乌鸦传媒

DALLAS -- Drugs that improve endothelial function appeared promising for people with lacunar strokes resulting from small vessel disease (SVD), according to LACI-2 study findings that pave the way for a larger phase III trial.

Individuals taking isosorbide mononitrate and cilostazol together for a year following lacunar ischemic stroke had a significant reduction in the combined outcome of recurrent stroke, myocardial infarction, functional dependency, death, and cognitive impairment (48.6% vs 69.6% for controls not on either drug, adjusted HR 0.58, 95% CI 0.37-0.92).

While isosorbide mononitrate and cilostazol individually had no effect on the combined endpoint, isosorbide mononitrate in particular had a significant association with reduced recurrent strokes at 12 months (2.2% vs 8.3%, P=0.014), reported Joanna Wardlaw, MD, a neuroimaging specialist at the University of Edinburgh in Scotland, during the American Stroke Association's International Stroke Conference (ISC).

What's more, safety events were rare in LACI-2. Extracranial hemorrhages were recorded in 1.1% of the cohort, intracranial hemorrhages in 0, and deaths in 1.1%. Moreover, there was no evidence of drug-drug interaction between isosorbide mononitrate and cilostazol.

Study findings suggest potential for a specific treatment for lacunar strokes, which account for up to a quarter of all ischemic stokes and are related to SVD of the brain. Affected patients are often left with cognitive impairment despite low dependency and stroke recurrence, according to Wardlaw.

Indeed, cognitive impairment was the major contributor to outcomes in the trial. As was the case with LACI-2's composite clinical result, only combination isosorbide mononitrate and cilostazol -- not either drug alone -- managed to reduce the risk of cognitive impairment, according to fellow LACI-2 investigator Philip Bath, DSc, a stroke specialist at the University of Nottingham in England.

"It is great to see that the combination treatment is safe and potentially effective ... It is exciting to see stroke prevention in small vessel disease moving forward," commented Shadi Yaghi, MD, a vascular neurologist at Brown University and Rhode Island Hospital in Providence, who was not involved with the study.

"It is difficult to draw conclusions, however, about the underlying pathophysiology of lacunar stroke based on the study, as cilostazol has also been suggested to be effective in patients with intracranial atherosclerosis as well," Yaghi cautioned in an email to 乌鸦传媒.

It is believed that the intrinsic problem of lacunar strokes is tissue damage and impaired vasodilation in the small vessel endothelium. This is the rationale behind the hypothesis that endothelium-stabilizing drugs like isosorbide mononitrate and cilostazol might improve function and reduce damage.

Both drugs are widely available and inexpensive. Isosorbide mononitrate is a nitrate used to treat and prevent ischemic heart disease with no long-term data in stroke or cognition. Cilostazol is an antiplatelet and vasodilator preferred in Asia to prevent stroke.

Proving the benefit of the two agents will require a larger phase III trial. This LACI-3 trial is in preparation, Wardlaw told the ISC audience.

LACI-2 was conducted as a 2×2 factorial trial that had 363 adults randomized to one of four treatments for 1 year: 25-mg oral isosorbide mononitrate twice a day, 100-mg oral cilostazol twice a day, both medications, or neither medication. Doses were increased over 4 weeks to test tolerability.

Recruitment occurred at 26 stroke centers throughout the U.K. Eligible participants had a lacunar stroke and showed independent function. The cohort had a median age of 64 years, and approximately 31% were women. Groups were well balanced after randomization.

Nearly 90% of participants had a visible index infarct on imaging, the vast majority lacunar, with only 3% involving the middle cerebral artery or posterior cerebral artery.

Most patients were on antiplatelets (97%) and antihypertensives (76%) at baseline. Contraindications to either trial drug were noted in 12%.

LACI-2's overall results and cognition findings were consistent across prespecified subgroups.

The trial was nevertheless not powered for efficacy and subgroup analysis, and its data may be considered hypothesis-generating due to lack of adjustment for multiplicity. Other limitations included the open-label nature of the study and the issue of missing cognition data.

"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," Wardlaw said.

"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," she added.

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