Cilostazol may prevent cardioembolic stroke in patients undergoing antiplatelet therapy Nobutaka Horie1,2, Makio Kaminogo2, Tsuyoshi Izumo1,2, Kentaro Hayashi1, Akira Tsujino2,3, Izumi Nagata1,2 1
Department of Neurosurgery, Nagasaki University School of Medicine, Japan, 2Retrospective Study of Stroke Risk in Antithrombotic Therapy (RESTATE) Group, Nagasaki, Japan, 3Department of Neurology and Strokology, Nagasaki University School of Medicine, Japan Objectives: Randomised trials have shown the efficacy of antiplatelet therapy with cilostazol to prevent secondary ischaemic stroke. Recently, cilostazol has been reported to prevent the development and/or recurrence of atrial fibrillation (AF), which can potentially prevent cardioembolic stroke in patients undergoing antiplatelet therapy. Herein, we examined the impact of prior antiplatelet therapy with cilostazol on the incidence of cardioembolic stroke, which had not been fully investigated. Methods: Using the multicenter retrospective study of stroke risk in antithrombotic therapy (RESTATE) database, we analysed consecutive patients with primary or secondary stroke under single antiplatelet therapy. We evaluated the characteristics of ischaemic stroke based on the type of antiplatelet agent used: aspirin, ticlopidine/clopidogrel or cilostazol. Results: Of 1069 consecutive patients with primary or secondary stroke during antithrombotic therapy from January to December 2012, 615 patients received single antiplatelet therapy (293 and 322 cases of primary and secondary strokes, respectively). Interestingly, the percentage of cardioembolic infarction was significantly lower in patients taking cilostazol compared with other agents. Multivariate regression analysis found that age (OR: 1.03, 95% CI: 1.01–1.06, P50.0029), serum creatinine (OR: 1.17, 95% CI: 1.03–1.34, P50.0198), aspirin (OR: 1.75, 95% CI: 1.00–3.22, P50.0486), cilostazol (OR: 0.19, 95% CI: 0.03–0.73, P50.0125), and smoking (OR: 1.86, 95% CI: 1.16–2.94, P50.0102) were independently associated with cardioembolic stroke. Conclusions: Cilostazol may prevent cardioembolic stroke in patients undergoing antiplatelet therapy. This could be a novel strategy for cardioembolic stroke prevention potentially by affecting cardiac remodelling, in contrast to secondary anticoagulant therapy.
Keywords: Cardioembolic stroke, Antiplatelet therapy, Cilostazol, Atrial fibrillation, Recurrence
Introduction Antiplatelet therapy is indicated for both the management of acute ischaemic stroke and for its prevention.1 Aspirin has been widely used for the prevention of recurrent stroke in patients with transient ischaemic attack (TIA) and ischaemic stroke of arterial origin because it is effective and inexpensive. Evidence from recent randomised trials indicates that other antiplatelet agents can reduce the risk of ischaemic stroke.2 Cilostazol is an antiplatelet drug that inhibits phosphodiesterase 3, increases cyclic adenosine monophosphate concentrations, and consequently inhibits platelet aggregation. Cilostazol also has vasodilatory activity, inhibits vascular smooth muscle proliferation and protects the
Correspondence to: Nobutaka Horie, Department of Neurosurgery, Nagasaki University School of Medicine, 1-7-1 Sakamoto, Nagasaki 8528501, Japan. Email: [email protected]
ß W. S. Maney and Son Ltd 2015 DOI 10.1179/1743132815Y.0000000021
vascular wall and endothelium in vivo and in vitro.3,4 The cilostazol: a study in long-term effects (CASTLE) study results showed that treatment with cilostazol reduced the risk of cerebrovascular events from 6.1 to 3.2%, and the absolute risk reduction was 3% compared with placebo without affecting cardiovascular mortality or bleeding.5,6 Cilostazol for prevention of secondary stroke (CSPS 2) group also reported noninferiority, and possible superiority, of cilostazol to aspirin for stroke prevention after an ischaemic stroke with fewer haemorrhagic complications.7 Efficacy of dual antiplatelet therapy (DAPT) to prevent recurrent stroke and haemorrhagic complications is controversial8; thus, DAPT is under study in ongoing randomised trials.9,10 Nevertheless, selection of antiplatelet agents according to stroke subtypes seems relevant to optimise antiplatelet therapy. Whether to use single antiplatelet or DAPT is also a topic of debate.
