{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,28]],"date-time":"2026-07-28T09:06:21Z","timestamp":1785229581206,"version":"3.55.0"},"reference-count":24,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"7","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Stroke"],"published-print":{"date-parts":[[2023,7]]},"abstract":"<jats:sec>\n            <jats:title>BACKGROUND:<\/jats:title>\n            <jats:p>White matter hyperintensities of presumed vascular origin (WMH) are the most prominent imaging feature of cerebral small vessel disease (cSVD). Previous studies suggest a link between cSVD burden and intracerebral hemorrhage and worse functional outcome after thrombolysis in acute ischemic stroke. We aimed to determine the impact of WMH burden on efficacy and safety of thrombolysis in the MRI-based randomized controlled WAKE-UP trial of intravenous alteplase in unknown onset stroke.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>METHODS:<\/jats:title>\n            <jats:p>The design of this post hoc study was an observational cohort design of a secondary analysis of a randomized trial. WMH volume was quantified on baseline fluid-attenuated inversion recovery images of patients randomized to either alteplase or placebo in the WAKE-UP trial. Excellent outcome was defined as score of 0-1 on the modified Rankin Scale after 90 days. Hemorrhagic transformation was assessed on follow-up imaging 24-36 hours after randomization. Treatment effect and safety were analyzed by fitting multivariable logistic regression models.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>RESULTS:<\/jats:title>\n            <jats:p>\n              Quality of scans was sufficient in 441 of 503 randomized patients to delineate WMH. Median age was 68 years, 151 patients were female, and 222 patients were assigned to receive alteplase. Median WMH volume was 11.4 mL. Independent from treatment, WMH burden was statistically significantly associated with worse functional outcome (odds ratio, 0.72 [95% CI, 0.57\u20130.92]), but not with higher chances of any hemorrhagic transformation (odds ratio, 0.78 [95% CI, 0.60\u20131.01]). There was no interaction of WMH burden and treatment group for the likelihood of excellent outcome (\n              <jats:italic>P<\/jats:italic>\n              =0.443) or any hemorrhagic transformation (\n              <jats:italic>P<\/jats:italic>\n              =0.151). In a subgroup of 166 patients with severe WMH, intravenous thrombolysis was associated with higher odds of excellent outcome (odds ratio, 2.40 [95% CI, 1.19\u20134.84]) with no significant increase in the rate of hemorrhagic transformation (odds ratio, 1.96 [95% CI, 0.80\u20134.81]).\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>CONCLUSIONS:<\/jats:title>\n            <jats:p>Although WMH burden is associated with worse functional outcome, there is no association with treatment effect or safety of intravenous thrombolysis in patients with ischemic stroke of unknown onset.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>REGISTRATION:<\/jats:title>\n            <jats:p>\n              URL:\n              <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"uri\" xlink:href=\"https:\/\/www.clinicaltrials.gov\">https:\/\/www.clinicaltrials.gov<\/jats:ext-link>\n              ; Unique identifier: NCT01525290.\n            <\/jats:p>\n          <\/jats:sec>","DOI":"10.1161\/strokeaha.122.040247","type":"journal-article","created":{"date-parts":[[2023,5,25]],"date-time":"2023-05-25T09:00:46Z","timestamp":1685005246000},"page":"1718-1725","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":14,"title":["Intravenous Thrombolysis in Patients With White Matter Hyperintensities in the WAKE-UP Trial"],"prefix":"10.1161","volume":"54","clinical-trial-number":[{"clinical-trial-number":"nct01525290","registry":"10.18810\/clinical-trials-gov"}],"author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5302-0801","authenticated-orcid":true,"given":"Benedikt M.","family":"Frey","sequence":"first","affiliation":[{"name":"Klinik und Poliklinik f\u00fcr Neurologie, Kopf- und Neurozentrum, University Medical Center Hamburg-Eppendorf, Germany (B.M.F., F.S., B.C., E.B., A.K., E.S., C.G., G.T.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-0903-7897","authenticated-orcid":true,"given":"Farhad","family":"Shenas","sequence":"additional","affiliation":[{"name":"Klinik und Poliklinik f\u00fcr Neurologie, Kopf- und Neurozentrum, University Medical Center Hamburg-Eppendorf, Germany (B.M.F., F.S., B.C., E.B., A.K., E.S., C.G., G.T.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Florent","family":"Boutitie","sequence":"additional","affiliation":[{"name":"Hospices Civils de Lyon, Service de Biostatistique, F-69003 Lyon, France; Universit\u00e9 Lyon 1, France; CNRS, UMR 5558, Laboratoire de Biom\u00e9trie et Biologie Evolutive, Equipe Biostatistique-Sant\u00e9, Villeurbanne, France (F.B.