Dual Antiplatelet Therapy Using Cilostazol in Patients With Stroke and Intracranial Arterial Stenosis

Shinichiro Uchiyama, Kazunori Toyoda, Katsuhiro Omae, Ryotaro Saita, Kazumi Kimura, Haruhiko Hoshino, Nobuyuki Sakai, Yasushi Okada, Kortaro Tanaka, Hideki Origasa, Hiroaki Naritomi, Kiyohiro Houkin, Keiji Yamaguchi, Masanori Isobe, Kazuo Minematsu, Masayasu Matsumoto, Teiji Tominaga, Hidekazu Tomimoto, Yasuo Terayama, Satoshi Yasuda, Takenori Yamaguchi, Shinichiro Uchiyama, Kazunori Toyoda, Katsuhiro Omae, Ryotaro Saita, Kazumi Kimura, Haruhiko Hoshino, Nobuyuki Sakai, Yasushi Okada, Kortaro Tanaka, Hideki Origasa, Hiroaki Naritomi, Kiyohiro Houkin, Keiji Yamaguchi, Masanori Isobe, Kazuo Minematsu, Masayasu Matsumoto, Teiji Tominaga, Hidekazu Tomimoto, Yasuo Terayama, Satoshi Yasuda, Takenori Yamaguchi

Abstract

Background Long-term benefit of dual antiplatelet therapy (DAPT) over single antiplatelet therapy (SAPT) for the prevention of recurrent stroke has not been established in patients with intracranial arterial stenosis. We compared the efficacy and safety of DAPT with cilostazol and clopidogrel or aspirin to those of SAPT with clopidogrel or aspirin in patients with intracranial arterial stenosis, who were recruited to the Cilostazol Stroke Prevention Study for Antiplatelet Combination trial, a randomized controlled trial in high-risk Japanese patients with ischemic stroke. Methods and Results We compared the vascular and hemorrhagic events between DAPT and SAPT in patients with ischemic stroke and symptomatic or asymptomatic intracranial arterial stenosis of at least 50% in a major intracranial artery. Patients were placed in two groups: 275 were assigned to receive DAPT and 272 patients SAPT. The risks of ischemic stroke (hazard ratio [HR], 0.47; 95% CI, 0.23-0.95); and composite of stroke, myocardial infarction, and vascular death (HR, 0.48; 95% CI, 0.26-0.91) were lower in DAPT than SAPT, whereas the risk of severe or life-threatening bleeding (HR, 0.72; 95% CI, 0.12-4.30) did not differ between the 2 treatment groups. Conclusions DAPT using cilostazol was superior to SAPT with clopidogrel or aspirin for the prevention of recurrent stroke and vascular events without increasing bleeding risk among patients with intracranial arterial stenosis after stroke. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT01995370.

Keywords: antiplatelet therapy; cilostazol; intracranial artery; stroke; vascular event.

Conflict of interest statement

Uchiyama reports grant support, honoraria, advisory board fees, and lecture fees from Bayer, Boehringer Ingelheim, Bristol‐Myers Squibb, Daiichi Sankyo, Takeda, Healios, Otsuka, Sanofi, and the Japan Cardiovascular Research Foundation. Toyoda reports honoraria from Bayer, Bristol‐Myers Squibb, Daiichi Sankyo, Takeda, and Boehringer Ingelheim. T Yamaguchi reports honoraria from Bristol‐Myers Squibb, Daiichi Sankyo, and Pfizer. Kimura reports lecture fees and research funding from Bayer, Boehringer Ingelheim, Bristol‐Myers Squibb, Daiichi Sankyo, Medtronic, Pfizer, and Teijin. Hoshino reports honoraria from Daiichi Sankyo and Pfizer. Sakai reports grant support and lecture fees from Asahi‐Intec, Daiichi Sankyo, Medtronic, NeuroVasc, Stryker, and Terumo. Houkin reports honoraria as trial principal investigator from Healios. K Yamaguchi reports lecture fee from Daiichi Sankyo. Minematsu reports honoraria from Bayer, Bristol‐Myers Squibb, CSL Behring, Daiichi Sankyo, EPS Corporation, Fuji Film Pharma, Healios, Mitsubishi Tanabe, Nippon Chemiphar, Otsuka, Pfizer, Sanofi, and Stryker. Terayama reports grant support, consulting fees, and honoraria from Boehringer Ingelheim, Bristol‐Myers Squibb, and Daiichi Sankyo. Yasuda reports grant support, lecture fees, and clinical trial fees from Abbott, Bristol‐Myers Squibb, Daiichi Sankyo, and Takeda. The remaining authors have no disclosures to report.

