{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,5]],"date-time":"2026-11-05T13:54:50Z","timestamp":1793886890381,"version":"4.8.0"},"reference-count":26,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,5,29]],"date-time":"2026-05-29T00:00:00Z","timestamp":1780012800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Neurol."],"abstract":"<jats:sec>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>This study aims to systematically evaluate the efficacy and safety of different intravenous thrombolytic agents in patients with acute ischemic stroke (IS) who present between 4.5 and 24 h after symptom onset. A network meta-analysis was conducted to compare the available treatments and provide evidence to support clinical decision-making and inform updates to clinical guidelines.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>A systematic search was conducted in PubMed, Embase, the Cochrane Library, and Web of Science, covering the period from the inception of each database to February 1, 2026. Randomized controlled trials (RCTs) comparing different intravenous thrombolytic regimens within the extended time window were included. Primary outcomes included a modified Rankin Scale score of 0\u20131 at 90 days, mRS 0\u20132 at 90 days, improvement in the National Institutes of Health Stroke Scale at 24 h, reperfusion at 24 h, symptomatic intracranial hemorrhage at 36 h, and mortality at 90 days. A network meta-analysis using a frequentist random-effects model was conducted to report relative risks and 95% confidence intervals. Interventions were ranked using the cumulative ranked area under the curve, and the certainty of the evidence was assessed using the GRADE\/CINeMA framework.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>A total of 10 RCTs (2,409 patients) were included, involving five interventions: alteplase (rt-PA), tenaplase (TNK), JX10, standard of care (SoC), and placebo (PBO). For the primary outcome of 90-day mRS 0\u20132, compared with SoC, rt-PA significantly increased the proportion of functionally independent patients (RR = 1.21, 95% CI 1.06\u20131.38, low certainty), JX10 (RR = 1.50, 95% CI 0.87\u20132.58, very low certainty) and TNK (RR = 1.07, 95% CI 0.93\u20131.23, low certainty) showed a trend toward improvement but did not reach statistical significance. The SUCRA ranking showed that JX10 (87.7%) and rt-PA (77.0%) ranked first and second, respectively. Regarding the early surrogate endpoint of 24-h reperfusion, rt-PA (RR = 2.65, 95% CI 1.57\u20134.46, low certainty) was superior to SoC and ranked first in the SUCRA ranking (99.9%). Regarding safety, rt-PA significantly increased the risk of 36-h SICH compared with SoC (RR = 5.82, 95% CI 1.47\u201322.95, low certainty), while JX10 had the highest risk of bleeding (SUCRA 82.1%). There were no statistically significant differences in 90-day mortality rates among the interventions. The certainty of the evidence was predominantly low to very low, primarily limited by risk of bias, imprecision, and indirectness.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>\n                      In patients with acute IS within 4.5\u201324 h of onset, rt-PA significantly improves functional independence at 90 days and 24-h reperfusion, but increases the risk of symptomatic intracranial hemorrhage. The ranking analysis suggested JX10 might have a favorable functional outcome profile, but this finding is derived from a single, small-sample, dose-exploratory study\n                      <jats:italic>n<\/jats:italic>\n                      = 90 with no direct comparative data against other thrombolytics. Consequently, the evidence for JX10 is considered hypothesis-generating only, and its clinical efficacy and safety remain unestablished. Given the high risk of hemorrhage, its clinical application is not yet supported. The therapeutic advantages of TNK have not been fully demonstrated, though its safety profile is relatively superior. Clinical decision-making requires individualized consideration based on imaging screening, bleeding risk assessment, and patient preference. There is an urgent need for larger-scale, rigorously designed head-to-head RCTs to provide higher-quality evidence for expanding the time window for thrombolytic therapy.