Dual thrombolysis offers no additional safety advantage over alteplase alone

Diederik W. Dippel, M.D., Ph.D.

Results from an open-label, randomized, controlled clinical trial (NCT04256473) in patients with mild ischemic stroke who are not candidates for endovascular therapy show that dual thrombolysis with low-dose bolus alteplase and mutant pro-urokinase is safe. , was found not to result in fibrinogen depletion. however, this approach is not superior to intravenous alteplase alone.

was announced in JAMA NeurologyThe modified intent-to-treat population (mITT) received either a 5 mg intravenous bolus of alteplase and a 40 mg intravenous infusion of mutant pro-urokinase or 0.9 mg/kg intravenous alteplase. Performed from August 2019 to March 2022, this cohort had a median baseline National Institutes of Health stroke scale score of 3 (IQR, 2–5). Adult patients from four stroke centers in the Netherlands were followed after 30 days and neuroimaging after 24 hours to determine the primary outcome of intracranial hemorrhage (ICH).

In total, ICH occurred in 16 of 121 (13.2%) patients in the intervention group and 16 (13.7%) of 117 patients in the alteplase alone or control groups (adjusted OR, 0.98, 95% CI, 0.46-2.12). Led by Diederik W. Dippel, MD, Ph.D., Erasmus MC Neurology, the results were similar for his targeted mITT, targeted modified treatments, and protocol-by-protocol analysis.

“Further evaluation of thrombolytic therapy with mutant pro-urokinase in large trials is needed to improve outcomes in patients with larger ischemic stroke,” write Dippel et al. “Overall, in patients with mild ischemic stroke who are eligible for treatment with intravenous thrombolytics but who are not eligible for treatment with EVT, intravenous variant We were unable to demonstrate the superiority of dual thrombolysis with pro-urokinase.”

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For secondary outcomes, the intervention group compared to the control group at 1 hour (adjusted β = 65 mg/dL; 95% CI, 26-105) and 3 hours (adjusted β = 47 mg/dL; 95%). showed higher fibrinogen levels than CI, 2-93 mg/dL) and after 24 hours (adjusted β = 51 mg/dL; 95% CI, 10-92 mg/dL). The investigators found no significant between-group differences in safety outcomes and no clinically relevant differences in treatment effects based on prespecified subgroups. Symptomatic ICH did not occur in the intervention group but occurred in 3 of 117 (2.6%) in the control group.

By 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 121 patients (1.7%) in the intervention group and 4 of 117 patients (3.4%) in the control group. Both groups included 2 individuals each with progressive stroke or new ischemic stroke.

This study was limited by the fact that we excluded patients eligible for EVT, largely because the investigators reasoned that subsequent EVT might interfere with the assessment of intervention efficacy. Furthermore, Dippel et al. noted that “although our results may be generalizable to all patients indicated for treatment with intravenous thrombolytic agents, patients with large vascular occlusions require further evaluation.” wrote.

1. Van der Ende N, Roozenbeek, R, Smagge LE, et al. Safety and efficacy of double thrombolysis with mutant pro-urokinase and low-dose alteplase for ischemic stroke: a randomized clinical trial. JAMA Neurol. Published online May 22, 2023. doi:10.1001/jamaneurol.2023.1262

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