Well then write up a proposed protocol on this and get it distributed to all stroke hospitals in the world AND ENSURE staff doctors get trained in its' use.
Combination of Two Common Cariovascular Drugs Could Improve Outcomes in Lacunar Stroke
The trial also showed signs that the drug combination could potentially improve cognitive outcomes in lacunar stroke, although larger trials will be needed to confirm these findings.
LACI-2, the second largest trial ever in lacunar stroke, was designed to assess the feasibility, drug tolerability, safety, and effects of one year of treatment with isosorbide mononitrate (ISMN) and cilostazol on vascular, functional, and cognitive outcomes in patients with this type of stroke.
Lacunar stroke, which occurs in the small penetrating arteries deep within the brain, causes approximately 25 percent of ischemic strokes and is associated with significant morbidity and mortality, including major physical and cognitive disabilities. There is no proven treatment to improve outcomes after a lacunar stroke.
“There appeared to be some potential benefits that will need to be confirmed in a larger phase 3 trial," lead author Joanna M. Wardlaw, MD, FAHA, said at a presentation of the LACI-2 preliminary results during the American Stroke Association's International Conference in February 2023.
“We
saw good hints of efficacy, particularly for isosorbide mononitrate on
reducing recurrent stroke and cognitive impairment, and we also found
that both medications together seemed to work synergistically, rather
than counteracting any benefit," said Dr. Wardlaw, professor of applied
neuroimaging, honorary consultant neuroradiologist, head of neuroimaging
sciences, and director of Edinburgh Imaging at Edinburgh University in
Scotland. “This is very encouraging since no study has previously found
any medications that positively affect cognitive impairment in small
vessel disease strokes. So, we cautiously hope that these medications
may have wider implications for other types of small vessel disease."
Study Details
Between February 2018 and May 2022, the LACI-2 investigators enrolled 363 adults who had experienced lacunar stroke from 26 stroke centers across the United Kingdom. In addition to their standard prescribed stroke medications, study participants were randomized to a year in one of four treatment groups: 40 to 60 mg/day of oral ISMN alone, 200 mg/day of oral cilostazol alone, both medications, or neither medication.
Participants in the LACI-2 trial had characteristics typical of lacunar ischemic stroke, including being younger compared with all patients with stroke; additionally, “more were men, few strokes had embolic sources, and patients had low rates of dependence and death (1.3 percent) but high rates of cognitive impairment (58.9 percent)."
Participants with indications for, or contraindications to, one study drug could be randomized to the other drug.
At one year, 358 of those initially enrolled were still participating in the study, with 95 percent of participants taking at least half of medication doses, meeting the study's feasibility outcome. The trial also met safety criteria, with relatively few adverse events.
Although the trial was not powered to evaluate efficacy, the composite efficacy outcome—which included vascular events, dependence, cognition, and death—showed signs of benefit with either of the drugs alone and a significantly lower rate with the combination compared with neither drug (48.6 percent vs. 69.6 percent). Overall, the absolute reduction in participants with any cognitive impairment was 18.7 percent (46.7 percent with ISMN-cilostazol and 65.4 percent with neither drug).
Individually, although it did not reduce the composite outcome, ISMN reduced recurrent stroke or transient ischemic attack (TIA)—2.2 percent with ISMN vs. 8.3 percent without; p=0.01)—and improved quality of life (p=0.03), reduced global Stroke Impact Scale (p=0.005), reduced global clinical outcomes (p=0.004), reduced cognitive impairment (p=0.008), and tended to reduce dependence. The absolute reduction in participants with any cognitive impairment was 10.4 percent (54.4 percent with ISMN and 64.8 percent without ISMN).
Cilostazol alone did not reduce
the composite outcome, recurrent stroke, or TIA, nor did it improve
quality of life or global clinical outcome. It did reduce dependence
(with a modified Rankin Scale score of 3 to 6: 8.8 percent with
cilostazol vs. 17.3 percent without; p=0.006). Cilostazol did not reduce cognitive impairment but tended to improve mood, as measured by the Zung depression scale (p=0.06).
“This is a great study and great news for the field of small vessel disease," said Jose Rafael Romero, MD, associate professor of neurology and a member of the Stroke Unit at Boston University Chobanian & Avedisian School of Medicine, which has several ongoing clinical trials for acute stroke treatment and secondary prevention.
“There is a strong signal that there could be more targeted treatment for these patients, not only in stroke risk reduction but [also] with an apparent effect on cognitive outcomes. Small vessel disease is a major underlying cause of dementia, and I would argue that every type of dementia has some component of small vessel disease, so the public health impact of interventions like these can be enormous."
The successful achievement of the study's safety endpoint is strengthened by the fact that the two drugs were administered in addition to standard of care, including single or dual antiplatelet therapy. “In combination with those drugs, cilostazol and ISMN did not increase the risk of major bleeding and showed a safe profile, which makes these findings even stronger," Dr. Romero said.
The LACI-3 trial is now preparing to address many of these questions, and other trials are also being proposed to funders around the world.
“I'm very optimistic about these findings," Dr. Romero said. “I think they are likely to lead us toward a big change for the treatment of small vessel disease in a very positive way."
Look for more in-depth discussion in an upcoming issue of Neurology Today.
Disclosures
Dr. Romero had no disclosures.
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