Repurposing two cheap and common drugs could become the first treatment for people who have experienced a lacunar stroke, said researchers.
Lacunar strokes affect at least 35,000 people in the UK each year. Cerebral small vessel disease is a common cause of this type of stroke, and it is the most common cause of vascular cognitive impairment and dementia.
However, the authors of a new study, published in JAMA Neurology, noted there were currently no specific effective treatments for lacunar strokes.
The research was led by the universities of Edinburgh and Nottingham, and the UK Dementia Research Institute, with the aim of determining if modulators of cerebrovascular endothelial function – including isosorbide mononitrate (ISMN, a nitric oxide donor) and cilostazol (a phosphodiesterase-3 inhibitor) – could improve long-term outcomes after lacunar ischaemic stroke.
The researchers performed an investigator-initiated, open-label, blinded end-point, randomised trial with a 2 x 2 factorial design – the Lacunar Intervention Trial-2 (LACI-2) – to inform the design of large phase 3 trials, by testing the feasibility, drug tolerability, safety, and effects of one-year ISMN and cilostazol treatment on vascular, functional, and cognitive outcomes in patients with lacunar stroke.
Efforts Now Focussed on Halting Damage
For the trial, 363 participants, with a median age of 64 years (69.1% male), were recruited from 26 UK hospital stroke centres between 5 February 2018 and 31 May 2021, with 12-month follow-up data on 358 participants. The median time between stroke and randomisation was 79 days.
Included participants had clinical lacunar ischaemic stroke, were independent, aged over 30 years, had compatible brain imaging findings, capacity to consent, and had no contraindications to, or indications for, the study drugs.
All patients continued their usual prescribed medications, which included guideline-based stroke prevention treatment, and lifestyle advice, and were randomised to ISMN (40-60 mg/d), cilostazol (200 mg/d), ISMN-cilostazol (40-60 and 200 mg/d, respectively), or no study drug. Participants started their allocated drug(s) the day after randomisation at a low dose, escalating to the full or maximum tolerated dose by 4 weeks.
Professor Joanna Wardlaw, chair of applied neuroimaging at the University of Edinburgh and foundation chair of the UK Dementia Research Institute, said: "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."
Both Drugs Already Licensed and Inexpensive
At 12 months, 98.6% of the participants were retained in the study, with 94.5% taking 50% or more of the allocated drug. No safety concerns were highlighted at this stage.
ISMN was found to reduce recurrent stroke and cognitive impairment; cilostazol
reduced dependence and improved mood; and ISMN-cilostazol reduced the composite of adverse vascular, dependence, and cognitive outcomes at 1 year, compared with those who did not take the drugs.
The beneficial effects were strengthened when the two drugs were taken together, the researchers reported. Participants who took both drugs were nearly 20% less likely to have problems with their thinking and memory compared with the group that did not take either drug. "They were also more independent and reported a better quality of life," emphasised the authors.
"The two inexpensive licensed drugs could be available as a treatment for lacunar strokes within five years, if the results are confirmed in further trials," they said.
Professor Wardlaw cautioned, though, that larger trials were needed before either drug could be recommended as a treatment, and the team were planning to test the drugs in a larger 4-year clinical trial.
However, Professor Wardlaw hoped that since the two drugs were already widely available for other circulatory disorders, and were both inexpensive, "it shouldn't take too long to move our findings from research into everyday clinical practice".
Professor Sir Nilesh Samani, British Heart Foundation medical director, commented that the "promising" findings provided a "long-awaited positive step" towards the first treatments becoming available for lacunar strokes. He said that that the study's findings also opened "new avenues" of research into other conditions related to small vessel disease, such as vascular dementia.
The LACI-2 trial was funded by the British Heart Foundation, with support from the Alzheimer’s Society, UK Dementia Research Institute, Fondation Leducq, NHS Research Scotland, Stroke Association and Garfield-Weston Foundation, and the NIHR. Prof O’Brien is an Emeritus NIHR Senior Investigator and supported by the NIHR Cambridge Biomedical Research Centre. Prof Bath is a Stroke Association Professor of Stroke Medicine and is an Emeritus NIHR Senior Investigator.