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Published in: Current Cardiology Reports 5/2014

01-05-2014 | New Therapies for Cardiovascular Disease (KW Mahaffey, Section Editor)

Intracranial Hemorrhage and Novel Anticoagulants for Atrial Fibrillation: What Have We Learned?

Author: Graeme J. Hankey

Published in: Current Cardiology Reports | Issue 5/2014

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Abstract

Intracranial hemorrhage (ICH) affects 0.2-0.5 % of atrial fibrillation (AF) patients taking a novel oral anticoagulant (NOAC) each year. About two thirds of ICHs are intracerebral and one quarter subdural. The 30-day case fatality of NOAC-associated ICH was similar to that of warfarin-associated ICH in two trials. Consistent predictors of ICH are increasing age, a history of prior stroke or TIA, and concomitant use of an antiplatelet drug. Compared to warfarin, the NOACs significantly reduce the risk of ICH by half (risk ratio = 0.44; 95 % CI: 0.37 to 0.51). Compared to aspirin, apixaban has a similar risk of ICH (risk ratio = 0.84; 95 % CI, 0.38 to 1.87). Current treatments for NOAC-associated ICH include nonactivated and activated prothrombin complex concentrate, which reverse the anticoagulant effects of the NOACs, but their effects on bleeding and patient outcome are not known. Future treatments for NOAC-associated ICH promise to include specific antidotes to dabigatran (e.g., aDabi-Fab, PER977) and factor Xa inhibitors (e.g., r-Antidote PRT064445, PER977).
Literature
1.
go back to reference Fang MC, Go AS, Chang Y, Hylek EM, Henault LE, Jensvold NG, et al. Death and disability from warfarin-associated intracranial and extracranial hemorrhages. Am J Med. 2007;120:700–5.PubMedCentralPubMedCrossRef Fang MC, Go AS, Chang Y, Hylek EM, Henault LE, Jensvold NG, et al. Death and disability from warfarin-associated intracranial and extracranial hemorrhages. Am J Med. 2007;120:700–5.PubMedCentralPubMedCrossRef
2.
go back to reference Connolly SJ, Ezekowitz MD, Yusuf S, Eikelboom J, Oldgren J, Parekh A, et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med. 2009;361:1139–51.PubMedCrossRef Connolly SJ, Ezekowitz MD, Yusuf S, Eikelboom J, Oldgren J, Parekh A, et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med. 2009;361:1139–51.PubMedCrossRef
3.
go back to reference Patel MR, Mahaffey KW, Garg J, Pan G, Singer D, Hacke W, et al. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med. 2011;365:883–91.PubMedCrossRef Patel MR, Mahaffey KW, Garg J, Pan G, Singer D, Hacke W, et al. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med. 2011;365:883–91.PubMedCrossRef
4.
go back to reference Granger CB, Alexander JH, McMurray JJV, Lopes RD, Hylek EH, Hanna M, et al. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med. 2011;365:981–92.PubMedCrossRef Granger CB, Alexander JH, McMurray JJV, Lopes RD, Hylek EH, Hanna M, et al. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med. 2011;365:981–92.PubMedCrossRef
5.
go back to reference Connolly SJ, Eikelboom J, Joyner C, Diener HC, Hart R, Golitsyn S, et al. Apixaban in patients with atrial fibrillation. N Engl J Med. 2011;364:806–17.PubMedCrossRef Connolly SJ, Eikelboom J, Joyner C, Diener HC, Hart R, Golitsyn S, et al. Apixaban in patients with atrial fibrillation. N Engl J Med. 2011;364:806–17.PubMedCrossRef
6.
go back to reference Flaker GC, Eikelboom JW, Shestakovska O, Connolly SJ, Kaatz S, Budaj A, 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 unsuitable for vitamin K antagonist treatment (AVERROES) trial. Stroke. 2012;43:3291–7.PubMedCrossRef Flaker GC, Eikelboom JW, Shestakovska O, Connolly SJ, Kaatz S, Budaj A, 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 unsuitable for vitamin K antagonist treatment (AVERROES) trial. Stroke. 2012;43:3291–7.PubMedCrossRef
7.
