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patients given placebo. The benefit was similar 1 year after stroke.299 The major risk of treatment was symptomatic brain hemorrhage, which occurred in 6.4% of patients treated with rtPA and 0.6% of patients given placebo. However, the death rate in the 2 treatment groups was similar at 3 months (17% versus 20%) and 1 year (24% versus 28%).66,299 Although the presence of edema or mass effect on baseline CT scan was associated with higher risk of symptomatic intracranial hemorrhage, follow-up study demonstrated that the presence of early ischemic changes on CT scan was not associated with adverse outcome.100,266 Indeed, in the Australian trial of streptokinase, early CT evidence of edema was not associated with an increased risk of hemorrhagic conversion.301 The likelihood of favorable outcome also was affected by the severity of deficits and the patient’s age. Patients with mild to moderate strokes (NIHSS score <20) and persons younger than 75 years of age had the greatest potential for a favorable response to treatment.302 The chances of a complete or nearly complete recovery among patients with severe stroke (NIHSS score of ≥20) improved with treatment, but overall success in this group of critically ill patients was low.302 In 2 large trials, the European Cooperative Acute Stroke Study (ECASS) and ECASS-II, intravenous rtPA was not more effective than placebo in improving neurological outcomes 3 months after stroke.303,304 The dosage of rtPA used in ECASS was marginally higher than that used in the NINDS trials, and patients were treated up to 6 hours after stroke. Patients with CT evidence of low attenuation (edema and/or ischemia) involving more than one third of the territory of the MCA were less likely to have a good outcome after treatment with rtPA than were those who received placebo.98,305 However, the numbers were small, and the difference did not reach statistical significance. A post hoc analysis concluded that the patients treated within 3 hours appeared to benefit from rtPA.306 In the ECASS-II trial, 800 patients were assigned randomly to treatment with either rtPA (0.9 mg/kg IV) or placebo. More than one third of the patients in each group made an excellent recovery, and no significant benefit was noted from treatment. A post hoc analysis of ECASS-II showed that the likelihood of either death or dependency was lower among the patients treated with rtPA.303 The trial included vigorous methodology to avoid recruitment of patients with CT changes consistent with multilobar infarctions.98 As a result, the strokes among the patients admitted in ECASS-II were less severe than in the other studies, and the generally more favorable prognosis among patients may have reduced the likelihood of detecting a therapeutic effect. Still, the rate of symptomatic intracranial hemorrhage was increased with rtPA treatment (8.8% versus 3.4%). An American trial tested rtPA up to 5 hours after stroke.307 Results were similar in that approximately one third of the patients in both treatment groups made an excellent recovery. The rate of symptomatic hemorrhage was higher in the treatment group (7% versus 1.1%). Subsequent to the approval of rtPA for treatment of patients with acute ischemic stroke, several groups reported on the utility of the treatment in a community setting.269,308–313 Some groups reported rates of intracranial hemorrhage and favorable outcomes that are similar to those found in the NINDS trials, but others have not. It is now clear that the risk of hemorrhage is proportional to the degree to which the NINDS protocol is not followed.269,314,315 Besides a risk of intracranial hemorrhage, other potential adverse experiences include systemic bleeding, myocardial rupture if the agent is given within a few days of acute myocardial
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