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2434-1822","authenticated-orcid":true,"given":"Bastian","family":"Cheng","sequence":"additional","affiliation":[{"name":"Klinik und Poliklinik f\u00fcr Neurologie, Kopf- und Neurozentrum, University Medical Center Hamburg-Eppendorf, Germany (B.M.F., F.S., B.C., E.B., A.K., E.S., C.G., G.T.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8677-2447","authenticated-orcid":true,"given":"Tae-Hee","family":"Cho","sequence":"additional","affiliation":[{"name":"Department of Stroke Medicine, Universit\u00e9 Claude Bernard Lyon 1, CREATIS CNRS UMR 5220-INSERM U1206, INSA-Lyon; Hospices Civils de Lyon, France (T.-H.C., N.N.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5073-4665","authenticated-orcid":true,"given":"Martin","family":"Ebinger","sequence":"additional","affiliation":[{"name":"Centrum f\u00fcr Schlaganfallforschung Berlin (CSB), Charit\u00e9 - Universit\u00e4tsmedizin Berlin, Berlin, Germany (M. Ebinger, M. Endres, J.B.F., I.G.)."},{"name":"Neurologie der Rehaklinik Medical Park Humboldtm\u00fchle, Berlin, Germany (M. Ebinger)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6520-3720","authenticated-orcid":true,"given":"Matthias","family":"Endres","sequence":"additional","affiliation":[{"name":"Centrum f\u00fcr Schlaganfallforschung Berlin (CSB), Charit\u00e9 - Universit\u00e4tsmedizin Berlin, Berlin, Germany (M. Ebinger, M. Endres, J.B.F., I.G.)."},{"name":"Klinik und Hochschulambulanz f\u00fcr Neurologie, Charit\u00e9-Universit\u00e4tsmedizin Berlin, Germany (M. Endres)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7936-6958","authenticated-orcid":true,"given":"Jochen B.","family":"Fiebach","sequence":"additional","affiliation":[{"name":"Centrum f\u00fcr Schlaganfallforschung Berlin (CSB), Charit\u00e9 - Universit\u00e4tsmedizin Berlin, Berlin, Germany (M. Ebinger, M. Endres, J.B.F., I.G.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jens","family":"Fiehler","sequence":"additional","affiliation":[{"name":"Department of Diagnostic and Interventional Neuroradiology, University Medical Center Hamburg-Eppendorf, Germany (J.F.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4904-8251","authenticated-orcid":true,"given":"Ivana","family":"Galinovic","sequence":"additional","affiliation":[{"name":"Centrum f\u00fcr Schlaganfallforschung Berlin (CSB), Charit\u00e9 - Universit\u00e4tsmedizin Berlin, Berlin, Germany (M. Ebinger, M. Endres, J.B.F., I.G.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ewgenia","family":"Barow","sequence":"additional","affiliation":[{"name":"Klinik und Poliklinik f\u00fcr Neurologie, Kopf- und Neurozentrum, University Medical Center Hamburg-Eppendorf, Germany (B.M.F., F.S., B.C., E.B., A.K., E.S., C.G., G.T.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2591-1807","authenticated-orcid":true,"given":"Alina","family":"K\u00f6nigsberg","sequence":"additional","affiliation":[{"name":"Klinik und Poliklinik f\u00fcr Neurologie, Kopf- und Neurozentrum, University Medical Center Hamburg-Eppendorf, Germany (B.M.F., F.S., B.C., E.B., A.K., E.S., C.G., G.T.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5729-2935","authenticated-orcid":true,"given":"Eckhard","family":"Schlemm","sequence":"additional","affiliation":[{"name":"Klinik und Poliklinik f\u00fcr Neurologie, Kopf- und Neurozentrum, University Medical Center Hamburg-Eppendorf, Germany (B.M.F., F.S., B.C., E.B., A.K., E.S., C.G., G.T.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2517-4413","authenticated-orcid":true,"given":"Salvador","family":"Pedraza","sequence":"additional","affiliation":[{"name":"Department of Radiology, Institut de Diagnostic per la Image (IDI), Hospital Dr Josep Trueta, Institut d\u2019Investigaci\u00f3 Biom\u00e8dica de Girona (IDIBGI), Parc Hospitalari Mart\u00ed i Juli\u00e0 de Salt, Girona, Spain (S.P.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4948-5956","authenticated-orcid":true,"given":"Robin","family":"Lemmens","sequence":"additional","affiliation":[{"name":"Department of Neurology, University Hospitals Leuven, Belgium (R.L.)."},{"name":"KU Leuven \u2013 University of Leuven, Department of Neurosciences, Experimental Neurology, Belgium (R.L.)."},{"name":"VIB, Center for Brain &amp; Disease Research, Laboratory of Neurobiology, Campus Gasthuisberg, Belgium (R.L.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6614-8417","authenticated-orcid":true,"given":"Vincent","family":"Thijs","sequence":"additional","affiliation":[{"name":"Florey Institute of Neuroscience and Mental Health, University of Melbourne, Victoria, Australia (V.T.)."},{"name":"Austin Health, Department of Neurology, Heidelberg, VIC, Australia (V.T.