Effect of intravenous urokinase vs best medicine treatment on functional outcome for patients with acute minor stroke (TRUST): a randomized controlled trial

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Abstract

Background

The benefits of intravenous thrombolysis in patients with acute minor stroke remain controversial. For the aim of providing a better therapeutic strategy, high-quality trials are required to validate the efficacy of thrombolytic medicine other than intravenous recombinant tissue plasminogen and tenecteplase. In the trial, we evaluate the efficacy and safety of urokinase (UK) in acute minor stroke.

Methods

This multicenter, open-label, blinded-endpoint, randomized controlled clinical trial enrolled patients with minor stroke within 6 h of symptom onset, with a NIHSS score ≤ 5. The trial was conducted at 25 hospitals in China between October 2020 and February 2023. Eligible patients were randomized to the UK group (1,000,000 U) or the best medicine treatment group. The responsible investigator recommended and implemented the best medicine treatment based on guidelines. The primary endpoint was an excellent functional outcome, defined as a modified Rankin scale (mRS) score of 0–1 at 90 days. The primary safety outcome was symptomatic intracranial hemorrhage (sICH) within 36 h.

Results

A total of 999 patients were enrolled in the trial, the median age was 64 years, 371 (36.9%) were women; the median (IQR) NIHSS score was 3 (2–4). At 90 days, the primary endpoint was observed in 427 patients (84.9%) in the UK group and 425 patients (85.7%) in the control group (adjusted risk ratio [RR] 1.00, 95% CI 0.96–1.05, p = 0.87). A total of 3 patients in the UK-treated (0.6%) group experienced sICH compared to 1 patient (0.2%) in the control group (RR 1.83, 95% CI 0.16–20.27, p = 0.62).

Conclusions

For patients with acute minor stroke treated within 6 h of symptom onset, UK intravenous thrombolysis treatment was not found to be beneficial in terms of excellent functional outcome at 90 days, whereas it was safe.

Trial registration

ClinicalTrials.gov Identifier: NCT04420351.

Supplementary Information

The online version contains supplementary material available at 10.1186/s12916-024-03820-2.

Related collections

Most cited references 21

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Guidelines for the Early Management of Patients With Acute Ischemic Stroke: 2019 Update to the 2018 Guidelines for the Early Management of Acute Ischemic Stroke: A Guideline for Healthcare Professionals From the American Heart Association/American Stroke Association

William J. Powers, Alejandro A Rabinstein, Teri Ackerson … (2019)

Background and Purpose- The purpose of these guidelines is to provide an up-to-date comprehensive set of recommendations in a single document for clinicians caring for adult patients with acute arterial ischemic stroke. The intended audiences are prehospital care providers, physicians, allied health professionals, and hospital administrators. These guidelines supersede the 2013 Acute Ischemic Stroke (AIS) Guidelines and are an update of the 2018 AIS Guidelines. Methods- Members of the writing group were appointed by the American Heart Association (AHA) Stroke Council's Scientific Statements Oversight Committee, representing various areas of medical expertise. Members were not allowed to participate in discussions or to vote on topics relevant to their relations with industry. An update of the 2013 AIS Guidelines was originally published in January 2018. This guideline was approved by the AHA Science Advisory and Coordinating Committee and the AHA Executive Committee. In April 2018, a revision to these guidelines, deleting some recommendations, was published online by the AHA. The writing group was asked review the original document and revise if appropriate. In June 2018, the writing group submitted a document with minor changes and with inclusion of important newly published randomized controlled trials with >100 participants and clinical outcomes at least 90 days after AIS. The document was sent to 14 peer reviewers. The writing group evaluated the peer reviewers' comments and revised when appropriate. The current final document was approved by all members of the writing group except when relationships with industry precluded members from voting and by the governing bodies of the AHA. These guidelines use the American College of Cardiology/AHA 2015 Class of Recommendations and Level of Evidence and the new AHA guidelines format. Results- These guidelines detail prehospital care, urgent and emergency evaluation and treatment with intravenous and intra-arterial therapies, and in-hospital management, including secondary prevention measures that are appropriately instituted within the first 2 weeks. The guidelines support the overarching concept of stroke systems of care in both the prehospital and hospital settings. Conclusions- These guidelines provide general recommendations based on the currently available evidence to guide clinicians caring for adult patients with acute arterial ischemic stroke. In many instances, however, only limited data exist demonstrating the urgent need for continued research on treatment of acute ischemic stroke.

