Antithrombotics in intracerebral hemorrhage in the era of novel agents and antidotes: A review

Main Article Content

Dimitrios Giakoumettis
Dimitrios A. Vrachatis
Dimitrios Panagopoulos
Asimina Loukina
Georgios Tsitsinakis
Katerina Apostolopoulou
Georgios Giannopoulos
Sotiria Giotaki
Spyridon Deftereos
Marios S. Themistocleous

Keywords

ICH, antiplatelets, antithrombotic agents, anticoagulation, thromboembolism

Abstract

Intracerebral hemorrhage (ICH)1 is characterized by the pathological accumulation of blood within the brain parenchyma, most commonly associated with hypertension, arteriovenous malformations, or trauma. However, it can also present in patients receiving antithrombotic drugs, either anticoagulants such as acenocoumarol/warfarin—novel oral anticoagulants or antiplatelets, for the prevention and treatment of thromboembolic disease. The purpose of this review is to present current bibliographic data regarding ICH irrespective of the cause, as well as post-hemorrhage use of antithrombotic agents. Moreover, this review attempts to provide guidelines concerning the termination, inversion, and of course resumption of antithrombotic therapy.

We reviewed the most recently presented available data for patients who dealt with intracerebral hemorrhagic events while on antithrombotic agents (due to atrial fibrillation, prosthetic mechanical valves or recent/recurrent deep vein thrombosis). Furthermore, we examined and compared the thromboembolic risk, the bleeding risk, as well as the re-bleeding risk in two groups: patients receiving antithrombotic therapy versus patients not on antithrombotic therapy. Antithrombotic therapy is of great importance when indicated, though it does not come without crucial side-effects, such as ICH. Optimal timing of withdrawal, reversal, and resumption of antithrombotic treatment should be determined by a multidisciplinary team consisting of a stroke specialist, a cardiologist, and a neurosurgeon, who will individually approach the needs and risks of each patient.
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References

1. Sutherland GR, Auer RN. Primary intracerebral hemorrhage. J Clin Neurosci. 2006;13(5):511–17. https://doi.org/10.1016/j.jocn.2004.12.012
2. Qureshi AI, Tuhrim S, Broderick JP, Batjer HH, Hondo H, Hanley DF. Spontaneous intracere-bral hemorrhage. New Eng J Med. 2001; 344(19):1450–60. https://doi.org/10.1056/NEJM 200105103441907
3. Intiso D, Stampatore P, Zarrelli MM, et al. Incidence of first-ever ischemic and hemorrhagic stroke in a well-defined community of southern Italy, 1993–1995. Eur J Neurol. 2003;10(5):559–65. https://doi.org/10.1046/j.1468-1331.2003.00648.x
4. Keep RF, Hua Y, Xi G. Intracerebral haemor-rhage: Mechanisms of injury and therapeutic targets. Lancet Neurol. 2012;11(8):720–31. https://doi.org/10.1016/S1474-4422(12) 70104-7
5. Greenberg CH, Frosch MP, Goldstein JN, Rosand J, Greenberg SM. Modeling intracere-bral hemorrhage growth and response to antico-agulation. PLoS One. 2012;7(10):e48458. https:// doi.org/10.1371/journal.pone.0048458
6. Barras CD, Tress BM, Christensen S, et al. Density and shape as CT predictors of intracerebral hemorrhage growth. Stroke. 2009;40(4): 1325–31. https://doi.org/10.1161/STROK EAHA.108. 536888
7. Cebral JR, Vazquez M, Sforza DM, et al. Analysis of hemodynamics and wall mechanics at sites of cerebral aneurysm rupture. J Neurointerv Surg. 2015;7(7):530–6. https://doi.org/10.1136/ neurintsurg-2014-011247
