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Recombinant tissue plasminogen activator (rtPA; alteplase) is the only thrombolytic agent licensed for the treatment of patients with acute ischemic stroke. One of the conditions of licensing in the European Union was the initiation of the Safe Implementation of Thrombolysis in Stroke-Monitoring Study (SITS-MOST) to examine the safety of this treatment in routine clinical practice.To determine whether intravenous alteplase administered within 3 h of ischemic stroke is as safe and effective in routine clinical practice as in randomized controlled trials (RCTs).SITS-MOST was a prospective, open-label, observational monitoring study. Recognized stroke centers in the European Union, Norway, and Iceland were eligible for participation if they practiced thrombolytic treatment for acute stroke with routine monitoring of patients, and were affiliated with the European Medicines Agency (EMEA). Centers were designated as 'experienced' if they had participated in at least one previous randomized European Cooperative Acute Stroke Study or had performed five or more thrombolytic procedures before joining SITS-MOST. Patients were recruited if they were between 18 and 80 years of age and presented within 3 h of ischemic stroke. Exclusion criteria included a stroke severity score of 25 or greater on the NIH Stroke Scale (NIHSS), occurrence of stroke within the previous 3 months, previous stroke with persistent functional deficiency and treated diabetes, or treatment with anticoagulants at stroke onset. Patients received 0.9 mg/kg body weight intravenous alteplase and underwent CT or MRI after 22-36 h.The primary study end points were symptomatic intracerebral hemorrhage and death within 3 months of stroke onset. The secondary outcome measure was functional independence (modified Rankin score 0-2) at 3 months.Between December 2002 and April 2006, a total of 6,483 patients from 285 centers (50% designated as experienced) in 14 countries were enrolled in SITS-MOST. The mean age of patients was 68 years and 60.2% were male. Stroke severity was mild (NIHSS score 1-7) in 23% of patients, moderate (NIHSS score 8-14) in 37%, and severe (NIHSS score ≥15) in 40%. The median dose of alteplase was 68 mg (inter-quartile range 60-77 mg). At 3 months follow-up, symptomatic intracerebral hemorrhage had occurred in 7.3% (95% CI 6.7-7.9%) of patients in SITS-MOST compared with 8.6% (95% CI 6.3-11.6%) of patients in pooled RCTs. There was no difference in the number of intracerebral hemorrhages between new and experienced centers. There were a total of 701 deaths during the study, 13.7% of which were attributable to alteplase therapy. Patients in SITS-MOST had lower mortality (11.3% vs 17.3%) and greater functional independence at 3 months (54.8% vs 50.1%) than those in pooled RCTs.Intravenous alteplase administered within 3 h of stroke onset is at least as safe and effective in routine clinical practice as in RCTs, even in centers with little previous experience of thrombolytic treatment.