Limitations and Strengths
death, bleeding, ischemic strokes, ischemic heart disease, cognitive impairment, atherothromboembolic stroke, stroke, lacunar stroke, ischemic stroke, lacunar ischemic stroke, peripheral vascular disease, acute stroke, infarct, infarction
BLEEDING, ISCHEMIC STROKES, STROKE, RECRUITMENT, LACUNAR STROKE, ISCHEMIC STROKE, SECONDARY, EVENTS, ACUTE STROKE, INFARCT, INFARCTION
This study has some limitations. Placebo was not available, although the follow-up coordinators were carefully masked to the allocated drug. During the trial, 8 follow-up coordinators worked from 2 separate centers, decreasing the likelihood of unmasking. The COVID-19 pandemic affected recruitment (4-month suspension in 2020 and a slow restart) and in-person follow-up (Trail Making Test Part B, blood pressure, and MRI results), and it may have contributed to the 10.9% of patients missing central follow-up. The comparison of ISMN-cilostazol vs no drugs was underpowered. Owing to safety concerns, we excluded patients who were dependent (mRS score >2) or lacked capacity to consent, but future trials could include these patients. While lacunar ischemic stroke affects men more than women (2:1 ratio),The LACI-2 trial also had several strengths. The web-based randomization minimization ensured that key prognostic variables and identifying information were secure and balanced at baseline. The distribution of trial work between 2 coordinating sites helped reduce the risk of systematic bias or unmasking. The trial benefitted from the UK National Institute for Health Research Clinical Research Network infrastructure. The pragmatic approach to patient inclusion reflected clinical practice and reduced barriers to recruitment and cost (eg, there were very few nonlacunar ischemic strokes and no stroke mimics), despite not mandating MRI. This improved the generalizability of LACI-2, since MRI is not universally accessible or tolerated. We included patients with clinically definite lacunar stroke but no relevant imaging-visible infarct, since they have similar recurrent stroke and dependence rates as those with visible infarction.The composite outcome (recurrent stroke, cognitive impairment, functional impairment, and death) reflected the main outcomesBoth ISMN and cilostazol have been widely used for ischemic heart disease, peripheral vascular disease, or secondary prevention of atherothromboembolic stroke for years, with known, acceptable safety profiles. Despite concerns that adverse symptoms attributable to these drugs would discourage compliance, most patients remained in the trial (taking ≥50% of the allocated drug) for 1 year. The study drugs were administered in addition to guideline-based stroke secondary prevention (mostly clopidogrel in the UK) with no increased bleeding with cilostazol, consistent with findings reported in systematic reviews.The lack of effect of cilostazol on recurrent stroke observed here differs from meta-analyses of secondary ischemic stroke prevention,To our knowledge, NO donors have not been studied previously long term in patients with lacunar stroke or cSVD. Very short-term glyceryl trinitrate did not improve outcomes in acute stroke trials (n >5500),In the LACI-2 trial, effects on outcomes were achieved without changes in blood pressure. Intensive vs guideline blood pressure reduction had limited effects on cognition, recurrent stroke, or cSVD lesion progression in lacunar stroke.Results from LACI-2 demonstrate the strengths of composite and global analyses, compensating for low individual recurrent vascular events (5.3% for stroke and 1.1% for MI), and dependence rates (14.6%) that make it difficult to power cSVD trials using traditional stroke outcomes. This trial also shows the value of clinical end points, including cognition, in cSVD trials.