go back to reference Ogawa S, Shinohara Y, Kanmuri K. Safety and efficacy of the oral direct factor xa inhibitor apixaban in Japanese patients with non-valvular atrial fibrillation. -The ARISTOTLE-J study. Circ J. 2011;75:1852–9.PubMedCrossRef Ogawa S, Shinohara Y, Kanmuri K. Safety and efficacy of the oral direct factor xa inhibitor apixaban in Japanese patients with non-valvular atrial fibrillation. -The ARISTOTLE-J study. Circ J. 2011;75:1852–9.PubMedCrossRef
8.
go back to reference Hori M, Matsumoto M, Tanahashi N, Momomura S, Uchiyama S, Goto S, et al. Rivaroxaban vs. warfarin in Japanese patients with atrial fibrillation – the J-ROCKET AF study. Circ J. 2012;76:2104–11.PubMedCrossRef Hori M, Matsumoto M, Tanahashi N, Momomura S, Uchiyama S, Goto S, et al. Rivaroxaban vs. warfarin in Japanese patients with atrial fibrillation – the J-ROCKET AF study. Circ J. 2012;76:2104–11.PubMedCrossRef
9.
go back to reference Giugliano RP, Ruff CT, Braunwald E, Murphy SA, Wiviott SD, Halperin JL, et al. Edoxaban versus warfarin in patients with atrial fibrillation. N Engl J Med. 2013;369:2093–2104. doi:10.1056/NEJMoa1310907. Giugliano RP, Ruff CT, Braunwald E, Murphy SA, Wiviott SD, Halperin JL, et al. Edoxaban versus warfarin in patients with atrial fibrillation. N Engl J Med. 2013;369:2093–2104. doi:10.​1056/​NEJMoa1310907.
10.
go back to reference Ruff CT, Giugliano RP, Braunwald E, Hoffman EB, Deenadayalu N, Ezekowitz MD, 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. 2013. doi:10.1016/S0140-6736(13)62343-0.PubMed Ruff CT, Giugliano RP, Braunwald E, Hoffman EB, Deenadayalu N, Ezekowitz MD, 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. 2013. doi:10.​1016/​S0140-6736(13)62343-0.PubMed
11.•
go back to reference Connolly SJ, Wallentin L, Ezekowitz MD, et al. The long-term multicenter observational study of dabigatran treatment in patients with atrial fibrillation (RELY-ABLE) study. Circulation. 2013;128:237–43. Longer-term follow-up study of rates of ICH among patients assigned dabigatran in the RE-LY trial who continued to take dabigatran for a further 2.3 years (median) after the last RE-LY trial visit.PubMedCrossRef Connolly SJ, Wallentin L, Ezekowitz MD, et al. The long-term multicenter observational study of dabigatran treatment in patients with atrial fibrillation (RELY-ABLE) study. Circulation. 2013;128:237–43. Longer-term follow-up study of rates of ICH among patients assigned dabigatran in the RE-LY trial who continued to take dabigatran for a further 2.3 years (median) after the last RE-LY trial visit.PubMedCrossRef
12.•
go back to reference Larsen TB, Rasmussen LH, Skjøth F, et al. Efficacy and safety of dabigatran etexilate and warfarin in “real-world” patients with atrial fibrillation: a prospective nationwide cohort study. J Am Coll Cardiol. 2013;61:2264–73. Recent prospective nationwide cohort study in Denmark showing that in “everyday clinical practice” the rates of ICH with dabigatran (both doses) were lower than the rates of ICH with warfarin. The findings support the external validity (generalisabilty) in “the real world: of the results observed in the large phase III clinical trials of NOACs vs warfarin.PubMedCrossRef Larsen TB, Rasmussen LH, Skjøth F, et al. Efficacy and safety of dabigatran etexilate and warfarin in “real-world” patients with atrial fibrillation: a prospective nationwide cohort study. J Am Coll Cardiol. 2013;61:2264–73. Recent prospective nationwide cohort study in Denmark showing that in “everyday clinical practice” the rates of ICH with dabigatran (both doses) were lower than the rates of ICH with warfarin. The findings support the external validity (generalisabilty) in “the real world: of the results observed in the large phase III clinical trials of NOACs vs warfarin.PubMedCrossRef
13.