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9535-022X","authenticated-orcid":true,"given":"Keith W.","family":"Muir","sequence":"additional","affiliation":[{"name":"Institute of Neuroscience &amp; Psychology, University of Glasgow, University Avenue, Glasgow, United Kingdom (K.W.M.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0594-4409","authenticated-orcid":true,"given":"Norbert","family":"Nighoghossian","sequence":"additional","affiliation":[{"name":"Department of Stroke Medicine, Universit\u00e9 Claude Bernard Lyon 1, CREATIS CNRS UMR 5220-INSERM U1206, INSA-Lyon; Hospices Civils de Lyon, France (T.-H.C., N.N.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1363-0266","authenticated-orcid":true,"given":"Claus Z.","family":"Simonsen","sequence":"additional","affiliation":[{"name":"Department of Neurology, Aarhus University Hospital, Denmark (C.Z.S.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6484-8882","authenticated-orcid":true,"given":"Christian","family":"Gerloff","sequence":"additional","affiliation":[{"name":"Klinik und Poliklinik f\u00fcr Neurologie, Kopf- und Neurozentrum, University Medical Center Hamburg-Eppendorf, Germany (B.M.F., F.S., B.C., E.B., A.K., E.S., C.G., G.T.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4785-1449","authenticated-orcid":true,"given":"G\u00f6tz","family":"Thomalla","sequence":"additional","affiliation":[{"name":"Klinik und Poliklinik f\u00fcr Neurologie, Kopf- und Neurozentrum, University Medical Center Hamburg-Eppendorf, Germany (B.M.F., F.S., B.C., E.B., A.K., E.S., C.G., G.T.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"name":"on behalf of the WAKE-UP Investigators","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","reference":[{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.1016\/S1474-4422(13)70124-8"},{"key":"e_1_3_3_3_2","doi-asserted-by":"publisher","DOI":"10.3389\/fneur.2019.00238"},{"key":"e_1_3_3_4_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41582-018-0014-y"},{"key":"e_1_3_3_5_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.neubiorev.2018.04.003"},{"key":"e_1_3_3_6_2","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.0000000000007142"},{"key":"e_1_3_3_7_2","doi-asserted-by":"publisher","DOI":"10.1161\/STROKEAHA.116.014096"},{"key":"e_1_3_3_8_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1804355"},{"key":"e_1_3_3_9_2","doi-asserted-by":"publisher","DOI":"10.1016\/S1474-4422(11)70192-2"},{"key":"e_1_3_3_10_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuroimage.2016.07.018"},{"key":"e_1_3_3_11_2","doi-asserted-by":"publisher","DOI":"10.2214\/ajr.149.2.351"},{"key":"e_1_3_3_12_2","doi-asserted-by":"publisher","DOI":"10.1001\/jamaneurol.2019.0351"},{"key":"e_1_3_3_13_2","doi-asserted-by":"publisher","DOI":"10.1161\/STROKEAHA.121.034480"},{"key":"e_1_3_3_14_2","doi-asserted-by":"publisher","DOI":"10.1002\/hbm.25301"},{"key":"e_1_3_3_15_2","doi-asserted-by":"publisher","DOI":"10.1093\/braincomms\/fcaa001"},{"key":"e_1_3_3_16_2","doi-asserted-by":"publisher","DOI":"10.1186\/s42466-020-00087-9"},{"key":"e_1_3_3_17_2","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.0b013e3181a18823"},{"key":"e_1_3_3_18_2","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/aww259"},{"key":"e_1_3_3_19_2","doi-asserted-by":"publisher","DOI":"10.1161\/STROKEAHA.117.018653"},{"key":"e_1_3_3_20_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.STR.0000239321.53203.ea"},{"key":"e_1_3_3_21_2","doi-asserted-by":"publisher","DOI":"10.1177\/0271678X18800463"},{"key":"e_1_3_3_22_2","doi-asserted-by":"publisher","DOI":"10.1002\/hbm.22959"},{"key":"e_1_3_3_23_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.biopsych.2008.03.024"},{"key":"e_1_3_3_24_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuroimage.2017.03.024"},{"key":"e_1_3_3_25_2","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.0000000000013055"}],"container-title":["Stroke"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.ahajournals.org\/doi\/full\/10.1161\/STROKEAHA.122.040247","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,5,13]],"date-time":"2024-05-13T14:43:48Z","timestamp":1715611428000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.ahajournals.org\/doi\/10.1161\/STROKEAHA.122.040247"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,7]]},"references-count":24,"journal-issue":{"issue":"7","published-print":{"date-parts":[[2023,7]]}},"alternative-id":["10.1161\/STROKEAHA.122.040247"],"URL":"https:\/\/doi.org\/10.1161\/strokeaha.122.040247","relation":{},"ISSN":["0039-2499","1524-4628"],"issn-type":[{"value":"0039-2499","type":"print"},{"value":"1524-4628","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,7]]},"assertion":[{"value":"2022-08-03","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2023-04-21","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2023-05-25","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}