LACI-2 sets stage for cilostazol-isosorbide combo in lacunar stroke

The combination of cilostazol and isosorbide mononitrate boosts functional and cognitive outcomes in patients who have had lacunar strokes (subcortical infarcts <20 mm in diameter) in the phase II LACI-2* trial.

After 1 year, there was a reduction in the composite clinical outcome of recurrent stroke/transient ischaemic attack, myocardial infarction (MI), cognitive impairment, dependency (mRS>2**), and death. [ISC 2023, abstracts LB04 and LB12]

Cilostazol and isosorbide combo regimen was feasible and well tolerated, setting the stage for a more-definitive phase III study.

Better together

“When used together, they seemed to have more benefits than either drug on its own,” reported study author Dr Joanna Wardlaw from the Edinburgh University in Edinburgh, UK. “This is good evidence that the combination strategy is working together positively.”

However, while the results are promising she cautioned that the benefits need to be confirmed in a larger phase III trial.

Lacunar or small vessel strokes account for up to 25 percent of all ischaemic strokes. [Stroke 1997;28:491–499] While the condition may be labeled as a mild stroke on the NIHSS***, up to 60 percent of patients develop cognitive impairment and eventually dementia.There is no specific treatment for lacunar stroke, making it an important target for new therapeutic approaches.

Exciting results

As lacunar stroke is believed to be caused by endothelial dysfunction in the small vessels of the brain, “therapies that stabilize or replicate endothelial function may be helpful in this setting,” said Dr Phillip Bath from the University of Nottingham, England, whose presentation focused on cognitive impairment within the LACI-2 cohort.  “Patients report cognitive impairment as a dreaded outcome of a stroke. Hence, the current findings are particularly important and need to be investigated more thoroughly.”

Cilostazol is already used widely in Asia for stroke prevention whereas isosorbide mononitrate is used to relieve angina in patients with ischaemic heart disease.

LACI-2 picked up where LACI-1 trial left off and further assessed the safety and tolerability of the combination therapy, including its impact on clinical and cognitive endpoints.

LACI-2 population

At least 363 patients (median age 64 years, 31 percent female) from across 26 sites in the UK were randomly assigned to receive either cilostazol 200 mg daily alone, isosorbide mononitrate 40–60 mg daily alone, both medications or neither medication for 1 year.  All patients received other guideline-recommended therapy for stroke prevention.

They completed phone surveys at 6 and 12 months to assess health status, including recurrent stroke, MI, cognitive tests, symptoms, quality-of-life surveys, and had brain imaging at 12 months.

Ninety-eight percent of patients were still taking the combination therapy at 12 months. Cilostazol and isosorbide mononitrate appeared safe and were well tolerated, with few deaths or haemorrhage.

For the composite efficacy outcome, there were hints of benefit with either drug taken alone and a significantly lower rate when taken together vs neither (48.6 percent vs 69.6 percent; adjusted hazard ratio [aHR] 0.58, 95 percent confidence interval [CI], 0.36–0.92).

Patients taking both drugs also had better functional outcomes according to the ordinal shift in modified Rankin Scale scores (adjusted odds ratio [aOR], 0.51, 95 percent CI, 0.28–0.93).

Cognitive impairment accounted for most of the events observed for the composite endpoint, but taking both drugs led to large reductions in cognitive impairment (HR, 0.44) and dependency (HR, 0.14). These findings were consistent in sensitivity analyses and across subgroups, with no evidence of an adverse interaction between cilostazol and isosorbide.

“Both medications work synergistically rather than counteracting any benefit. This is encouraging as no study has previously found any medications that positively affect cognitive impairment in small vessel disease strokes,” said Wardlaw. “We hope these medications would have wider implications for other types of small vessel disease.”

Plans for a phase III trial (LACI-3) are underway, she concluded.