Факторы, влияющие на эффективность и безопасность системного тромболизиса у пациентов с ишемическим инсультом

Системный тромболизис с использованием рекомбинантного тканевого активатора плазминогена (rt-PA) является наиболее эффективным и безопасным методом терапии при ишемическом инсульте (ИИ) в первые 4,5 ч от начала развития заболевания. На безопасность и эффективность (или отсутствие таковой) реперфузионной терапии у больных с ИИ могут оказывать влияние множество факторов, связанных со временем начала ее проведения, возрастом больного, наличием и размером области мозга с потенциально обратимыми изменениями, локализацией очага поражения мозга, особенностями системной локальной гемодинамики, степенью повреждения гематоэнцефалического барьера. Геморрагическая трансформация очага поражения головного мозга при ИИ является серьезным осложнением тромболитической терапии (ТЛТ). Анализ и выявление предикторов геморрагических осложнений, проведение ТЛТ с учетом клинико-патогенетических особенностей заболевания, локализации очага поражения и степени выраженности ранних нейровизуализационных признаков, данных дополнительных методов исследования будут способствовать более безопасному и эффективному применению данного метода лечения у пациентов с ИИ.

1. Available from: http://www.eso-stroke.org

2. Jauch EC, Saver JL, Adams HP Jr, et al.; American Heart Association Stroke Council; Council on Cardiovascular Nursing; Council on Peripheral Vascular Disease; Council on Clinical Cardiology. Guidelines for the early management of patients with acute ischemic stroke: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke. 2013;44:870–947. DOI: http://dx.doi.org/10.1161/STR.0b013e318284056a.

3. Tillet WS, Garner RL. The fibrinolytic activity of hemolytic streptococci. J Exp Med. 1933;58:485–520. DOI: http://dx.doi.org/10.1084/jem.58.4.485.

4. Fletcher AP, Alkjaersig N, Smyrniotis FE, Sherry S. The treatment of patients suffering from early myocardial infarction with massive and prolonged streptokinase therapy. Trans Assoc Am Phys. 1958;71:287–96.

5. Del Zoppo GJ, Zeumer H, Harker LA. Thrombolytic therapy in acute stroke: Possibilities and hazards. Stroke. 1986;17:595–607. DOI: http://dx.doi.org/10.1161/01.STR.17.4.595.

6. Ringelstein EB, Zeumer H. The role of continuous-wave Doppler sonography in the diagnosis and management of basilar and vertebral artery occlusions, with special reference to its application during local fibrinolysis. J Neurol. 1982;228:161–70. DOI: http://dx.doi.org/10.1007/BF00313728.

7. Zeumer H, Hacke W, Ringelstein EB. Local intraarterial thrombolysis in vertebrobasilar thromboembolic disease. Am J Neuroradiol. 1983;4(3):401–4.

8. Solis OJ, Roberson GR, Taveras JM, et al. Cerebral angiography in acute cerebral infarction. Rev Interam Radiol. 1977;2(1):19–25.

9. Matsuo O, Kosugi T, Mihara H, et al. Retrospective study on the efficacy of using urokinase therapy. Acta Haem Jap. 1979;42:684–8.

10. Multicentre Acute Stroke Trial – Italy (Mast-I) Group. Randomised controlled trial of streptokinase, aspirin, and combination of both in treatment of acute ischaemic stroke. Lancet. 1995 Dec 9;346(8989):1509–14. DOI: http://dx.doi.org/10.1016/S0140- 6736(95)92049-8.

11. Multicentre Acute Stroke Trial – Europe tudy Group. Thrombolytic therapy with streptokinase in acute ischemic stroke. N Engl J Med. 1996 Jul 18;335(3):145–50. DOI: http://dx.doi.org/10.1056/NEJM199607183350301.

12. Yasaka M, Chambers BR, Davis SM, Donnan GA. Streptokinase in acute stroke: effect on reperfusion and recanalization. Australian Streptokinase Trial Study Group. Neurology. 1998 Mar;50(3):626–32. DOI: http://dx.doi.org/10.1212/WNL.50.3.626.

