Safety and Efficacy of Dual Thrombolytic Therapy With Mutant Prourokinase and Small Bolus Alteplase for Ischemic Stroke
Authors: van der Ende Nadinda A. M. , Roozenbeek Bob , Smagge Lucas E. M. , Luijten Sven P. R. , Aerden Leo A. M. , Kraayeveld Petra , van den Wijngaard Ido R. , Lycklama à Nijeholt Geert J. , den Hertog Heleen M. , Flach H. Zwenneke , Postma Alida A. , Roosendaal Stefan D. , Krietemeijer G. Menno , Yo Lonneke S. F. , de Maat Moniek P. M. , Nieboer Daan , Del Zoppo Gregory J. , Meurer William J. , Lingsma Hester F. , van der Lugt Aad , Dippel Diederik W. J. ,   DUMAS Investigators, Dippel Diederik W.J. , van der Lugt Aad , van der Ende Nadinda A.M. , Roozenbeek Bob , de Maat Moniek P.M. , Aerden Leo A.M. , van den Wijngaard Ido R. , den Hertog Heleen M. , Kraayeveld Petra , Lycklama a Nijeholt Geert J. , Flack H. Zwenneke , Hill Michael D. , Rempel Jeremy , Lowe Ann M. , Lingsma Hester F. , van Leeuwen Nikki , Nieboer Daan , Del Zoppo Gregory J. , Rijken Dingeman C. , Cohen Adam , Gurewich Victor , Smagge Lucas E.M. , Roosendaal Stefan D. , Postma Alida A. , Yo Lonneke S.F. , Krietemeijer G. Menno , Sterrenberg Martin , El Ghannouti Naziha , Priem Debby , Batenburg Monique , Ponjee Eva , Eilander Rieke , de Meris Joke , Dofferhoff-Vermeulen Tamara , den Hartog Sanne J. , Kremer Stijn , Luijten Sven P.R. , Heiligers Leontien , Lansbergen-Engel Angela , Jager Karin 
Published: May 2023

ImportanceDual thrombolytic treatment with small bolus alteplase and mutant prourokinase has the potential to be a safer and more efficacious treatment for ischemic stroke than alteplase alone because mutant prourokinase is designed to act only on degraded fibrin without affecting circulating fibrinogen.ObjectiveTo assess the safety and efficacy of this dual thrombolytic treatment compared with alteplase.Design, Setting, and ParticipantsThis controlled, open-label randomized clinical trial with a blinded end point was conducted from August 10, 2019, to March 26, 2022, with a total follow-up of 30 days. Adult patients with ischemic stroke from 4 stroke centers in the Netherlands were enrolled.InterventionsPatients were randomized (1:1) to receive a bolus of 5 mg of intravenous alteplase and 40 mg of an intravenous infusion of mutant prourokinase (intervention) or usual care with 0.9 mg/kg of intravenous alteplase (control).Main Outcomes and MeasuresThe primary outcome was any intracranial hemorrhage (ICH) on neuroimaging at 24 hours. Secondary outcomes included functional outcome at 30 days, symptomatic ICH, and fibrinogen levels within 24 hours. Analyses were by intention to treat. Treatment effects were adjusted for baseline prognostic factors.ResultsA total of 268 patients were randomized, and 238 (median [IQR] age, 69 [59-77] years; 147 [61.8%] male) provided deferred consent and were included in the intention-to-treat population (121 in the intervention group and 117 in the control group). The median baseline score on the National Institutes of Health Stroke Scale was 3 (IQR, 2-5). Any ICH occurred in 16 of 121 patients (13.2%) in the intervention group and 16 of 117 patients (13.7%) in the control group (adjusted odds ratio, 0.98; 95% CI, 0.46-2.12). Mutant prourokinase led to a nonsignificant shift toward better modified Rankin Scale scores (adjusted common odds ratio, 1.16; 95% CI, 0.74-1.84). Symptomatic ICH occurred in none of the patients in the intervention group and 3 of 117 patients (2.6%) in the control group. Plasma fibrinogen levels at 1 hour remained constant in the intervention group but decreased in the control group (β = 65 mg/dL; 95% CI, 26-105 mg/dL).Conclusions and RelevanceIn this trial, dual thrombolytic treatment with small bolus alteplase and mutant prourokinase was found to be safe and did not result in fibrinogen depletion. Further evaluation of thrombolytic treatment with mutant prourokinase in larger trials to improve outcomes in patients with larger ischemic strokes is needed. Overall, in patients with minor ischemic stroke who met indications for treatment with intravenous thrombolytics but were not eligible for treatment with endovascular therapy, dual thrombolytic therapy with intravenous mutant prourokinase was not superior to treatment with intravenous alteplase alone.Trial RegistrationClinicalTrials.gov Identifier: NCT04256473