Abstract
Background: In Japan, Pakistan and Vietnam, 0.6 mg of Alteplase per kilogram body weight within 3 hours was approved for standard guideline, although the safety and efficacy in acute ischemic stroke within 4.5 hours has not been established. We conducted four-month prospective study to compare the safety and efficacy of 0.6 mg, 0.75 mg and 0.9 mg of Alteplase per kilogram body weight.
Methods: In cohort A, the patients were randomly assigned to receive intravenous 0.6 mg or 0.75 mg or 0.9 mg of Alteplase per kilogram body weight in a 1:1:1. Interim analysis was performed after complete cohort A. In cohort B, patients were assigned to receive 0.9 mg of Alteplase per kilogram body weight (standard-dose). The primary end points were death, favorable outcome at discharge and 90-day and intra-cerebral hemorrhage. The secondary end points were good outcomes, Improved mRS at discharged and 90-day, number of patients with length of hospital stay <7 days and overall complications.
Results: In Cohort A, 78 were randomly assigned to receive 0.6 mg or 0.75 mg (low-dose) or 0.9 mg of intravenous Alteplase per kilogram body weight. Less patients had favorable outcomes in 0.6 mg and 7.5 mg than 0.9 mg of Alteplase per kilogram body weight at discharge (P=0.0004) and at 90-day (P=0.05). In Cohort B, 330 were assigned to receive standard-dose Alteplase. Finally, 408 patients were enrolled with median time of Alteplase administration by 2 hours 49 min. There was no different onset to needle and death between low-dose and standard-dose Alteplase (P=0.82 and P=0.85). Less patients had favorable outcome and intra-cerebral hemorrhage with low-dose than standard-dose Alteplase (favorable outcomes: Relative risk (RR), 1.18; 95% confidence interval (CI), 1.09 to 1.27; P <0.001 at discharge and RR, 1.25; 95%CI, 1.07 to 1.46; P=0.003 at 90 day, intra-cerebral hemorrhage: RR, 0.05; 95%CI, 0.00 to 0.95; P=0.04. Less patients had improved modified Rankin Scale [mRS] at 90-day with low-dose than standard-dose Alteplase (RR, 1.66; 95%CI, 1.22 to 2.25; P=0.001; especially in the patients with initial systolic blood pressure <180 mmHg ; RR, 1.86; 95%CI, 1.35 to 2.56; P=0.0001). In patients with initial systolic blood pressure >180 mmHg, low-dose Alteplase group had more patients with mRS of 0-3 at 90-day and less patients with of mRS 4-6 at 90-day than standard-dose Alteplase (P=0.002). There was no significant different in length of stay and overall complications with low-dose than standard-dose Alteplase (P=0.15).
Conclusion: As compared with standard-dose, intravenous low-dose Alteplase administered within 4.5 hours after the onset of stroke significant less favorable outcome, intra-cerebral hemorrhage, but not different in death, especially in the patients with initial systolic blood pressure <180 mmHg. However, patients with initial systolic blood pressure >180 mmHg, intravenous low-dose Alteplase had less patients with disability and death and more patient’s recovery with mRS of 0-3 at 90-day. (ClinicalTrial.gov Number, NCT03847883).
Low-Dose vs Standard-Dose Alteplase in Acute Lacunar Ischemic Stroke: The ENCHANTED Trial