go back to reference Southworth MR, Reichman ME, Unger EF. Dabigatran and postmarketing reports of bleeding. N Engl J Med. 2013;368:1272–4.PubMedCrossRef Southworth MR, Reichman ME, Unger EF. Dabigatran and postmarketing reports of bleeding. N Engl J Med. 2013;368:1272–4.PubMedCrossRef
14.
go back to reference Al-Shahi Salman R, Labovitz DL, Stapf C. Spontaneous intracerebral haemorrhage. BMJ. 2009;339:b2586.PubMedCrossRef Al-Shahi Salman R, Labovitz DL, Stapf C. Spontaneous intracerebral haemorrhage. BMJ. 2009;339:b2586.PubMedCrossRef
15.••
go back to reference Hart RG, Diener HC, Yang S, Connolly SJ, Wallentin L, Reilly PA, et al. Intracranial hemorrhage in atrial fibrillation patients during anticoagulation with warfarin or dabigatran: the RE-LY trial. Stroke. 2012;43:1511–7. A detailed analysis of ICH in the RE-LY trial cohort showing that the clinical spectrum of ICH was similar for patients given warfarin and dabigatran, the absolute rates of ICH at all sites and both fatal and traumatic ICHs were lower with dabigatran than with warfarin, and the most important modifiable independent risk factor for ICH was concomitant aspirin use.PubMedCrossRef Hart RG, Diener HC, Yang S, Connolly SJ, Wallentin L, Reilly PA, et al. Intracranial hemorrhage in atrial fibrillation patients during anticoagulation with warfarin or dabigatran: the RE-LY trial. Stroke. 2012;43:1511–7. A detailed analysis of ICH in the RE-LY trial cohort showing that the clinical spectrum of ICH was similar for patients given warfarin and dabigatran, the absolute rates of ICH at all sites and both fatal and traumatic ICHs were lower with dabigatran than with warfarin, and the most important modifiable independent risk factor for ICH was concomitant aspirin use.PubMedCrossRef
16.•
go back to reference Hankey GJ, Stevens SR, Piccini JP, Lokhnygina Y, Mahaffey KW, Halperin JL, et al. Predictors of intracranial hemorrhage among anticoagulated patients with atrial fibrillation: insights from the rivaroxaban once-daily oral direct factor Xa inhibition compared with vitamin K antagonism for prevention of stroke and embolism trial in atrial fibrillation (ROCKET AF). Stroke. 2012;43:A152. A detailed analysis of the rate, predictors, and outcome of ICH among the cohort of AF patients allocated rivaroxaban or warfarin in the ROCKET-AF trial. Hankey GJ, Stevens SR, Piccini JP, Lokhnygina Y, Mahaffey KW, Halperin JL, et al. Predictors of intracranial hemorrhage among anticoagulated patients with atrial fibrillation: insights from the rivaroxaban once-daily oral direct factor Xa inhibition compared with vitamin K antagonism for prevention of stroke and embolism trial in atrial fibrillation (ROCKET AF). Stroke. 2012;43:A152. A detailed analysis of the rate, predictors, and outcome of ICH among the cohort of AF patients allocated rivaroxaban or warfarin in the ROCKET-AF trial.
17.
go back to reference Lauer A, Pfeilschifter W, Schaffer CB, Lo EH, Foerch C. Intracerebral haemorrhage associated with antithrombotic treatment: translational insights from experimental studies. Lancet Neurol. 2013;12:394–405.PubMedCentralPubMedCrossRef Lauer A, Pfeilschifter W, Schaffer CB, Lo EH, Foerch C. Intracerebral haemorrhage associated with antithrombotic treatment: translational insights from experimental studies. Lancet Neurol. 2013;12:394–405.PubMedCentralPubMedCrossRef
18.
go back to reference Zhou W, Schwarting S, Illanes S, et al. Hemostatic therapy in experimental intracerebral hemorrhage associated with the direct thrombin inhibitor dabigatran. Stroke. 2011;42:3594–9.PubMedCrossRef Zhou W, Schwarting S, Illanes S, et al. Hemostatic therapy in experimental intracerebral hemorrhage associated with the direct thrombin inhibitor dabigatran. Stroke. 2011;42:3594–9.PubMedCrossRef
19.
