefPubMed

86.

Dager WE, Roberts AJ, Nishijima DK. Effect of low and moderate dose FEIBA to reverse major bleeding in patients on direct oral anticoagulants. Thromb Res. 2019;173:71–6. https://doi.org/10.1016/j.thromres.2018.11.009.CrossRefPubMed

87.

Arellano-Rodrigo E, Lopez-Vilchez I, Galan AM, et al. Coagulation factor concentrates fail to restore alterations in fibrin formation caused by rivaroxaban or dabigatran in studies with flowing blood from treated healthy volunteers. Transfus Med Rev. 2015;29(4):242–9. https://doi.org/10.1016/j.tmrv.2015.08.001.CrossRefPubMed

88.

Gerner ST, Kuramatsu JB, Sembill JA, et al. Association of prothrombin complex concentrate administration and hematoma enlargement in non-vitamin K antagonist oral anticoagulant-related intracerebral hemorrhage. Ann Neurol. 2018;83(1):186–96. https://doi.org/10.1002/ana.25134.CrossRefPubMed

89.

Beurskens DMH, Huckriede JP, Schrijver R, et al. The anticoagulant and nonanticoagulant properties of heparin. Thromb Haemost. 2020;120(10):1371–83. https://doi.org/10.1055/s-0040-1715460.CrossRefPubMed

90.

Garcia DA, Baglin TP, Weitz JI, et al. Parenteral anticoagulants: antithrombotic therapy and prevention of thrombosis, 9th ed: American college of chest physicians evidence-based clinical practice guidelines. Chest. 2012;141(2 Suppl):e24S-e43S. https://doi.org/10.1378/chest.11-2291.CrossRefPubMedPubMedCentral

91.

Bakchoul T, Jouni R, Warkentin TE. Protamine (heparin)-induced thrombocytopenia: a review of the serological and clinical features associated with anti-protamine/heparin antibodies. J Thromb Haemost. 2016;14(9):1685–95. https://doi.org/10.1111/jth.13405.CrossRefPubMed

92.

Schulman S, Bijsterveld NR. Anticoagulants and their reversal. Transfus Med Rev. 2007;21(1):37–48. https://doi.org/10.1016/j.tmrv.2006.08.002.CrossRefPubMed

93.

van Veen JJ, Maclean RM, Hampton KK, et al. Protamine reversal of low molecular weight heparin: clinically effective? Blood Coagul Fibrinolysis. 2011;22(7):565–70. https://doi.org/10.1097/MBC.0b013e3283494b3c.CrossRefPubMed

94.

Young G, Yonekawa KE, Nakagawa PA, et al. Recombinant activated factor VII effectively reverses the anticoagulant effects of heparin, enoxaparin, fondaparinux, argatroban, and bivalirudin ex vivo as measured using thromboelastography. Blood Coagul Fibrinolysis. 2007;18(6):547–53. https://doi.org/10.1097/MBC.0b013e328201c9a9.CrossRefPubMed

95.

Lauritzen B, Hedner U, Johansen PB, et al. Recombinant human factor VIIa and a factor VIIa-analogue reduces heparin and low molecular weight heparin (LMWH)-induced bleeding in rats. J Thromb Haemost. 2008;6(5):804–11. https://doi.org/10.1111/j.1538-7836.2008.02933.x.CrossRefPubMed

96.

Ingerslev J, Vanek T, Culic S. Use of recombinant factor VIIa for emergency reversal of anticoagulation. J Postgrad Med. 2007;53(1):17–22. https://doi.org/10.4103/0022-3859.30322.CrossRefPubMed

97.

Chan S, Kong M, Minning DM, et al. Assessment of recombinant factor VIIa as an antidote for bleeding induced in the rabbit by low molecular weight heparin. J Thromb Haemost. 2003;1(4):760–5. https://doi.org/10.1046/j.1538-7836.2003.00101.x.CrossRefPubMed

98.

