The European Cooperative Acute Stroke Study (ECASS) I was the first large-scale prospective, multicenter, double-blinded, randomized clinical trial of rtPA in the treatment of acute ischemic stroke (13). Eligible patients were between 18 and 80 years of age and presented within 6 hr of onset of a moderate-to-severe acute ischemic stroke. Patients with strokes severe enough to cause an impaired level of consciousness or forced head and eye deviation were excluded. Patients with rapidly improving symptoms or mild strokes were also excluded. Importantly, patients with CT scans that showed ICH, hypoattenuation exceeding a third of the MCA territory, or diffuse sulcal effacement of one entire brain hemisphere were excluded. Eligible patients received either 1.1 mg/kg of alteplase or placebo over 60 min (10% as a bolus).
The study sought to address two primary hypotheses: (i) a difference would be observed between the two groups in respect to activities of daily living (defined as a 15-point difference on the Barthel Index) at three months, and (ii) a difference would be observed in the global clinical conditions (defined as a difference of one grade on the Modified Rankin Scale, mRS) at three months, with a secondary endpoint of 30-day mortality.
The study enrolled 620 patients (the intent-to-treat population) at 75 centers in 14 European countries. The median time to treatment was 4 hr. The investigators also prospectively felt that a fair number of major protocol violators might be randomized. They therefore designated a target population who met all of the inclusion and exclusion criteria. Of a total of 109 (17%) protocol violators, 66 had abnormal CT scans before treatment.
In the intent-to-treat population, no significant differences were noted in 3-month means of the Barthel Index or mRS. The 30-day mortality was not significantly higher in the rtPA group versus placebo. The parenchymal hematoma rate and deaths associated with hemorrhage were significantly higher in the target group versus placebo group. When excluding major protocol violators and analyzing the prospectively designated target population, a significant decrease was reported in the mRS (2 vs. 3), as well as a significant increase in subjects with an mRS of 0 to 1 in the treatment versus placebo groups.
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