Cilostazol and Isosorbide Mononitrate Evaluated as Therapy for Lacunar Stroke in LACI-2 Preliminary Study

February 9, 2023—The American Stroke Association (ASA) announced that a preliminary study of two widely used cardiovascular medications—cilostazol and isosorbide mononitrate—in > 350 patients confirmed that the two medications were well tolerated and safe for patients who have experienced lacunar strokes, which occur in small blood vessels deep in the brain. The results suggest the medications may help improve patient outcomes.

The findings from LACI-2 were presented as late-breaking science at ASA’s International Stroke Conference 2023 held February 8-10 in Dallas, Texas, and virtually.

LACI-2 lead investigator Joanna M. Wardlaw, MD, is Professor of Applied Neuroimaging, honorary consultant neuroradiologist, Head of Neuroimaging Sciences, and Director of Edinburgh Imaging at Edinburgh University in Edinburgh, Scotland. She is also Foundation Chair of the UK Dementia Research Institute, which is headquartered in London, United Kingdom. The study’s colead investigator is Philip M. Bath, DSc, UK Stroke Association Professor of Medicine at the University of Nottingham in Nottingham, United Kingdom.

Dr. Wardlaw commented in the ASA press release, “Currently, there is no proven treatment to prevent poor outcomes after lacunar stroke, so the ultimate goal with this research is to evaluate if medications with potential modes of action on the inner lining of blood vessels might help improve small vessel function and prevent or slow long-term brain damage after lacunar stroke.”

The ASA press release noted that the medications in the study are commonly prescribed for other cardiac conditions. Isosorbide mononitrate is used to treat chest pain by relaxing blood vessels and decreasing blood pressure. Cilostazol, which improves the flow of blood by relaxing the blood vessels and reducing blood clotting, is often prescribed for patients with peripheral artery disease.

According to ASA, LACI-2 is the second largest trial conducted in lacunar stroke. It examined whether such a trial was feasible among patients with lacunar strokes and if the medications would be well tolerated for 1 year after lacunar stroke.

The investigators also analyzed safety and other outcomes, including recurrent stroke, cognitive impairment, dependency, mood, and quality of life. This detailed information is needed for the next stage of research, a phase 3 trial, which would include more study participants. Results of the analysis on cognitive status at 1 year were presented separately in the same ISC Main Event session on February 9.

As summarized in the ASA press release, the investigators enrolled 363 adults (average age, 64 years; 31% women) who had experienced lacunar stroke from 26 stroke centers throughout the United Kingdom from February 2018 to May 2022. All study patients continued to take their usual prescribed medications as per stroke guidelines, including those that reduce blood clotting, lower blood pressure, and/or lower cholesterol—all of which may lower the risk of a second or recurrent stroke.

Patients were randomly assigned to one of four treatment groups: 40 to 60 mg/day of oral isosorbide mononitrate alone, 200 mg/day of oral cilostazol alone, both medications, or neither medication for 1 year. The patients completed phone surveys at 6 and 12 months to assess health status, including recurrent stroke and heart problems, cognitive tests, symptoms, and quality-of-life surveys. Brain imaging was performed at 12 months.

As reported by ASA, the study met its initial goals to determine if a larger trial was feasible and if the medications were safe and tolerable. After 1 year, 358 of the adults were still participating in the study, with 95% of participants taking at least half of the medication doses prescribed for the trial.

The investigators also found that safety criteria were met, with four deaths, four episodes of bleeding outside of the brain, and no excessive falls or dizziness. Some patients experienced mild symptoms (such as headaches), which were expected.

Additionally, some potential benefits from the medication groups were seen, including data that indicated the group who took the combined isosorbide mononitrate and cilostazol had a reduction in the amount of assistance they needed with everyday living tasks, a reduction in cognitive impairment, and positive impacts on mood and quality of life. Isosorbide mononitrate alone reduced recurrent stroke, cognitive impairment, and improved quality of life; cilostazol alone reduced the need for daily assistance.

Dr. Wardlaw stated, “There appeared to be some potential benefits that will need to be confirmed in a larger phase 3 trial. We saw good hints of efficacy, particularly for isosorbide mononitrate on reducing recurrent stroke and cognitive impairment, and we also found that both medications together seemed to work synergistically, rather than counteracting any benefit. This is very encouraging since no study has previously found any medications that positively affect cognitive impairment in small vessel disease strokes. So, we cautiously hope that these medications may have wider implications for other types of small vessel disease.”

As noted by ASA, the study’s limitations include its relatively small size of 363 patients and that it was not designed to measure efficacy, so the results showing effectiveness should be interpreted cautiously. It was open label; however, the follow-up staff for the study were unaware of which treatment the patients were assigned. Additionally, the investigators did not collect data on race or ethnicity, and many ethnic groups were suspected to be underrepresented.