Background: The Effect of Cilostazol in Acute Lacunar Infarction Based on Pulsatility Index of the Transcranial Doppler (ECLIPse) study showed a significant decrease in the transcranial Doppler (TCD) pulsatility index (PI) with cilostazol treatment at 90 days after acute lacunar infarction. The aim of the present study was to perform a subgroup analysis of the ECLIPse study in order to explore the effect of cilostazol in acute lacunar infarction based on cerebral white matter hyperintensities (WMH) volume. Methods: The ECLIPse study was a multicenter, randomized, double-blind, placebo-controlled trial that evaluated the difference between the efficacy of cilostazol and a placebo to reduce the PI in patients with acute lacunar infarction using serial TCD examinations. The primary outcome was changes in the PIs of the middle cerebral artery (MCA) and basilar artery at 14 and 90 days from the baseline TCD study. For this subgroup analysis, using semi-automated computerized software, the WMH volume was measured for those subjects for whom fluid-attenuated inversion recovery (FLAIR) images were available. Results: Of the 203 patients in eight hospitals in the ECLIPse study, 130 participants from six hospitals were included in this subgroup analysis. Cilostazol was given to 63 patients (48.5%) and placebo to 67 patients (51.5%). All baseline characteristics were well balanced across the two groups, and there were no significant differences in these characteristics except in the changes of PI from the baseline to the 90-day point. There was a significant decrease of TCD PIs at 90-day study from baseline in the cilostazol group (p = 0.02). The mean WMH volume was 11.57 cm3 (0.13-68.45, median 4.86) and the mean MCA PI was 0.95 (0.62-1.50). The changes in PIs from the baseline to 14 days and to 90 days were 0.09 (-0.21 to 0.33) and 0.10 (-0.22 to 0.36). While there were no significant correlations between WMH volume and the changes in PIs, a trend of inverse correlation was observed between the WMH volume and the changes in PIs from the baseline to the 90-day point. For the subgroup analysis, the WMH volume was dichotomized based on its median value (4.90 cm3). Cilostazol decreased the TCD PIs significantly at the 90-day point in patients with WMH volumes ≤4.9 cm3 (p = 0.002). Significant treatment effects were observed in the cilostazol group. Conclusions: This study showed that cilostazol decreased cerebral arterial pulsatility in patients with WMH. Our findings indicate the unique effect of cilostazol in small vessel disease (SVD), especially in patients with mild WMH changes. Further clinical trials focusing on WMH volume and clinical outcomes are required to assess the unique efficacy of cilostazol in SVD.

Han SW, Lee SS, Kim SH, Lee JH, Kim GS, Kim OJ, Koh IS, Lee JY, Suk SH, Lee SI, Nam HS, Kim WJ, Yong SW, Lee KY, Park JH: Effect of cilostazol in acute lacunar infarction based on pulsatility index of transcranial doppler (eclipse): a multicenter, randomized, double-blind, placebo-controlled trial. Eur Neurol 2012;69:33-40.
Webb AJ, Simoni M, Mazzucco S, Kuker W, Schulz U, Rothwell PM: Increased cerebral arterial pulsatility in patients with leukoaraiosis: arterial stiffness enhances transmission of aortic pulsatility. Stroke 2012;43:2631-2636.
Mok V, Ding D, Fu J, Xiong Y, Chu WW, Wang D, Abrigo JM, Yang J, Wong A, Zhao Q, Guo Q, Hong Z, Wong KS: Transcranial doppler ultrasound for screening cerebral small vessel disease: a community study. Stroke 2012;43:2791-2793.
Heliopoulos I, Artemis D, Vadikolias K, Tripsianis G, Piperidou C, Tsivgoulis G: Association of ultrasonographic parameters with subclinical white-matter hyperintensities in hypertensive patients. Cardiovascular Psychiatry and Neurology 2012;2012:616572.
Kidwell CS, el-Saden S, Livshits Z, Martin NA, Glenn TC, Saver JL: Transcranial doppler pulsatility indices as a measure of diffuse small-vessel disease. J Neuroimaging 2001;11:229-235.
Purkayastha S, Fadar O, Mehregan A, Salat DH, Moscufo N, Meier DS, Guttmann CR, Fisher ND, Lipsitz LA, Sorond FA: Impaired cerebrovascular hemodynamics are associated with cerebral white matter damage. J Cereb Blood Flow Metab 2014;34:228-234.
Windham BG, Griswold ME, Shibata D, Penman A, Catellier DJ, Mosley TH Jr: Covert neurological symptoms associated with silent infarcts from midlife to older age: the atherosclerosis risk in communities study. Stroke 2012;43:1218-1223.
Kang HJ, Stewart R, Park MS, Bae KY, Kim SW, Kim JM, Shin IS, Cho KH, Yoon JS: White matter hyperintensities and functional outcomes at 2 weeks and 1 year after stroke. Cerebrovasc Dis 2013;35:138-145.