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Systematic trial registration<\/jats:title>\n                    <jats:p>\n                      <jats:ext-link>https:\/\/www.crd.york.ac.uk\/PROSPERO\/view\/CRD420261350208<\/jats:ext-link>\n                      , identifier: CRD420261350208\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fneur.2026.1845353","type":"journal-article","created":{"date-parts":[[2026,5,29]],"date-time":"2026-05-29T04:56:56Z","timestamp":1780030616000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":2,"title":["Intravenous thrombolysis for acute ischemic stroke in the extended time window of 4.5\u201324 h: a systematic review and network meta-analysis of randomized controlled trials"],"prefix":"10.3389","volume":"17","author":[{"given":"Xiaoqi","family":"Yu","sequence":"first","affiliation":[{"name":"Second Clinical College, Liaoning University of Traditional Chinese Medicine","place":["Shenyang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiuye","family":"Sun","sequence":"additional","affiliation":[{"name":"Department of Rehabilitation, The Second Affiliated Hospital of Liaoning University of Traditional Chinese Medicine","place":["Shenyang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fang","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Rehabilitation, The Second Affiliated Hospital of Liaoning University of Traditional Chinese Medicine","place":["Shenyang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,5,29]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"e70558","DOI":"10.1002\/mco2.70558","article-title":"Stroke: epidemiology, risk factors, signaling pathways, and clinical management","volume":"6","author":"Ren","year":"2025","journal-title":"MedComm"},{"key":"B2","doi-asserted-by":"publisher","first-page":"1873","DOI":"10.1016\/S0140-6736(25)01637-X","article-title":"Burden of 375 diseases and injuries, risk-attributable burden of 88 risk factors, and healthy life expectancy in 204 countries and territories, including 660 subnational locations, 1990-2023: a systematic analysis for the Global Burden of Disease Study 2023","volume":"406","year":"2025","journal-title":"Lancet"},{"key":"B3","doi-asserted-by":"publisher","first-page":"2167","DOI":"10.1016\/j.jacc.2025.08.015","article-title":"Global, regional, and national burden of cardiovascular diseases and risk factors in 204 countries and territories, 1990-2023","volume":"86","year":"2025","journal-title":"J Am Coll Cardiol"},{"key":"B4","doi-asserted-by":"publisher","first-page":"13","DOI":"10.1136\/jnnp-2025-335954","article-title":"Global burden of disease study highlights the global, regional and national trends of stroke","volume":"97","author":"Yang","year":"2026","journal-title":"J Neurol Neurosurg Psychiatry"},{"key":"B5","doi-asserted-by":"publisher","first-page":"937","DOI":"10.1007\/s12975-021-00916-2","article-title":"Four decades of ischemic penumbra and its implication for ischemic stroke","volume":"12","author":"Yang","year":"2021","journal-title":"Transl Stroke Res"},{"key":"B6","doi-asserted-by":"publisher","first-page":"1265","DOI":"10.1016\/S0140-6736(24)01410-7","article-title":"Endovascular management of acute stroke","volume":"404","author":"Nguyen","year":"2024","journal-title":"Lancet"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1161\/STR.0000000000000513.","article-title":"2026 Guideline for the early management of patients with acute ischemic stroke: a guideline from the American Heart Association\/American Stroke Association","author":"Prabhakaran","year":"2026","journal-title":"Stroke"},{"key":"B8","doi-asserted-by":"publisher","first-page":"821","DOI":"10.1007\/s11239-025-03135-w","article-title":"From \u201ctime is brain\u201d to \u201ctime is collaterals\u201d: updates on the role of cerebral collateral circulation in stroke","volume":"58","author":"Marilena","year":"2025","journal-title":"J Thromb Thrombolysis"},{"key":"B9","doi-asserted-by":"publisher","first-page":"1490476","DOI":"10.3389\/fneur.2024.1490476","article-title":"Thrombolytic therapy for patients with acute ischemic stroke: systematic review and network meta-analysis of randomized trials","volume":"15","author":"Sun LCY Li","year":"2025","journal-title":"Front Neurol"},{"key":"B10","doi-asserted-by":"publisher","first-page":"777","DOI":"10.7326\/M14-2385","article-title":"The PRISMA extension statement for reporting of systematic reviews incorporating network meta-analyses of health care interventions: checklist and explanations","volume":"162","author":"Hutton","year":"2015","journal-title":"Ann Intern Med"},{"key":"B11","doi-asserted-by":"publisher","first-page":"l4898","DOI":"10.1136\/bmj.l4898","article-title":"RoB 2: a revised tool for assessing risk of bias in randomised trials","volume":"366","author":"Sterne","year":"2019","journal-title":"BMJ"},{"key":"B12","doi-asserted-by":"publisher","first-page":"184","DOI":"10.5853\/jos.2024.05715","article-title":"Tenecteplase beyond 45 hours in acute ischemic stroke: a systematic review and meta-analysis of randomized clinical trials","volume":"27","author":"Aladawi","year":"2025","journal-title":"J