{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,19]],"date-time":"2026-10-19T18:23:26Z","timestamp":1792434206494,"version":"4.5.0"},"reference-count":30,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"10","license":[{"start":{"date-parts":[[2025,10,1]],"date-time":"2025-10-01T00:00:00Z","timestamp":1759276800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Stroke"],"published-print":{"date-parts":[[2025,10]]},"abstract":"<jats:sec>\n                    <jats:title>BACKGROUND:<\/jats:title>\n                    <jats:p>White matter hyperintensities and reduced cerebral blood flow are hallmarks of cerebral small vessel disease (CSVD). We tested the feasibility of daily treatment with the vasoactive drug tadalafil in patients with CSVD and its effects on cognition and imaging markers of CSVD.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>METHODS:<\/jats:title>\n                    <jats:p>The ETLAS-2 trial (Effect of Tadalafil in Lacunar Stroke) was a randomized, placebo-controlled, double-blind, parallel phase II trial testing 3 months of daily tadalafil 20 mg versus placebo in patients with CSVD and previous stroke or transient ischemic attack. Participants were included from the Capital Region of Denmark from 2022 to 2024. Outcomes were assessed at baseline and after 3 months. A binary logistic regression model with the treatment group as a covariate was used to calculate the primary outcome of feasibility (\u226590% study drug compliance). Secondary outcomes included the Montreal Cognitive Assessment, magnetic resonance imaging markers of CSVD (Standards for Reporting Vascular Changes on Neuroimaging criteria), blood pressure, and adverse events.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>RESULTS:<\/jats:title>\n                    <jats:p>\n                      We included 76 participants (20 female, mean age, 68.0\u00b18.9 years). Seventy-one initiated treatment, and 26 of 38 participants with tadalafil were \u226590% compliant versus 31 of 33 with placebo (odds ratio, 0.13 [95% CI, 0.03\u20130.69];\n                      <jats:italic toggle=\"yes\">P<\/jats:italic>\n                      =0.030). There was a female preponderance in tadalafil dropouts, with 46% of females stopping treatment, compared with only 16% of males. Adverse events occurred in 76% of participants with tadalafil versus 36% with placebo (odds ratio, 5.49 [95% CI, 1.81\u201318.07];\n                      <jats:italic toggle=\"yes\">P<\/jats:italic>\n                      =0.001). A trend toward lower white matter hyperintensity volume at follow-up was observed in the tadalafil group in the unadjusted per-protocol analysis (relative change, 0.939 [95% CI, 0.881\u20131.001];\n                      <jats:italic toggle=\"yes\">P<\/jats:italic>\n                      =0.054). No differences were observed in cognition, mental well-being, or blood pressure.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>CONCLUSIONS:<\/jats:title>\n                    <jats:p>In participants with CSVD, adherence to tadalafil was significantly lower than to placebo and did not meet the prespecified compliance threshold. We observed a nonsignificant reduction in white matter hyperintensity volume after tadalafil, which warrants larger and prolonged studies with reduced tadalafil doses to explore potential benefits in CSVD.<\/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: NCT05173896.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1161\/strokeaha.125.051602","type":"journal-article","created":{"date-parts":[[2025,7,28]],"date-time":"2025-07-28T09:00:15Z","timestamp":1753693215000},"page":"2846-2857","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":8,"title":["Tadalafil Treatment in Patients With Cerebral Small Vessel Disease: The ETLAS-2 Randomized Clinical Trial"],"prefix":"10.1161","volume":"56","clinical-trial-number":[{"clinical-trial-number":"nct05173896","registry":"10.18810\/clinical-trials-gov"}],"author":[{"ORCID":"https:\/\/orcid.org\/0009-0007-9975-8709","authenticated-orcid":true,"given":"Joakim","family":"\u00d6lmestig","sequence":"first","affiliation":[{"name":"Neurovascular Research Unit, Department of Neurology (J.O., M.B.T., C.K.), Copenhagen University Hospital\u2013Herlev and Gentofte, Denmark."