Cyarto EV, Lautenschlager NT, Desmond PM, Ames D, Szoeke C, Salvado O, Sharman MJ, Ellis KA, Phal PM, Masters CL, Rowe CC, Martins RN, Cox KL: Protocol for a randomized controlled trial evaluating the effect of physical activity on delaying the progression of white matter changes on MRI in older adults with memory complaints and mild cognitive impairment: the AIBL active trial. BMC Psychiatry 2012;12:167.
Kalaria RN, Erkinjuntti T: Small vessel disease and subcortical vascular dementia. J Clin Neurol 2006;2:1-11.
Pantoni L: Cerebral small vessel disease: from pathogenesis and clinical characteristics to therapeutic challenges. Lancet Neurol 2010;9:689-701.
Wardlaw JM, Smith C, Dichgans M: Mechanisms of sporadic cerebral small vessel disease: insights from neuroimaging. Lancet Neurol 2013;12:483-497.
Wardlaw JM, Smith EE, Biessels GJ, Cordonnier C, Fazekas F, Frayne R, Lindley RI, O'Brien JT, Barkhof F, Benavente OR, Black SE, Brayne C, Breteler M, Chabriat H, Decarli C, de Leeuw FE, Doubal F, Duering M, Fox NC, Greenberg S, Hachinski V, Kilimann I, Mok V, Oostenbrugge R, Pantoni L, Speck O, Stephan BC, Teipel S, Viswanathan A, Werring D, Chen C, Smith C, van Buchem M, Norrving B, Gorelick PB, Dichgans M: Neuroimaging standards for research into small vessel disease and its contribution to ageing and neurodegeneration. Lancet Neurol 2013;12:822-838.
Rost NS, Rahman RM, Biffi A, Smith EE, Kanakis A, Fitzpatrick K, Lima F, Worrall BB, Meschia JF, Brown RD Jr, Brott TG, Sorensen AG, Greenberg SM, Furie KL, Rosand J: White matter hyperintensity volume is increased in small vessel stroke subtypes. Neurology 2010;75:1670-1677.
Knottnerus IL, Ten Cate H, Lodder J, Kessels F, van Oostenbrugge RJ: Endothelial dysfunction in lacunar stroke: a systematic review. Cerebrovasc Dis 2009;27:519-526.
Gouw AA, Seewann A, van der Flier WM, Barkhof F, Rozemuller AM, Scheltens P, Geurts JJ: Heterogeneity of small vessel disease: a systematic review of MRI and histopathology correlations. J Neurol Neurosurg Psychiatry 2011;82:126-135.
Ovbiagele B, Saver JL: Cerebral white matter hyperintensities on MRI: current concepts and therapeutic implications. Cerebrovasc Dis 2006;22:83-90.
Debette S, Markus HS: The clinical importance of white matter hyperintensities on brain magnetic resonance imaging: systematic review and meta-analysis. BMJ 2010;341:c3666.
Mayer F, Mayer N, Chinn L, Pinsonneault RL, Kroetz D, Bainton RJ: Evolutionary conservation of vertebrate blood-brain barrier chemoprotective mechanisms in drosophila. J Neurosci 2009;29:3538-3550.
Goto S: Cilostazol: potential mechanism of action for antithrombotic effects accompanied by a low rate of bleeding. Atheroscler Suppl 2005;6:3-11.
Kim KS, Park HS, Jung IS, Park JH, Ahn KT, Jin SA, Park YK, Kim JH, Lee JH, Choi SW, Jeong JO, Seong IW: Endothelial dysfunction in the smokers can be improved with oral cilostazol treatment. J Cardiovasc Ultrasound 2011;19:21-25.
Birns J, Jarosz J, Markus HS, Kalra L: Cerebrovascular reactivity and dynamic autoregulation in ischaemic subcortical white matter disease. J Neurol Neurosurg Psychiatry 2009;80:1093-1098.
Huang Y, Cheng Y, Wu J, Li Y, Xu E, Hong Z, Li Z, Zhang W, Ding M, Gao X, Fan D, Zeng J, Wong K, Lu C, Xiao J, Yao C: Cilostazol as an alternative to aspirin after ischaemic stroke: a randomised, double-blind, pilot study. Lancet Neurol 2008;7:494-499.
Kwon SU, Cho Y-J, Koo J-S, Bae H-J, Lee Y-S, Hong K-S, Lee JH, Kim JS: Cilostazol prevents the progression of the symptomatic intracranial arterial stenosis: the multicenter double-blind placebo-controlled trial of cilostazol in symptomatic intracranial arterial stenosis. Stroke 2005;36:782-786.
Douglas JS Jr, Holmes DR Jr, Kereiakes DJ, Grines CL, Block E, Ghazzal ZM, Morris DC, Liberman H, Parker K, Jurkovitz C, Murrah N, Foster J, Hyde P, Mancini GB, Weintraub WS: Coronary stent restenosis in patients treated with cilostazol. Circulation 2005;112:2826-2832.
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