ECASS

Dzialowski I, Hill MD, Coutts SB, Demchuk AM, Kent DM, Wunderlich O, von Kummer R. Extent of early ischemic changes on computed tomography (CT) before thrombolysis prognostic value of the Alberta Stroke Program Early CT Score in ECASS II. Stroke 2006 37 973-978. 

Hacke W, Kaste M, Fieschi C, Toni D, Lesaffre E, von Kummer R, Boy sen G, Bluhmki E, Hoxter G, Mahagne MH. Intravenous thrombolysis with recombinant tissue plasminogen activator for acute hemispheric stroke. The European Cooperative Acute Stroke Study (ECASS). JAMA 1995 274 1017-1025. 

Three large randomized trials, the European Cooperative Acute Stroke Study (ECASS) parts I and II, and the Alteplase Thrombolysis for Acute Noninterven-tional Therapy in Ischemic Stroke (ATLANTIS), have investigated the efficacy of IV rt-PA in acute stroke beyond the 3-hour window. All three studies showed high rates of sICH complicating rt-PA treatment, and no overall efficacy of rt-PA. 

ECASS-II was designed to test a lower dose of rt-PA (0.9 mg/kg) during the same 0-6-hours time period after stroke onset, using similar inclusion criteria as in ECASS-I. ° The primary endpoint was the proportion with a favorable outcome on the mRS scale (defined as a score of 0 or 1). There was no difference in this outcome between rt-PA-treated and placebo controls (40% vs. 37%, p = 0.28). A separate analysis of the 158 subjects enrolled within 3 hours of stroke onset also showed no difference in the proportion with a favorable outcome (42% vs. 38%, p = 0.63) this result, however, must be treated with caution because in ECASS-II there was a substantially lower number of patients treated within 3 hours of stroke onset, compared to the 1995 NINDS rt-PA study. Parenchymal hematoma on post-treatment CT was seen in 12% of rt-PA-treated and 3% of placebo patients (p < 0.001). The 90-day mortality rate was 11 % for the rt-PA group and 11 % for the placebo group (p = 0.54). Protocol violations were much less frequent in ECASS-II compared to ECASS-I (9% vs. 18%), probably because of standardized training in CT interpretation at the study sites. 

The combined experience with IV rt-PA treatment beyond 3 hours, therefore, suggests reduced effectiveness compared to treatment within 3 hours. A pooled analysis of the ATLANTIS, ECASS, and NINDS rt-PA studies confirmed that the odds of a favorable 3-month outcome, defined as minimal or no poststroke disability on the BI, mRS, and NIHSS, decreased with increasing stroke onset to start of treatment time (OTT) (p = 0.005). The odds ratios for favorable outcome with rt-PA treatment were 2.8 (95% Cl 1.8. 5) for OTT 0-90 minutes, 1.6 (95% Cl 1.1-2.2) for 91-180 minutes, 1.4 (95% Cl 1.1-1.9) for 181-270 minutes, and 1.2 (95% Cl 0.9-1.5) for 271-360 minutes. This finding, that earlier treatment is associated with more therapeutic efficacy, supports the adage that in the delivery of acute stroke therapy time is brain. " The rate of sICH was not associated with OTT. ... 

A combined analysis of the ATLANTIS, ECASS-11, and NINDS rt-PA study data found that females had a greater benefit from rt-PA than males (p = 0.04), despite similar initial stroke severity and rates of slCH." This finding may not be relevant to the clinical, FDA-approved use of rt-PA, because most of the analyzed subjects from ATLANTIS and ECASS-11 were randomized greater than 3 hours after stroke onset. Therefore, sex should not be a criterion for patient selection for thrombolysis. 

E, Davis S, Donnan G, Schneider D, Diez-Tejedor E, Trouillas R Randomised double-blind placebo-controlled trial of thrombol3ffic therapy with intravenous alteplase in acute ischaemic stroke (ECASS II). Second European-Australasian Acute Stroke Study Investigators. Lancet. 1998 352 1245-1251. 

Hacke W, Donnan G, Fieschi C, Kaste M, von Kummer R, Broderick JR, Brott T, Frankel M, Grotta JC, Haley EC, Jr., Kwiatkowski T, Levine SR, Lewandowski C, Lu M, Lyden R, Marler JR, Patel S, Tilley BC, Albers G, Bluhmki E, Wilhelm M, Hamilton S. Association of outcome with early stroke treatment Pooled analysis of ATLANTIS, ECASS, and NINDS rt-PA stroke trials. Lancet. 2004 363 768-774. 

Fiorelli M, Bastianello S, von Kummer R, del Zoppo GJ, Larrue V, Lesaffre E, Ringleb AP, Lorenzano S, Manelfe C, Bozzao L. Hemorrhagic transformation within 36 hours of a cerebral infarct Relationships with early clinical deterioration and 3-month outcome in the european cooperative acute stroke study i (ECASS i) cohort. Stroke. 1999 30 2280-2284. 

Larrue V, von Kummer RR, Muller A, Bluhmki E. Risk factors for severe hemorrhagic transformation in ischemic stroke patients treated with recombinant tissue plasminogen activator A secondary analysis of the european-australasian acute stroke study (ECASS II). Stroke. 2001 32 438 1. 

OR 1.81, 95% Cl 1.46-2.24), most of which were related to symptomatic intracranial hemorrhage (OR 3.37, 95% Cl 2.68. 22). In addition, a pooled analysis of six major randomized placebo-controlled IV rt-PA stroke trials (Alteplase Thrombolysis for Acute Noninterventional Therapy in Ischemic Stroke (ATLANTIS) I and II, European Cooperative Acute Stroke Study (ECASS) I and II, and NINDS I and II), including 2775 patients who were treated with IV rt-PA or placebo within 360 minutes of stroke onset, confirmed the beneht up to 3 hours and suggested a potential beneht beyond 3 hours for some patients. The pattern of a decreasing chance of a favorable 3-month outcome as the time interval from stroke onset to start of treatment increased was consistent with the findings of the original NINDS study. ... 

The ATLANTIS, ECASS and NINDS rt-PA Study Group Investigators. Association of outcome with early stroke treatment pooled analysis of ATLANTIS, ECASS, and NINDS rt-PA stroke trials. Lancet 2004 363 768-74. 

Fibrinolytic agents. Intravenous fibrinolysis has been assessed in at least six major international studies. Streptokinase has been abandoned (haemorrhage) while rt-PA is given in the 3-6 hour therapeutic window (secondary analysis disclosed significant results on the RANKIN scale at 3 months (NINDS) and at 3 months (ECASS II)). 

European Cooperative Acute Stroke Study (ECASS). JAMA... 

A pooled analysis of individual patient data from the NINDS, ECASS I and II and the Alteplase Thrombolysis for Acute Noninterventional Therapy in Ischemic Stroke (ATLANTIS) trials (Hacke et al. 2004), which represents 99% of patients randomized in trials of rt-PA in stroke, has confirmed that benefit from thrombolysis decreases with time since stroke onset, being most beneficial if given within 90 minutes (odds ratio for favorable outcome of 2.8) (Fig. 21.1), although benefit was still present at 4.5 hours (now confirmed in ECASS III). However, it is clear that many patients will not benefit at this time point and, conversely, that other patients may benefit up to and beyond six hours in view of the fact that the ischemic penumbra may extend for much longer periods in some patients (Baron 2001). At present, only approximately 1% of UK patients receive thrombolysis (Intercollegiate Working Party on Stroke 2006) and 1-6% in North America. 

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