Figures

Figure 1. Flow chart of patients.
Figure 1. Flow chart of patients.
Efficacy analysis was conducted for vascular events including any stroke, ischemic stroke, and composite vascular events of stroke, myocardial infarction, and vascular death in all randomized patients. Safety analysis was conducted for any bleeding and severe or life‐threatening bleeding in patients excluding those who never received a dose (1 in the DAPT group and 3 in the SAPT group). DAPT indicates dual antiplatelet therapy; ICAS, intracranial arterial stenosis; ITT, intention to treat; and SAPT, single antiplatelet therapy.
Figure 2. The Kaplan‐Meier curves for the…
Figure 2. The Kaplan‐Meier curves for the time to the first event of ischemic stroke (A), composite of stroke, myocardial infarction, and vascular death (B), and severe or life‐threatening bleeding (C).
Intention‐to‐treat analysis for (A) and (B) and safety analysis for (C). HR indicates hazard ratio.

References

    1. Sacco RL, Kargman DE, Gu Q, Zamanillo MC. Race‐ethnicity and determinants of intracranial atherosclerotic cerebral infarction. The Northern Manhattan Stroke Study. Stroke. 1995;26:14–20. doi: 10.1161/01.STR.26.1.14
    1. Hoshino T, Uchiyama S, Wong LKS, Sissani L, Albers GW, Bornstein NM, Caplan LR, Donnan GA, Ferro JM, Hennerici MG, et al. Differences in characteristics and outcomes between Asian and non‐Asian patients in the . Stroke. 2017;48:1779–1787. doi: 10.1161/STROKEAHA.117.016874
    1. Uchiyama S, Hoshino T, Sissani L, Linsay MT, Kamiyama K, Nakase T, Kitagawa K, Minematsu K, Todo K, Okada Y, et al. Japanese versus non‐Japanese patients with transient ischemic attack or minor stroke: subanalysis of . J Stroke Cerebrovasc Dis. 2019;28:2232–2241. doi: 10.1016/j.jstrokecerebrovasdis.2019.05.005
    1. Amarenco P, Lavallée PC, Monteiro Tavares L, Labreuche J, Albers GW, Abboud H, Anticoli S, Audebert H, Bornstein NM, Caplan LR, et al. Five‐year risk of stroke after TIA or minor ischemic stroke. N Engl J Med. 2018;378:2182–2190. doi: 10.1056/NEJMoa1802712
    1. Hurford R, Wolters FJ, Li L, Lau KK, Küker W, Rothwell PM, on behalf of the Oxford Vascular Study Phenotyped Cohort . Prevalence, predictors, and prognosis of symptomatic intracranial stenosis in patients with transient ischemic attack and minor stroke: a population‐based cohort study. Lancet Neurol. 2020;19:413–421. doi: 10.1016/S1474-4422(20)30079-X
    1. Uchiyama S. Intensive medical management of intracranial arterial stenosis. Lancet Neurol. 2020;19:371–373. doi: 10.1016/S1474-4422(20)30100-9
    1. Chimowitz MI, Kokkinos J, Strong J, Brown MB, Levine SR, Silliman S, Pessin MS, Weichel E, Sila CA, Furlan AJ, et al. The warfarin‐aspirin symptomatic intracranial disease study. Neurology. 1995;45:1488–1493. doi: 10.1212/WNL.45.8.1488
    1. Chimowitz MI, Lynn MJ, Derdeyn CP, Turan TN, Fiorella D, Lane BF, Janis LS, Lutsep HL, Barnwell SL, Waters MF, et al. Stenting versus aggressive medical therapy for intracranial arterial stenosis. N Engl J Med. 2011;365:993–1003. doi: 10.1056/NEJMoa1105335
    1. Kleindorfer DO, Towfighi A, Chaturvedi S, Cockroft KM, Gutierrez J, Lombardi‐Hill D, Kamel H, Kernan WN, Kittner SJ, Leira EC, et al. 2021 guidelines for the prevention of stroke in patients with stroke and transient ischemic attack: a guideline from the American Heart Association/American Stroke Association. Stroke. 2021;52:e364–e467. doi: 10.1161/STR.0000000000000375
    1. Wang Y, Wang Y, Zhao X, Liu L, Wang D, Wang C, Wang C, Li H, Meng X, Cui L, et al. Clopidogrel with aspirin in acute minor stroke or transient ischemic attack. N Engl J Med. 2013;369:11–19. doi: 10.1056/NEJMoa1215340