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Tissue Plasminogen Activator for Acute Ischemic Stroke

(1996)

Thrombolytic therapy for acute ischemic stroke has been approached cautiously because there were high rates of intracerebral hemorrhage in early clinical trials. We performed a randomized, double-blind trial of intravenous recombinant tissue plasminogen activator (t-PA) for ischemic stroke after recent pilot studies suggested that t-PA was beneficial when treatment was begun within three hours of the onset of stroke. The trial had two parts. Part 1 (in which 291 patients were enrolled) tested whether t-PA had clinical activity, as indicated by an improvement of 4 points over base-line values in the score of the National Institutes of Health stroke scale (NIHSS) or the resolution of the neurologic deficit within 24 hours of the onset of stroke. Part 2 (in which 333 patients were enrolled) used a global test statistic to assess clinical outcome at three months, according to scores on the Barthel index, modified Rankin scale, Glasgow outcome scale, and NIHSS: In part 1, there was no significant difference between the group given t-PA and that given placebo in the percentages of patients with neurologic improvement at 24 hours, although a benefit was observed for the t-PA group at three months for all four outcome measures. In part 2, the long-term clinical benefit of t-PA predicted by the results of part 1 was confirmed (global odds ratio for a favorable outcome, 1.7; 95 percent confidence interval, 1.2 to 2.6). As compared with patients given placebo, patients treated with t-PA were at least 30 percent more likely to have minimal or no disability at three months on the assessment scales. Symptomatic intracerebral hemorrhage within 36 hours after the onset of stroke occurred in 6.4 percent of patients given t-PA but only 0.6 percent of patients given placebo (P < 0.001). Mortality at three months was 17 percent in the t-PA group and 21 percent in the placebo group (P = 0.30). Despite an increased incidence of symptomatic intracerebral hemorrhage, treatment with intravenous t-PA within three hours of the onset of ischemic stroke improved clinical outcome at three months.

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European Stroke Organisation (ESO) guidelines on intravenous thrombolysis for acute ischaemic stroke

Eivind Berge, William Whiteley, Heinrich Audebert … (2021)

Intravenous thrombolysis is the only approved systemic reperfusion treatment for patients with acute ischaemic stroke. These European Stroke Organisation (ESO) guidelines provide evidence-based recommendations to assist physicians in their clinical decisions with regard to intravenous thrombolysis for acute ischaemic stroke. These guidelines were developed based on the ESO standard operating procedure and followed the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) methodology. The working group identified relevant clinical questions, performed systematic reviews and meta-analyses of the literature, assessed the quality of the available evidence, and wrote recommendations. Expert consensus statements were provided if not enough evidence was available to provide recommendations based on the GRADE approach. We found high quality evidence to recommend intravenous thrombolysis with alteplase to improve functional outcome in patients with acute ischemic stroke within 4.5 h after symptom onset. We also found high quality evidence to recommend intravenous thrombolysis with alteplase in patients with acute ischaemic stroke on awakening from sleep, who were last seen well more than 4.5 h earlier, who have MRI DWI-FLAIR mismatch, and for whom mechanical thrombectomy is not planned. These guidelines provide further recommendations regarding patient subgroups, late time windows, imaging selection strategies, relative and absolute contraindications to alteplase, and tenecteplase. Intravenous thrombolysis remains a cornerstone of acute stroke management. Appropriate patient selection and timely treatment are crucial. Further randomized controlled clinical trials are needed to inform clinical decision-making with regard to tenecteplase and the use of intravenous thrombolysis before mechanical thrombectomy in patients with large vessel occlusion.

