Thrombolyse jenseits des Zeitfensters von 3 h

Zusammenfassung

Die aktuelle Zulassung für die intravenöse Thrombolysebehandlung in Europa ist auf ein 4, 5 Stundenzeitfenster nach Symptombeginn begrenzt. Mit dem Nachweis der Wirksamkeit und Sicherheit von rt-PA im 4,5 h Zeitfenster in der ECASS III-Studie wurde ein Meilenstein in der Therapie des akuten ischämischen Schlaganfalls erbracht. Obschon damit mehr Patienten das Krankenhaus innerhalb des Thrombolysezeitfensters erreichen können, muss jeder Patient so schnell wie möglich nach Symptombeginn behandelt werden, um die Chance auf ein gutes klinisches Outcome zu erhöhen. Bei einem beträchtlichen Anteil der Patienten ist der genaue Symptombeginn nicht bekannt, die Symptome werden beim Aufwachen erstmals bemerkt oder die Patienten erreichen die Notaufnahmen erst nach 4,5 h. Die vorliegende Übersichtsarbeit stellt zunächst die Ergebnisse der ECASS-3 Studie vor dem Hintergrund der großen älteren intravenösen Thrombolysestudien dar. Die Selektion von Patienten für die Thrombolyse im verlängerten Zeitfenster mithilfe multimodaler bildgebender Verfahren wird beschrieben. Ferner werden laufende MRT basierte Studien und Daten zur Wirksamkeit anderer Fibrinolytika als rt-PA beim Schlaganfall dargestellt.

Abstract

The approval of intravenous rt-PA for thrombolysis is limited in Europe to a 4.5-h time window after symptom onset. The landmark ECASS-3 trial demonstrated the efficacy and safety of rt-PA in the 4.5 h time window. Although as a result more patients qualify for intravenous thrombolysis within this extended time window, every patient must be treated as soon as possible after symptom onset to increase the chance of a good clinical outcome. Nevertheless, in a significant proportion of patients the exact onset of symptoms is not known, symptoms are noticed for the first time after waking up or patients reach the emergency rooms later than 4.5 h. The present review first presents the results of ECASS-3-trial against the background of the large older intravenous thrombolysis trials. Selection of patients for thrombolysis in an extended time window by using multimodal imaging technqiues is described. Furthermore, current MRI-based studies and data on the efficacy of fibrinolytic-drugs others than rt-PA in stroke are presented.

Schlüsselwörter

Thrombolyse - ECASS - rt-PA - Zeitfenster

Keywords

thrombolysis - ECASS - rt-PA - time window

• Literatur

• 1 Gerloff C, Rosenkranz M, Müller-Jensen A. Hamburg gegen den Schlaganfall. Hamburger Aerzteblatt 2007; 450
• 2 GROUP TNIONDASr-PSS . Tissue plasminogen activator for acute ischemic stroke. The National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group. N Engl J Med 1995; 333: 1581-1587
• 3 Hommel M, Boissel JP, Cornu C et al. Termination of trial of streptokinase in severe acute ischaemic stroke. MAST Study Group. Lancet 1995; 345: 57
• 4 Donnan GA, Hommel M, Davis SM et al. Streptokinase in acute ischaemic stroke. Steering Committees of the ASK and MAST-E trials. Australian Streptokinase Trial. Lancet 1995; 346: 56
• 5 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: 1017-1025
• 6 Veltkamp R, Ringleb PA, Hacke W. Thrombolyse. In: Hermann DM, Steiner T, Diener H-C. (eds.) Vaskuläre Neurologie. Stuttgart: Georg Thieme Verlag KG; 2010
