A combination of two drugs has shown promising results, including a reduction in cognitive impairment in patients who have had a lacunar stroke, and is seen as a new therapeutic approach for patients with cerebral small vessel disease.

The drugs — isosorbide mononitrate and cilostazol — stabilize endothelial function, which is a new therapeutic target for patients with small-vessel disease stroke.

The phase 2 LACI-2 study, evaluating these drugs individually and in combination in patients with lacunar stroke, showed promising trends toward reductions in recurrent stroke, cognitive impairment, and dependency, some of which became significant when the drugs were given together. There was also some suggestion of positive impacts on mood and quality of life.

“Isosorbide mononitrate was associated with a reduction in recurrent stroke, a tendency toward a reduction in dependency and a reduction in cognitive impairment, and cilostazol also seemed to reduce dependency,” study investigator Joanna M. Wardlaw, MD, professor of applied neuroimaging at Edinburgh University, Edinburgh, UK reported.

“When used together, they seemed to have more benefits than either drug on its own. So this is good preliminary evidence that the drugs are working together in a positive way,” she commented to theheart.org | Medscape Cardiology.

But she cautioned that these potential benefits will need to be confirmed in a larger phase 3 trial.

The LACI-2 study was presented February 9 at the International Stroke Conference (ISC) 2023 in Dallas by Wardlaw and co-investigator Philip Bath, DSc, professor of medicine at the University of Nottingham, Nottingham, UK.

They both highlighted the effect seen on cognitive impairment.

“We saw a significant reduction in the number of patients with cognitive impairment with the two drugs together in this phase 2 study,” Wardlaw said. “This is very encouraging since no study has previously found any medications that positively affect cognitive impairment in small-vessel disease strokes. We cautiously hope that these medications may have wider implications for other types of small vessel disease as well.”

Bath added: “The results on cognitive impairment are particularly important. Many patients rate cognitive impairment as one of the most dreaded outcomes of a stroke even if they also have quite significant physical disability. People simply don’t want to lose their memory and thinking ability.”

“The results of LACI-2 also raise interesting questions about whether these drugs would be beneficial for other types of small vessel disease which do not present as stroke, but maybe may manifest as headaches or memory impairment,” he noted.

“Very Intriguing Results”

Outside experts were enthusiastic about these preliminary results.

In an ISC highlights presentation, program chair Tudor Jovin, MD, Cooper Neurological Institute, Cherry Hill, New Jersey, said: “It is refreshing to finally see some positive signals in studies in small vessel stroke. This is an area where we haven’t had answers for a long time.”

He described the reduction in cognitive impairment seen in the study as “very intriguing and very important.”

“I think we have underestimated the burden that cognitive impairment has in stroke, and the burden in general in society of vascular cognitive impairment. This is a very promising approach that definitely deserves to be investigated more thoroughly in a larger trial.”

Commenting for theheart.org | Medscape Cardiology, Mitchell Elkind, MD, professor of neurology and epidemiology at Columbia University Irving Medical Center, New York City, said this study “provides evidence that points us in at least two important directions.”

“First, it suggests that endothelial dysfunction, or problems with the lining of the blood vessels, may be an important contributor to small vessel disease and the cognitive decline that often accompanies it. This is a new mechanism of action and different from blood clotting, blood pressure, and other conventional targets of treatment,” Elkind said.

“Second, and more generally, it suggests that stroke trials, particularly in the subtype of small vessel disease, can and should explore not only the incidence of recurrent acute events but also the steady decline that occurs after stroke. Post-stroke cognitive decline is a relatively new area of stroke research.”

Wardlaw noted that lacunar stroke is a common type of ischemic stroke, but it has been rather neglected in terms of research. It is assumed to be caused by atherosclerosis of the small vessel but there is now mounting evidence suggesting that it is a result of problems in the endothelium of the small vessels.  

“We looked for potential available drugs that targeted endothelial dysfunction. Both the drugs we tested are already widely used — isosorbide mononitrate for the treatment of coronary artery disease and angina, and cilostazol mainly in Asia for stroke prevention,” she said.  

LACI-2 was primarily a feasibility study looking at whether it was possible to recruit enough patients who had had a lacunar stroke and would take the drugs, individually or in combination, for up to a year. Outcomes were investigated on an exploratory basis.

The study enrolled 363 patients who had experienced lacunar stroke from 26 stroke centers throughout the UK. They were randomly assigned to one of four treatment groups for 1 year:

• 40 to 60 mg/day of oral isosorbide mononitrate alone

• 200 mg/day of oral cilostazol alone

• both medications

• neither medication

Patients completed phone surveys at 6 and 12 months to assess health status, including recurrent stroke, myocardial infarction (MI), cognitive tests, symptoms, quality-of-life surveys, and they also had brain imaging at 12 months.

Results showed 98% of patients were still taking their study medication at 1 year and the drugs appeared to be safe on top of usual care with few deaths or hemorrhages in the study.

The composite outcome including recurrent stroke, MI, cognitive impairment, dependency (mRS >2) and death was reduced by 20% in the isosorbide mononitrate alone group (adjusted hazard ratio [HR] 0.80; 95% CI, 0.59 – 1.09).

The composite endpoint was reduced by 23% in the cilostazol group (HR 0.77; 95% CI 0.57 – 1.05) and by 42% in the combination group (HR 0.58, 95% CI, 0.36 – 0.92) compared with those taking neither drug.

Isosorbide mononitrate alone showed trends toward a reduction in recurrent stroke, cognitive impairment and dependency, whereas cilostazol alone reduced dependency with a trend toward a reduction in cognitive impairment. When used together, the drugs showed large reductions in cognitive impairment (HR 0.44; 95% CI, 0.19 – 0.99) and dependency (HR 0.14; 95% CI, 0.03 – 0.59).

During the highlights session, Jovin commented: “It is obvious that the investigators have put a lot of thought into the design of this trial. Presumably because of the composite score they were able to increase the power. We are used to trials which require thousands of patients but here we are able to see significant results, although exploratory, with just a few hundred patients.”

Bath stressed that this was only a phase 2 study. “We now need to see if we can confirm these results in a larger phase 3 study.” That study, LACI-3, is planned to start later this year.

Bath also suggested that it would be interesting to investigate whether these drugs would work in other types of ischemic stroke such as those caused by large artery disease or cardioembolic strokes, as well as other forms of small vessel disease such as patients with vascular cognitive impairment.

“There are many areas to investigate in future. It might be that in a few years’ time these drugs may be standard of care across many different forms of small vessel disease,” he said.

Wardlaw noted that lacunar strokes are generally quite mild strokes, which could be one of the reasons why they have not been the target of much research to date.

But Bath added: “While they may be labeled as a mild stroke on the NIHSS scale, patients can still be quite badly affected. About half of patients with a lacunar stroke develop cognitive impairment and eventually dementia — that is certainly not mild.”

The study was funded primarily by the British Heart Foundation, with support from the UK Alzheimer’s Society, the UK Dementia Research Institute, the Stroke Association, the Fondation Leducq, NHS Research Scotland, and the UK National Institutes of Health Research Clinical Research Networks. Bath is an advisor to CoMind, DiaMedica, Phagenesis, and Roche. Wardlaw reports no relevant financial relationships.

International Stroke Conference (ISC) 2023: Presentation LB4 and LB12. Presented February 9, 2023.

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