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, a randomised clinical trial

Blair, Gordon W.; Appleton, Jason P.; Flaherty, Katie; Doubal, Fergus; Sprigg, Nikola; Dooley, Richard; Richardson, Carla; Hamilton, Iona; Law, Zhe Kang; Shi, Yulu; Stringer, Michael S.; Thrippleton, Michael J.; Boyd, Julia; Shuler, Kirsten; Bath, Philip M.; Wardlaw, Joanna M.

Abstract

Background
Lacunar stroke, a frequent clinical manifestation 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 25 mg bd, cilostazol 100 mg 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, vascular function, and neuroimaging. 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%) females, 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 (Chi-square p = 0.007) with cilostazol versus no cilostazol.
nterpretation
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.

Citation

Blair, G. W., Appleton, J. P., Flaherty, K., Doubal, F., Sprigg, N., Dooley, R., Richardson, C., Hamilton, I., Law, Z. K., Shi, Y., Stringer, M. S., Thrippleton, M. J., Boyd, J., Shuler, K., Bath, P. M., & Wardlaw, J. M. (2019). 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, a randomised clinical trial. eClinicalMedicine, 11, 34-43. https://doi.org/10.1016/j.eclinm.2019.04.001

• Journal Article Type: Article
• Acceptance Date: Apr 2, 2019
• Online Publication Date: Apr 23, 2019
• Publication Date: Apr 23, 2019
• Deposit Date: May 3, 2019
• Publicly Available Date: May 15, 2019
• Journal: EClinicalMedicine
• Electronic ISSN: 2589-5370
• Publisher: Elsevier
• Peer Reviewed: Peer Reviewed
• Volume: 11
• Pages: 34-43
• DOI: https://doi.org/10.1016/j.eclinm.2019.04.001
• Public URL: https://nottingham-repository.worktribe.com/output/2018718
• Publisher URL: https://www.thelancet.com/journals/eclinm/article/PIIS2589-5370(19)30058-6/fulltext
• Contract Date: May 3, 2019