• 7 Clark WM, Wissman S, Albers GW et al. Recombinant tissue-type plasminogen activator (Alteplase) for ischemic stroke 3 to 5 h after symptom onset. The ATLANTIS Study: a randomized controlled trial. Alteplase Thrombolysis for Acute Noninterventional Therapy in Ischemic Stroke. JAMA 1999; 282: 2019-2026
• 8 Wahlgren N, Ahmed N, Dávalos A et al. Thrombolysis with alteplase for acute ischaemic stroke in the Safe Implementation of Thrombolysis in Stroke-Monitoring Study (SITS-MOST): an observational study. Lancet 2007; 369: 275-282
• 9 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: 768-774
• 10 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). Second European-Australasian Acute Stroke Study Investigators. Lancet 1998; 352: 1245-1251
• 11 Köhrmann M, Jüttler E, Fiebach JB et al. MRI versus CT-based thrombolysis treatment within and beyond the 3 h time window after stroke onset: a cohort study. Lancet Neurol 2006; 5: 661-667
• 12 Hacke W, Kaste M, Bluhmki E et al. Thrombolysis with alteplase 3–4.5 h after acute ischemic stroke. New Engl J Med 2008; 359: 1317-1329
• 13 Wardlaw JM, Zoppo G, Yamaguchi T et al. Thrombolysis for acute ischaemic stroke. Cochrane database of systematic reviews (Online) 2003; CD000213
• 14 Lees KR, Bluhmki E, von Kummer R et al. Time to treatment with intravenous alteplase and outcome in stroke: an updated pooled analysis of ECASS, ATLANTIS, NINDS, and EPITHET trials. Lancet 2010; 375: 1695-1703
• 15 Wahlgren N, Ahmed N, Dávalos A et al. Thrombolysis with alteplase 3–4.5 h after acute ischaemic stroke (SITS-ISTR): an observational study. Lancet 2008; 372: 1303-1309
• 16 Ahmed N, Wahlgren N, Grond M et al. Implementation and outcome of thrombolysis with alteplase 3–4.5 h after an acute stroke: an updated analysis from SITS-ISTR. Lancet Neurol 2010; 9: 866-874
• 17 Whiteley W, Lindley R, Wardlaw J et al. Third international stroke trial. Int J Stroke 2006; 1: 172-176
• 18 Sandercock P, Wardlaw J, Lindley R. Where are we now with intravenous thrombolysis for acute ischaemic stroke?. Int J Stroke 2010; 5: 381-382
• 19 Sandercock P. Imaging perfusion deficits and thrombolysis safety and efficacy in acute ischaemic stroke: the Third International Stroke Trial. Available at: http://controlled-trials.com/ISRCTN25765518 Accessed: August, 1^st 2011
• 20 del Zoppo GJ, Saver JL, Jauch EC et al. Council AHAS. Expansion of the time window for treatment of acute ischemic stroke with intravenous tissue plasminogen activator: a science advisory from the American Heart Association/American Stroke Association. Stroke 2009; 2945-2948
• 21 Hacke W, DGN E. Akuttherapie des ischämischen Schlaganfalls. In: Leitlinien der DGN: Deutsche Gesellschaft für Neurologie 2009;
• 22 Boehringer Ingelheim gains approval of extended 4.5 h time-window for Actilyse^® in acute ischaemic stroke for majority of EU countries. Available at: http://www.boehringer-ingelheim.com/news/news_releases/press_releases/2011/04_november_2011_alteplase.html Accessed: November 5^th, 2011
• 23 George MG, Tong X, McGruder H et al. Paul Coverdell National Acute Stroke Registry Surveillance – four states, 2005–2007. MMWR Surveillance summaries : Morbidity and mortality weekly report Surveillance summaries/CDC 2009; 58: 1-23
