Dr Joanna WardlawJoanna M. Wardlaw, CBE, FRCP, FRSE, FMedSci
A recent trial led by Joanna M. Wardlaw, CBE, FRCP, FRSE, FMedSci, found that a combination approach of isosorbide mononitrate and cilostazol is well tolerated without any safety concerns when the dose is escalated in patients with lacunar stroke.

The LACI-1 trial, funded by the Alzheimer’s Society and conducted by the Universities of Edinburgh and Nottingham, and their respective NHS hospitals, found that, of 57 patients, 64% achieved a full dose and 87% more than a half dose, with no difference between cilostazol and isosorbide mononitrate, nor between the use of single or dual drugs. The only differences between the groups were that pulse rate (mean difference [MD], 6.4; 95% CI, 1.2 to 11.7; P = .02) and platelet count (MD 35.7; 95% CI, 2.8 to 68.7; P = .03) were higher, and white matter hyperintensities were reduced more (Chi-square P = .007) with cilostazol versus no cilostazol.

To find out more about what prompted the study of this dual approach with isosorbide mononitrate and cilostazol, as well as what the physician community needs to know, NeurologyLive® spoke with Wardlaw, Chair of Applied Neuroimaging, Head of Neuroimaging Sciences and Edinburgh Imaging, University of Edinburgh, in an interview. 

NeurologyLive®: What prompted this research with isosorbide mononitrate and cilostazol?

Joanna M. Wardlaw, CBE, FRCP, FRSE, FMedSci: Lacunar stroke is a type of small vessel disease; small vessel disease is the commonest cause of vascular dementia and also worsens symptoms in Alzheimer disease. Patients have a high risk of recurrent stroke and also of cognitive decline after lacunar stroke. There are no established treatments to prevent or treat small vessel disease. The authors did a big search for treatments that might help to prevent small vessel disease stroke and dementia and found the two drugs tested here in the LACI-1 trial. They have been used widely for stroke prevention in the Far East (cilostazol) or for angina in Europe (Isosorbide mononitrate) but not for stroke or dementia prevention in the West. They are known to have promising effects to help the small blood vessels function better to deliver oxygen to the brain, and to help the brain wiring to repair. They might work even better together. The first step was to see if patients with small vessel disease could take the drugs, to get some evidence for safety and efficacy and to lay the infrastructure for larger trials. SO that is what we did.

What are the key takeaways for the physician community from this study?

Patients with small vessel stroke were able to take cilostazol and isosorbide mononitrate in addition to their usual stroke prevention tablets, there were no safety concerns, there was some evidence that the drugs helped the blood vessels to work better, and the information helped set up a larger trial, LACI-2, which is now ongoing in the UK.  

Were any findings surprising or unexpected?

We were surprised, but pleased, that the patients were able to take both drugs together without getting any worse adverse effects. We were pleased to find evidence of the blood vessels working a bit better. There were no unexpected findings.

What makes this treatment approach unique?

Most stroke prevention focuses on stopping blood clots or reducing blood pressure or lowering fat levels in the blood—i.e. stopping atheroma or clots; most dementia prevention focuses on trying to block abnormal proteins (amyloid or tau) from building up in the brain, and so far, they have not worked.

But small vessel stroke is not due to clots or atheroma, and, like much of cognitive decline and dementia, it involves small blood vessel dysfunction. These 2 drugs tackle the small blood vessel dysfunction directly and may also help repair brain wiring, so the approach is completely different from what is traditionally used in stroke and dementia research to date.
REFERENCE
Blair GW, Appleton JP, Flaherty K, et al. 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. EClinical Medicine. Published online April 23, 2019. doi: 10.1016/j.eclinm.2019.04.001.