Systemische Thrombolysetherapie des akuten Hirninfarktes: Kaum noch Platz für Zweifel

Zusammenfassung

Die Zulassung von rt-PA zur Behandlung der akuten zerebralen Ischämie im 3-Stunden-Zeitfenster stützte sich bislang im Wesentlichen auf den 2. Teil der 1995 publizierten NINDS-Studie mit 333 Patienten. Im 3–6-Stunden-Zeitfenster konnte bislang keine Thrombolysestudie per se die Effektivität von rt-PA nachweisen. Allerdings erbrachte die kombinierte Analyse 6 systemischer Thrombolysestudien (NINDS, ECASS, ATLANTIS; n = 2 775) deutliche Hinweise auf das Vorliegen einer rt-PA-Effektivität bis zu 4,5 Stunden nach Symptombeginn ohne relevante Auswirkung auf die Rate von Blutungskomplikationen. Die Zulassung von rt-PA in Europa war an die Führung eines Thrombolyseregisters geknüpft (SITS-MOST). Hierin konnte die Sicherheit und Effektivität der rt-PA-Therapie an 6 483 behandelten Patienten eindrücklich bestätigt werden. Darüber hinaus forderte die europäische Zulassungsbehörde eine randomisierte Patientenstudie mit einem Zeitfenster über 3 Stunden. Die hierfür konzipierte Studie (ECASS3) konnte an 821 eingeschlossenen Patienten die Effektivität und Sicherheit auch im Zeitfenster zwischen 3 und 4,5 Stunden nachweisen. Das heißt umgekehrt allerdings nicht, dass man nun mehr Zeit hat, Patienten mit einem ischämischen Schlaganfall zu behandeln. Weiterhin gilt, dass die Behandlung mit rt-PA so früh wie möglich initiiert werden muss, um dem Patienten die größtmögliche Chance auf ein gutes Outcome zu geben.

Abstract

So far, the approval of rt-PA for the treatment of acute ischemic stroke within a 3-hour time window was based essentially on the second part of the 1995 published NINDS trial which enrolled 333 patients. For the time window between 3 and 6 hours after stroke onset, so far no single rt-PA trial has proved any efficacy. However, the combined analysis of six thrombolysis trials (NINDS, ECASS, ATLANTIS, n = 2 775) strongly indicated an efficacy of rt-PA for up to 4.5 hours, with no significant increase in bleeding complications. The European Evaluation of Medicines Agency (EMEA) granted limited approval for rt-PA in 2002. Limitation one was the request for an observational safety study. Subsequently, the Safe Implementation of Thrombolysis in Stroke-Monitoring Study (SITS-MOST) was undertaken. SITS-MOST enrolled 6 483 patients and could convincingly confirm the safety and efficacy of rt-PA. Limitation two was the request for a randomised controlled trial with rt-PA beyond the 3-hour time window. The trial conceived for this request – ECASS3 – convincingly proved the efficacy and safety for rt-PA administered between 3 and 4.5 hours after stroke onset. However, this does not mean that there is more time for stroke teams to treat acute ischemic stroke patients. To give patients the best possible chance for a good clinical outcome it remains essential to start rt-PA treatment as soon as possible.

Schlüsselwörter

Hirninfarkt - Thrombolyse - randomisierte Studie

Key words

stroke - thrombolysis - randomised trial

Literatur

• 1 The National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group . Tissue plasminogen activator for acute ischemic stroke.  N Engl J Med. 1995;  333 1581-1587
• 2 Albers G W, Olivot J M. Intravenous alteplase for ischaemic stroke.  Lancet. 2007;  369 249-250
• 3 Kane I, Sandercock P, Wardlaw J. Magnetic resonance perfusion diffusion mismatch and thrombolysis in acute ischaemic stroke: a systematic review of the evidence to date.  J Neurol Neurosurg Psychiatry. 2007;  78 485-491
• 4 Furlan A J, Eyding D, Albers G W. et al . Dose Escalation of Desmoteplase for Acute Ischemic Stroke (DEDAS): evidence of safety and efficacy 3 to 9 hours after stroke onset.  Stroke. 2006;  37 1227-1231
• 5 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
• 6 Hacke W, Kaste M, Fieschi C. et al . Intravenous thrombolysis with recombinant tissue plasminogen activator for acute stroke.  JAMA. 1995;  274 1017-1025
• 7 Hacke W, Bluhmki E, Steiner T. et al . Dichotomized efficacy end points and global end-point analysis applied to the ECASS Intention-to-Treat Data Set.  Stroke. 1998;  29 2073-2075
• 8 Adams Jr H P, del Zoppo G, Alberts M J. et al . Guidelines for the early management of adults with ischemic stroke: a guideline from the American Heart Association / American Stroke Association Stroke Council, Clinical Cardiology Council, Cardiovascular Radiology and Intervention Council, and the Atherosclerotic Peripheral Vascular Disease and Quality of Care Outcomes in Research Interdisciplinary Working Groups: the American Academy of Neurology affirms the value of this guideline as an educational tool for neurologists.  Stroke. 2007;  38 1655-1711
• 9 ESO Writing Committee . Guidelines for management of ischaemic stroke and transient ischaemic attack 2008.  Cerebrovasc Dis. 2008;  25 457-507
• 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).  Lancet. 1998;  352 1245-1251
• 11 Clark W M, Wissman S, Albers G W. 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 2019-2026
• 12 Wahlgren N, Ahmed N, Davalos 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
• 13 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
• 14 Wahlgren N, Ahmed N, Davalos A. et al . Thrombolysis with alteplase 3–4.5 h after acute ischaemic stroke (SITS-ISTR): an observational study.  Lancet. 2008;  372 1303-1309
• 15 Hacke W, Kaste M, Bluhmki E. et al . Thrombolysis with alteplase 3 to 4.5 hours after acute ischemic stroke.  N Engl J Med. 2008;  359 1317-1329
• 16 Kummer R von, Allen K L, Holle R. et al . Acute stroke: usefulness of early CT findings before thrombolytic therapy [see comments].  Radiology. 1997;  205 327-333
• 17 Shuaib A, Lees K R, Lyden P. et al . NXY-059 for the treatment of acute ischemic stroke.  N Engl J Med. 2007;  357 562-571
• 18 AbESST investigators . Emergency administration of abciximab for treatment of patients with acute ischemic stroke: results of a randomized phase 2 trial.  Stroke. 2005;  36 880-890
• 19 IMS investigators . The Interventional Management of Stroke (IMS) II Study.  Stroke. 2007;  38 2127-2135
• 20 Rha J H, Saver J L. The impact of recanalization on ischemic stroke outcome: a meta-analysis.  Stroke. 2007;  38 967-973
• 21 Lindley R I, Sandercock P. IST-3. http://www.dcn.ed.ac.uk/ist3/; Access date: 10.10.2006