• 24 Serena J, Dávalos A, Segura T et al. Stroke on awakening: looking for a more rational management. Cerebrovascular diseases (Basel, Switzerland). 2003. 16. 128-133
• 25 Elliott WJ. Circadian variation in the timing of stroke onset: a meta-analysis. Stroke 1998; 29: 992-996
• 26 Bornstein NM, Gur AY, Fainshtein P et al. Stroke during sleep: epidemiological and clinical features. Cerebrovascular diseases (Basel, Switzerland) 1999; 9: 320-322
• 27 Lago A, Geffner D, Tembl J et al. Circadian variation in acute ischemic stroke: a hospital-based study. Stroke 1998; 29: 1873-1875
• 28 Ricci S, Celani MG, Vitali R et al. Diurnal and seasonal variations in the occurrence of stroke: a community-based study. Neuroepidemiology 1992; 11: 59-64
• 29 Anderson N, Feigin V, Bennett D et al. Diurnal, weekly, and seasonal variations in stroke occurrence in a population-based study in Auckland, New Zealand. The New Zealand medical journal 2004; 117: U1078
• 30 Silva GS, Lima FO, Camargo ECS et al. Wake-up stroke: clinical and neuroimaging characteristics. Cerebrovascular diseases (Basel, Switzerland). 2010. 29. 336-342
• 31 Mackey J, Kleindorfer D, Sucharew H et al. Population-based study of wake-up strokes. Neurology 2011; 76: 1662-1667
• 32 Boode B, Welzen V, Franke C et al. Estimating the number of stroke patients eligible for thrombolytic treatment if delay could be avoided. Cerebrovascular diseases (Basel, Switzerland). 2007. 23. 294-298
• 33 Thomalla G, Rossbach P, Rosenkranz M et al. Negative fluid-attenuated inversion recovery imaging identifies acute ischemic stroke at 3 h or less. Ann Neurol 2009; 65: 724-732
• 34 Aoki J, Kimura K, Iguchi Y et al. FLAIR can estimate the onset time in acute ischemic stroke patients. J Neurol Sc 2010; 293: 39-44
• 35 Gaudinski MR, Henning EC, Miracle A et al. Establishing final infarct volume: stroke lesion evolution past 30 days is insignificant. Stroke 2008; 39: 2765-2768
• 36 Schwamm LH, Koroshetz WJ, Sorensen AG et al. Time course of le­sion development in patients with acute stroke: serial diffusion- and hemodynamic-weighted magnetic resonance imaging. Stroke 1998; 29: 2268-2276
• 37 Schaefer PW, Gonzalez RG, Hunter G et al. Diagnostic value of apparent diffusion coefficient hyperintensity in selected patients with acute neurologic deficits. J Neuroimaging 2001; 11: 369-380
• 38 Oppenheim C, Samson Y, Dormont D et al. DWI prediction of symptomatic hemorrhagic transformation in acute MCA infarct. J Neuroradiol 2002; 29: 6-13
• 39 Tong DC, Adami A, Moseley ME et al. Relationship between apparent diffusion coefficient and subsequent hemorrhagic transformation following acute ischemic stroke. Stroke 2000; 31: 2378-2384
• 40 Loh P-S, Butcher KS, Parsons MW et al. Apparent diffusion coefficient thresholds do not predict the response to acute stroke thrombolysis. Stroke 2005; 36: 2626-2631
• 41 Fiehler J, Foth M, Kucinski T et al. Severe ADC decreases do not predict irreversible tissue damage in humans. Stroke 2002; 33: 79-86
• 42 van Lookeren Campagne M, Thomas GR, Thibodeaux H et al. Secondary reduction in the apparent diffusion coefficient of water, increase in cerebral blood volume, and delayed neuronal death after middle cerebral artery occlusion and early reperfusion in the rat. J Cereb Blood Flow Metab 1999; 19: 1354-1364