13. Seifried E, Tanswell P, Ellbrü ck D, et al. Pharmacokinetics and haemostatic status during consecutive infusions of recombinant tissuetype plasminogen activator in patients with acute myocardial infarction. Thromb Haemostas. 1989;61(3):497–501.

14. Tanswell P, Tebbe U, Neuhaus K-L, et al. Pharmacokinetics and fibrin specificity of Alteplase during accelerated infusions in acute myocardial infarction. J Am Coll Cardiol. 1992;19:1071–5. DOI: http://dx.doi.org/10.1016/0735-1097(92)90297-Z.

15. Brott TG, Haley EC Jr, Levy DE, et al. Urgent therapy for stroke. Part I. Pilot study of tissue plasminogen activator administered within 90 minutes. Stroke. 1992;23:632–40. DOI: http://dx.doi.org/10.1161/01.STR.23.5.632.

16. Haley EC Jr, Levy DE, Brott TG, et al. Urgent therapy for stroke. Part II. Pilot study of tissue plasminogen activator administered 91–180 minutes from onset. Stroke. 1992;23:641–5. DOI: http://dx.doi.org/10.1161/01.STR.23.5.641.

17. Tissue plasminogen activator for acute ischemic stroke. The National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group. New Engl J Med. 1995;333(24):1581–7.

18. Hacke W, Kaste M, Fieschi C, et al. Intravenous thrombolysis with recombinant tissue plasminogen activator for acute hemispheric stroke the european cooperative acute stroke study (ECASS). JAMA. 1995;274(13):1017–25.

19. Hacke W, Kaste M, Fieschi C, et al. Randomised double-blind placebo-controlled trial of thrombolytic therapy with intravenous alteplase in acute ischaemic stroke (ECASS II). Lancet. 1998;352(9136):1245–51.DOI: http://dx.doi.org/10.1016/S0140-6736(98)08020-9.

20. Clark WM, Wissman S, Albers GW, et al. Recombinant tissue-type plasminogen activator (Alteplase) for ischemic stroke 3 to 5 hours after symptom onset. The ATLANTIS Study: a randomized controlled trial. Alteplase Thrombolysis for Acute Noninterventional Therapy in Ischemic Stroke. JAMA. 1999;282:2019–26. DOI: http://dx.doi.org/ 10.1001/jama.282.21.2019.

21. Hacke W, Kaste M, Bluhmki E, et al.; ECASS Investigators. Thrombolysis with alteplase 3 to 4.5 hours after acute ischemic stroke. N Engl J Med. 2008;359:1317–29. DOI: 10.1056/NEJMoa0804656.

22. Sandercock P, Wardlaw JM, Lindley RI, et al.; IST-3 collaborative group. The benefits and harms of intravenous thrombolysis with recombinant tissue plasminogen activator within 6 h of acute ischaemic stroke (the third international stroke trial [IST-3]): a randomised controlled trial. Lancet. 2012;379(9834):2352–63. DOI: http://dx.doi.org/10.1016/S0140- 6736(12)60768-5.

23. Indyk JA, Chen ZL, Tsirka SE, Strickland S. Laminin chain expression suggests that laminin-10 is a major isoform in the mouse hippocampus and is degraded by the tissue plasminogen activator/plasmin protease cascade during excitotoxic injury. Neuroscience. 2003;116:359–71. DOI: http://dx.doi.org/10.1016/S0306-4522(02)00704-2.

24. Lo EH, Broderick JP, Moscowitz MA. tPA and proteolysis in the neurovascular unit. Stroke. 2004;35(2):354–6. DOI: http://dx.doi.org/10.1161/01.STR.0000115164.80010.8A.

25. Furlan AJ, Eyding D, Albers GW, et al.; DEDAS Investigators. Dose escalation of desmoteplase for acute ischemic stroke (dedas): evidence of safety and efficacy 3 to 9 hours after stroke onset. Stroke. 2006;37:1227–31. DOI: http://dx.doi.org/10.1161/ 01.STR.0000217403.66996.6d.