8. Lieu AS, Hwang SL, Howng SL, Chai CY. Brain tumors with hemorrhage. J Formos Med Assoc. 1999;98(5):365–7.
9. Little JR, Dial B, Belanger G, Carpenter S. Brain hemorrhage from intracranial tumor. Stroke. 1979;10(3):283–8. https://doi.org/10.1161/01. STR.10.3.283
10. Broderick JP, Brott T, Tomsick T, Miller R, Huster G. Intracerebral hemorrhage more than twice as common as subarachnoid hemorrhage. J Neurosurg. 1993;78(2):188–91. https://doi.org/ 10.3171/jns.1993.78.2.0188
11. Feigin VL, Lawes CM, Bennett DA, Barker-Collo SL, Parag V. Worldwide stroke incidence and early case fatality reported in 56 popula-tion-based studies: A systematic review. Lancet Neurol. 2009;8(4):355–69. https://doi.org/10. 1016/S1474-4422(09)70025-0
12. van Asch CJ, Luitse MJ, Rinkel GJ, van der Tweel I, Algra A, Klijn CJ. Incidence, case fatal-ity, and functional outcome of intracerebral hae-morrhage over time, according to age, sex, and ethnic origIn: A systematic review and meta-anal-ysis. Lancet Neurol. 2010;9(2):167–76. https:// doi.org/10.1016/S1474-4422(09)70340-0
13. Flaherty ML, Woo D, Haverbusch M, et al. Racial variations in location and risk of intrace-rebral hemorrhage. Stroke. 2005;36(5):934–7. https://doi.org/10.1161/01.STR.0000160756. 72109.95
14. Grysiewicz RA, Thomas K, Pandey DK. Epidemiology of ischemic and hemorrhagic stroke: Incidence, prevalence, mortality, and risk factors. Neurol Clin. 2008;26(4):871–95, vii. https://doi.org/10.1016/j.ncl.2008.07.003
15. Bakris G, Ali W, Parati G. ACC/AHA versus ESC/ESH on hypertension guidelines: JACC guideline comparison. J Am Coll Cardiol. 2019;73(23):3018–26. https://doi.org/10.1016/j. jacc.2019.03.507
16. O'Donnell MJ, Xavier D, Liu L, et al. Risk fac-tors for ischaemic and intracerebral haemor-rhagic stroke in 22 countries (the INTERSTROKE study): A case-control study. Lancet. 2010;376 (9735):112–23. https://doi.org/10.1016/S0140-6736(10)60834-3
17. Ariesen MJ, Claus SP, Rinkel GJ, Algra A. Risk factors for intracerebral hemorrhage in the gen-eral population: A systematic review. Stroke. 2003;34(8):2060–5. https://doi.org/10.1161/01. STR.0000080678.09344.8D
18. Maas MB, Rosenberg NF, Kosteva AR, Prabhakaran S, Naidech AM. Coagulopathy dis-proportionately predisposes to lobar intracerebral hemorrhage. Neurocrit Care. 2013;18 (2):166–9. https://doi.org/10.1007/s12028-012-9814-x
19. Vernooij MW, van der Lugt A, Ikram MA, et al. Prevalence and risk factors of cerebral microbleeds: The Rotterdam scan study. Neurology. 2008;70(14):1208–14. https://doi.org/ 10.1212/01.wnl.0000307750.41970.d9
20. Vermeer SE, Algra A, Franke CL, Koudstaal PJ, Rinkel GJ. Long-term prognosis after recovery from primary intracerebral hemor-rhage. Neurology. 2002;59(2):205–9. https://doi. org/10.1212/WNL.59.2.205
21. Bailey RD, Hart RG, Benavente O, Pearce LA. Recurrent brain hemorrhage is more frequent than ischemic stroke after intracranial hemor-rhage. Neurology. 2001;56(6):773–7. https://doi. org/10.1212/WNL.56.6.773
22. Fang MC, Chang Y, Hylek EM, et al. Advanced age, anticoagulation intensity, and risk for intra-cranial hemorrhage among patients taking warfarin for atrial fibrillation. Ann Intern Med. 2004;141(10):745–52. https://doi.org/10.7326/ 0003-4819-141-10-200411160-00005
23. Wieberdink RG, Poels MM, Vernooij MW, et al. Serum lipid levels and the risk of intracerebral hemorrhage: The Rotterdam study. Arterioscler Thromb Vasc Biol. 2011;31(12):2982–9. https://doi.org/10.1161/ ATVBAHA.111.234948
24. Sarwar N, Gao P, Seshasai SR, et al. Diabetes mellitus, fasting blood glucose concentration, and risk of vascular disease: A collaborative meta-analysis of 102 prospective studies. Lancet. 2010;375(9733):2215–22. https://doi.org/10.1016/ S0140-6736(10)60484-9
25. Cicero AFG, Fogacci F, Giovannini M, et al. Interaction between low-density lipoprotein-cho-lesterolaemia, serum uric level and incident hypertension: Data from the Brisighella Heart Study. J Hypertens. 2019;37(4):728–31. https:// doi.org/10.1097/HJH.0000000000001927
26. Juvela S, Hillbom M, Palomaki H. Risk factors for spontaneous intracerebral hemorrhage. Stroke. 1995;26(9):1558–64. https://doi.org/10. 1161/01.STR.26.9.1558
