Recombinant tissue-type plasminogen activator (alteplase) for ischemic stroke 3 to 5 hours after symptom onset - The ATLANTIS study: A randomized controlled trial

Context Recombinant tissue-type plasminogen activator (rt-PA) improves outc omes for patients with acute ischemic stroke, but current approved use is l imited to within 3 hours of symptom onset. This restricts the number of pat ients who can be treated, since most stroke patients present more than 3 ho urs after symptom onset. Objective To test the efficacy and safety of rt-PA in patients with acute i schemic stroke when administered between 3 and 5 hours after symptom onset. Design The Alteplase ThromboLysis for Acute Noninterventional Therapy in Is chemic Stroke (ATLANTIS) study is a phase 3, placebo-controlled, double-bli nd randomized study conducted between December 1993 and July 1998, with up to 90 days of follow-up. Setting One hundred forty university and community hospitals in North Ameri ca. Patients An intent-to-treat population of 613 acute ischemic stroke patient s was enrolled, with 547 of these treated as assigned within 3 to 5 hours o f symptom onset. A total of 39 others were treated within 3 hours of sympto m onset, 24 were treated more than 5 hours after symptom onset, and 3 never received any study drug. Intervention Administration of 0.9 mg/kg of rt-PA (n = 272) or placebo (n = 275) intravenously over 1 hour. Main Outcome Measures Primary efficacy was an excellent neurologic recovery at day 90 (National Institutes of Health Stroke Scale [NIHSS] score of les s than or equal to 1); secondary end points included excellent recovery on functional outcome measures (Barthel index, modified Rankin scale, and Glas gow Outcome Scale) at days 30 and 90. Serious adverse events were also asse ssed. Results In the target population, 32% of the placebo and 34% of rt-PA patie nts had an excellent recovery at 90 days (P = .65). There were no differenc es on any of the secondary functional outcome measures. In the first 10 day s treatment with rt-PA significantly increased the rate of symptomatic intr acerebral hemorrhage (ICH) (1.1% vs 7.0% [P<.001]), a symptomatic ICH (4.7% vs 11.4% [P = .004]), and fatal ICH (0.3% vs 3.0% [P<.001]). Mortality at 90 days was 6.9% with placebo and 11.0% with rt-PA (P = .09). Results in th e intent-to-treat population were similar. Conclusions This study found no significant rt-PA benefit on the 90-day eff icacy end points in patients treated between 3 and 5 hours. The risk of sym ptomatic ICH increased with rt-PA treatment. These results do not support t he use of intravenous rt-PA for stroke treatment beyond 3 hours.