ABSTRACT

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 2×2-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).

Competing Interest Statement

The authors have declared no competing interest.

Clinical Trial

ISRCTN14911850: https://www.isrctn.com/ISRCTN14911850

Clinical Protocols

https://www.medrxiv.org/content/10.1101/2022.05.31.22275743v2.full.pdf

https://pmc.ncbi.nlm.nih.gov/articles/PMC7538764/pdf/10.1177_2396987320920110.pdf

Funding Statement

The LACI-2 trial was funded by the British Heart Foundation (BHF, grant CS/15/5/31475), with support from the Alzheimer?s Society (grant AS-PG-14?033), UK Dementia Research Institute (which is funded by the UK Medical Research Council, Alzheimer?s Society and Alzheimer?s Research UK), Fondation Leducq (grant 16/05 CVD), NHS Research Scotland (FD), Stroke Association and Garfield-Weston Foundation (grant TSA LECT 2015/04; FD), and the BHF and National Institute of Health & care Research (PMB).

Author Declarations

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

Yes

The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

LACI-2 received approvals from the UK competent authority (Medicines and Healthcare products Regulatory Agency, MHRA), the national ethics committee (Health Research Authority, HRA 17/EM/0077) and Research and Development approvals (2017/0209/TMF) from each hospital.

I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.

Yes

I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).

Yes

I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable.

Yes

Data Availability

The CI, with approval from the TSC as necessary, will consider all reasonable requests to share individual participant data on provision of a protocol detailing aims, hypotheses, analyses, tables, figures and publication plan. Where possible, we will perform the analyses; alternatively, de-identified data and a data dictionary will be provided for remote analyses, subject to signed data access agreement.

Non-standard abbreviations and acronymsacORadjusted common odds ratioaORadjusted odds ratiocSVDcerebral small vessel diseaseDSM5-7LDiagnostic and Statistical Manual version 5-7-levelISMNisosorbide-mononitrateLACI-2LACunar Intervention Trial-2MWDMann-Whitney differenceNO-cAMP-PDE5nitric oxide-cyclic guanosine monophosphate-phosphodiesterase-5PGI2-cAMP-PDE3prostacyclin-cyclic adenosine monophosphate-phosphodiesterase-3PROBEprospective randomised open-label, blinded-endpoint