27. McEvoy AW, Kitchen ND, Thomas DG. Intracerebral haemorrhage and drug abuse in  young adults. Br J Neurosurg. 2000;14(5):449–54. https://doi.org/10.1080/026 88690050175247
28. McEvoy AW, Kitchen ND, Thomas DG. Lesson of the week: Intracerebral haemorrhage in young adults: The emerging importance of drug misuse. Br Med J. 2000;320(7245):1322–4. https://doi. org/10.1136/bmj.320.7245.1322
29. Huhtakangas J, Tetri S, Juvela S, Saloheimo P, Bode MK, Hillbom M. Effect of increased war-farin use on warfarin-related cerebral hemor-rhage: A longitudinal population-based study. Stroke. 2011;42(9):2431–5. https://doi.org/10. 1161/STROKEAHA.111.615260
30. 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.00002 50340.05202.8b
31. Neau JP, Couderq C, Ingrand P, Blanchon P, Gil R. Intracranial hemorrhage and oral anticoagulant treatment. Cerebrovasc Dis. 2001;11(3):195–200. https://doi.org/10.1159/ 000047638
32. Elkind MS, Sacco RL. Direct thrombin inhibi-tion: A novel approach to stroke prevention in patients with atrial fibrillation. Stroke. 2004;35(6):1519–22. https://doi.org/10.1161/01. STR.0000128883.89984.52
33. He J, Whelton PK, Vu B, Klag MJ. Aspirin and risk of hemorrhagic stroke: A meta-analysis of randomized controlled trials. JAMA. 1998; 280(22):1930–5. https://doi.org/10.1001/jama. 280.22.1930
34. Hart RG, Boop BS, Anderson DC. Oral antico-agulants and intracranial hemorrhage. Facts and hypotheses. Stroke. 1995;26(8):1471–7. https:// doi.org/10.1161/01.STR.26.8.1471
35. Sjalander A, Engstrom G, Berntorp E, Svensson P. Risk of haemorrhagic stroke in patients with  oral anticoagulation compared with the  general population. J Intern Med. 2003;254(5):434–8. https://doi.org/10.1046/j. 1365-2796.2003.01209.x
36. Hart RG, Tonarelli SB, Pearce LA. Avoiding central nervous system bleeding during anti-thrombotic therapy: Recent data and ideas. Stroke. 2005;36(7):1588–93. https://doi.org/10. 1161/01.STR.0000170642.39876.f2
37. Gorter JW. Major bleeding during anticoagula-tion after cerebral ischemia: Patterns and risk factors. Stroke Prevention In Reversible Ischemia Trial (SPIRIT). European Atrial Fibrillation Trial (EAFT) study groups. Neurology. 1999;53(6):1319–27. https://doi.org/10.1212/ WNL.53.6.1319
38. Aboyans V, Ricco JB, Bartelink ML, et al. [2017 ESC guidelines on the diagnosis and treatment of peripheral arterial diseases, in collaboration with the European Society for Vascular Surgery (ESVS)]. Kardiol Pol. 2017;75(11):1065–160.
39. 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

40. Connolly SJ, Eikelboom J, Joyner C, et al. Apixaban in patients with atrial fibrillation. N Engl J Med. 2011;364(9):806–17. https://doi. org/10.1056/NEJMoa1007432
41. Flaker GC, Eikelboom JW, Shestakovska O, et al. Bleeding during treatment with aspirin versus apixaban in patients with atrial fibrillation unsuitable for warfarIn: The apixaban versus acetylsalicylic acid to prevent stroke in atrial fibrillation patients who have failed or are unsuit-able for vitamin K antagonist treatment (AVERROES) trial. Stroke. 2012;43(12):3291–7. https://doi.org/10.1161/STROKEAHA. 112.664144
42. Connolly SJ, Ezekowitz MD, Yusuf S, et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med. 2009;361(12):1139–51. https://doi.org/10.1056/NEJMoa0905561
43. Connolly SJ, Ezekowitz MD, Yusuf S, Reilly PA, Wallentin L. Newly identified events in the RE-LY trial. N Engl J Med. 2010;363(19):1875–6. https:// doi.org/10.1056/NEJMc1007378
44. 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
45. Claassen DO, Kazemi N, Zubkov AY, Wijdicks
EF, Rabinstein AA. Restarting anticoagulation therapy after warfarin-associated intracerebral hemorrhage. Arch Neurol. 2008;65(10):1313–18. https://doi.org/10.1001/archneur.65.10.1313
46. Molina CA, Selim MH. The dilemma of resuming anticoagulation after intracranial hem-orrhage: Little evidence facing big fears. Stroke. 2011;42(12):3665–6. https://doi.org/10.1161/ STROKEAHA.111.631689
47. Steiner T. Resumption of oral anticoagulation after warfarin-associated intracerebral hemor-rhage: Yes. Stroke. 2011;42(12):3661–2. https:// doi.org/10.1161/STROKEAHA.111.621797
