The rtPA (Alteplase) 0-to 6-hour acute stroke trial, part A (A0276g) - Results of a double-blind, placebo-controlled, multicenter study

Background and Purpose-The Thrombolytic Therapy in Acute Ischemic :Stroke S tudy, which started in August of 1991, was designed to assess the efficacy and safety of intravenous rtPA (alteplase) in patients with acute (0 to 6 h ours) ischemic stroke. In October 1993 enrollment was halted because of Saf ety Committee (DMSB) concerns. In December 1993 the time window was changed to 0 to 5 hours, and it was decided to restart enrollment as a separate st udy (part B). We report here the results of the original study (part A), fo cusing on evaluating the safety and efficacy of rtPA given between 0 and 6 hours after stroke onset. Methods This investigation was a phase II, placebo-controlled, double-blind , randomized study utilizing 0.9 mg/kg IV rtPA or placebo over 1 hour, whic h was conducted at university and community sites in North America. Except for time to treatment, enrollment criteria were very similar to those of th e NINDS rtPA stroke study. Primary efficacy end points were the number of p atients with a decrease of 4 or more points on the National Institutes of H ealth Stroke Scale (NIHSS) at 24 hours and day 30, along with infarct volum e at day 30. Secondary end paints included mortality and functional recover ies on the Barthel Index and Modified Rankin scale at days 30 and 90. Results-A total of 142 patients were enrolled at 42 sites in North America, including 22 <3 hours (15%) and 46 between 5 and 6 hours (32%). The groups were well matched on baseline characteristics, including NIHSS (mean of 13 for both). For the primary end points, a higher percentage of rtPA patient s had a 4-point improvement at 24 hours (placebo 21%, rtPA 40%; P=0.02); ho wever, this early effect was reversed by 30 days, with more placebo patient s having a 4-point improvement (75%) than patients treated with rtPA (60%, P< 0.01). Treatment with rtPA significantly increased the rate of symptomat ic intracerebral hemorrhage within 10 days (11% versus 0%, P<0.01) and mort ality at 90 days (23% versus 7%, P<0.01). Conclusions This study found no significant rtPA benefit on any of the plan ned efficacy end points at 30 and 90 days in patients heated between 0 and 6 hours after stroke onset. These negative results apply to patients treate d after 3 hours, because only 15% of the patients were enrolled before 3 ho urs. The risk of symptomatic intracerebral hemorrhage was increased with rt PA treatment, particularly in patients treated between 5 and 6 hours after onset. These results do not support the use of intravenous rtPA for stroke treatment >3 hours after onset.