    1. Johnston SC, Easton JD, Farrant M, Barsan W, Conwit RA, Elm JJ, Kim AS, Lindblad AS, Palsesch YY. Clopidogrel and aspirin in acute ischemic stroke and high‐risk TIA. N Engl J Med. 2018;379:215–225. doi: 10.1056/NEJMoa1800410
    1. Hao Q, Tampi M, O’Donnell M, Foroutan F, Siemieniuk RAC, Guyatt G. Clopidogrel plus aspirin versus aspirin alone for acute minor ischemic stroke of high risk transient ischemic attack: systematic review and meta‐analysis. BMJ. 2018;363:k5108. doi: 10.1136/bmj.k5108
    1. Toyoda K, Uchiyama S, Yamaguchi T, Easton JD, Kimura K, Hoshino H, Sakai N, Okada Y, Tanaka K, Origasa H, et al. Dual antiplatelet therapy using cilostazol for secondary prevention in patients with high‐risk ischaemic stroke in Japan: a multicentre, open‐label, randomised controlled trial. Lancet Neurol. 2019;18:539–548. doi: 10.1016/S1474-4422(19)30148-6
    1. Kwon SU, Cho YJ, Koo JS, Bae HJ, Lee YS, Hong KS, Lee JH, Kim JS. Cilostazol prevents the progression of the symptomatic intracranial arterial stenosis. Stroke. 2005;36:782–786. doi: 10.1161/01.STR.0000157667.06542.b7
    1. Uchiyama S, Sakai N, Toi S, Ezura M, Okada Y, Takagi M, Nagai Y, Matsubara Y, Minematsu K, Suzuki N, et al. Final results of cilostazol‐aspirin therapy against recurrent stroke with intracranial artery stenosis (CATHARSIS). Cerebrovasc Dis Extra. 2015;5:1–13. doi: 10.1159/000369610
    1. Hurford R, Wolters FJ, Linxin Li L, Lau KK, Wilhelm Küker W, Rothwell PM. Prognosis of asymptomatic intracranial stenosis in patients with transient ischemic attack and minor stroke. JAMA Neurol. 2020;77:947–954. doi: 10.1001/jamaneurol.2020.1326
    1. Ota H, Eto M, Kano MR, Ogawa S, Iijima K, Akishita M, Ouchi Y. Cilostazol inhibits oxidative stress–induced premature senescence via upregulation of Sirt1 in human endothelial cells. Arterioscler Thromb Vasc Biol. 2008;28:1634–1639. doi: 10.1161/ATVBAHA.108.164368
    1. Lee HR, Park KY, Jeong YJ, Heo TH. Comparative effectiveness of different antiplatelet agents at reducing TNF‐driven inflammatory responses in a mouse model. Clin Exp Pharmacol Physiol. 2020;47:432–438. doi: 10.1111/1440-1681.13211
    1. Katakami N, Kim YS, Kawamori R, Yamasaki Y. The phosphodiesterase inhibitor cilostazol induces regression of carotid atherosclerosis in subjects with type 2 diabetes mellitus. Principle results of the Diabetic Atherosclerosis Prevention by Cilostazol (DAPC) study: a randomized trial. Circulation. 2010;121:2584–2591. doi: 10.1161/CIRCULATIONAHA.109.892414
    1. Uchiyama S, Demaerschalk BM, Goto S, Shinohara Y, Gotoh F, Stone WM, Money SR, Kwon SU. Stroke prevention by cilostazol in patients with atherothrombosis: meta‐analysis of placebo‐controlled randomized trials. J Stroke Cerebrovasc Dis. 2009;18:482–490. doi: 10.1016/j.jstrokecerebrovasdis.2009.07.010
    1. Shinohara Y, Katayama Y, Uchiyama S, Yamaguchi T, Handa S, Matsuoka K, Ohashi Y, Tanahashi N, Yamamoto H, Genka C, et al. Cilostazol for prevention of secondary stroke (CSPS 2): an aspirin‐controlled, double‐blind, randomised non‐inferiority trial. Lancet Neurol. 2010;9:959–968. doi: 10.1016/S1474-4422(10)70198-8
    1. Rothwell PM, Algra A, Chen Z, Diener HC, Norrving B, Mehta Z. Effects of aspirin on risk and severity of early recurrent stroke after transient ischaemic attack and ischaemic stroke: time‐course analysis of randomised trials. Lancet. 2016;388:365–375. doi: 10.1016/S0140-6736(16)30468-8

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