MacLaren R, Weber LA, Brake H, et al. A multicenter assessment of recombinant factor VIIa off-label usage: clinical experiences and associated outcomes. Transfusion. 2005;45(9):1434–42. https://doi.org/10.1111/j.1537-2995.2005.00548.x.CrossRefPubMed

99.

Bijsterveld NR, Moons AH, Boekholdt SM, et al. Ability of recombinant factor VIIa to reverse the anticoagulant effect of the pentasaccharide fondaparinux in healthy volunteers. Circulation. 2002;106(20):2550–4. https://doi.org/10.1161/01.cir.0000038501.87442.02.CrossRefPubMed

100.

Lisman T, Bijsterveld NR, Adelmeijer J, et al. Recombinant factor VIIa reverses the in vitro and ex vivo anticoagulant and profibrinolytic effects of fondaparinux. J Thromb Haemost. 2003;1(11):2368–73. https://doi.org/10.1046/j.1538-7836.2003.00536.x.CrossRefPubMed

101.

Godier A, Durand M, Emmerich J, et al. Efficacy of prothrombin complex concentrate to reverse the anticoagulant effect of the pentasaccharide fondaparinux in a rabbit model. Thromb Haemost. 2011;105(1):161–8. https://doi.org/10.1160/th10-07-0434.CrossRefPubMed

102.

Desmurs-Clavel H, Huchon C, Chatard B, et al. Reversal of the inhibitory effect of fondaparinux on thrombin generation by rFVIIa, aPCC and PCC. Thromb Res. 2009;123(5):796–8. https://doi.org/10.1016/j.thromres.2008.07.007.CrossRefPubMed

103.

Shenoi RA, Kalathottukaren MT, Travers RJ, et al. Affinity-based design of a synthetic universal reversal agent for heparin anticoagulants. Sci Transl Med. 2014;6(260):260ra150. https://doi.org/10.1126/scitranslmed.3009427.CrossRefPubMed

104.

Kalathottukaren MT, Creagh AL, Abbina S, et al. Comparison of reversal activity and mechanism of action of UHRA, andexanet, and PER977 on heparin and oral FXa inhibitors. Blood Adv. 2018;2(16):2104–14. https://doi.org/10.1182/bloodadvances.2016003616.CrossRefPubMedPubMedCentral

105.

Huang Q, Zhao H, Shui M, et al. Heparin reversal by an oligoethylene glycol functionalized guanidinocalixarene. Chem Sci. 2020;11(35):9623–9. https://doi.org/10.1039/d0sc03922e.CrossRefPubMedPubMedCentral

106.

Ansell JE, Laulicht BE, Bakhru SH, et al. Ciraparantag safely and completely reverses the anticoagulant effects of low molecular weight heparin. Thromb Res. 2016;146:113–8. https://doi.org/10.1016/j.thromres.2016.07.008.CrossRefPubMed

107.

Steffel J, Collins R, Antz M, et al. 2021 European heart rhythm association practical guide on the use of non-vitamin K antagonist oral anticoagulants in patients with atrial fibrillation. Europace. 2021;23(10):1612–76. https://doi.org/10.1093/europace/euab065.CrossRefPubMed

108.

Puy L, Forman R, Cordonnier C, et al. Protecting the brain, from the heart: safely mitigating the consequences of thrombosis in intracerebral hemorrhage survivors with atrial fibrillation. Stroke. 2022;53(7):2152–60. https://doi.org/10.1161/strokeaha.122.036888.CrossRefPubMed

109.

Nielsen PB, Larsen TB, Skjøth F, et al. Restarting anticoagulant treatment after intracranial hemorrhage in patients with atrial fibrillation and the impact on recurrent stroke, mortality, and bleeding: a nationwide cohort study. Circulation. 2015;132(6):517–25. https://doi.org/10.1161/circulationaha.115.015735.CrossRefPubMed

110.

Ottosen TP, Grijota M, Hansen ML, et al. Use of antithrombotic therapy and long-term clinical outcome among patients surviving intracerebral hemorrhage. Stroke. 2016;47(7):1837–43. https://doi.org/10.1161/strokeaha.116.012945.CrossRefPubMed

111.

