{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,5]],"date-time":"2026-11-05T12:52:07Z","timestamp":1793883127218,"version":"4.7.0"},"reference-count":30,"publisher":"American Medical Association (AMA)","issue":"7","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JAMA Neurol"],"published-print":{"date-parts":[[2023,7,1]]},"abstract":"\n Importance<\/jats:title>\n Cerebral small vessel disease (cSVD) is a common cause of stroke (lacunar stroke), is the most common cause of vascular cognitive impairment, and impairs mobility and mood but has no specific treatment.<\/jats:p>\n <\/jats:sec>\n \n Objective<\/jats:title>\n To test the feasibility, drug tolerability, safety, and effects of 1-year isosorbide mononitrate (ISMN) and cilostazol treatment on vascular, functional, and cognitive outcomes in patients with lacunar stroke.<\/jats:p>\n <\/jats:sec>\n \n Design, Setting, and Participants<\/jats:title>\n The Lacunar Intervention Trial-2 (LACI-2) was an investigator-initiated, open-label, blinded end-point, randomized clinical trial with a 2\u2009\u00d7\u20092 factorial design. The trial aimed to recruit 400 participants from 26 UK hospital stroke centers between February 5, 2018, and May 31, 2021, with 12-month follow-up. Included participants had clinical lacunar ischemic stroke, were independent, were aged older than 30 years, had compatible brain imaging findings, had capacity to consent, and had no contraindications to (or indications for) the study drugs. Data analysis was performed on August 12, 2022.<\/jats:p>\n <\/jats:sec>\n \n Interventions<\/jats:title>\n All patients received guideline stroke prevention treatment and were randomized to ISMN (40-60 mg\/d), cilostazol (200 mg\/d), ISMN-cilostazol (40-60 and 200 mg\/d, respectively), or no study drug.<\/jats:p>\n <\/jats:sec>\n \n Main Outcomes<\/jats:title>\n The primary outcome was recruitment feasibility, including retention at 12 months. Secondary outcomes were safety (death), efficacy (composite of vascular events, dependence, cognition, and death), drug adherence, tolerability, recurrent stroke, dependence, cognitive impairment, quality of life (QOL), and hemorrhage.<\/jats:p>\n <\/jats:sec>\n \n Results<\/jats:title>\n \n Of the 400 participants planned for this trial, 363 (90.8%) were recruited. Their median age was 64 (IQR, 56.0-72.0) years; 251 (69.1%) were men. The median time between stroke and randomization was 79 (IQR, 27.0-244.0) days. A total of 358 patients (98.6%) were retained in the study at 12 months, with 257 of 272 (94.5%) taking 50% or more of the allocated drug. Compared with those participants not receiving that particular drug, neither ISMN (adjusted hazard ratio [aHR], 0.80 [95% CI, 0.59 to 1.09];\n P<\/jats:italic>\n \u2009=\u2009.16) nor cilostazol (aHR, 0.77 [95% CI, 0.57 to 1.05];\n P<\/jats:italic>\n \u2009=\u2009.10) alone reduced the composite outcome in 297 patients. Isosorbide mononitrate reduced recurrent stroke in\u2009353 patients (adjusted odds ratio [aOR], 0.23 [95% CI, 0.07 to 0.74];\n P<\/jats:italic>\n \u2009=\u2009.01) and cognitive impairment in\u2009308 patients (aOR, 0.55 [95% CI, 0.36 to 0.86];\n P<\/jats:italic>\n \u2009=\u2009.008). Cilostazol reduced dependence in\u2009320 patients (aHR, 0.31 [95% CI, 0.14 to 0.72];\n P<\/jats:italic>\n \u2009=\u2009.006). Combination ISMN-cilostazol reduced the composite (aHR, 0.58 [95% CI, 0.36 to 0.92];\n P<\/jats:italic>\n \u2009=\u2009.02), dependence (aOR, 0.14 [95% CI, 0.03 to 0.59];\n P<\/jats:italic>\n \u2009=\u2009.008), and any cognitive impairment (aOR, 0.44 [95% CI, 0.23 to 0.85];\n P<\/jats:italic>\n \u2009=\u2009.02) and improved QOL (adjusted mean difference, 0.10 [95% CI, 0.03 to 0.17];\n P<\/jats:italic>\n \u2009=\u2009.005) in 153 patients. There were no safety concerns.\n <\/jats:p>\n <\/jats:sec>\n \n Conclusions and Relevance<\/jats:title>\n These results show that the LACI-2 trial was feasible and ISMN and cilostazol were well tolerated and safe. These agents may reduce recurrent stroke, dependence, and cognitive impairment after lacunar stroke, and they could prevent other adverse outcomes in cSVD. Therefore, both agents should be tested in large phase 3 trials.<\/jats:p>\n <\/jats:sec>\n \n Trial Registration<\/jats:title>\n \n ClinicalTrials.gov Identifier:\n NCT03451591<\/jats:ext-link>\n <\/jats:p>\n <\/jats:sec>","DOI":"10.1001\/jamaneurol.2023.1526","type":"journal-article","created":{"date-parts":[[2023,5,24]],"date-time":"2023-05-24T06:30:37Z","timestamp":1684909837000},"page":"682","source":"Crossref","is-referenced-by-count":150,"title":["Isosorbide Mononitrate and Cilostazol Treatment in Patients With Symptomatic Cerebral Small Vessel Disease"],"prefix":"10.1001","volume":"80","author":[{"given":"Joanna M.","family":"Wardlaw","sequence":"first","affiliation":[{"name":"Centre for Clinical Brain Sciences, UK Dementia Research Institute, University of Edinburgh, Edinburgh, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lisa J.","family":"Woodhouse","sequence":"additional","affiliation":[{"name":"Stroke Trials Unit, Mental Health and 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