• 43 Li F, Liu K-F, Silva MD et al. Acute postischemic renormalization of the apparent diffusion coefficient of water is not associated with reversal of astrocytic swelling and neuronal shrinkage in rats. AJNR y 2002; 23: 180-188
• 44 Li F, Han SS, Tatlisumak T et al. Reversal of acute apparent diffusion coefficient abnormalities and delayed neuronal death following transient focal cerebral ischemia in rats. Ann Neurol 1999; 46: 333-342
• 45 Donnan GA, Baron JC, Ma H et al. Penumbral selection of patients for trials of acute stroke therapy. Lancet Neurol 2009; 8: 261-269
• 46 del Zoppo GJ, Sharp FR, Heiss W-D et al. Heterogeneity in the penumbra. J J Cereb Blood Flow Metab 2011;
• 47 Dzialowski I CT Based Definition of a Tissue Window for Acute Stroke Thrombolysis (CT-DEFINE). Available at: http://clinicaltrials.gov/ct2/show/NCT00463281
• 48 Wintermark M, Meuli R, Browaeys P et al. Comparison of CT perfusion and angiography and MRI in selecting stroke patients for acute treatment. Neurology 2007; 68: 694-697
• 49 Schellinger PD, Thomalla G, Fiehler J et al. MRI-based and CT-based thrombolytic therapy in acute stroke within and beyond established time windows: an analysis of 1210 patients. Stroke 2007; 38: 2640-2645
• 50 Davis SM, Donnan GA, Parsons MW et al. Effects of alteplase beyond 3 h after stroke in the Echoplanar Imaging Thrombolytic Evaluation Trial (EPITHET): a placebo-controlled randomised trial. Lancet neurology 2008; 7: 299-309
• 51 Schellinger PD. EPITHET: failed chance or new hope?. Lancet Neurol 2008; 7: 286-287
• 52 Goldstein LB. Magnetic resonance imaging profiles predict clinical response to early reperfusion: the DEFUSE study. Current atherosclerosis reports 2007; 9: 258-259
• 53 Mlynash M, Lansberg MG, De Silva DA et al. Refining the definition of the malignant profile: insights from the DEFUSE-EPITHET pooled data set. Stroke 2011; 42: 1270-1275
• 54 Wang Y, Wang Y ITAIS: Imaging-based Thrombolysis Trial in Acute Ischemic Stroke. Available at: http://www.strokecenter.org/trials/TrialDetail.aspx?tid=680 Accessed: July 31, 2011
• 55 Wang Y ITAIS-II – Imaging-based Thrombolysis trial in Acute Ischemic Stroke-II. Available at: http://www.controlled-trials.com/ISRCTN12033002/ISRCTN12033002 Accessed: July 31, 2011
• 56 Wang Y ITAIS- III – Imaging-based Thrombolysis trial in Acute Ischemic Stroke -III. Available at: http://www.controlled-trials.com/ISRCTN03887874/ISRCTN03887874 Accessed: July 31, 2011
• 57 Wang Y, Liao X, Zhao X et al. Imaging-based thrombolysis trial in acute ischemic stroke-II (ITAIS-II). Int J Stroke 2009; 4: 49-53 discussion 49
• 58 Donnan G, Davis S Extending the Time for Thrombolysis in Emergency Neurological Deficits (EXTEND). Available at: http://clinicaltrials.gov/ct2/show/NCT00887328?term=NCT00887328&rank=1 Accessed: July 31, 2011
• 59 Michel P, Wintermark M, Reichhart MD et al. Perfusion-CT guided intravenous thrombolysis at 3 to 6 h: feasibility and safety study. In: XVI European Stroke Conference Glasgow. United Kingdom; 2007
• 60 Konstas AA, Wintermark M, Lev MH. CT perfusion imaging in acute stroke. Neuroimaging clinics of North America 2011; 21: 215-238 ix