go back to reference Zhou W, Zorn M, Nawroth P, Bütehorn U, Perzborn E, Heitmeier S, et al. Hemostatic therapy in experimental intracerebral hemorrhage associated with rivaroxaban. Stroke. 2013;44:771–8.PubMedCrossRef Zhou W, Zorn M, Nawroth P, Bütehorn U, Perzborn E, Heitmeier S, et al. Hemostatic therapy in experimental intracerebral hemorrhage associated with rivaroxaban. Stroke. 2013;44:771–8.PubMedCrossRef
20.
go back to reference Pfeilschifter W, Bohmann F, Baumgarten P, et al. Thrombolysis with recombinant tissue plasminogen activator under dabigatran anticoagulation in experimental stroke. Ann Neurol. 2012;71:624–33.PubMedCrossRef Pfeilschifter W, Bohmann F, Baumgarten P, et al. Thrombolysis with recombinant tissue plasminogen activator under dabigatran anticoagulation in experimental stroke. Ann Neurol. 2012;71:624–33.PubMedCrossRef
21.
go back to reference Sun L, Zhou W, Ploen R, Zorn M, Veltkamp R. Anticoagulation with dabigatran does not increase secondary intracerebral haemorrhage after thrombolysis in experimental cerebral ischaemia. Thromb Haemost. 2013;110:153–61.PubMedCrossRef Sun L, Zhou W, Ploen R, Zorn M, Veltkamp R. Anticoagulation with dabigatran does not increase secondary intracerebral haemorrhage after thrombolysis in experimental cerebral ischaemia. Thromb Haemost. 2013;110:153–61.PubMedCrossRef
22.
go back to reference Bohmann F, Mirceska A, Pfeilschifter J, et al. No influence of dabigatran anticoagulation on hemorrhagic transformation in an experimental model of ischemic stroke. PLoS One. 2012;7:e40804.PubMedCentralPubMedCrossRef Bohmann F, Mirceska A, Pfeilschifter J, et al. No influence of dabigatran anticoagulation on hemorrhagic transformation in an experimental model of ischemic stroke. PLoS One. 2012;7:e40804.PubMedCentralPubMedCrossRef
23.
go back to reference Gliem M, Hermsen D, van Rooijen N, Hartung HP, Jander S. Secondary intracerebral hemorrhage due to early initiation of oral anticoagulation after ischemic stroke: an experimental study in mice. Stroke. 2012;43:3352–7.PubMedCrossRef Gliem M, Hermsen D, van Rooijen N, Hartung HP, Jander S. Secondary intracerebral hemorrhage due to early initiation of oral anticoagulation after ischemic stroke: an experimental study in mice. Stroke. 2012;43:3352–7.PubMedCrossRef
24.
go back to reference Hylek EM, Singer DE. Risk factors for intracranial hemorrhage in outpatients taking warfarin. Ann Intern Med. 1994;120:897–902.PubMedCrossRef Hylek EM, Singer DE. Risk factors for intracranial hemorrhage in outpatients taking warfarin. Ann Intern Med. 1994;120:897–902.PubMedCrossRef
25.
go back to reference Sjoblom L, Hardemark HG, Lindgren A, Norrving B, Fahlen M, Samuelsson M, et al. Management and prognostic features of intracerebral hemorrhage during anticoagulant therapy: a Swedish multicenter study. Stroke. 2001;32:2567–74.PubMedCrossRef Sjoblom L, Hardemark HG, Lindgren A, Norrving B, Fahlen M, Samuelsson M, et al. Management and prognostic features of intracerebral hemorrhage during anticoagulant therapy: a Swedish multicenter study. Stroke. 2001;32:2567–74.PubMedCrossRef
26.
go back to reference Hylek EM, Evans-Molina C, Shea C, Henault LE, Regan S. Major hemorrhage and tolerability of warfarin in the first year of therapy among elderly patients with atrial fibrillation. Circulation. 2007;115:2689–96.PubMedCrossRef Hylek EM, Evans-Molina C, Shea C, Henault LE, Regan S. Major hemorrhage and tolerability of warfarin in the first year of therapy among elderly patients with atrial fibrillation. Circulation. 2007;115:2689–96.PubMedCrossRef
27.