Stroke"},{"key":"B13","doi-asserted-by":"publisher","first-page":"123653","DOI":"10.1016\/j.jns.2025.123653","article-title":"Novel thrombolytic agents for acute ischemic stroke: a comprehensive review of current evidence","volume":"476","author":"Hotz","year":"2025","journal-title":"J Neurol Sci"},{"key":"B14","doi-asserted-by":"publisher","first-page":"166","DOI":"10.1101\/2025.09.22.25336273","article-title":"Extended thrombolysis in acute ischemic stroke: a Bayesian meta-analysis and umbrella review","volume":"101","author":"Garg","year":"2026","journal-title":"Am J Emerg Med"},{"key":"B15","doi-asserted-by":"publisher","first-page":"215","DOI":"10.2139\/ssrn.4912720","article-title":"Safety outcomes following intravenous thrombolysis in acute ischemic stroke: a systematic review and network meta-analysis: X. Yao et al","volume":"40","author":"Yao","year":"2026","journal-title":"CNS Drugs"},{"key":"B16","doi-asserted-by":"publisher","first-page":"1730677","DOI":"10.3389\/fneur.2025.1730677","article-title":"Comparison of tenecteplase vs. alteplase in addition to thrombectomy in patients with ischemic stroke caused by large vessel occlusion within 45 h: a network meta-analysis","volume":"16","author":"Li","year":"2025","journal-title":"Front Neurol"},{"key":"B17","doi-asserted-by":"publisher","first-page":"2786","DOI":"10.1161\/STROKEAHA.124.048464","article-title":"Anti-inflammatory thrombolytic JX10 (TMS-007) in late presentation of acute ischemic stroke","volume":"55","author":"Niizuma","year":"2024","journal-title":"Stroke"},{"key":"B18","doi-asserted-by":"publisher","first-page":"1795","DOI":"10.1056\/NEJMoa1813046","article-title":"Thrombolysis guided by perfusion imaging up to 9 hours after onset of stroke","volume":"380","author":"Ma","year":"2019","journal-title":"N Engl J Med"},{"key":"B19","doi-asserted-by":"publisher","first-page":"788","DOI":"10.1001\/jama.2025.12063","article-title":"Alteplase for acute ischemic stroke at 45 to 24 hours: the HOPE randomized clinical trial","volume":"334","author":"Zhou","year":"2025","journal-title":"JAMA"},{"key":"B20","doi-asserted-by":"publisher","first-page":"1288","DOI":"10.1056\/NEJMoa2413344","article-title":"Alteplase for posterior circulation ischemic stroke at 45 to 24 hours","volume":"392","author":"Yan","year":"2025","journal-title":"N Engl J Med"},{"key":"B21","doi-asserted-by":"publisher","first-page":"3332","DOI":"10.1161\/STROKEAHA.125.052511","article-title":"Efficacy of Tenecteplase in large vessel occlusion stroke within 24 hours of symptom onset: the ETERNAL-LVO randomized controlled trial","volume":"56","author":"Yogendrakumar","year":"2025","journal-title":"Stroke"},{"key":"B22","doi-asserted-by":"publisher","first-page":"203","DOI":"10.1056\/NEJMoa2402980","article-title":"Tenecteplase for ischemic stroke at 4","volume":"391","author":"Xiong","year":"2024","journal-title":"N Engl J Med"},{"key":"B23","doi-asserted-by":"publisher","first-page":"701","DOI":"10.1056\/NEJMoa2310392","article-title":"Tenecteplase for stroke at 45 to 24 hours with perfusion-imaging selection","volume":"390","author":"Albers","year":"2024","journal-title":"N Engl J Med"},{"key":"B24","doi-asserted-by":"publisher","first-page":"344","DOI":"10.1161\/STROKEAHA.124.048375","article-title":"Tenecteplase thrombolysis for stroke up to 24 hours after onset with perfusion imaging selection: the CHABLIS-T II randomized clinical trial","volume":"56","author":"Cheng","year":"2025","journal-title":"Stroke"},{"key":"B25","doi-asserted-by":"publisher","first-page":"483","DOI":"10.1177\/1747493019840938","article-title":"Extending the time window for intravenous thrombolysis in acute ischemic stroke using magnetic resonance imaging-based patient selection","volume":"14","author":"Ringleb","year":"2019","journal-title":"Int J Stroke"},{"key":"B26","doi-asserted-by":"publisher","first-page":"371","DOI":"10.5853\/jos.2023.00668","article-title":"Intravenous tenecteplase for acute ischemic stroke within 45-24 hours of onset (ROSE-TNK): a phase 2, randomized, multicenter study","volume":"25","author":"Wang","year":"2023","journal-title":"J Stroke"}],"container-title":["Frontiers in Neurology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fneur.2026.1845353\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,5,29]],"date-time":"2026-05-29T04:56:57Z","timestamp":1780030617000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fneur.2026.1845353\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,5,29]]},"references-count":26,"alternative-id":["10.3389\/fneur.2026.1845353"],"URL":"https:\/\/doi.org\/10.3389\/fneur.2026.1845353","relation":{},"ISSN":["1664-2295"],"issn-type":[{"value":"1664-2295","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,5,29]]},"article-number":"1845353"}}