48. Schulman S. Resumption of oral anticoagula-tion after warfarin-associated intracerebral hem-orrhage: No. Stroke. 2011;42(12):3663–4. https:// doi.org/10.1161/STROKEAHA.111.621813
49. Lansberg MG, O’Donnell MJ, Khatri P, et al. Antithrombotic and thrombolytic therapy for ischemic stroke: Antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians evidence-based  clinical practice guidelines. Chest. 2012;141(2  Suppl):e601S–36S. https://doi.org/ 10.1378/chest.141.4.1129b
50. Zia E, Engstrom G, Svensson PJ, Norrving B, Pessah-Rasmussen H. Three-year survival and stroke recurrence rates in patients with primary intracerebral hemorrhage. Stroke. 2009;40(11): 3567–73. https://doi.org/10.1161/STROKE AHA.109.556324
51. Saloheimo P, Juvela S, Hillbom M. Use of aspi-rin, epistaxis, and untreated hypertension as risk factors for primary intracerebral hemorrhage in  middle-aged and elderly people. Stroke. 2001;32(2):399–404. https://doi.org/10.1161/01. STR.32.2.399
52. Bae H, Jeong D, Doh J, Lee K, Yun I, Byun B. Recurrence of bleeding in patients with hyper-tensive intracerebral hemorrhage. Cerebrovasc Dis. 1999;9(2):102–8. https://doi.org/10.1159/ 000015906
53. Passero S, Burgalassi L, D'Andrea P, Battistini N. Recurrence of bleeding in patients with pri-mary intracerebral hemorrhage. Stroke. 1995; 26(7):1189–92. https://doi.org/10.1161/01.STR. 26.7.1189
54. Meretoja A, Strbian D, Putaala J, et al. SMASH-U: A proposal for etiologic classifica-tion of intracerebral hemorrhage. Stroke. 2012;43(10):2592–7. https://doi.org/10.1161/ STROKEAHA.112.661603
55. Huttner HB, Schellinger PD, Hartmann M, et al. Hematoma growth and outcome in treated neurocritical care patients with intracerebral hemorrhage related to oral anticoagulant ther-apy: Comparison of acute treatment strategies using Vitamin K, fresh frozen plasma, and prothrombin complex concentrates. Stroke. 2006;37(6):1465–70. https://doi.org/10.1161/01. STR.0000221786.81354.d6
56. Yasaka M, Minematsu K, Naritomi H, Sakata T, Yamaguchi T. Predisposing factors for enlarge-ment of intracerebral hemorrhage in patients treated with warfarin. Thromb Haemost. 2003;89(2):278–83. https://doi.org/10.1055/ s-0037-1613443
57. Bjorck S, Palaszewski B, Friberg L, Bergfeldt L. Atrial fibrillation, stroke risk, and warfarin ther-apy revisited: A population-based study. Stroke. 2013;44(11):3103–8. https://doi.org/10.1161/ STROKEAHA.113.002329
58. Haim M, Hoshen M, Reges O, Rabi Y, Balicer R, Leibowitz M. Prospective national study of the prevalence, incidence, manage-ment and outcome of a large contemporary cohort of patients with incident non-valvular atrial fibrillation. J Am Heart Assoc. 2015;4(1):e001486. https://doi.org/10.1161/ JAHA.114.001486
59. Gage BF, Waterman AD, Shannon W, Boechler M, Rich MW, Radford MJ. Validation of clinical classification schemes for predicting stroke: Results from the National Registry of Atrial Fibrillation. JAMA. 2001;285(22):2864–70. https://doi.org/10.1001/jama.285.22.2864
60. Hart RG, Pearce LA, Aguilar MI. Meta-analysis: Antithrombotic therapy to prevent stroke in patients who have nonvalvular atrial fibrillation. Ann Intern Med. 2007;146(12):857–67. https://doi. org/10.7326/0003-4819-146-12-200706190-00007
61. Pisters R, Lane DA, Nieuwlaat R, de Vos CB, Crijns HJ, Lip GY. A novel user-friendly score (HAS-BLED) to assess 1-year risk of major bleeding in patients with atrial fibrillation: The Euro Heart Survey. Chest. 2010;138(5):1093– 100. https://doi.org/10.1378/chest.10-0134
62. Gage BF, Yan Y, Milligan PE, et al. Clinical classi-fication schemes for predicting hemorrhage: Results from the National Registry of Atrial Fibrillation (NRAF). Am Heart J. 2006;151(3): 713–19. https://doi.org/10.1016/j.ahj.2005.04.017
63. Fang MC, Go AS, Chang Y, et al. A new risk scheme to predict warfarin-associated hemor-rhage: The ATRIA (Anticoagulation and Risk Factors in Atrial Fibrillation) Study. J Am Coll Cardiol. 2011;58(4):395–401. https://doi.org/10. 1016/j.jacc.2011.03.031
64. O'Brien EC, Simon DN, Thomas LE, et al. The ORBIT bleeding score: A simple bedside score to  assess bleeding risk in atrial fibrillation. Eur  Heart J. 2015;36(46):3258–64. https://doi. org/10.1093/eurheartj/ehv476