go back to reference Poli D, Antonucci E, Grifoni E, Abbate R, Gensini GF, Prisco D. Bleeding risk during oral anticoagulation in atrial fibrillation patients older than 80 years. J Am Coll Cardiol. 2009;54:999–1002.PubMedCrossRef Poli D, Antonucci E, Grifoni E, Abbate R, Gensini GF, Prisco D. Bleeding risk during oral anticoagulation in atrial fibrillation patients older than 80 years. J Am Coll Cardiol. 2009;54:999–1002.PubMedCrossRef
28.
go back to reference Poli D, Antonucci E, Testa S, Tosetto A, Ageno W, Palareti G, et al. Bleeding risk in very old patients on vitamin K antagonist treatment: results of a prospective collaborative study on elderly patients followed by Italian Centres for Anticoagulation. Circulation. 2011;124:824–9.PubMedCrossRef Poli D, Antonucci E, Testa S, Tosetto A, Ageno W, Palareti G, et al. Bleeding risk in very old patients on vitamin K antagonist treatment: results of a prospective collaborative study on elderly patients followed by Italian Centres for Anticoagulation. Circulation. 2011;124:824–9.PubMedCrossRef
29.
go back to reference 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. doi:10.1001/jamaneurol.2013.4021.PubMed 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. doi:10.​1001/​jamaneurol.​2013.​4021.PubMed
31.
go back to reference Higgins JPT, Green S (editors). Cochrane handbook for systematic reviews of interventions Version 5.1.0 [updated March 2011]. The Cochrane Collaboration, 2011. Available from http://handbook.cochrane.org/ (accessed 27 Nov 2013). Higgins JPT, Green S (editors). Cochrane handbook for systematic reviews of interventions Version 5.1.0 [updated March 2011]. The Cochrane Collaboration, 2011. Available from http://​handbook.​cochrane.​org/​ (accessed 27 Nov 2013).
32.
go back to reference Sandercock P. The authors say: ‘the data are not so robust because of heterogeneity’ - so, how should I deal with this systematic review? Meta-analysis and the clinician. Cerebrovasc Dis. 2011;31:615–20.PubMedCrossRef Sandercock P. The authors say: ‘the data are not so robust because of heterogeneity’ - so, how should I deal with this systematic review? Meta-analysis and the clinician. Cerebrovasc Dis. 2011;31:615–20.PubMedCrossRef
33.
go back to reference Song F, Loke YK,Walsh T, Glenny AM, Eastwood AJ, Altman DG. Methodological problems in the use of indirect comparisons for evaluating healthcare interventions: survey of published systematic reviews. BMJ. 2009;338:b1147. doi:10.1136/bmj.b1147. Song F, Loke YK,Walsh T, Glenny AM, Eastwood AJ, Altman DG. Methodological problems in the use of indirect comparisons for evaluating healthcare interventions: survey of published systematic reviews. BMJ. 2009;338:b1147. doi:10.​1136/​bmj.​b1147.
35.
go back to reference Rosenberg RD, Aird WC. Vascular-bed–specific hemostasis and hypercoagulable states. N Engl J Med. 1999;340:1555–64.PubMedCrossRef Rosenberg RD, Aird WC. Vascular-bed–specific hemostasis and hypercoagulable states. N Engl J Med. 1999;340:1555–64.PubMedCrossRef
36.
go back to reference Fleck RA, Rao LV, Rapaport SI, Varki N. Localization of human tissue factor antigen by immunostaining with monospecific, polyclonal anti-human tissue factor antibody. Thromb Res. 1990;59:421–37.PubMedCrossRef Fleck RA, Rao LV, Rapaport SI, Varki N. Localization of human tissue factor antigen by immunostaining with monospecific, polyclonal anti-human tissue factor antibody. Thromb Res. 1990;59:421–37.PubMedCrossRef
38.
go back to reference Dale B, Eikelboom JW, Weitz JI, Young E, Paikin JS, Coppens M, et al. Dabigatran attenuates thrombin generation to a lesser extent than warfarin: could this explain their differential effects on intracranial hemorrhage and myocardial infarction? J Thromb Thrombolysis. 2013;35:295–301.PubMedCrossRef Dale B, Eikelboom JW, Weitz JI, Young E, Paikin JS, Coppens M, et al. Dabigatran attenuates thrombin generation to a lesser extent than warfarin: could this explain their differential effects on intracranial hemorrhage and myocardial infarction? J Thromb Thrombolysis. 2013;35:295–301.PubMedCrossRef
39.