26. Hacke W, Albers G, Al-Rawi Y., et al. The Desmoteplase in Acute Ischemic Stroke Trial (DIAS). A phase II MRI – based 9-hour window acute stroke thrombolysis trial with intravenous desmoteplase. Stroke. 2005;36:66–73. DOI: http://dx.doi.org/10.1161/01.STR. 0000149938.08731.2c.

27. Hacke W, Furlan AJ, Al-Rawi Y, et al. Intravenous desmoteplase in patients with acute ischaemic stroke selected by MRI perfusiondiffusion weighted imaging or perfusion CT (DIAS-2): a prospective, randomised, doubleblind, placebo-controlled study. Lancet Neurol. 2009;8(2):141–50. DOI: http://dx.doi.org/10.1016/S1474-4422(08)70267-9.

28. Kratzschmar J, Haendler B, Langer G, et al. The plasminogen activator family from the salivary gland of the vampire bat Desmodus rotundus: cloning and expression. Gene. 1991;105:229–37. DOI: http://dx.doi.org/10.1016/0378-1119(91)90155-5.

29. Lopez-Atalaya JP, Roussel BD, Ali C, et al. Recombinant desmodus rotundus salivary plasminogen activator crosses the blood-brain barrier through a low-density lipoprotein receptorrelated protein-dependent mechanism without exerting neurotoxic effects. Stroke. 2007;38:1036–43. DOI: http://dx.doi.org/10.1161/01. STR.0000258100.04923.84.

30. Hacke W, Donnan G, Fieschi C, et al. Association of outcome with early stroke treatment: pooled analysis of ATLANTIS, ECASS, and NINDS rt-PA stroke trials. Lancet. 2004;363:768–74. DOI: http://dx.doi.org/10.1016/S0140-6736(04)15692-4.

31. Bray BD, Campbell J, Cloud GC, et al.; Intercollegiate Stroke Working Party Group. Bigger, Faster? Associations between hospital thrombolysis volume and speed of thrombolysis administration in acute ischemic stroke. Stroke. 2013;44:3129–35. DOI: http://dx.doi.org/10.1161/ STROKEAHA.113.001981.

32. Carlson MD, Leber S, Deveikis J, Silverstein FS. Successful use of rt-PA in pediatric stroke. Neurology. 2001;57:157–8. DOI: http://dx.doi.org/10.1212/WNL.57.1.157.

33. Engelter ST, Bonati LH, Lyrer PA. Intravenous thrombolysis in stroke patients of 80 versus 80 years of age – a systematic review across cohort studies. Age Ageing. 2006;35:572–80. DOI: http://dx.doi.org/10.1093/ageing/afl104.

34. Mateen FJ, Buchan AM, Hill MD; CASES Investigators. Outcomes of thrombolysis for acute ischemic stroke in octogenarians versus nonagenarians. Stroke. 2010;41:1833–5. DOI: http://dx.doi.org/10.1161/STROKEAHA. 110.586438.

35. Khaw KT, Barrett-Connor E, Suarez L, Criqui MH. Predictors of stroke associated mortality in the elderly. Stroke. 1984;15:244–8. DOI: http://dx.doi.org/10.1161/ 01.STR.15.2.244.

36. Wardlaw JM, Murray V, Berge E, Del Zoppo GJ. Thrombolysis for acute ischemic stroke. Cochrane Database Syst Rev. 2009 Oct 7;(4):CD000213. DOI: 10.1002/14651858.CD000213.pub2.

37. Anzini A, Niaz A, Durastanti L, et al. Thrombolysis in young patients: the SITSMOST data. Cerebrovasc Dis. 2008;25 (Suppl 2):3.

38. Putaala J, Metso TM, Metso AJ, et al. Thrombolysis in young adults with ischemic stroke. Stroke. 2009;40:2085–91. DOI: http://dx.doi.org/10.1161/ STROKEAHA.108.541185.

39. Holroyd-Leduc JM, Kapral MK, Austin PC, Tu JV. Sex differences and similarities in the management and outcome of stroke. Stroke. 2000;31:1833–7. DOI: http://dx.doi.org/10.1161/01.STR.31.8.1833.

