Context Recombinant tissue-type plasminogen activator (rt-PA) improves outcomes
for patients with acute ischemic stroke, but current approved use is limited
to within 3 hours of symptom onset. This restricts the number of patients
who can be treated, since most stroke patients present more than 3 hours after
Objective To test the efficacy and safety of rt-PA in patients with acute ischemic
stroke when administered between 3 and 5 hours after symptom onset.
Design The Alteplase ThromboLysis for Acute Noninterventional Therapy in Ischemic
Stroke (ATLANTIS) study is a phase 3, placebo-controlled, double-blind randomized
study conducted between December 1993 and July 1998, with up to 90 days of
Setting One hundred forty university and community hospitals in North America.
Patients An intent-to-treat population of 613 acute ischemic stroke patients
was enrolled, with 547 of these treated as assigned within 3 to 5 hours of
symptom onset. A total of 39 others were treated within 3 hours of symptom
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 ≤1); secondary end points
included excellent recovery on functional outcome measures (Barthel index,
modified Rankin scale, and Glasgow Outcome Scale) at days 30 and 90. Serious
adverse events were also assessed.
Results In the target population, 32% of the placebo and 34% of rt-PA patients
had an excellent recovery at 90 days (P = .65). There
were no differences on any of the secondary functional outcome measures. In
the first 10 days treatment with rt-PA significantly increased the rate of
symptomatic intracerebral 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 the intent-to-treat population were similar.
Conclusions This study found no significant rt-PA benefit on the 90-day efficacy
end points in patients treated between 3 and 5 hours. The risk of symptomatic
ICH increased with rt-PA treatment. These results do not support the use of
intravenous rt-PA for stroke treatment beyond 3 hours.