• 61 Thomalla G, Cheng B, Ebinger M et al. DWI-FLAIR mismatch for the identification of patients with acute ischaemic stroke within 4.5 h of symptom onset (PRE-FLAIR): a multicentre observational study. Lancet Neurol 2011; 10: 978-986
• 62 Barreto AD, Martin-Schild S, Hallevi H et al. Thrombolytic therapy for patients who wake-up with stroke. Stroke 2009; 40: 827-832
• 63 Cho A-H, Sohn S-I, Han M-K et al. Safety and efficacy of MRI-based thrombolysis in unclear-onset stroke. A preliminary report. Cerebrovascular diseases (Basel, Switzerland). 2008. 25. 572-579
• 64 Schwamm L MR WITNESS: A Study of Intravenous Thrombolysis With Alteplase in MRI-Selected Patients. Available at: http://clinicaltrials.gov/ct2/show/NCT01282242 Accessed: August 1 ^st 2011
• 65 Hemmen TM Study for the Use of Alteplase in Patients Who Awaken With Stroke (AWOKE). Available at: http://clinicaltrials.gov/ct2/show/NCT01150266?term=AWOKE&rank=1 Accessed: August 1^st 2011
• 66 Wu O, Schwamm LH, Sorensen AG. Imaging stroke patients with unclear onset times. Neuroimaging clinics of North America 2011; 21: 327-344
• 67 Ebinger M, Endres M Update Stroke Conference 2011: European Stroke Conference 2011, Hamburg, Germany. Available at: http://www.dsg-info.de/images/stories/DSG/PDF/Kongresse/2011/20th_European_Stroke_Conference_20110703_ME.pdf Accessed: August 1^st 2011
• 68 Hacke W, Albers G, Al-Rawi Y et al. The Desmoteplase in Acute Ischemic Stroke Trial (DIAS): a phase II MRI-based 9-h window acute stroke thrombolysis trial with intravenous desmoteplase. Stroke 2005; 36: 66-73
• 69 Furlan AJ, Eyding D, Albers GW et al. Dose Escalation of Desmoteplase for Acute Ischemic Stroke (DEDAS): evidence of safety and efficacy 3 to 9 h after stroke onset. Stroke 2006; 37: 1227-1231
• 70 Hacke W, Furlan AJ, Al-Rawi Y et al. Intravenous desmoteplase in patients with acute ischaemic stroke selected by MRI perfusion-diffusion weighted imaging or perfusion CT (DIAS-2): a prospective, randomised, double-blind, placebo-controlled study. Lancet Neurol 2009; 8: 141-150
• 71 Mishra NK, Albers GW, Davis SM et al. Mismatch-based delayed thrombolysis: a meta-analysis. Stroke; a journal of cerebral circulation 2010; 41: e25-e33
• 72 Lundbeck ASH. Efficacy and Safety Study of Desmoteplase to Treat Acute Ischemic Stroke (DIAS-3). Available at: http://clinicaltrials.gov/ct2/show/NCT00790920?term=NCT00790920&rank=1 Accessed: August 2^nd, 2011
• 73 Ancrod for the treatment of acute ischemic brain infarction . The Ancrod Stroke Study Investigators. Stroke; a journal of cerebral circulation 1994; 25: 1755-1759
• 74 Hennerici MG, Kay R, Bogousslavsky J et al. Intravenous ancrod for acute ischaemic stroke in the European Stroke Treatment with Ancrod Trial: a randomised controlled trial. Lancet 2006; 368: 1871-1878
• 75 Levy DE, del Zoppo GJ, Demaerschalk BM et al. Ancrod in acute ischemic stroke: results of 500 subjects beginning treatment within 6 h of stroke onset in the ancrod stroke program. Stroke 2009; 40: 3796-3803
• 76 Emergency administration of abciximab for treatment of patients with acute ischemic stroke: results of a randomized phase 2 trial. Stroke 2005; 36: 880-890
• 77 Adams Jr HP, Effron MB, Torner J et al. Emergency administration of abciximab for treatment of patients with acute ischemic stroke: results of an international phase III trial: Abciximab in Emergency Treatment of Stroke Trial (AbESTT-II). Stroke 2008; 39: 87-99