Lee SR, Choi EK, Kwon S, et al. Oral anticoagulation in asian patients with atrial fibrillation and a history of intracranial hemorrhage. Stroke. 2020;51(2):416–23. https://doi.org/10.1161/strokeaha.119.028030.CrossRefPubMed

112.

Tsai CT, Liao JN, Chiang CE, et al. Association of ischemic stroke, major bleeding, and other adverse events with warfarin use vs non-vitamin k antagonist oral anticoagulant use in patients with atrial fibrillation with a history of intracranial hemorrhage. JAMA Netw Open. 2020;3(6): e206424. https://doi.org/10.1001/jamanetworkopen.2020.6424.CrossRefPubMedPubMedCentral

113.

Lin SY, Chang YC, Lin FJ, et al. Post-intracranial hemorrhage antithrombotic therapy in patients with atrial fibrillation. J Am Heart Assoc. 2022;11(6): e022849. https://doi.org/10.1161/jaha.121.022849.CrossRefPubMedPubMedCentral

114.

Poli L, Grassi M, Zedde M, et al. Anticoagulants resumption after warfarin-related intracerebral haemorrhage: the multicenter study on cerebral hemorrhage in Italy (MUCH-Italy). Thromb Haemost. 2018;118(3):572–80. https://doi.org/10.1055/s-0038-1627454.CrossRefPubMed

115.

Nielsen PB, Larsen TB, Skjøth F, et al. Outcomes associated with resuming Warfarin treatment after hemorrhagic stroke or traumatic intracranial hemorrhage in patients with atrial fibrillation. JAMA Intern Med. 2017;177(4):563–70. https://doi.org/10.1001/jamainternmed.2016.9369.CrossRefPubMedPubMedCentral

116.

Pennlert J, Overholser R, Asplund K, et al. Optimal timing of anticoagulant treatment after intracerebral hemorrhage in patients with atrial fibrillation. Stroke. 2017;48(2):314–20. https://doi.org/10.1161/strokeaha.116.014643.CrossRefPubMed

117.

Murthy SB, Gupta A, Merkler AE, et al. Restarting anticoagulant therapy after intracranial hemorrhage: a systematic review and meta-analysis. Stroke. 2017;48(6):1594–600. https://doi.org/10.1161/strokeaha.116.016327.CrossRefPubMedPubMedCentral

118.

Chai-Adisaksopha C, Iorio A, Hillis C, et al. Warfarin resumption following anticoagulant-associated intracranial hemorrhage: a systematic review and meta-analysis. Thromb Res. 2017;160:97–104. https://doi.org/10.1016/j.thromres.2017.11.001.CrossRefPubMed

119.

Park YA, Uhm JS, Pak HN, et al. Anticoagulation therapy in atrial fibrillation after intracranial hemorrhage. Heart Rhythm. 2016;13(9):1794–802. https://doi.org/10.1016/j.hrthm.2016.05.016.CrossRefPubMed

120.

Witt DM, Clark NP, Martinez K, et al. Risk of thromboembolism, recurrent hemorrhage, and death after warfarin therapy interruption for intracranial hemorrhage. Thromb Res. 2015;136(5):1040–4. https://doi.org/10.1016/j.thromres.2015.10.002.CrossRefPubMed

121.

Hindricks G, Potpara T, Dagres N, et al. 2020 ESC Guidelines for the diagnosis and management of atrial fibrillation developed in collaboration with the European association for cardio-thoracic surgery (EACTS): the task force for the diagnosis and management of atrial fibrillation of the European Society of Cardiology (ESC) developed with the special contribution of the european heart rhythm association (EHRA) of the ESC. Eur Heart J. 2021;42(5):373–498. https://doi.org/10.1093/eurheartj/ehaa612.CrossRefPubMed

122.

Chao TF, Liu CJ, Liao JN, et al. Use of oral anticoagulants for stroke prevention in patients with atrial fibrillation who have a history of intracranial hemorrhage. Circulation. 2016;133(16):1540–7. https://doi.org/10.1161/circulationaha.115.019794.CrossRefPubMed

123.