40. Kapral MK, Fang J, Hill MD, et al.; Investigators of the Registry of the Canadian Stroke Network. Sex differences in stroke care and outcomes: results from the registry of the canadian stroke network. Stroke. 2005;36:809–14. DOI: http://dx.doi.org/10.1161/01.STR. 0000157662.09551.e5.

41. Meseguer E, Mazighi M, Labreuche J, et al. Outcomes of intravenous recombinant tissue plasminogen activator therapy according to gender: a clinical registry study and systematic review. Stroke. 2009;40:2104–10. DOI: http://dx.doi.org/10.1161/STROKEAHA. 108.546325.

42. Savitz SI1, Schlaug G, Caplan L, Selim M. Arterial occlusive lesions recanalize more frequently in women than in men after intravenous tissue plasminogen activator administration for acute stroke. Stroke. 2005;36:1447–51. DOI: http://dx.doi.org/10.1161/01.STR. 0000170647.42126.a8.

43. Kent DM, Price LL, Ringleb P, et al. Sex-based differences in response to recombinant tissue plasminogen activator in acute ischemic stroke: a pooled analysis of randomized clinical trials. Stroke. 2005;36:62–5. DOI: http://dx.doi.org/10.1161/01.STR. 0000150515.15576.29.

44. Fö rster A, Gass A, Kern R, et al. Gender differences in acute ischemic stroke: etiology, stroke patterns and response to thrombolysis. Stroke. 2009;40:2428–32. DOI: http://dx.doi.org/10.1161/STROKEAHA.109.548750.

45. Tafreshi GM, Raman R, Ernstrom K, et al. Gender differences in acute stroke treatment: the University of California San Diego experience. Stroke. 2010;41:1755–7. DOI: http://dx.doi.org/10.1161/STROKEAHA. 110.584136.

46. Pessin M, del Zoppo GJ, Estol C. Thtombolytic agents in the treatment of stroke. Clin Neuropharmacol. 1990;13:271–89. DOI: http://dx.doi.org/10.1097/00002826- 199008000-00001.

47. Okada Y, Yamaguchi T, Minematsu K, et al. Hemorrhagic transformation in cerebral embolism. Stroke. 1989;20:598–603. DOI: http://dx.doi.org/10.1161/01.STR.20.5.598.

48. Lodder J, Krijne-Kubat B, Broekman J. Cerebral hemorrhagic infarction at autopsy: cardiac embolic cause and the relationship to the cause of death. Stroke. 1986;17:626–9. DOI: http://dx.doi.org/10.1161/01.STR.17.4.626.

49. Generalized efficacy of t-PA for acute stroke. Subgroup analysis of the NINDS t-PA Stroke Trial. Stroke. 1997;28:2119–25. DOI: http://dx.doi.org/10.1161/01.STR.28.11.2119.

50. Fiorelly M, Bastianello S, von Kummer R, et al.; ECASS I Study Group. Hemorrhagic transformation within 36 hours of a cerebral infarct. Relationship with early clinical deterioration and 3-month outcome in the ECASS I cohort. Stroke. 1999;30:2280–4. DOI: http://dx.doi.org/10.1161/01.STR.30.11.2280.

51. Molina CA, Alvarez-Sabin J, Montaner J, et al. Thrombolysis-related hemorragic infarction: a marker of early reperfusion, reduced infarct size, and improved outcome in patients with proximal middle cerebral artery occlusion. Stroke. 2002;33;1551–6. DOI: http://dx.doi.org/10.1161/01. STR.0000016323.13456.E5.

52. Neumann-Haefelin T, Hoelig S, Berkefeld J, et al. Leukoaraiosis is a risk factor for symptomatic intracerebral hemorrhage after thrombolysis for acute Stroke. Stroke. 2006;37:2463–6. DOI: http://dx.doi.org/10.1161/01.STR.0000239321.53203.ea.

53. Dubey N, Bakshi R, Wasay M, Dmochowski J. Early computed tomography hypodensity predicts hemorrhage after intravenous tissue plasminogen activator in acute ischemic stroke. J Neuroimaging. 2001;11:184–8. DOI: http://dx.doi.org/10.1111/j.1552- 6569.2001.tb00031.x.