40.
go back to reference Keep RF, Hua Y, Xi G. Intracerebral haemorrhage: mechanisms of injury and therapeutic targets. Lancet Neurol. 2012;11:720–31.PubMedCrossRef Keep RF, Hua Y, Xi G. Intracerebral haemorrhage: mechanisms of injury and therapeutic targets. Lancet Neurol. 2012;11:720–31.PubMedCrossRef
41.
go back to reference Morgenstern LB, Hemphill 3rd JC, Anderson C, Becker K, Broderick JP, Connolly Jr ES, et al. Guidelines for the management of spontaneous intracerebral hemorrhage: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke. 2010;41:2108–29.PubMedCrossRef Morgenstern LB, Hemphill 3rd JC, Anderson C, Becker K, Broderick JP, Connolly Jr ES, et al. Guidelines for the management of spontaneous intracerebral hemorrhage: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke. 2010;41:2108–29.PubMedCrossRef
42.
go back to reference Al-Shahi Salman R. Haemostatic drug therapies for acute spontaneous intracerebral haemorrhage. Cochrane Database Syst Rev. 2009;4, CD005951.PubMed Al-Shahi Salman R. Haemostatic drug therapies for acute spontaneous intracerebral haemorrhage. Cochrane Database Syst Rev. 2009;4, CD005951.PubMed
43.
go back to reference Anderson CS, Heeley E, Huang Y, Wang J, Stapf C, Delcourt C, et al. Rapid blood-pressure lowering in patients with acute intracerebral hemorrhage. N Engl J Med. 2013;368:2355–65.PubMedCrossRef Anderson CS, Heeley E, Huang Y, Wang J, Stapf C, Delcourt C, et al. Rapid blood-pressure lowering in patients with acute intracerebral hemorrhage. N Engl J Med. 2013;368:2355–65.PubMedCrossRef
44.
go back to reference Gregson BA, Broderick JP, Auer LM, Batjer H, Chen XC, Juvela S, et al. Individual patient data subgroup meta-analysis of surgery for spontaneous supratentorial intracerebral hemorrhage. Stroke. 2012;43:1496–504.PubMedCentralPubMedCrossRef Gregson BA, Broderick JP, Auer LM, Batjer H, Chen XC, Juvela S, et al. Individual patient data subgroup meta-analysis of surgery for spontaneous supratentorial intracerebral hemorrhage. Stroke. 2012;43:1496–504.PubMedCentralPubMedCrossRef
45.
go back to reference Mendelow AD, Gregson BA, Rowan EN, Murray GD, Gholkar A, Mitchell PM, et al. Early surgery versus initial conservative treatment in patients with spontaneous supratentorial lobar intracerebral haematomas (STICH II): a randomised trial. Lancet. 2013;382:397–408.PubMedCentralPubMedCrossRef Mendelow AD, Gregson BA, Rowan EN, Murray GD, Gholkar A, Mitchell PM, et al. Early surgery versus initial conservative treatment in patients with spontaneous supratentorial lobar intracerebral haematomas (STICH II): a randomised trial. Lancet. 2013;382:397–408.PubMedCentralPubMedCrossRef
46.
go back to reference 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;124:1573–9.PubMedCrossRef 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;124:1573–9.PubMedCrossRef
47.
