Thomas Raphael Meinel, MD
@TotoMynell
Small-vessel disease, including manifest stroke, but more frequently covert lesions, is a silent pandemic contributing considerably to dementia, frailty, gait problems and mood disorders worldwide.1 The imaging spectrum of small-vessel disease includes white matter hyperintensities (WMH), lacunes, acute small subcortical infarcts, cerebral microbleeds and dilated perivascular spaces.2
It is thus of utmost importance that Kim et al. undertook the work to perform a multicenter, double-blind, randomized controlled trial3 on whether cilostazol slow release (200 mg) as compared to aspirin (100 mg) might be able to slow down WMH progression over the follow-up duration of two years. For this trial, Korean patients aged 50-85 with (45%) and without (55%) manifest stroke were recruited from memory clinics or neurology outpatient clinics referred for memory problems, gait disturbances, personality changes or secondary prevention after a small subcortical infarction or TIA between 2013 and 2016. They had to have at least moderately severe WMH and at least one lacune. Exclusion criteria included contraindications to antiplatelets, significant atherosclerosis or cardioembolic heart disease amongst others. The methods included sophisticated brain imaging and neurocognitive assessments.
The final study cohort of the modified intention to treat analysis included 102 patients randomized to cilostazol and 116 patients randomized to aspirin (mean age 74 years, 64% female, 47% prior stroke, mean MMSE 24 points). The brain image frailty at baseline was considerable with participants having a mean of 7 (sic!) lacunes, 45 mL of WMH and 6 cerebral microbleeds.
After 2 years, there was no effect for the primary outcome of WMH volume, which increased in both treatment arms without differences between the two drugs. There was also no difference in incident lacunes, cerebral microbleeds or brain volume. None of the neurocognitive or functional scales showed a significant between-group difference. However, cilostazol reduced the hazards for manifest ischemic vascular events compared with aspirin (hazard ratio 0.11 [95% CI 0.02–0.89]), and there was a trend for reduction of incident manifest stroke for patients randomized to cilostazol (hazard ratio 0.17 [95% CI 0.02 -1.34]).
Difficulties of the trial were attrition of more than 20% of patients in the cilostazol arm and 10% in the aspirin arm because no efficacy evaluation could be done due to decline to participate, adverse events, study violation or adverse events. Also, the sample-size and follow-up were too short to draw a definite conclusion on a possible effect. Additionally, the incorporation of many imaging and neurocognitive subitems comes at the cost of multiple testing. Hence, the significant difference in the peak height of the mean diffusivity histogram in normal-appearing white matter (favoring cilostazol) has to be taken with caution and might be a chance finding.
The authors have to be applauded for their effort to compare two antithrombotics in a high-quality trial although the feasibility and validity of the trial were limited due to the limitations mentioned above. The logistic problems of the trial urge funders and trialists worldwide to perform future trials in large cooperations with longer follow-up durations. Future trials on covert small vessel disease should also include an arm without antithrombotics as the recent ESO guideline suggested against the use of antithrombotics especially in older adults when no other indication exists. Due to the frequency of the disease and the large impact on QALYs, there is an urgent need to address this vascular high-risk population aiming at different targets such as antithrombotics, targeted blood pressure and lipid lowering strategies, multimodal interventions, as well as atrial fibrillation detection.4 As the authors mentioned, the inclusion of a cohort with severe brain frailty might come too late, hence preventive trials addressing individuals with covert small vessel disease at an earlier stage seem more promising.
References:
1. Wardlaw JM, Debette S, Jokinen H, De Leeuw F-E, Pantoni L, Chabriat H, Staals J, Doubal F, Rudilosso S, Eppinger S, et al. ESO Guideline on covert cerebral small vessel disease. Eur. Stroke J. 2021;6:IV–IV.
2. Wardlaw JM, Smith EE, Biessels GJ, Cordonnier C, Fazekas F, Frayne R, Lindley RI, O’Brien JT, Barkhof F, Benavente OR, et al. Neuroimaging standards for research into small vessel disease and its contribution to ageing and neurodegeneration. Lancet Neurol. 2013;12:822–838.
3. Kim BC, Youn YC, Jeong JH, Han HJ, Kim JH, Lee J-H, Park KH, Park KW, Kim E-J, Oh MS, et al. Cilostazol Versus Aspirin on White Matter Changes in Cerebral Small Vessel Disease: A Randomized Controlled Trial. Stroke. 2021.
4. Meinel TR, Kaesmacher J, Roten L, Fischer U. Covert Brain Infarction: Towards Precision Medicine in Research, Diagnosis, and Therapy for a Silent Pandemic. Stroke. 2020;51:2597–2606.