54. Intracerebral hemorrhage after intravenous t-PA therapy for ischemic stroke. The NINDS t-PA Stroke Study Group. Stroke. 1997;28:2109–18. DOI: http://dx.doi.org/10.1161/01.STR.28. 11.2109.

55. Barber PA, Demchuk AM, Zhang J, Buchan AM. Validity and reliability of a quantitative computed tomography score in predicting outcome of hyperacute stroke before thrombolytic therapy. ASPECTS Study Group. Alberta Stroke Programme Early CT Score. Lancet. 2000;355:1670–4. DOI: http://dx.doi.org/10.1016/S0140- 6736(00)02237-6.

56. Dzialowski I, Hill MD, Coutts SB, et al. Extent of early ischemic changes on computed tomography (ct) before thrombolysis: prognostic value of the Alberta Stroke Program Eearly CT Score in ECASS II. Stroke. 2006;37:973–8. DOI: http://dx.doi.org/10.1161/01. STR.0000206215.62441.56.

57. Lindsberg PJ, Hä ppö lä O, Kallela M, et al. Door to thrombolysis: ER reorganization and reduced delays to acute stroke treatment. Neurology. 2006;67:334–6. DOI: http://dx.doi.org/10.1212/01.wnl. 0000224759.44743.7d.

58. Martin-Schild S, Morales MM, Khaja AM, et al. Is the drip-and-ship approach to delivering thrombolysis for acute ischemic stroke safe? J Emerg Med. 2011 Aug;41(2):135–41. DOI: 10.1016/j.jemermed.2008.10.018. Epub 2009 Mar 9

59. Mayer TE, Hamann GF, Brueckmann HJ. Treatment of basilar artery embolism with a mechanical extraction device: necessity of flow reversal. Stroke. 2002;33:2232–5. DOI: http://dx.doi.org/10.1161/01.STR. 0000024524.71680.C6.

60. Hacke W, Zeumer H, Ferbert A, et al. Intra-arterial thrombolytic therapy improves outcome in patients with acute vertebrobasilar occlusive disease. Stroke. 1988;19:1216–22. DOI: http://dx.doi.org/10.1161/01. STR.19.10.1216.

61. Brandt T, von Kummer R, Muller-Kuppers M, Hacke W. Thrombolytic therapy of acute basilar artery occlusion. Variables affecting recanalization and outcome. Stroke. 1996;27:875–81. DOI: http://dx.doi.org/10.1161/01. STR.27.5.875.

62. Schonewille WJ, Wijman CA, Michel P, et al. Treatment and outcomes of acute basilar artery occlusion in the Basilar Artery International Cooperation Study (BASICS): a prospective registry study. Lancet Neurol. 2009;8:724–30. DOI: http://dx.doi.org/10.1016/S1474- 4422(09)70173-5.

63. Martin-Schild S, Morales MM, Khaja AM, et al. Is the drip-and-ship approach to delivering thrombolysis for acute ischemic stroke safe? J Emerg Med. 2009.

64. Silverman IE, Beland DK, Chhabra J, McCullough LD. The «Drip-and-ship» approach: starting IV t-Pa for acute ischemic stroke at outside hospitals prior to transfer to a regional stroke center. Conn Med. 2005;69:613–20.

65. Pfefferkorn T, Mayer TE, Opherk C, et al. Staged escalation therapy in acute basilar artery occlusion: Intravenous thrombolysis and ondemand consecutive endovascular mechanical thrombectomy: Preliminary experience in 16 patients. Stroke. 2008;39:1496–500. DOI: http://dx.doi.org/10.1161/STROKEAHA. 107.505123.

66. Pfefferkorn T, Holtmannspotter M, Schmidt C, et al. Drip, ship, and retrieve: cooperative recanalization therapy in acute basilar artery occlusion. Stroke. 2010;41:722–6. DOI: http://dx.doi.org/10.1161/STROKEAHA. 109.567552.