Tolerability, Safety and Intermediary Pharmacological Effects of Cilostazol and Isosorbide Mononitrate, Alone and Combined, in Patients with Lacunar Ischaemic Stroke: The LACunar Intervention-1 (LACI-1) Trial

Background  Lacunar stroke, a form of small vessel disease (SVD), differs pathologically from other ischaemic stroke subtypes and has no specific long-term secondary prevention. Licenced drugs, isosorbide mononitrate (ISMN) and cilostazol, have relevant actions to prevent SVD progression. Methods  We recruited independent patients with clinically confirmed lacunar ischaemic stroke without cognitive impairment to a prospective randomised clinical trial, LACunar Intervention-1 (LACI-1). We randomised patients using a central web-based system, 1:1:1:1 with minimisation, to masked ISMN 25mg bd, cilostazol 100md bd, both ISMN and cilostazol started immediately, or both with start delayed. We escalated doses to target over two weeks, sustained for eight weeks. Primary outcome was the proportion achieving target dose. Secondary outcomes included symptoms, safety (haemorrhage, recurrent vascular events), cognition, haematology and vascular function. LACI-1 was powered (80%, alpha 0·05) to detect 35% (90% versus 55%) difference between the proportion reaching target dose on one versus both drugs at 55 patients. Registration ISRCTN12580546. Findings LACI-1 enrolled 57 participants between March 2016 and August 2017: 18 (32%) female, mean age 66 (SD 11, range 40-85) years, onset-randomisation 203 (range 6-920) days. Most achieved full (64%) or over half (87%) dose, with no difference between cilostazol vs ISMN, single vs dual drugs. Headache and palpitations increased initially then declined similarly with dual versus single drugs. There was no between-group difference in BP, pulse-wave velocity, haemoglobin or platelet function, but pulse rate was higher (mean difference, MD, 6·4, 95%CI 1·2-11·7, p=0·02), platelet count higher (MD 35·7, 95%CI 2·8, 68·7, p=0·03) and white matter hyperintensities reduced more (p=0·007) with cilostazol versus no cilostazol. Interpretation  Cilostazol and ISMN are well tolerated when the dose is escalated, without safety concerns, in patients with lacunar stroke. Larger trials with longer term follow-up are justified. Trial Registration Number: ISRCTN12580546 Funding: Alzheimer's Society (AS-PG-14-033) Declaration of Interest: JMW, PB, NS, FD, GB, KF, RD, MJT, IG received funding from the Alzheimer’s Society (ASPG-14-033); FD, PB, NS, JMW report funding from the UK Stroke Association; FD also reports funding from NHS Research Scotland; GB also received funding from Edinburgh and Lothians Health Foundation and the Stroke Association Princess Margaret Research Development Fellowship scheme; YS received funding from the China Scholarships Council; MJT also received funding from NHS Lothian Research and Development Office; JMW also received funding from the Scottish Funding Council; JMW, FD, MJT, MS and GB also received funding from European Union Horizon 2020 (666881, ‘SVDs@Target’) and the Fondation Leducq (16 CVD 05). NS, PB, JMW, JPA also received funding from the British Heart Foundation; PB, NS, JPA, also received funding from the National Institutes of Health Research (NIHR) HTA Programme; PB, NS, CR also received funding from the NIHR Clinical Research network (CRN) East Midlands PB is a NIHR Senior Investigator. Ethical Approval: The trial was approval by the Scotland A Research Ethics Committee (Ref 15/SS/0154), the Medicines and Healthcare Regulatory Agency (Ref 01384/0244/001-0001) and NHS R D (Ref 2015/0354/TMF) and all participants gave written informed consent.