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Randomized Controlled Trial
. 2023 Jul 1;80(7):714-722.
doi: 10.1001/jamaneurol.2023.1262.

Safety and Efficacy of Dual Thrombolytic Therapy With Mutant Prourokinase and Small Bolus Alteplase for Ischemic Stroke: A Randomized Clinical Trial

Nadinda A M van der Ende  1   2 , Bob Roozenbeek  1 , Lucas E M Smagge  2 , Sven P R Luijten  1   2 , Leo A M Aerden  3 , Petra Kraayeveld  4 , Ido R van den Wijngaard  5 , Geert J Lycklama À Nijeholt  6 , Heleen M den Hertog  7 , H Zwenneke Flach  8 , Alida A Postma  9 , Stefan D Roosendaal  10 , G Menno Krietemeijer  11 , Lonneke S F Yo  11 , Moniek P M de Maat  12 , Daan Nieboer  13 , Gregory J Del Zoppo  14   15 , William J Meurer  16   17   18 , Hester F Lingsma  13 , Aad van der Lugt  2 , Diederik W J Dippel  1 ; DUMAS Investigators
Collaborators, Affiliations
Randomized Controlled Trial

Safety and Efficacy of Dual Thrombolytic Therapy With Mutant Prourokinase and Small Bolus Alteplase for Ischemic Stroke: A Randomized Clinical Trial

Nadinda A M van der Ende et al. JAMA Neurol. .

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.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr van den Wijngaard reported receiving personal fees from Philips and being a stockholder in Neurophyxia outside the submitted work. Dr Postma reported receiving grants from Siemens Healthineers and Bayer Healthcare outside the submitted work. Dr Meurer reported receiving funding from Berry Consultants, which received funds from Thrombolytic Science, to create and implement adaptive design during the conduct of the study. Dr van der Lugt reported receiving grants from Stryker, Penumbra, Medtronic, and Cerenovus outside the submitted work. Dr Dippel reported receiving grants from Stryker, Medtronic, and Cerenovus outside the submitted work. No other disclosures were reported.

Figures

Figure.
Figure.. CONSORT Flow Diagram of Patient Process Throughout the Trial
EVT indicates endovascular therapy; ITT, intention to treat; IV, intravenous; IVT, intravenous thrombolytics; m-proUK, mutant prourokinase; mRS, modified Rankin Scale; and NIHSS, National Institutes of Health Stroke Scale.
See this image and copyright information in PMC

References

    1. Wardlaw JM, Murray V, Berge E, del Zoppo GJ. Thrombolysis for acute ischaemic stroke. Cochrane Database Syst Rev. 2014;2014(7):CD000213. doi:10.1002/14651858.CD000213.pub3 - DOI - PMC - PubMed
    1. National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group . Tissue plasminogen activator for acute ischemic stroke. N Engl J Med. 1995;333(24):1581-1587. doi:10.1056/NEJM199512143332401 - DOI - PubMed
    1. Goyal M, Menon BK, van Zwam WH, et al. ; HERMES Collaborators . Endovascular thrombectomy after large-vessel ischaemic stroke: a meta-analysis of individual patient data from five randomised trials. Lancet. 2016;387(10029):1723-1731. doi:10.1016/S0140-6736(16)00163-X - DOI - PubMed
    1. Duvekot MHC, Venema E, Rozeman AD, et al. ; PRESTO Investigators . Comparison of eight prehospital stroke scales to detect intracranial large-vessel occlusion in suspected stroke (PRESTO): a prospective observational study. Lancet Neurol. 2021;20(3):213-221. doi:10.1016/S1474-4422(20)30439-7 - DOI - PubMed
    1. del Zoppo GJ, Poeck K, Pessin MS, et al. . Recombinant tissue plasminogen activator in acute thrombotic and embolic stroke. Ann Neurol. 1992;32(1):78-86. doi:10.1002/ana.410320113 - DOI - PubMed

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