In plain English
AI plain-English summary A 1,300-patient UK trial is testing whether two cheap, already-licensed drugs can prevent the cognitive decline that often follows a lacunar stroke—the type caused by damage to the brain’s tiny blood vessels. Lacunar strokes make up a quarter of all ischaemic strokes. They are often mild in terms of physical disability, but many patients later develop thinking and memory problems—a concern patients themselves have ranked as a top priority. Current preventive treatments do little to protect cognition or reduce the risk of a second stroke. Earlier, smaller trials of the drugs isosorbide mononitrate and cilostazol showed promising signals: fewer recurrent strokes, less cognitive decline, and improved quality of life. If LACI-3 confirms those results, the NHS Medicines Repurposing Programme could extend the drugs’ licences for this new use. Both are inexpensive, already widely available, and used for other conditions. The impact would be immediate and global: a simple, low-cost tablet regimen to protect the thinking abilities of hundreds of thousands of stroke survivors each year, without requiring new infrastructure or expensive diagnostics.
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Research question: Do oral isosorbide mononitrate (ISMN) and/or cilostazol, prevent cognitive impairment, dependency, adverse vascular outcomes, death, and improve quality of life, after lacunar (small vessel) ischaemic stroke? Background: Lacunar ischaemic stroke, a type of small vessel disease (SVD), accounts for 25% of ischaemic strokes. Typically these are neurologically ‘minor’ strokes, so usually not physically disabling, but cognitive impairment is common, a James Lind Alliance priority, and main concern of patients. Current secondary prevention treatments have little benefit on recurrent stroke, cognition or dependency. LACI-1 (n=57, 8wks) and LACI-2 (n=363, 1yr) trials tested ISMN and cilostazol, alone and together, meeting feasible/tolerable targets, found no safety concerns and showed possible clinical efficacy: ISMN reduced recurrent stroke, cognitive decline and improved QoL; cilostazol reduced dependency; ISMN+cilostazol reduced cognitive decline, dependency, composite outcome including recurrent stroke, and improved QoL. Long term cilostazol reduced recurrent stroke in other trials. Aims, objectives: To determine if long term ISMN and/or cilostazol improve outcomes after lacunar ischaemic stroke and should be used in clinical practice. 1ry objective: Does ISMN+/-cilostazol reduce cognitive impairment? 2ry objectives: Does ISMN+/-cilostazol reduce dependency, recurrent stroke, death, improve mood, QoL. Methods: Pragmatic phase III, prospective, randomised, controlled, open label, 2x2 factorial, blinded outcome (PROBE) trial. Pragmatic design, modest data collection will optimise enrolment, blinding will minimise bias. Setting: 60 UK hospital stroke services. Participants: Patients with clinical lacunar ischaemic stroke, compatible brain imaging, aged >30, with capacity to consent. Exclusion: mainly indications for/contraindications to, either drug. Intervention: Daily oral ISMN 50mg, cilostazol 200mg, both, or neither, randomised 1:1:1:1, started 1 day post randomisation for 18 months. Patients with contra-indications/indications to one drug may be randomised to the other drug. All receive usual guideline stroke prevention (antiplatelet, antihypertensive, lipid lowering, lifestyle advice). Outcomes: Central blinded follow-up (cognition, dependency, recurrent stroke, mood, QoL). Primary: DSM-5 7-level ordinal cognition at 18 months. Secondary: Dependency (modified Rankin Scale), recurrent stroke, MI, death, composite, mood, QoL, safety, cost efficiency at 18 months. Sample size: n=1300 is needed, 650 ISMN v 650 no ISMN, to detect a 30% reduction (OR 0.70) in cognitive impairment, MCID 0.27, at 90% power, alpha 5%, 15% data losses, rounded up. Timelines: 52month study; June’24 approvals, Sept’24 initiate sites, Nov’24 start randomising; Jun’25 most sites set up, continue randomising and follow-up; stop randomising Apr’27; end follow-up Feb’28; analyse and report results Nov’28. Impact and dissemination: Both drugs are inexpensive, widely available, licenced for other diseases. If LACI-3 confirms LACI-2's results, then NHS England Medicines Repurposing Programme will help extend ISMN's and/or cilostazol's UK licences, with potential global impact on vascular cognitive decline, the main concern of lacunar stroke patients. Oral presentation at a major conference with high impact journal publication will ensure rapid dissemination and guideline inclusion; PPI groups will inform dissemination to the public via multiple channels.