65. Poli D, Antonucci E, Dentali F, et al. Recurrence of ICH after resumption of anticoagulation with VK antagonists: CHIRONE study. Neurology. 2014;82(12):1020–6. https://doi.org/10.1212/ WNL.0000000000000245
66. Eckman MH, Rosand J, Knudsen KA, Singer DE, Greenberg SM. Can patients be anticoagu-lated after intracerebral hemorrhage? A decision analysis. Stroke. 2003;34(7):1710–16. https://doi. org/10.1161/01.STR.0000078311.18928.16
67. Gorelick PB, Weisman SM. Risk of hemorrhagic stroke with aspirin use: An update. Stroke. 2005;36(8):1801–7. https://doi.org/10.1161/01. STR.0000174189.81153.85
68. Hart RG, Halperin JL, McBride R, Benavente O, Man-Son-Hing M, Kronmal RA. Aspirin for the primary prevention of stroke and other major vascular events: Meta-analysis and hypotheses. Arch Neurol. 2000;57(3):326–32. https://doi. org/10.1001/archneur.57.3.326
69. Hart RG, Benavente O, Pearce LA. Increased risk of intracranial hemorrhage when aspirin is combined with warfarIn: A meta-analysis and hypothesis. Cerebrovasc Dis. 1999;9(4):215–17. https://doi.org/10.1159/000015958
70. van Walraven C, Hart RG, Singer DE, et al. Oral anticoagulants vs aspirin in nonvalvular atrial fibrillation: An individual patient meta-analysis. JAMA. 2002;288(19):2441–8. https://doi.org/10. 1001/jama.288.19.2441
71. Cappelleri JC, Fiore LD, Brophy MT, Deykin D, Lau J. Efficacy and safety of combined anticoag-ulant and antiplatelet therapy versus anticoagu-lant monotherapy after mechanical heart-valve replacement: A meta analysis. Am Heart J. 1995;130(3 Pt 1):547–52. https://doi.org/10.1016/ 0002-8703(95)90365-8
72. Pezzini A, Grassi M, Paciaroni M, et al. Antithrombotic medications and the etiology of intracerebral hemorrhage: MUCH-Italy. Neurology. 2014;82(6):529–35. https://doi. org/10.1212/WNL.0000000000000108
73. Sacco S, Marini C, Toni D, Olivieri L, Carolei A. Incidence and 10-year survival of intracerebral hemorrhage in a population-based registry. Stroke. 2009;40(2):394–9. https://doi.org/10. 1161/STROKEAHA.108.523209
74. 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 ran-domised trials. Lancet. 2014;383(9921):955–62. https://doi.org/10.1016/S0140-6736(13)62343-0
75. Chatterjee S, Sardar P, Biondi-Zoccai G, Kumbhani DJ. New oral anticoagulants and the risk of intracranial hemorrhage: Traditional and Bayesian meta-analysis and mixed treatment comparison of randomized trials of new oral anticoagulants in atrial fibrillation. JAMA Neurol. 2013;70(12):1486–90. https://doi.org/10. 1001/jamaneurol.2013.4021
76. Ogata T, Yasaka M, Wakugawa Y, Inoue T, Ibayashi S, Okada Y. Deep venous thrombosis after acute intracerebral hemorrhage. J Neurol Sci. 2008;272(1–2):83–6. https://doi.org/10.1016/ j.jns.2008.04.032
77. Skaf E, Stein PD, Beemath A, Sanchez J, Bustamante MA, Olson RE. Venous thrombo-embolism in patients with ischemic and hemor-rhagic stroke. Am J Cardiol. 2005;96(12):1731–3. https://doi.org/10.1016/j.amjcard.2005.07.097
78. Christensen MC, Dawson J, Vincent C. Risk of thromboembolic complications after intracere-bral hemorrhage according to ethnicity. Adv Ther. 2008;25(9):831–41. https://doi.org/10.1007/ s12325-008-0092-0
79. Orken DN, Kenangil G, Ozkurt H, et al. Prevention of deep venous thrombosis and pulmonary embo-lism in patients with acute intracerebral hemor-rhage. Neurologist. 2009;15(6):329–31. https://doi. org/10.1097/NRL.0b013e3181a93bac
80. Maramattom BV, Weigand S, Reinalda M, Wijdicks EF, Manno EM. Pulmonary complica-tions after intracerebral hemorrhage. Neurocrit Care. 2006;5(2):115–19. https://doi.org/10.1385/ NCC:5:2:115
81. Goldstein JN, Fazen LE, Wendell L, et al. Risk of thromboembolism following acute intracere-bral hemorrhage. Neurocrit Care. 2009;10(1):28– 34. https://doi.org/10.1007/s12028-008-9134-3
82. Agnelli G, Piovella F, Buoncristiani P, et al. Enoxaparin plus compression stockings compared with compression stockings alone in the prevention of venous thromboembolism after elective neuro-surgery. N Engl J Med. 1998;339(2):80–5. https:// doi.org/10.1056/NEJM199807093390204
