Dr Joanna WardlawJoanna M. Wardlaw, CBE, FRCP, FRSE, FMedSci
When the dose is escalated, a combination approach of 25-mg isosorbide mononitrate and 100-mg cilostazol (Pletal, Cadila Pharmaceuticals) has been shown in a study to be well tolerated, without any safety concerns, in patients with lacunar stroke.1

Ultimately, in this trial of 57 patients, dubbed the LACI-1 trial, the majority of patients achieved a full (64%) or over half (87%) dose, with no difference between cilostazol and isosorbide mononitrate, nor between the use of single or dual drugs. Initially, headache and palpitations increased, though they declined in a similar fashion for the combination and single drug groups. There was no between-group difference in blood pressure, pulse-wave velocity, hemoglobin, or platelet function.

“[Isosorbide mononitrate and cilostazol] 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,” lead author Joanna M. Wardlaw, CBE, FRCP, FRSE, FMedSci, Chair of Applied Neuroimaging, Head of Neuroimaging Sciences and Edinburgh Imaging, University of Edinburgh, told NeurologyLive. “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.”

Lacunar stroke, a small vessel disease (SVD) manifestation, differs pathologically from other ischemic stroke subtypes, with no long-term preventions developed specifically for it. Although, these agents have mechanism of action relevant to the prevention of SVD progression, with 5 trials in Asian countries showing a relationship between cilostazol and reduced incidence of recurrent stroke (odds ratio [OR], 0.64; 95% CI, 0.51 to 0.79; n = 4780), as well as dementia (adjusted hazard ratio [HR], 0.75; 95%CI 0.61 to 0.92; P <.001 for dose trend; n = 9148).

“Small vessel disease is the commonest cause of vascular dementia and also worsens symptoms in Alzheimer disease,” Wardlaw explained. “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.”

In the LACI-1 trial, the full cohort was randomized to 1 of 4 groups: a combination group with a delayed start of treatment (n = 15), a combination group with no delay (n = 14), an isosorbide mononitrate only group (n = 15), and a cilostazol only group (n = 13). The 97% (n = 55) were taking clopidogrel (Plavix, Bristol-Myers Squibb) for secondary stroke prevention and 3% (n = 2) were taking aspirin.

All told, 72% (n = 40) were taking full or partial doses, the primary outcome, by the end of the 8-week treatment period. Tolerance was slightly better for isosorbide mononitrate alone, with 87% (n = 13) achieving a full or partial dose compared to 69% (n = 9) of those on cilostazol alone (any isosorbide mononitrate versus no isosorbide mononitrate achieving full dose: OR, 3.77; 95% CI, 0.98 to 14.46; P = .053; any cilostazol versus no cilostazol achieving full dose: OR, 0.39; 95% CI, 0.11 to 1.34, P = .14). Combination groups showed similar tolerance to the individual groups (combination versus one drug alone achieving full dose: OR, 0.84; 95% CI, 0.27 to 2.64; P = .77).

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

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.

"There hasn't been a new drug for dementia for 15 years, so finding evidence that these cheap existing drugs could prevent dementia after a stroke would be a huge breakthrough,” James Pickett, PhD, head of Research at Alzheimer's Society, said in a statement.2 “It's promising to see that these two drugs are safe to use and we'll be excited to see the results of the next stage of testing in a couple of years, which will show whether these drugs can be an effective treatment."
REFERENCES
1. 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.
2. Drugs to prevent stroke and dementia show promise in early trial [press release]. Edinburgh, Scotland: University of Edinburgh; Published April 25, 2019. eurekalert.org/pub_releases/2019-04/uoe-dtp042419.php. Accessed April 26, 2019.