Nielsen PB, Skjøth F, Søgaard M, et al. Non-vitamin K antagonist oral anticoagulants versus Warfarin in atrial fibrillation patients with intracerebral hemorrhage. Stroke. 2019;50(4):939–46. https://doi.org/10.1161/strokeaha.118.023797.CrossRefPubMedPubMedCentral

124.

Sembill JA, Wieser CY, Sprügel MI, et al. Initiating anticoagulant therapy after ICH is associated with patient characteristics and treatment recommendations. J Neurol. 2018;265(10):2404–14. https://doi.org/10.1007/s00415-018-9009-2.CrossRefPubMed

125.

Effects of oral anticoagulation for atrial fibrillation after spontaneous intracranial haemorrhage in the UK: a randomised, open-label, assessor-masked, pilot-phase, non-inferiority trial. Lancet Neurol. 2021; 20(10):842–853.https://doi.org/10.1016/s1474-4422(21)00264-7.

126.

Schreuder F, van Nieuwenhuizen KM, Hofmeijer J, et al. Apixaban versus no anticoagulation after anticoagulation-associated intracerebral haemorrhage in patients with atrial fibrillation in the Netherlands (APACHE-AF): a randomised, open-label, phase 2 trial. Lancet Neurol. 2021;20(11):907–16. https://doi.org/10.1016/s1474-4422(21)00298-2.CrossRefPubMed

127.

Ivany E, Lane DA, Dan GA, et al. Antithrombotic therapy for stroke prevention in patients with atrial fibrillation who survive an intracerebral haemorrhage: results of an EHRA survey. Europace. 2021;23(5):806–14. https://doi.org/10.1093/europace/euaa423.CrossRefPubMed

128.

Steffel J, Verhamme P, Potpara TS, et al. The 2018 European heart rhythm association practical guide on the use of non-vitamin K antagonist oral anticoagulants in patients with atrial fibrillation. Eur Heart J. 2018;39(16):1330–93. https://doi.org/10.1093/eurheartj/ehy136.CrossRefPubMed

129.

Biffi A, Urday S, Kubiszewski P, et al. Combining imaging and genetics to predict recurrence of anticoagulation-associated intracerebral hemorrhage. Stroke. 2020;51(7):2153–60. https://doi.org/10.1161/strokeaha.120.028310.CrossRefPubMedPubMedCentral

130.

Kozberg MG, Perosa V, Gurol ME, et al. A practical approach to the management of cerebral amyloid angiopathy. Int J Stroke. 2021;16(4):356–69. https://doi.org/10.1177/1747493020974464.CrossRefPubMed

131.

Mac Grory B, Flood S, Schrag M, et al. Anticoagulation resumption after stroke from atrial fibrillation. Curr Atheroscler Rep. 2019;21(8):29. https://doi.org/10.1007/s11883-019-0790-x.CrossRefPubMed

132.

Suda S, Iguchi Y, Yagita Y, et al. Resumption of oral anticoagulation in patients with non-valvular atrial fibrillation after intracerebral hemorrhage: a sub-analysis of the PASTA registry study. J Neurol Sci. 2023;453: 120810. https://doi.org/10.1016/j.jns.2023.120810.CrossRefPubMed

133.

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(7):840–55. https://doi.org/10.1111/ijs.12309.CrossRefPubMed

134.

Wiegele M, Schöchl H, Haushofer A, et al. Diagnostic and therapeutic approach in adult patients with traumatic brain injury receiving oral anticoagulant therapy: an Austrian interdisciplinary consensus statement. Crit Care. 2019;23(1):62. https://doi.org/10.1186/s13054-019-2352-6.CrossRefPubMedPubMedCentral

135.

Byrnes MC, Irwin E, Roach R, et al. Therapeutic anticoagulation can be safely accomplished in selected patients with traumatic intracranial hemorrhage. World J Emerg Surg. 2012;7(1):25. https://doi.org/10.1186/1749-7922-7-25.CrossRefPubMedPubMedCentral

136.

