Dual Thrombolytic Treatment Provides No Additive Safety Benefit Over Alteplase Alone

Diederik W. Dippel, MD, PhD

Findings from a controlled, open-label, randomized clinical trial (NCT04256473) of patients with minor ischemic stroke not eligible for endovascular therapy showed that dual thrombolytic treatment with small bolus alteplase and mutant prourokinase was found to be safe and did not result in fibrinogen depletion; however, this approach was not superior to treatment with intravenous alteplase alone.

Published in JAMA Neurology, the modified intent-to-treat population (mITT) included 238 individuals randomly assigned 1:1 to receive either a bolus of 5 mg of intravenous alteplase and 40 mg of an intravenous infusion of mutant prourokinase or usual care with 0.9 mg/kg of intravenous alteplase. Conducted from August 2019 to March 2022, the median baseline National Institutes of Health Stroke Scale score was 3 (IQR, 2-5) for the cohort. Adult patients across 4 stroke centers in the Netherlands were followed up after 30 days, with the primary outcome of any intracranial hemorrhage (ICH) on neuroimaging at 24 hours.

In total, ICH occurred in 16 of 121 patients (13.2%) in the intervention group and 16 of 117 patients (13.7%) on the alteplase alone group, or control (adjusted OR, 0.98; 95% CI, 0.46-2.12). Led by Diederik W. Dippel, MD, PhD, Department of Neurology, Erasmus MC, the findings were similar in the targeted mITT, targeted modified receiving-treatment, and per-protocol analyses.

"Further evaluation of thrombolytic treatment with mutant prourokinase in larger trials to improve outcomes in patients with larger ischemic strokes is needed," Dippel et al wrote. "Overall, in patients with minor ischemic stroke who met the indications for treatment with intravenous thrombolytics but who are not eligible for treatment with EVT, we could not prove superiority of dual thrombolytic therapy with intravenous mutant prourokinase over treatment with intravenous alteplase alone."

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On secondary outcomes, the intervention group demonstrated higher fibrinogen levels than the control group at 1 hour (adjusted ß = 65 mg/dL; 95% CI, 26-105), at 3 hours (adjusted ß = 47 mg/dL; 95% CI, 2-93 mg/dL) and at 24 hours (adjusted ß = 51 mg/dL; 95% CI, 10-92 mg/dL). Investigators identified no significant between-group differences in safety outcomes, and no clinically relevant differences in treatment effects based on prespecified subgroups. Symptomatic ICH occurred in no patients in the intervention group and 3 of 117 patients (2.6%) in the control group.

Up to day 30, a total of 38 serious adverse events (AEs) were recorded in 15.7% (n = 19) of patients in the intervention group and 16.2% (n = 19) of patients in the control group. Death occurred in 2 of the 121 patients (1.7%) in the intervention group and 4 of the 117 patients (3.4%) in the control group. Both groups had 2 individuals each who demonstrated stroke progression or new ischemic stroke.

The study was limited by the fact that it excluded patients eligible for EVT, mainly because investigators reasoned that subsequent EVT might disturb the assessment of the intervention effect. Additionally, Dippel et al wrote, "our results may be generalizable to all patients with an indication for treatment with intravenous thrombolytics, but this needs further evaluation for patients with a large vessel occlusion."

REFERENCE
1. Van der Ende N, Roozenbeek, R, Smagge LE, et al. Safety and efficacy of dual thrombolytic therapy with mutant prourokinase and small bolus alteplase for ischemic stroke: a randomized clinical trial. JAMA Neurol. published online May 22, 2023. doi:10.1001/jamaneurol.2023.1262