go back to reference Dinkelaar J, Molenaar PJ, Ninivaggi M, de Laat B, Brinkman HJ, Leyte A. In vitro assessment, using thrombin generation, of the applicability of prothrombin complex concentrate as an antidote for Rivaroxaban. J Thromb Haemost. 2013;11:1111–8.PubMedCrossRef Dinkelaar J, Molenaar PJ, Ninivaggi M, de Laat B, Brinkman HJ, Leyte A. In vitro assessment, using thrombin generation, of the applicability of prothrombin complex concentrate as an antidote for Rivaroxaban. J Thromb Haemost. 2013;11:1111–8.PubMedCrossRef
48.
go back to reference Marlu R, Hodaj E, Paris A, et al. Effect of non-specific reversal agents on anticoagulant activity of dabigatran and rivaroxaban: a randomised crossover ex vivo study in healthy volunteers. Thromb Haemost. 2012;108:217–24.PubMedCrossRef Marlu R, Hodaj E, Paris A, et al. Effect of non-specific reversal agents on anticoagulant activity of dabigatran and rivaroxaban: a randomised crossover ex vivo study in healthy volunteers. Thromb Haemost. 2012;108:217–24.PubMedCrossRef
49.
go back to reference Fukuda T, Honda Y, Kamisato C, Morishima Y, Shibano T. Reversal of anticoagulant effects of edoxaban, an oral, direct factor Xa inhibitor, with haemostatic agents. Thromb Haemost. 2012;107:253–9.PubMedCrossRef Fukuda T, Honda Y, Kamisato C, Morishima Y, Shibano T. Reversal of anticoagulant effects of edoxaban, an oral, direct factor Xa inhibitor, with haemostatic agents. Thromb Haemost. 2012;107:253–9.PubMedCrossRef
50.
go back to reference Godier A, Miclot A, Le Bonniec B, Durand M, Fischer AM, Emmerich J, et al. Evaluation of prothrombin complex concentrate and recombinant activated factor VII to reverse rivaroxaban in a rabbit model. Anesthesiology. 2012;116(1):94–102.PubMedCrossRef Godier A, Miclot A, Le Bonniec B, Durand M, Fischer AM, Emmerich J, et al. Evaluation of prothrombin complex concentrate and recombinant activated factor VII to reverse rivaroxaban in a rabbit model. Anesthesiology. 2012;116(1):94–102.PubMedCrossRef
51.
go back to reference Martin AC, Le Bonniec B, Fischer AM, Marchand-Leroux C, Gaussem P, Samama CM, et al. Evaluation of recombinant activated factor VII, prothrombin complex concentrate, and fibrinogen concentrate to reverse apixaban in a rabbit model of bleeding and thrombosis. Int J Cardiol. 2013;168(4):4228–33.PubMedCrossRef Martin AC, Le Bonniec B, Fischer AM, Marchand-Leroux C, Gaussem P, Samama CM, et al. Evaluation of recombinant activated factor VII, prothrombin complex concentrate, and fibrinogen concentrate to reverse apixaban in a rabbit model of bleeding and thrombosis. Int J Cardiol. 2013;168(4):4228–33.PubMedCrossRef
52.•
go back to reference Schiele F, van Ryn J, Canada K, Newsome C, Sepulveda E, Park J, et al. A specific antidote for dabigatran: functional and structural characterization. Blood. 2013;121:3554–62. This study presents promising data for the effectiveness of a monoclonal antibody against dabigatran (aDabi-Fab) in rapidly reversing the anticoagulant effects of dabigatran, as measured by the thrombin time and aPTT, in a rat model.PubMedCrossRef Schiele F, van Ryn J, Canada K, Newsome C, Sepulveda E, Park J, et al. A specific antidote for dabigatran: functional and structural characterization. Blood. 2013;121:3554–62. This study presents promising data for the effectiveness of a monoclonal antibody against dabigatran (aDabi-Fab) in rapidly reversing the anticoagulant effects of dabigatran, as measured by the thrombin time and aPTT, in a rat model.PubMedCrossRef
53.
go back to reference Glund S, Stangier J, Schmohl M, De Smet M, Gansser D, Lang B, et al. A specific antidote for dabigatran: immediate, complete and sustained reversal of dabigatran induced anticoagulation in healthy male volunteers. Oral presentation number 17765 at 0930am on Monday November 18, 2013 at the American Heart Association Scientific Sessions (Room C140), Dallas, Texas, USA. Glund S, Stangier J, Schmohl M, De Smet M, Gansser D, Lang B, et al. A specific antidote for dabigatran: immediate, complete and sustained reversal of dabigatran induced anticoagulation in healthy male volunteers. Oral presentation number 17765 at 0930am on Monday November 18, 2013 at the American Heart Association Scientific Sessions (Room C140), Dallas, Texas, USA.
