Safety and feasibility of a lower dose intravenous TPA therapy for ischemic stroke beyond the first three hours

Background: The most common reason that patients do not receive intravenous tissue plasminogen activator (TPA) is the inability to meet the strict 3-hour treatment window. The risk/benefit ratio is more unfavorable beyond this time, but some patients might still benefit. We designed a pilot study with the hypothesis that lower dose TPA might be safe in selected patients treated beyond 3 h. Subjects and Methods: To determine the range of symptomatic hemorrhage and good outcome, we prospectively gave IV TPA 0.6mg/kg up to 60 mg (15% bolus, 85% infusion over 30 min) to patients with ischemic stroke beyond the first 3 h after last known to be normal. Other eligibility criteria were: NIH Stroke Scale > 4, normal head CT scan, and clinical suspicion or transcranial Doppler (TCD) evidence of a proximal arterial occlusion. Results: 28 patients were treated, median age 65 (range 24-88) years, median baseline NIHSS score 18 (range 7-34) points. TPA bolus was given 372 ± 158 min after stroke onset (range 189-720). Symptomatic hemorrhage occurred in 3/28 (11%) patients, including 1 fatal bleed. Overall mortality was 6/28 (21%). Partial or complete recanalization was found in 8/20 (40%) TCD monitored patients within 2 h after TPA bolus. Early major improvement occurred in 4/28 (14%) patients. Conclusions: Lower dose IV TPA in patients presenting beyond 3 h carries a risk of intracerebral hemorrhage. However, recanalization with dramatic recovery can still occur.