{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,7]],"date-time":"2026-08-07T15:47:50Z","timestamp":1786117670498,"version":"build-2736575974"},"reference-count":25,"publisher":"SAGE Publications","license":[{"start":{"date-parts":[[2026,8,1]],"date-time":"2026-08-01T00:00:00Z","timestamp":1785542400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"},{"start":{"date-parts":[[2026,8,1]],"date-time":"2026-08-01T00:00:00Z","timestamp":1785542400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.sagepub.com\/page\/policies\/text-and-data-mining-license"}],"content-domain":{"domain":["journals.sagepub.com"],"crossmark-restriction":true},"short-container-title":["Ther Adv Neurol Disord"],"published-print":{"date-parts":[[2026,8]]},"abstract":"<jats:sec>\n                    <jats:title>Introduction<\/jats:title>\n                    <jats:p>In the contemporary endovascular thrombectomy (EVT) era, treatment decisions are often made without routine perfusion imaging. However, perfusion remains central to intravenous thrombolysis (IVT) beyond 4.5 hours. Evidence across extended and very late windows remains uncertain.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Objectives<\/jats:title>\n                    <jats:p>To evaluate the efficacy and safety of perfusion-guided IVT beyond 4.5 hours after acute ischemic stroke and to assess the robustness of evidence across the 4.5\u20139 hour and 9\u201324 hour windows.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Design<\/jats:title>\n                    <jats:p>Time-stratified systematic review and meta-analysis of phase III randomized controlled trials.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Data Sources and Methods<\/jats:title>\n                    <jats:p>We systematically searched PubMed, Embase, and the Cochrane Library from inception to February 8, 2026. Phase III randomized controlled trials enrolling perfusion-selected AIS patients treated 4.5\u201324 hours from last known well were included; trials permitting stratification into 4.5\u20139 and 9\u201324 hours were prioritized. Outcomes included 90 days excellent outcome (mRS 0\u20131), favorable (mRS 0\u20132), good (mRS 0\u20133), mortality, and symptomatic intracerebral hemorrhage (sICH). Random-effects meta-analysis and trial sequential analysis (TSA) were performed.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Five randomized controlled trials (n=1,798) were included. IVT increased excellent outcome in both the 4.5\u20139 hour window (n=866; RR 1.30, 95% CI 1.08\u20131.56; I\n                      <jats:sup>2<\/jats:sup>\n                      =0%; absolute risk difference (ARD)=9.1%; NNT=11) and the 9\u201324 hour window (n=563; RR 1.41, 95% CI 1.10\u20131.79; I\n                      <jats:sup>2<\/jats:sup>\n                      =0%; ARD=11.1%; NNT=9). Across 4.5\u201324 hours, IVT improved favorable (RR 1.18, 95% CI 1.07\u20131.29; I\n                      <jats:sup>2<\/jats:sup>\n                      =0%) and good outcomes (RR 1.11, 95% CI 1.03\u20131.21; I\n                      <jats:sup>2<\/jats:sup>\n                      =0%), with no significant effect on mortality (RR 1.14, 95% CI 0.85\u20131.52; I\n                      <jats:sup>2<\/jats:sup>\n                      =0%). IVT increased sICH risk overall (RR 5.63, 95% CI 2.17\u201314.57; I\n                      <jats:sup>2<\/jats:sup>\n                      =0%; ARD=approximately 3.0%; NNH=33). TSA suggested that the cumulative evidence has not yet reached the required information size for firm conclusiveness.