},{"name":"Department of Clinical Medicine (J.O., H.C., H.K.I., H.R.S., C.K.), University of Copenhagen, Denmark."},{"name":"Danish Research Centre for Magnetic Resonance, Department of Radiology and Nuclear Medicine, Copenhagen University Hospital\u2013Amager and Hvidovre, Denmark (J.O., K.N.M., H.R.S.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3726-0781","authenticated-orcid":true,"given":"Kristian Nygaard","family":"Mortensen","sequence":"additional","affiliation":[{"name":"Danish Research Centre for Magnetic Resonance, Department of Radiology and Nuclear Medicine, Copenhagen University Hospital\u2013Amager and Hvidovre, Denmark (J.O., K.N.M., H.R.S.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marie Bjerregaard","family":"Thomas","sequence":"additional","affiliation":[{"name":"Neurovascular Research Unit, Department of Neurology (J.O., M.B.T., C.K.), Copenhagen University Hospital\u2013Herlev and Gentofte, Denmark."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4547-2944","authenticated-orcid":true,"given":"Birgitte","family":"Fagerlund","sequence":"additional","affiliation":[{"name":"Department of Psychology (B.F.), University of Copenhagen, Denmark."},{"name":"Child and Adolescent Mental Health Center, Copenhagen University Hospital, Mental Health Services CPH, Hellerup, Denmark (B.F.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nadia","family":"Naveed","sequence":"additional","affiliation":[{"name":"Department of Radiology (N.N., M.M.N.), Copenhagen University Hospital\u2013Herlev and Gentofte, Denmark."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-5519-2067","authenticated-orcid":true,"given":"Mette Maria","family":"Nordling","sequence":"additional","affiliation":[{"name":"Department of Radiology (N.N., M.M.N.), Copenhagen University Hospital\u2013Herlev and Gentofte, Denmark."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5159-8549","authenticated-orcid":true,"given":"Marie Katrine Klose","family":"Nielsen","sequence":"additional","affiliation":[{"name":"Section of Forensic Chemistry, Department of Forensic Medicine, Faculty of Health and Medical Sciences (M.K.K.N., B.S.R.), University of Copenhagen, Denmark."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8048-3222","authenticated-orcid":true,"given":"Brian Schou","family":"Rasmussen","sequence":"additional","affiliation":[{"name":"Section of Forensic Chemistry, Department of Forensic Medicine, Faculty of Health and Medical Sciences (M.K.K.N., B.S.R.), University of Copenhagen, Denmark."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7472-3194","authenticated-orcid":true,"given":"Hanne","family":"Christensen","sequence":"additional","affiliation":[{"name":"Department of Clinical Medicine (J.O., H.C., H.K.I., H.R.S., C.K.), University of Copenhagen, Denmark."},{"name":"Department of Neurology, Copenhagen University Hospital\u2013Bispebjerg and Frederiksberg, Denmark (H.C., H.R.S.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5880-6352","authenticated-orcid":true,"given":"Helle Klingenberg","family":"Iversen","sequence":"additional","affiliation":[{"name":"Department of Clinical Medicine (J.O., H.C., H.K.I., H.R.S., C.K.), University of Copenhagen, Denmark."},{"name":"Department of Neurology (H.K.I.), Copenhagen University Hospital\u2013Rigshospitalet, Glostrup, Denmark."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mai Bang","family":"Poulsen","sequence":"additional","affiliation":[{"name":"Department of Neurology, Copenhagen University Hospital\u2013North Zealand, Hiller\u00f8d, Denmark (M.B.P.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hartwig Roman","family":"Siebner","sequence":"additional","affiliation":[{"name":"Department of Clinical Medicine (J.O., H.C., H.K.I., H.R.S., C.K.), University of Copenhagen, Denmark."},{"name":"Danish Research Centre for Magnetic Resonance, Department of Radiology and Nuclear Medicine, Copenhagen University Hospital\u2013Amager and Hvidovre, Denmark (J.O., K.N.M., H.R.S.)."},{"name":"Department of Neurology, Copenhagen University Hospital\u2013Bispebjerg and Frederiksberg, Denmark (H.C., H.R.S.