Isosorbide mononitrate / cilostazol for lacunar cerebral small vessel disease- outcomes at 6 months in the LACI-2 trial

Background Lacunar stroke, a type of cerebral small vessel disease (cSVD), causes cognitive decline and dependency. The LACunar Intervention Trial-2 (LACI-2) trial showed that 12 months of treatment with isosorbide-mononitrate (ISMN) and/or cilostazol improved these outcomes. We tested whether this effect was present at 6 months, a pre-specified analysis. Methods LACI-2 assessed the feasibility, safety and proof-of-concept of one year of ISMN (40-60mg) and/or cilostazol (200 mg) using a prospective randomised open-label blinded-endpoint 2x2-factorial phase-2b design. Participants aged>30yrs had clinical lacunar stroke, compatible brain imaging and capacity to consent. Key outcomes included cognition (Diagnostic and Statistical Manual version 5-7-level, DSM5-7L), dependency, vascular events, mood, stroke impact and a global analysis of these. Results Baseline characteristics were balanced across 363 participants: median age 64 56-72 years, females 31% and median onset-to-randomisation 79 27-244 days. At 6 months, participants allocated to ISMN vs control had fewer vascular-cognition-dependency events (adjusted odds ratio, aOR 0.74, 95% confidence intervals 0.55-0.99) and an improved stroke impact scale score (Mann-Whitney difference, MWD -0.15, 95% CI -0.25, -0.05) and global analysis (MWD -0.06, 95% CI -0.11, -0.01). Cilostazol vs control reduced cognitive impairment (DSM5-7-level scale, acOR 0.64, 95% CI 0.41-0.99). Combined ISMN/cilostazol vs control (n=181) had improved cognition (DSM5-7L acOR 0.40, 95% CI 0.21-0.78) and mood (Zung aMD -6.94, 95% CI -12.25, -1.64), reduced stroke impact (-0.23, 95% CI -0.37, -0.09) and a better global outcome (MWD -0.10, 95% CI -0.17, -0.03). Conclusions Improvements in cognitive and functional outcomes were seen within 6 months of ISMN and/or cilostazol. Registration: ISRCTN14911850 : https://www.isrctn.com/ISRCTN14911850