83. Iorio A, Agnelli G. Low-molecular-weight and unfractionated heparin for prevention of venous thromboembolism in neurosurgery: A meta-anal-ysis. Arch Intern Med. 2000;160(15):2327–32. https://doi.org/10.1001/archinte.160.15.2327
84. Dickinson LD, Miller LD, Patel CP, Gupta SK. Enoxaparin increases the incidence of postopera-tive intracranial hemorrhage when initiated pre-operatively for deep venous thrombosis prophylaxis in patients with brain tumors. Neurosurgery. 1998;43(5):1074–81. https://doi. org/10.1097/00006123-199811000-00039
85. Fukamachi A, Koizumi H, Nagaseki Y, Nukui H. Postoperative extradural hemato-mas: Computed tomographic survey of 1105 intracranial operations. Neurosurgery. 1986; 19(4): 589–93. https://doi.org/10.1227/00006 123-198610000-00013
86. Geerts WH, Heit JA, Clagett GP, et al. Prevention of venous thromboembolism. Chest. 2001;119(1 Suppl):132S–75S. https://doi.org/10.1378/chest. 119.1_suppl.132S
87. Norwood SH, McAuley CE, Berne JD, et al. Prospective evaluation of the safety of enoxaparin prophylaxis for venous thromboembolism in patients with intracranial hemorrhagic  injuries. Arch Surg. 2002;137(6):696–701; discussion 701– 2. https://doi.org/10.1001/archsurg.137.6.696
88. Morgenstern LB, Hemphill JC3rd, Anderson C, et al. Guidelines for the management of spontaneous intracerebral hemorrhage: A guide-line for healthcare professionals from the American Heart Association/American Stroke Association. Stroke. 2010;41(9):2108–29. https:// doi.org/10.1161/STR.0b013e3181ec611b
89. Broderick J, Connolly S, Feldmann E, et al. Guidelines for the management of spontaneous intracerebral hemorrhage in adults: 2007 update: A guideline from the American Heart Association/ American Stroke Association Stroke Council, High Blood Pressure Research Council, and the Quality of Care and Outcomes in Research Interdisciplinary Working Group. Stroke. 2007;38(6):2001–23. https://doi.org/10.1161/STROKEAHA.107.183689
90. Cannegieter SC, Rosendaal FR, Briet E. Thromboembolic and bleeding complications in patients with mechanical heart valve prostheses. Circulation. 1994;89(2):635–41. https://doi. org/10.1161/01.CIR.89.2.635
91. Cannegieter SC, van der Meer FJ, Briet E, Rosendaal FR. Warfarin and aspirin after  heart-valve replacement. N Engl J Med. 1994;330(7):507–8; author reply 8–9. https://doi. org/10.1056/NEJM199402173300717
92. De Vleeschouwer S, Van Calenbergh F, van Loon J, Nuttin B, Goffin J, Plets C. Risk analysis of thrombo-embolic and recurrent bleeding events in the management of intracranial haem-orrhage due to oral anticoagulation. Acta Chir Belg. 2005;105(3):268–74. https://doi.org/10.108 0/00015458.2005.11679715
93. Hawryluk GW, Austin JW, Furlan JC, Lee JB, O'Kelly C, Fehlings MG. Management of antico-agulation following central nervous system hem-orrhage in patients with high thromboembolic risk. J Thromb Haemost. 2010;8(7):1500–8. https://doi.org/10.1111/j.1538-7836.2010.03882.x
94. Yung D, Kapral MK, Asllani E, Fang J, Lee DS. Reinitiation of anticoagulation after warfa-rin-associated intracranial hemorrhage and mor-tality risk: The Best Practice for Reinitiating Anticoagulation Therapy After Intracranial Bleeding (BRAIN) study. Can J Cardiol. 2012;28(1):33–9. https://doi.org/10.1016/j. cjca.2011.10.002
95. Kuramatsu JB, Gerner ST, Schellinger PD, et al. Anticoagulant reversal, blood pressure levels, and anticoagulant resumption in patients with anticoagulation-related intracerebral hemor-rhage. JAMA. 2015;313(8):824–36. https://doi. org/10.1016/j.cjca.2011.10.002
96. 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(3):209– 14. https://doi.org/10.1007/s004150050565
97. Gathier CS, Algra A, Rinkel GJ, van der Worp HB. Long-term outcome after anticoagula-tion-associated intracerebral haemorrhage with or without restarting antithrombotic therapy. Cerebrovasc Dis. 2013;36(1):33–7. https://doi. org/10.1159/000351151
98. Vahanian A, Alfieri O, Andreotti F, et al. Guidelines on the management of valvular heart disease (version 2012): The Joint Task Force on the Management of Valvular Heart Disease of  the European Society of Cardiology (ESC) and the European Association for Cardio-Thoracic Surgery (EACTS). Eur J Cardiothorac Surg. 2012;42(4):S1–44.