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>In the contemporary EVT era, perfusion-guided IVT may remain clinically relevant for selected patients treated beyond 4.5 hours, particularly those not eligible for thrombectomy or without immediate EVT access. Current phase III randomized evidence suggests improved functional outcomes but increased symptomatic intracerebral hemorrhage. However, TSA indicates that the evidence remains underpowered for definitive conclusions. Evidence for the 9\u201324 hour window is particularly limited and derived from China-based trials; therefore, these findings should be interpreted as hypothesis-supporting rather than conclusive.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1177\/17562864261474987","type":"journal-article","created":{"date-parts":[[2026,8,4]],"date-time":"2026-08-04T03:41:30Z","timestamp":1785814890000},"update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":0,"title":["Perfusion-guided thrombolysis beyond 4.5 hours for acute ischemic stroke: A time-stratified systematic review and meta-analysis"],"prefix":"10.1177","volume":"19","author":[{"ORCID":"https:\/\/orcid.org\/0009-0001-1484-8016","authenticated-orcid":false,"given":"Wen-Wen","family":"Tsai","sequence":"first","affiliation":[{"name":"Chi-Mei Medical Center"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kuan-Hsien","family":"Lu","sequence":"additional","affiliation":[{"name":"Chi-Mei Medical Center"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kuan-Hung","family":"Lin","sequence":"additional","affiliation":[{"name":"Chi-Mei Medical Center"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jheng-Yan","family":"Wu","sequence":"additional","affiliation":[{"name":"Chi Mei Medical Center"},{"name":"National Cheng Kung University"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chih-Cheng","family":"Lai","sequence":"additional","affiliation":[{"name":"Chi Mei Medical Center"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kuo Chuan","family":"Hung","sequence":"additional","affiliation":[{"name":"Chi Mei Medical Center"},{"name":"National Sun Yat-sen University"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yi-Ting","family":"Tsai","sequence":"additional","affiliation":[{"name":"National Cheng Kung University"},{"name":"Chi-Mei Medical Center"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meng-Tsang","family":"Hsieh","sequence":"additional","affiliation":[{"name":"Chi-Mei Medical Center"},{"name":"National Sun Yat-sen University"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"179","published-online":{"date-parts":[[2026,8,3]]},"reference":[{"key":"e_1_3_8_2_2","doi-asserted-by":"publisher","DOI":"10.1161\/STROKEAHA.118.022606"},{"key":"e_1_3_8_3_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(14)60584-5"},{"key":"e_1_3_8_4_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1804355"},{"key":"e_1_3_8_5_2","doi-asserted-by":"publisher","DOI":"10.1001\/jama.2025.12063"},{"key":"e_1_3_8_6_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2402980"},{"key":"e_1_3_8_7_2","doi-asserted-by":"publisher","DOI":"10.1177\/1747493019840938"},{"key":"e_1_3_8_8_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1813046"},{"key":"e_1_3_8_9_2","doi-asserted-by":"publisher","DOI":"10.1177\/2396987321989865"},{"key":"e_1_3_8_10_2","article-title":"Guideline for the Early Management of Patients With Acute Ischemic Stroke: A Guideline From the American Heart Association\/American Stroke Association","volume":"57","author":"Prabhakaran S","year":"2026","unstructured":"Prabhakaran S, Gonzalez NR, Zachrison KS, et al. Guideline for the Early Management of Patients With Acute Ischemic Stroke: A Guideline From the American Heart Association\/American Stroke Association. Stroke 2026; 57. https:\/\/doi.org\/10.1161\/STR.0000000000000513","journal-title":"Stroke"},{"key":"e_1_3_8_11_2","first-page":"20260205","article-title":"Tenecteplase for Acute Non-Large Vessel Occlusion 4.5 to 24 Hours