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Author and article information

Contributors

Yuming Xu: xuyuming@zzu.edu.cn

Bo Song: fccsongb@zzu.edu.cn

Journal

Journal ID (nlm-ta): BMC Med

Journal ID (iso-abbrev): BMC Med

Title: BMC Medicine

Publisher: BioMed Central (London )

ISSN (Electronic): 1741-7015

Publication date (Electronic): 6 January 2025

Publication date PMC-release: 6 January 2025

Publication date Collection: 2025

Volume: 23

Electronic Location Identifier: 6

Affiliations

[1 ]Department of Neurology, The First Affiliated Hospital of Zhengzhou University, ( https://ror.org/056swr059) Zhengzhou, China

[2 ]NHC Key Laboratory of Prevention and Treatment of Cerebrovascular Disease, Zhengzhou, China

[3 ]Department of Neurology, Kaifeng Central Hospital, ( https://ror.org/04ac7y941) Kaifeng, China

[4 ]Department of Neurology, Hua County People’s Hospital, Anyang, China

[5 ]Department of Neurology, Mengzhou Traditional Chinese Medicine Hospital, ( https://ror.org/05kqdk687) Jiaozuo, China

[6 ]Department of Neurology, Linzhou People’s Hospital, ( https://ror.org/01y8cpr39) Anyang, China

[7 ]Department of Neurology, Tongbai County People’s Hospital, ( https://ror.org/054767b18) Nanyang, China

[8 ]Department of Neurology, Tiantan Hospital, Capital Medical University, ( https://ror.org/013xs5b60) Beijing, China

[9 ]Department of Neurology, Huashan Hospital Affiliated to Fudan University, ( https://ror.org/05201qm87) Shanghai, China

[10 ]Department of Clinical Sciences, Liverpool School of Tropical Medicine, ( https://ror.org/03svjbs84) Liverpool, UK

[11 ]Cardio-Neurology Division, Massachusetts General Hospital, Harvard Medical School, ( https://ror.org/03vek6s52) Boston, MA USA

[12 ]Neuroprotection Research Laboratory, Massachusetts General Hospital, Harvard Medical School, ( https://ror.org/03vek6s52) Boston, MA USA

Article

Publisher ID: 3820

DOI: 10.1186/s12916-024-03820-2

PMC ID: 11702182

PubMed ID: 39757192

SO-VID: ae78b422-5019-43d6-9a2c-ffa6746e6ab5

License:

Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if you modified the licensed material. You do not have permission under this licence to share adapted material derived from this article or parts of it. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by-nc-nd/4.0/.

History

Date received : 31 July 2024

Date accepted : 11 December 2024

Custom metadata

ScienceOpen disciplines: Medicine

Keywords: minor stroke,intravenous thrombolysis,urokinase,antiplatelet therapy,function outcome

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ScienceOpen disciplines: Medicine

Keywords: minor stroke, intravenous thrombolysis, urokinase, antiplatelet therapy, function outcome

Effect of intravenous urokinase vs best medicine treatment on functional outcome for patients with acute minor stroke (TRUST): a randomized controlled trial

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Abstract

Background

Methods

Results

Conclusions

Trial registration

Supplementary Information

Related collections

Stroke MRI

Most cited references 21

Guidelines for the Early Management of Patients With Acute Ischemic Stroke: 2019 Update to the 2018 Guidelines for the Early Management of Acute Ischemic Stroke: A Guideline for Healthcare Professionals From the American Heart Association/American Stroke Association

Tissue Plasminogen Activator for Acute Ischemic Stroke

European Stroke Organisation (ESO) guidelines on intravenous thrombolysis for acute ischaemic stroke

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