99. Aguilar MI, Hart RG, Kase CS, et al. Treatment of warfarin-associated intracerebral hemor-rhage: Literature review and expert opinion. Mayo Clin Proc. 2007;82(1):82–92. https://doi. org/10.1016/S0025-6196(11)60970-1
100. Furie KL, Kasner SE, Adams RJ, et al. Guidelines for the prevention of stroke in patients with stroke or transient ischemic attack: A guideline for healthcare profession-als from the American Heart Association/ American Stroke Association. Stroke. 2011;42(1):227–76. https://doi.org/10.1161/STR. 0b013e3181f7d043
101. Punthakee X, Doobay J, Anand SS. Oral-anticoagulant-related intracerebral hemorrhage. Thromb Res. 2002;108(1):31–6. https://doi. org/10.1016/S0049-3848(02)00398-5
102. Phan TG, Koh M, Wijdicks EF. Safety of discontinuation of anticoagulation in patients with intracranial hemorrhage at high thrombo-embolic risk. Arch Neurol. 2000;57(12):1710–13. https://doi.org/10.1001/archneur.57.12.1710
103. Wijdicks EF, Schievink WI, Brown RD, Mullany CJ. The dilemma of discontinuation of anticoag-ulation therapy for patients with intracranial hemorrhage and mechanical heart valves. Neurosurgery. 1998;42(4):769–73. https://doi. org/10.1097/00006123-199804000-00053
104. Estol CJ, Kase CS. Need for continued use of anti-coagulants after intracerebral hemorrhage. Curr Treat Options Cardiovasc Med. 2003;5(3):201–9. https://doi.org/10.1007/s11936-003-0004-1
105. Chandra D, Gupta A, Grover V, Kumar Gupta V. When should you restart anticoagulation in patients who suffer an intracranial bleed who also have a prosthetic valve? Interact Cardiovasc Thorac Surg. 2013;16(4):520–3. https://doi. org/10.1093/icvts/ivs545
106. Passero S, Rocchi R, Rossi S, Ulivelli M, Vatti G. Seizures after spontaneous supratentorial intracerebral hemorrhage. Epilepsia. 2002;43(10): 1175–80. https://doi.org/10.1046/j.1528-1157. 2002.00302.x
107. Morgan T, Zuccarello M, Narayan R, Keyl P, Lane K, Hanley D. Preliminary findings of the minimally-invasive surgery plus rtPA for intrace-rebral hemorrhage evacuation (MISTIE) clinical trial. Acta Neurochir Suppl. 2008;105:147–51. https://doi.org/10.1007/978-3-211-09469-3_30
108. Nishihara T, Nagata K, Tanaka S, et al. Newly developed endoscopic instruments for the removal of intracerebral hematoma. Neurocrit Care. 2005;2(1):67–74. https://doi.org/10.1385/ NCC:2:1:067
109. Vespa P, McArthur D, Miller C, et al. Frameless stereotactic aspiration and thrombolysis of deep intracerebral hemorrhage is associated with reduction of hemorrhage volume and neurologi-cal improvement. Neurocrit Care. 2005;2(3):274– 81. https://doi.org/10.1385/NCC:2:3:274
110. Mendelow AD, Gregson BA, Fernandes HM, et al. Early surgery versus initial conservative treatment in patients with spontaneous supratentorial intracerebral haematomas in the International Surgical Trial in Intracerebral Haemorrhage (STICH): A randomised trial. Lancet. 2005;365(9457):387–97. https://doi. org/10.1016/S0140-6736(05)70233-6
111. Broderick JP, Brott T, Tomsick T, Huster G, Miller R. The risk of subarachnoid and intrace-rebral hemorrhages in blacks as compared with whites. N Engl J Med. 1992;326(11):733–6. https://doi.org/10.1056/NEJM199203123261103
112. Broderick JP, Brott TG, Duldner JE, Tomsick T, Huster G. Volume of intracerebral hemorrhage. A powerful and easy-to-use predictor of 30-day mortality. Stroke. 1993;24(7):987–93. https://doi. org/10.1161/01.STR.24.7.987
113. Hemphill JC, 3rd, Bonovich DC, Besmertis L, Manley GT, Johnston SC. The ICH score: A simple, reliable grading scale for intracerebral hemorrhage. Stroke. 2001;32(4):891–7. https:// doi.org/10.1161/01.STR.32.4.891
114. Hemphill JC, 3rd, Farrant M, Neill TA, Jr. Prospective validation of the ICH Score for 12-month functional outcome. Neurology. 2009;73(14):1088–94. https://doi.org/10.1212/ WNL.0b013e3181b8b332
115. Rost NS, Smith EE, Chang Y, et al. Prediction of  functional outcome in patients with primary intracerebral hemorrhage: The FUNC score. Stroke. 2008;39(8):2304–9. https://doi. org/10.1161/STROKEAHA.107.512202
