Heart Meds May Prevent Vascular Dementia After Stroke

Megan Brooks

May 06, 2019

Two drugs for heart disease and angina — cilostazol (Pletal, Otsuka) and isosorbide mononitrate (ISMN) (multiple brands) — have neuroprotective potential for patients with lacunar ischemic stroke, new research suggests.

Results of the phase 2 LACunar Intervention-1 (LACI-1) trial show that cilostazol and ISMN are well tolerated individually and together in patients with lacunar stroke as an add-on to conventional secondary stroke prevention and may improve vascular function and cognition.

The results were published online April 23 in EClinicalMedicine.

Synergistic Effect?

Lacunar stroke is a frequent clinical manifestation of small vessel disease, the most common cause of vascular dementia.

"Patients have a high risk of recurrent stroke and also of cognitive decline after lacunar stroke. There are no established treatments to prevent or treat small vessel disease," study investigator Joanna M. Wardlaw, MBChB(Hons), MD, of University of Edinburgh, United Kingdom, told Medscape Medical News.

Cilostazol and ISMN have "promising modes of action" to prevent progression of small vessel disease, including relaxing small blood vessels and reducing inflammation, she added.

In studies conducted in Asia-Pacific countries, cilostazol has been shown to reduce recurrent stroke and incident dementia. However, there is little experience with cilostazol in the treatment of lacunar stroke outside the Asia-Pacific region, nor is there experience with ISMN in the treatment of lacunar stroke anywhere, or of the drugs in combination, yet the effects are potentially synergistic.

"The purpose of LACI-1 was to see if patients with small vessel disease could take the drugs, to get some evidence for safety and efficacy, and to lay the infrastructure for larger trials," said Wardlaw.

The phase 2a, dose-escalation, prospective, randomized, open-label trial was conducted at two large stroke centers in the United Kingdom. In the trial, 39 men and 18 women (mean age, 66 years) with clinically confirmed lacunar ischemic stroke who were without cognitive impairment were randomly allocated to receive ISMN 25 mg twice daily; cilostazol 100 mg twice daily; both ISMN and cilostazol, started immediately; or both drugs, started after a delay. Doses were escalated to target over 2 weeks and were sustained for 8 weeks.

Most patients (64%) achieved the full target dose by the end of the treatment period (the primary outcome). There was no difference between cilostazol vs ISMN and single vs dual drugs.

There were no drug-related adverse events or bleeding complications, despite the fact that all participants also took prescribed antiplatelet drugs.

In addition, the trial showed that both drugs affect systemic hemodynamic function and may improve vasoreactivity in white matter, reduce white matter lesions, and improve cognitive performance. All of these secondary outcomes "require confirmation in larger trials," the researchers note.

LACI-1 also demonstrates that the drugs are safe for use in lacunar stroke patients, taken alone or in combination, and supports further testing in larger trials with clinical endpoints, they say.

LACI-2, which aims to enroll 400 patients with lacunar stroke and is funded by the British Heart Foundation, is underway. In LACI-2, patients with lacunar stroke will be treated with cilostazol and ISMN, alone or in combination, for a year to test the effects on recurrent stroke, cognition, tolerability, and safety.

"It is too early to say if the drugs will prevent progression of small vessel disease or recurrent lacunar stroke or cognitive decline, but LACI-2 will help," said Wardlaw.

Potential Breakthrough?

"There hasn't been a new drug for dementia for 15 years, so finding evidence that these cheap existing drugs could prevent dementia after a stroke would be a huge breakthrough," James Pickett, PhD, head of research at the Alzheimer's Society, said in a news release.

"It's promising to see that these two drugs are safe to use, and we'll be excited to see the results of the next stage of testing in a couple of years, which will show whether these drugs can be an effective treatment," added Pickett.

LACI-1 was funded primarily by the Alzheimer's Society, with support from the UK Stroke Association, the British Heart Foundation, the European Union, the National Institutes of Health Research, and National Health Service Research Scotland. The authors have disclosed no relevant financial relationships.

EClinicalMedicine. Published online April 23, 2019. Full text

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