• 78 Warach SJ ReoPro and Retavase to Treat Acute Stroke. Available at: http://clinicaltrials.gov/ct2/show/NCT00046293?term=ROSIE&rank=1 Accessed: August 2^nd, 2011
• 79 Donnan GA, Davis SM, Chambers BR et al. Streptokinase for acute ischemic stroke with relationship to time of administration: Australian Streptokinase (ASK) Trial Study Group. JAMA 1996; 276: 961-966
• 80 Randomised controlled trial of streptokinase, aspirin, and combina­tion of both in treatment of acute ischaemic stroke . Multicentre Acute Stroke Trial – Italy (MAST-I) Group. Lancet 1995; 346: 1509-1514
• 81 Thrombolytic therapy with streptokinase in acute ischemic stroke . The Multicenter Acute Stroke Trial – Europe Study Group. N Engl J Med 1996; 335: 145-150
• 82 Schellinger PD, Fiebach J, Ringleb PA et al. Thrombolysis in cerebral ischemia. An overview. Nervenarzt 2001; 72: 590-599
• 83 Hu H-H, Teng MM-H, Hsu L-C et al. A pilot study of a new thrombolytic agent for acute ischemic stroke in Taiwan within a five-hour window. Stroke 2006; 37: 918-919
• 84 Wang D Tenecteplase For Ischemic Lacunar Stroke – TNKilas. Available at: http://www.strokecenter.org/trials/TrialDetail.aspx?tid=598 Accessed: August 3^rd, 2011
• 85 Intravenous Thrombolysis with Urokinase for Acute Cerebral Infarctions: The Study Group of a 5-Year National Project of the People’s Republic of China Available at: http://www.strokecenter.org/trials/TrialDetail.aspx?tid=421 Accessed: August 3^rd, 2011
• 86 Hill MD VASTT – The V10153 Acute Stroke Thrombolysis Trial. Available at: http://www.strokecenter.org/trials/TrialDetail.aspx?tid=735 Accessed: August 3^rd, 2011
• 87 Hacke W, Zeumer H, Ferbert A et al. Intra-arterial thrombolytic therapy improves outcome in patients with acute vertebrobasilar occlusive disease. Stroke 1988; 19: 1216-1222
• 88 Schonewille WJ, Algra A, Serena J et al. Outcome in patients with basilar artery occlusion treated conventionally. J Neurol Neurosurg Psychiatry 2005; 76: 1238-1241
• 89 Lindsberg PJ, Mattle HP. Therapy of basilar artery occlusion: a systematic analysis comparing intra-arterial and intravenous thrombolysis. Stroke 2006; 37: 922-928
• 90 Schellinger PD, Hacke W. Intra-arterial thrombolysis is the treatment of choice for basilar thrombosis: pro. Stroke 2006; 37: 2436-2437
• 91 Ford GA. Intra-arterial thrombolysis is the treatment of choice for basilar thrombosis: con. Stroke 2006; 37: 2438-2439
• 92 Lindsberg PJ, Soinne L, Tatlisumak T et al. Long-term outcome after intravenous thrombolysis of basilar artery occlusion. JAMA 2004; 292: 1862-1866
• 93 Schonewille WJ, Wijman CAC, Michel P et al. The basilar artery international cooperation study (BASICS). Int J Stroke 2007; 2: 220-223
• 94 Schonewille WJ, Wijman CAC, 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: 724-730
• 95 Sairanen T, Strbian D, Soinne L et al. Intravenous Thrombolysis of Basilar Artery Occlusion: Predictors of Recanalization and Outcome. Stroke 2011; 42: 2175-2179
• 96 Ringleb P, Steiner T, Veltkamp R et al. Standard Thrombolyse Neurologie Heidelberg (Version Jan. 2011). Available at: http://www.klinikum.uni-heidelberg.de/fileadmin/neurologie/pdf_downloads/Standard_Thrombolyse_2011.pdf Accessed: August 25^th, 2011