ISMN, Cilostazol Reduce Adverse Long-Term Outcomes in Lacunar Ischemic Stroke

The combination of isosorbide mononitrate and cilostazol is safe, well-tolerated, and feasible to reduce recurrent stroke, dependence, and cognitive impairment after a lacunar stroke.

Treatment with isosorbide mononitrate (ISMN) and cilostazol has been associated with reductions in recurrent stroke, cognitive impairment, and dependence among patients who experience a lacunar ischemic stroke, according to study findings published in JAMA Neurology.

The presence of cerebral small vessel disease (cSVD), which is a major cause of lacunar stroke, is linked to vascular cognitive impairment and mood/mobility issues. To date, there is no specific treatment available to prevent the occurrence. For the study, researchers evaluated whether modulators of cerebrovascular endothelial function, such as the nitric oxide donor ISMN and the phosphodiesterase-3 inhibitor cilostazol, improve patients’ long-term outcome after experiencing a lacunar stroke.

The investigator-initiated, open-label, blinded endpoint, randomized, 2×2 factorial Lacunar Intervention Trial-2 (LACI-2; Identifier: NCT03451591) was conducted at 26 stroke specialist hospitals located in the United Kingdom. The researchers aimed to recruit a total of 400 participants between February 5, 2018 and May 31, 2021, with a follow-up period of 12 months designated. Data analysis was carried out on August 22, 2022.

Participants were eligible for the trial if they had a clinical lacunar ischemic stroke, were independent, older than 30 years, and had compatible brain imaging findings as well as no contraindications to (or indications for) the study drugs included in the trial.

These results show that the LACI-2 trial was feasible and ISMN and cilostazol were well tolerated and safe.

The patients received standard stroke prevention medication and were randomly assigned to 1 of 4 groups: ISMN 40 to 60 mg/day, cilostazol 200 mg/day, ISMN 40 to 60 mg/day plus cilostazol 200 mg/day, or no study drug.

Primary outcome included recruitment feasibility, including 12-month retention. Secondary outcomes included safety (death), efficacy (composite of vascular events, dependency, cognition, and death), medication adherence, tolerance, recurrent stroke, dependence, cognitive impairment, quality of life (QoL), and hemorrhage.

Out of the 400 anticipated participants, 363 (251 men, 112 women; median age, 65 [range, 56.0-72.0 years]) were recruited over 24 active months. Patients’ median National Institutes of Health score was 0 (range, 0-2.0). The median time that elapsed between stroke and study randomization was 79.0 days (range, 27.0-244.0 days).

At 12-month follow-up, 98.6% (358 of 363) of the participants were retained in the study. Overall, 94.5% (257 of 272) of the participants were receiving treatment with ≥50% of the study drug.

The researchers found that compared with participants not receiving that particular agent, neither ISMN (adjusted hazard ratio [aHR], 0.80; 95% CI, 0.59-1.09; P =.16) nor cilostazol (aHR, 0.77; 95% CI, 0.57-1.05; P =.10) alone was associated with a reduction in the composite outcome in 297 participants.

Further, ISMN decreased the occurrence of recurrent stroke in 353 participants (adjusted odds ratio [aOR], 0.23; 95% CI, 0.07-0.74; P =.01) and cognitive impairment in 308 individuals (aOR, 0.55; 95% CI, 0.36-0.86; P =.006). Treatment with cilostazol was linked to reduced dependence in 320 participants (aHR, 0.31; 95% CI, 0.14-0.72; P =.006).

Combination ISMN plus cilostazol reduced the composite outcome (aHR, 0.58; 95% CI, 0.36-0.92; P =.02), dependence (aOR, 0.14; 95% CI, 0.03-0.59; P = .008), and any cognitive impairment (aOR, 0.44; 95% CI, 0.23-0.85; P =.02). The combination therapy also improved quality of life (adjusted mean difference, 0.10; 95% CI, 0.03-0.17; P =.005) in 153 participants. No safety concerns were reported.

Study limitations included the fact that placebo treatment was not available. In addition, the COVID-19 pandemic affected study recruitment, as well as in-person follow-up. Further, comparison of the combination ISMN plus cilostazol therapy vs treatment with no agent(s) was underpowered.

“These results show that the LACI-2 trial was feasible and ISMN and cilostazol were well tolerated and safe,” the investigators noted. “These agents may reduce recurrent stroke, dependence, and cognitive impairment after lacunar stroke, and they could prevent other adverse outcomes in cSVD. Therefore, both agents should be tested in large phase 3 trials,” they concluded.

Disclosure: Some of the study authors have declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of authors’ disclosures. 


Wardlaw JM, Woodhouse LJ, Mhlanga II, et al; Lacunar Intervention Trial-2 (LACI-2) Investigator Group. Isosorbide mononitrate and cilostazol treatment in patients with symptomatic cerebral small vessel disease: the Lacunar Intervention Trial-2 (LACI-2) randomized clinical trial. JAMA Neurol. Published online May 24, 2023. doi:10.1001/jamaneurol.2023.1526