54.•
go back to reference Lu G, DeGuzman FR, Hollenbach SJ, Karbarz MJ, Abe K, Lee G, et al. A specific antidote for reversal of anticoagulation by direct and indirect inhibitors of coagulation factor Xa. Nat Med. 2013;19:446–51. This study presents promising data for the effectiveness of a recombinant antidote to the factor Xa inhibitors (PRT064445), showing it rapidly reversed the anticoagulant effects of the Xa inhibitors and reduced Xa-mediated blood loss in animal models.PubMedCrossRef Lu G, DeGuzman FR, Hollenbach SJ, Karbarz MJ, Abe K, Lee G, et al. A specific antidote for reversal of anticoagulation by direct and indirect inhibitors of coagulation factor Xa. Nat Med. 2013;19:446–51. This study presents promising data for the effectiveness of a recombinant antidote to the factor Xa inhibitors (PRT064445), showing it rapidly reversed the anticoagulant effects of the Xa inhibitors and reduced Xa-mediated blood loss in animal models.PubMedCrossRef
55.
go back to reference Portola Pharmaceuticals. Phase 2 Healthy Volunteer Study to Evaluate the Ability of PRT064445 to Reverse the Effects of Several Blood Thinner Drugs on Laboratory Tests. 2012. Clinical Trials Identifier, NCT01758432. http://clinicaltrials.gov/show/NCT01758432 [accessed Dec 2013]. Portola Pharmaceuticals. Phase 2 Healthy Volunteer Study to Evaluate the Ability of PRT064445 to Reverse the Effects of Several Blood Thinner Drugs on Laboratory Tests. 2012. Clinical Trials Identifier, NCT01758432. http://​clinicaltrials.​gov/​show/​NCT01758432 [accessed Dec 2013].
56.
go back to reference Laulicht B, Bakhru S, Jiang X, et al. Antidote for new oral anticoagulants: mechanism of action and binding specificity of PER977. Presented at the XXIV Congress of the International Society on Thrombosis and Haemostasis, Amsterdam, June 29–July 4, 2013. abstract. Laulicht B, Bakhru S, Jiang X, et al. Antidote for new oral anticoagulants: mechanism of action and binding specificity of PER977. Presented at the XXIV Congress of the International Society on Thrombosis and Haemostasis, Amsterdam, June 29–July 4, 2013. abstract.
57.
go back to reference Laulicht B, Bakhru S, Lee C, Baker C, Jiang X, Mathiowitz E, et al. Small molecule antidote for anticoagulants. Circulation 126.21_MeetingAbstracts (2012):A11395-A11395. Laulicht B, Bakhru S, Lee C, Baker C, Jiang X, Mathiowitz E, et al. Small molecule antidote for anticoagulants. Circulation 126.21_MeetingAbstracts (2012):A11395-A11395.
58.
go back to reference Rybinnik I, Mullen MT, Messe S, Kasner SE, Cucchiara B. Treatment of acute stroke in patients on dabigatran: a survey of US Stroke Specialists. J Stroke Cerebrovasc Dis. 2013;22:1312–6.PubMedCrossRef Rybinnik I, Mullen MT, Messe S, Kasner SE, Cucchiara B. Treatment of acute stroke in patients on dabigatran: a survey of US Stroke Specialists. J Stroke Cerebrovasc Dis. 2013;22:1312–6.PubMedCrossRef
Metadata
Title
Intracranial Hemorrhage and Novel Anticoagulants for Atrial Fibrillation: What Have We Learned?
Author
Graeme J. Hankey
Publication date
01-05-2014
Publisher
Springer US
Published in
Current Cardiology Reports / Issue 5/2014
Print ISSN: 1523-3782
Electronic ISSN: 1534-3170
DOI
https://doi.org/10.1007/s11886-014-0480-9

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