After Ischemic Stroke: The OPTION Randomized Clinical Trial","volume":"335","author":"Ma G","year":"2026","unstructured":"Ma G, Mo R, Zuo Y, et al. Tenecteplase for Acute Non-Large Vessel Occlusion 4.5 to 24 Hours After Ischemic Stroke: The OPTION Randomized Clinical Trial. Jama 2026; 335: 20260205\u201320261147. https:\/\/doi.org\/10.1001\/jama.2026.0210","journal-title":"Jama"},{"key":"e_1_3_8_12_2","doi-asserted-by":"publisher","DOI":"10.1161\/STROKEAHA.124.048536"},{"key":"e_1_3_8_13_2","first-page":"107602962514141","article-title":"Efficacy and Safety of Intravenous Thrombolytics in Ischemic Stroke Beyond the 4.5-Hour Time Window: A Systematic Review and Meta-Analysis","volume":"32","author":"Waseem MH","year":"2026","unstructured":"Waseem MH, Abideen ZU, Ghori D, et al. Efficacy and Safety of Intravenous Thrombolytics in Ischemic Stroke Beyond the 4.5-Hour Time Window: A Systematic Review and Meta-Analysis. Clin Appl Thromb Hemost 2026; 32: 10760296251414133. https:\/\/doi.org\/10.1177\/10760296251414133","journal-title":"Clin Appl Thromb Hemost"},{"key":"e_1_3_8_14_2","doi-asserted-by":"publisher","DOI":"10.1136\/bmj.n71"},{"key":"e_1_3_8_15_2","doi-asserted-by":"publisher","DOI":"10.1136\/bmj.l4898"},{"key":"e_1_3_8_16_2","doi-asserted-by":"publisher","DOI":"10.1016\/0197-2456(86)90046-2"},{"key":"e_1_3_8_17_2","volume-title":"Cochrane Handbook for Systematic Reviews of Interventions","author":"Deeks JJHJ","year":"2022","unstructured":"Deeks JJHJ, Altman DG. Chapter 10: Analysing data and undertaking meta-analyses. In: Higgins JPTTJ, Chandler J, Cumpston M, et al. (eds). Cochrane Handbook for Systematic Reviews of Interventions. The Cochrane Collaboration, 2022. Version 63 (updated February 2022)."},{"key":"e_1_3_8_18_2","doi-asserted-by":"publisher","DOI":"10.1002\/9781119536604.ch13"},{"key":"e_1_3_8_19_2","volume-title":"Cochrane Handbook for Systematic Reviews of Interventions","author":"Higgins JPTGS","year":"2011","unstructured":"Higgins JPTGS. Cochrane Handbook for Systematic Reviews of Interventions. The Cochrane Collaboration, 2011. Version 5.1.0 [updated March 2011]."},{"key":"e_1_3_8_20_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jclinepi.2007.03.013"},{"key":"e_1_3_8_21_2","doi-asserted-by":"publisher","DOI":"10.4103\/ds.DS-D-22-00154"},{"key":"e_1_3_8_22_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jclinepi.2021.07.011"},{"key":"e_1_3_8_23_2","doi-asserted-by":"publisher","DOI":"10.3389\/fneur.2020.594613"},{"key":"e_1_3_8_24_2","doi-asserted-by":"publisher","DOI":"10.1161\/STR.0000000000000152"},{"key":"e_1_3_8_25_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jns.2020.117217"},{"key":"e_1_3_8_26_2","doi-asserted-by":"publisher","DOI":"10.1161\/STROKEAHA.119.025080"}],"container-title":["Therapeutic Advances in Neurological Disorders"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/journals.sagepub.com\/doi\/pdf\/10.1177\/17562864261474987","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/journals.sagepub.com\/doi\/full-xml\/10.1177\/17562864261474987","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/journals.sagepub.com\/doi\/pdf\/10.1177\/17562864261474987","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,6]],"date-time":"2026-08-06T14:17:22Z","timestamp":1786025842000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.sagepub.com\/doi\/10.1177\/17562864261474987"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8]]},"references-count":25,"alternative-id":["10.1177\/17562864261474987"],"URL":"https:\/\/doi.org\/10.1177\/17562864261474987","relation":{},"ISSN":["1756-2864","1756-2864"],"issn-type":[{"value":"1756-2864","type":"print"},{"value":"1756-2864","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,8]]},"article-number":"17562864261474987"}}