116. Clarke JL, Johnston SC, Farrant M, Bernstein R, Tong D, Hemphill JC 3rd, . External validation of the ICH score. Neurocrit Care. 2004;1(1):53–60. https://doi.org/10.1385/NCC:1:1:53
117. Garrett JS, Zarghouni M, Layton KF, Graybeal D, Daoud YA. Validation of clinical prediction scores in patients with primary intracerebral hemorrhage. Neurocrit Care. 2013;19(3):329–35. https://doi.org/10.1007/s12028-013-9926-y
118. Van Asch CJ, Velthuis BK, Greving JP, et al. External validation of the secondary intracerebral hemorrhage score in The Netherlands. Stroke. 2013;44(10):2904–6. https:// doi.org/10.1161/STROKEAHA.113.002386
119. Castellanos M, Leira R, Tejada J, Gil-Peralta A, Davalos A, Castillo J. Predictors of good out-come in medium to large spontaneous supraten-torial intracerebral haemorrhages. J Neurol Neurosurg Psychiatry. 2005;76(5):691–5. https:// doi.org/10.1136/jnnp.2004.044347
120. Kazui S, Naritomi H, Yamamoto H, Sawada T, Yamaguchi T. Enlargement of spontaneous intracerebral hemorrhage. Incidence and time course. Stroke. 1996;27(10):1783–7. https://doi. org/10.1161/01.STR.27.10.1783
121. Zazulia AR, Diringer MN, Derdeyn CP, Powers WJ. Progression of mass effect after intracerebral hemorrhage. Stroke. 1999;30(6):1167–73. https:// doi.org/10.1161/01.STR.30.6.1167
122. Mayer SA. Ultra-early hemostatic therapy for intracerebral hemorrhage. Stroke. 2003;34(1):224–9. https://doi.org/10.1161/01.STR.0000046 458.67968.E4
123. Burness CB. Idarucizumab: First global approval. Drugs. 2015;75(18):2155–61. https:// doi.org/10.1007/s40265-015-0508-5
124. Dalal J, Bhave A, Chaudhry G, Rana P. Reversal agents for NOACs: Connecting the dots. Indian Heart J. 2016;68(4):559–63. https://doi.org/10. 1016/j.ihj.2015.11.023
125. Connolly SJ, Gibson CM, Crowther M. Andexanet alfa for factor Xa inhibitor reversal. N Engl J Med. 2016;375(25):2499–500. https:// doi.org/10.1056/NEJMc1613270
126. Qureshi AI, Ezzeddine MA, Nasar A, et al. Prevalence of elevated blood pressure in 563,704 adult patients with stroke presenting to the ED in the United States. Am J Emerg Med. 2007;25(1):32– 8. https://doi.org/10.1016/j.ajem.2006.07.008
127. Zhang Y, Reilly KH, Tong W, et al. Blood pressure and clinical outcome among patients with acute stroke in Inner Mongolia, China. J  Hypertens. 2008;26(7):1446–52. https://doi. org/10.1097/HJH.0b013e328300a24a
128. Rodriguez-Luna D, Pineiro S, Rubiera M, et al. Impact of blood pressure changes and course on hematoma growth in acute intracerebral hemor-rhage. Eur J Neurol. 2013;20(9):1277–83. https:// doi.org/10.1111/ene.12180
129. Sakamoto Y, Koga M, Yamagami H, et al. Systolic blood pressure after intravenous antihy-pertensive treatment and clinical outcomes in hyperacute intracerebral hemorrhage: The stroke acute management with urgent risk-factor assess-ment and improvement-intracerebral hemor-rhage study. Stroke. 2013;44(7):1846–51. https:// doi.org/10.1161/STROKEAHA.113.001212
130. Nielsen PB, Larsen TB, Skjoth F, Gorst-Rasmussen A, Rasmussen LH, Lip GY. Restarting anticoagulant treatment after intracranial hemor-rhage 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
131. Group ESD, Steffel J, Roldan-Schilling V, 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
132. Kirchhof P, Benussi S, Kotecha D, et al. 2016 ESC Guidelines for the management of atrial fibrillation developed in collaboration with EACTS. The task force for the 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 endorsed by the European Stroke Organisation (ESO). Europace; 2016. https://doi.org/10.1093/eurheartj/ehw210
133. Ananthasubramaniam K, Beattie JN, Rosman HS, Jayam V, Borzak S. How safely and for how long can warfarin therapy be withheld in pros-thetic heart valve patients hospitalized with a major hemorrhage? Chest. 2001;119(2):478–84. https://doi.org/10.1378/chest.119.2.478