Nielsen PB, Johnsen SP. Letter by Nielsen and Johnsen regarding article, “optimal timing of anticoagulant treatment after intracerebral hemorrhage in patients with atrial fibrillation.” Stroke. 2017;48(4): e115. https://doi.org/10.1161/strokeaha.117.016747.CrossRefPubMed

137.

El Naamani K, Abbas R, Ghanem M, et al. Resuming anticoagulants in patients with intracranial hemorrhage: a meta-analysis and literature review. Neurosurgery. 2023. https://doi.org/10.1227/neu.0000000000002625.CrossRefPubMed

138.

Oldgren J, Åsberg S, Hijazi Z, et al. Early versus delayed non-vitamin k antagonist oral anticoagulant therapy after acute ischemic stroke in atrial fibrillation (TIMING): a registry-based randomized controlled noninferiority study. Circulation. 2022;146(14):1056–66. https://doi.org/10.1161/circulationaha.122.060666.CrossRefPubMedPubMedCentral

139.

Fischer U, Koga M, Strbian D, et al. Early versus later anticoagulation for stroke with atrial fibrillation. N Engl J Med. 2023;388(26):2411–21. https://doi.org/10.1056/NEJMoa2303048.CrossRefPubMed

140.

Best JG, Arram L, Ahmed N, et al. Optimal timing of anticoagulation after acute ischemic stroke with atrial fibrillation (OPTIMAS): protocol for a randomized controlled trial. Int J Stroke. 2022;17(5):583–9. https://doi.org/10.1177/17474930211057722.CrossRefPubMed

141.

Jiang M, Wang C, Zhang Y. Comparison of early and delayed anticoagulation therapy after ischemic stroke in patients with atrial fibrillation: a systematic review and meta-analysis. J Thromb Thrombolysis. 2023;56(4):603–13. https://doi.org/10.1007/s11239-023-02872-0.CrossRefPubMed

142.

Grosse GM, Hüsing A, Stang A, et al. Early or late initiation of dabigatran versus vitamin-K-antagonists in acute ischemic stroke or TIA: the PRODAST study. Int J Stroke. 2023;18(10):1169–77. https://doi.org/10.1177/17474930231184366.CrossRefPubMedPubMedCentral

Title: Reversal and resumption of anticoagulants in patients with anticoagulant-associated intracerebral hemorrhage
Authors: Jingfei Yang
Jie Jing
Shiling Chen
Xia Liu
Jiahui Wang
Chao Pan
Zhouping Tang
Publication date: 01-12-2024
Publisher: BioMed Central
Keywords: Anticoagulant
Direct Oral Anticoagulant
Direct Oral Anticoagulant
Dabigatran
Warfarin
Stroke
Rivaroxaban
Heparin
Published in: European Journal of Medical Research / Issue 1/2024
Electronic ISSN: 2047-783X
DOI: https://doi.org/10.1186/s40001-024-01816-5

At a glance: The STEP trials

Springer Medicine

Reversal and resumption of anticoagulants in patients with anticoagulant-associated intracerebral hemorrhage

Abstract

At a glance: The STEP trials

Springer Medicine

Abstract

Please log in to get access to this content

Other articles of this Issue 1/2024

Carrageenan maintains the contractile phenotype of vascular smooth muscle cells by increasing macromolecular crowding in vitro

Assessment of different continence definitions in the context of the randomized multicenter prospective LAP-01 trial—Does the best definition change over time?

Effects of different types of Ringer’s solution on patients with traumatic haemorrhagic shock: a prospective cohort study

A promising natural killer cell-based model and a nomogram for the prognostic prediction of clear-cell renal cell carcinoma

TFRC, associated with hypoxia and immune, is a prognostic factor and potential therapeutic target for bladder cancer

A non-linear connection between the total cholesterol to high-density lipoprotein cholesterol ratio and stroke risk: a retrospective cohort study from the China Health and Retirement Longitudinal Study