학술논문
Safety and Efficacy of Dual Thrombolytic Therapy With Mutant Prourokinase and Small Bolus Alteplase for Ischemic Stroke: A Randomized Clinical Trial.
Document Type
Academic Journal
Author
van der Ende NAM; Department of Neurology, Erasmus MC University Medical Center, Rotterdam, the Netherlands.; Department of Radiology and Nuclear Medicine, Erasmus MC University Medical Center, Rotterdam, the Netherlands.; Roozenbeek B; Department of Neurology, Erasmus MC University Medical Center, Rotterdam, the Netherlands.; Smagge LEM; Department of Radiology and Nuclear Medicine, Erasmus MC University Medical Center, Rotterdam, the Netherlands.; Luijten SPR; Department of Neurology, Erasmus MC University Medical Center, Rotterdam, the Netherlands.; Department of Radiology and Nuclear Medicine, Erasmus MC University Medical Center, Rotterdam, the Netherlands.; Aerden LAM; Department of Neurology, Reinier de Graaf, Delft, the Netherlands.; Kraayeveld P; Department of Radiology and Nuclear Medicine, Reinier de Graaf, Delft, the Netherlands.; van den Wijngaard IR; Department of Neurology, Haaglanden Medical Center, The Hague, the Netherlands.; Lycklama À Nijeholt GJ; Department of Radiology and Nuclear Medicine, Haaglanden Medical Center, The Hague, the Netherlands.; den Hertog HM; Department of Neurology, Isala, Zwolle, the Netherlands.; Flach HZ; Department of Radiology and Nuclear Medicine, Isala, Zwolle, the Netherlands.; Postma AA; Department of Radiology and Nuclear Medicine, School for Mental Health and Sciences, Maastricht University Medical Center, Maastricht, the Netherlands.; Roosendaal SD; Department of Radiology and Nuclear Medicine, Amsterdam University Medical Centers, Amsterdam, the Netherlands.; Krietemeijer GM; Department of Radiology and Nuclear Medicine, Catharina Hospital, Eindhoven, the Netherlands.; Yo LSF; Department of Radiology and Nuclear Medicine, Catharina Hospital, Eindhoven, the Netherlands.; de Maat MPM; Department of Hematology, Erasmus MC University Medical Center, Rotterdam, the Netherlands.; Nieboer D; Department of Public Health, Erasmus MC University Medical Center, Rotterdam, the Netherlands.; Del Zoppo GJ; Division of Hematology, Department of Medicine, University of Washington School of Medicine, Seattle.; Department of Neurology, University of Washington School of Medicine, Seattle.; Meurer WJ; Departments of Neurology, University of Michigan Medical School, Ann Arbor.; Departments of Emergency Medicine, University of Michigan Medical School, Ann Arbor.; Berry Consultants, Austin, Texas.; Lingsma HF; Department of Public Health, Erasmus MC University Medical Center, Rotterdam, the Netherlands.; van der Lugt A; Department of Radiology and Nuclear Medicine, Erasmus MC University Medical Center, Rotterdam, the Netherlands.; Dippel DWJ; Department of Neurology, Erasmus MC University Medical Center, Rotterdam, the Netherlands.
Source
Publisher: American Medical Association Country of Publication: United States NLM ID: 101589536 Publication Model: Print Cited Medium: Internet ISSN: 2168-6157 (Electronic) Linking ISSN: 21686149 NLM ISO Abbreviation: JAMA Neurol Subsets: MEDLINE
Subject
Language
English
Abstract
Importance: Dual 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.
Objective: To assess the safety and efficacy of this dual thrombolytic treatment compared with alteplase.
Design, Setting, and Participants: This 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.
Interventions: Patients 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 Measures: The 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.
Results: A 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 Relevance: In 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 Registration: ClinicalTrials.gov Identifier: NCT04256473.
Objective: To assess the safety and efficacy of this dual thrombolytic treatment compared with alteplase.
Design, Setting, and Participants: This 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.
Interventions: Patients 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 Measures: The 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.
Results: A 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 Relevance: In 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 Registration: ClinicalTrials.gov Identifier: NCT04256473.