Expansion of the Time Window for Treatment of Acute Ischemic Stroke With Intravenous Tissue Plasminogen Activator

Current guidelines for the management of patients with acute ischemic stroke published by the American Heart Association Stroke Council include specific recommendations for the administration of intravenous recombinant tissue plasminogen activator (rtPA).1 Despite its effectiveness in improving neurological outcomes, the majority of patients with ischemic stroke are not treated with rtPA, largely because they arrive after the currently approved 3-hour time limit for administration of the medication. One of the potential approaches to increase treatment opportunities has been the designation of a longer time window for treatment.2–4A recent prospective study, the European Cooperative Acute Stroke Study (ECASS)-3, has provided new data on rtPA (alteplase) treatment in the 3-to-4.5–hour window.5 The circumstances surrounding this study are important.In 2002, the European Medicines Evaluation Agency granted license for the use of rtPA for the treatment of ischemic stroke patients within 3 hours of symptom onset on condition of (1) the completion of a prospective registry of patient treatment experience with rtPA given within the 3-hour window from symptom onset (Safe Implementation of Thrombolysis in Stroke–Monitoring Study, or SITS-MOST)6 and (2) the completion of a prospective, randomized, placebo-controlled trial of rtPA administered between 3 and 4.5 hours after stroke onset, ECASS-3.5 SITS-MOST, which used a specified protocol, reported that the frequency of symptomatic intracerebral hemorrhage (per the SITS-MOST definition) at 24 hours after rtPA was 1.7% (95% confidence interval [CI] 1.4% to 2.0%; Figure 3 in Wahlgren et al6). The frequency of symptomatic intracerebral hemorrhage per the Cochrane/National Institute of Neurological Disorders and Stroke (NINDS) definition at 24 hours after rtPA was 7.3% (95% CI 6.7% to 7.9%). By comparison, this frequency was slightly less than 8.6% in data taken from a pool of randomized, controlled trials (Figure 2 in Wahlgren et al6). For efficacy, …