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4210-0523","authenticated-orcid":true,"given":"Christina","family":"Kruuse","sequence":"additional","affiliation":[{"name":"Neurovascular Research Unit, Department of Neurology (J.O., M.B.T., C.K.), Copenhagen University Hospital\u2013Herlev and Gentofte, Denmark."},{"name":"Department of Clinical Medicine (J.O., H.C., H.K.I., H.R.S., C.K.), University of Copenhagen, Denmark."},{"name":"Department of Brain and Spinal Cord Injury, Neuroscience Centre (C.K.), Copenhagen University Hospital\u2013Rigshospitalet, Glostrup, Denmark."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","reference":[{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.1016\/S1474-4422(19)30079-1"},{"key":"e_1_3_3_3_2","doi-asserted-by":"publisher","DOI":"10.1016\/S1474-4422(13)70124-8"},{"key":"e_1_3_3_4_2","doi-asserted-by":"publisher","DOI":"10.1016\/S1474-4422(23)00131-X"},{"key":"e_1_3_3_5_2","doi-asserted-by":"publisher","DOI":"10.1111\/bpa.12224"},{"key":"e_1_3_3_6_2","doi-asserted-by":"publisher","DOI":"10.1177\/1358836X0000500108"},{"key":"e_1_3_3_7_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.cir.0000131515.03336.f8"},{"key":"e_1_3_3_8_2","doi-asserted-by":"publisher","DOI":"10.1177\/0271678X16662891"},{"key":"e_1_3_3_9_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrd4228"},{"key":"e_1_3_3_10_2","doi-asserted-by":"publisher","DOI":"10.1186\/s13063-024-08402-4"},{"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":"10.1161\/STROKEAHA.109.564914"},{"key":"e_1_3_3_13_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.nicl.2023.103354"},{"key":"e_1_3_3_14_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1532-5415.2005.53221.x"},{"key":"e_1_3_3_15_2","doi-asserted-by":"publisher","DOI":"10.1017\/s003329170002691x"},{"key":"e_1_3_3_16_2","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.0000000000000837"},{"key":"e_1_3_3_17_2","doi-asserted-by":"publisher","DOI":"10.1345\/aph.1L691"},{"key":"e_1_3_3_18_2","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awg009"},{"key":"e_1_3_3_19_2","doi-asserted-by":"publisher","DOI":"10.1016\/s0090-4295(00)00649-x"},{"key":"e_1_3_3_20_2","doi-asserted-by":"publisher","DOI":"10.1093\/braincomms\/fcaa020"},{"key":"e_1_3_3_21_2","doi-asserted-by":"publisher","DOI":"10.1002\/alz.12559"},{"key":"e_1_3_3_22_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2125.2005.02553.x"},{"key":"e_1_3_3_23_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.124.324327"},{"key":"e_1_3_3_24_2","doi-asserted-by":"publisher","DOI":"10.1001\/jamaneurol.2023.1526"},{"key":"e_1_3_3_25_2","doi-asserted-by":"publisher","DOI":"10.1212\/01.wnl.0000147295.50029.67"},{"key":"e_1_3_3_26_2","doi-asserted-by":"publisher","DOI":"10.1001\/archneur.63.12.1730"},{"key":"e_1_3_3_27_2","doi-asserted-by":"publisher","DOI":"10.1177\/23969873211027002"},{"key":"e_1_3_3_28_2","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.0000000000008364"},{"key":"e_1_3_3_29_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.eclinm.2019.04.001"},{"key":"e_1_3_3_30_2","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.0000000000004328"},{"key":"e_1_3_3_31_2","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.0000000000213323"}],"container-title":["Stroke"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.ahajournals.org\/doi\/full\/10.1161\/STROKEAHA.125.051602","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,9,22]],"date-time":"2025-09-22T18:01:18Z","timestamp":1758564078000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.ahajournals.org\/doi\/10.1161\/STROKEAHA.125.051602"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,10]]},"references-count":30,"journal-issue":{"issue":"10","published-print":{"date-parts":[[2025,10]]}},"alternative-id":["10.1161\/STROKEAHA.125.051602"],"URL":"https:\/\/doi.org\/10.1161\/strokeaha.125.051602","relation":{},"ISSN":["0039-2499","1524-4628"],"issn-type":[{"value":"0039-2499","type":"print"},{"value":"1524-4628","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,10]]},"assertion":[{"value":"2025-03-24","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-06-16","order":1,"name":"revised","label":"Revised","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-06-25","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-07-28","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}