Edinburgh, UK—Lacunar ischemic strokes, caused by cerebral small vessel disease (cSVD), make up 25% of ischemic strokes. The small strokes often cause vascular dementia, as well as neuropsychiatric and mood disorders and impaired mobility.

Yet, no specific treatment exists for cSVD. A UK study team led by researchers from the University of Edinburgh looked for a solution and found that the repurposing of two inexpensive and common drugs appeared to be effective.

In a report in Journal of the American Medical Association Neurology, the researchers determined that the nitrate isosorbide mononitrate and the vasodilator cilostazol, which are already used to treat other heart and circulatory diseases, appeared to safely improve the debilitating outcomes caused by lacunar stroke.

“Now we understand more about what is triggering these small vessel strokes to attack the brain, we’ve been able to focus our efforts on treatments that can put a halt to this damage,” lead author Joanna Wardlaw, CBE, FRCP, FRSE, FMedSc, chair of applied neuroimaging at the University of Edinburgh and foundation chair at the UK Dementia Research Institute, explained in a press release. “We need to confirm these results in larger trials before either drug can be recommended as a treatment. However, as these drugs are already widely available for other circulatory disorders, and inexpensive, it shouldn’t take too long to move our findings from research into everyday clinical practice.”

The Lacunar Intervention Trial-2 (LACI-2), an investigator-initiated, open-label, blinded endpoint, randomized clinical trial with a 2 x 2 factorial design, sought to test the feasibility, drug tolerability, safety, and effects of 1-year isosorbide mononitrate (ISMN) and cilostazol treatment on vascular, functional, and cognitive outcomes in patients with lacunar stroke.

The goal of the trial was to recruit 400 participants from 26 UK hospital stroke centers between February 5, 2018, and May 31, 2021, with a 12-month follow-up. The study included participants who had clinical lacunar ischemic stroke, were independent, were aged older than 30 years, had compatible brain imaging findings, had the capacity to consent, and had no contraindications to (or indications for) the study drugs. Data analyses were performed on August 12, 2022.

With all patients receiving guideline stroke prevention treatment, the researchers randomized them to ISMN (40-60 mg/day), cilostazol (200 mg/day), ISMN-cilostazol (40-60 mg and 200 mg/day, respectively), or no study drug.

The primary outcome was defined as recruitment feasibility, including retention at 12 months. Secondary outcomes were safety (death), efficacy (composite of vascular events, dependence, cognition, and death), drug adherence, tolerability, recurrent stroke, dependence, cognitive impairment, quality of life (QoL), and hemorrhage.

Ultimately, 363 (90.8%) were recruited; their median age was 64 years (interquartile range [IQR] 56.0-72.0), and 251 (69.1%) were men. The median time between stroke and randomization was 79 days (IQR 27.0-244.0). The study retained 358 patients (98.6%) at 12 months, with 257 of 272 (94.5%) taking 50% or more of the allocated drug.

“Compared with those participants not receiving that particular drug, 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 reduced the composite outcome in 297 patients,” the authors wrote. “Isosorbide mononitrate reduced recurrent stroke in 353 patients (adjusted odds ratio [aOR] 0.23; 95% CI, 0.07-0.74]; P = .01) and cognitive impairment in 308 patients (aOR 0.55; 95% CI, 0.36-0.86; P = .008).”

They added, “Cilostazol reduced dependence in 320 patients (aHR 0.31; 95% CI, 0.14- 0.72; P = .006). Combination ISMN-cilostazol reduced the composite (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) and improved QoL (adjusted mean difference 0.10; 95% CI, 0.03-0.17; P = .005) in 153 patients. There were no safety concerns.”

The study team reported that their results indicated that the LACI-2 trial was feasible and ISMN and cilostazol were well tolerated and safe. “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 III trials,” according to the report.

The researchers’ hypothesis grew out of the suspicion that most lacunar ischemic strokes and cSVD result from an intrinsic perforating arteriolar disorder, with dysfunction of the small vessel endothelium affecting blood supply to subcortical tissues. They posited that drugs that stabilize endothelial function might prevent the long-term clinical, cognitive, and functional consequences of cSVD.

The study pointed out that ISMN, a nitric oxide (NO) donor, augments the NO-cyclic guanosine monophosphate phosphodiesterase PDE5-inhibitor pathway. Cilostazol, a PDE3 inhibitor, augments the prostacyclin-cyclic adenosine monophosphate pathway. “Endothelial function depends on both pathways; therefore, both ISMN and cilostazol could improve vascular endothelial function,” the authors wrote. “These agents are licensed for the treatment of vascular diseases, have known safety profiles, and have no direct interactions of concern in routine use.”

Sir Nilesh Samani, FRCP, FMedSci, medical director at the British Heart Foundation, which sponsored the study, added, “These promising findings provide a long-awaited positive step towards the first treatments becoming available for lacunar strokes, offering much-needed hope for thousands of people. Lacunar strokes are not the only way that cerebral small vessel disease can affect someone. These findings also open new avenues of research into other conditions related to small vessel disease, such as vascular dementia.”

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