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Interestingly, a recent study reported that cilostazol could prevent the development and/or recurrence of atrial fibrillation (AF) in patients with peripheral artery disease (PAD),11 which translates into potential cardioembolic stroke prevention in patients undergoing antiplatelet therapy. We aimed to clarify the impact of prior antiplatelet therapy with cilostazol on the incidence of cardioembolic stroke, which has not been fully investigated.
Methods Patient selection This was a substudy of the multicentre retrospective study of stroke risk in antithrombotic therapy (RESTATE), including 14 participating stroke centres in Nagasaki, Japan. Consecutive patients with primary or secondary stroke during antithrombotic therapy were enrolled. Patients taking a single antiplatelet agent, including aspirin, ticlopidine/clopidogrel or cilostazol were analysed. Inclusion criteria were ischaemic stroke owing to large artery atherosclerosis, small vessel occlusion including branch atheromatous disease (BAD), cardioembolic stroke and haemorrhagic stroke undergoing single antiplatelet therapy for more than 6 months. Cardioembolic stroke was defined as the presence of AF or a highrisk source of embolism identified on echocardiography or electrocardiography without any atherosclerosis-related stenosis or occlusion, according to Trial of ORG 10172 in Acute Stroke Treatment (TOAST) classification.12 Cryptogenic stroke was excluded in this study. Primary stroke was defined as the first stroke episode in patients undergoing antiplatelet therapy for primary stroke prevention, coronary disease or arteriosclerosis obliterans, without history of intracranial diseases. Secondary stroke was defined as chronically recurrent stroke in patients undergoing antiplatelet therapy for secondary prevention. Patients taking anticoagulants, including warfarin, and dual or triple antiplatelet agents were excluded. Data retrieved per patient included age, sex, presentation subtype, past history, laboratory data, medication, magnetic resonance imaging findings and antiplatelet agent used.
model-building procedure was performed for the parameters with Pv0.05 achieved in univariate analysis. The level of significance was set at Pv0.05.
Results Of 1069 consecutive patients with primary or secondary stroke during antithrombotic therapy from January to December 2012, 615 patients were undergoing single antiplatelet therapy (293 and 322 cases of primary and secondary stroke, respectively). Regarding the relationship between prior antiplatelet agent and stroke subtype, there were no relevant differences in prior stroke subtype and comorbidities among the groups. However, the percentage of cardioembolic stroke was significantly lower in patients taking cilostazol compared with other agents both in primary and secondary stroke presentation (Fig. 1, Table 1). Effects of various factors on cardioembolic stroke are shown in Table 2. Univariate analysis showed that age (P50.0003), aspirin (Pv0.0001), cilostazol (Pv0.0001), smoking (P50.0211), serum creatinine (P50.0108) and estimated glomerular filtration rate (P50.0039) significantly affected cardiogenic stroke incidence (Table 2). Multivariate logistic regression analysis indicated that age (OR: 1.03, 95% CI: 1.01–1.06, P50.0029), serum creatinine (OR: 1.17, 95% CI: 1.03–1.34, P50.0198), aspirin (OR: 1.75, 95% CI: 1.00–3.22, P50.0486), cilostazol (OR: 0.19, 95% CI: 0.03–0.73, P50.0125) and smoking (OR: 1.86, 95% CI: 1.16–2.94, P50.0102) were independently associated with cardioembolic stroke (Table 3).
Discussion Cardiac diseases and impaired cardiac function are predisposing factors for stroke. Atrial fibrillation is a common heart condition and an important risk factor for cardioembolic stroke, which has high mortality and morbidity. Notably, the prevalence of AF increased with age as well as cardiac failure, coronary heart disease and hypertension in the Framingham study.13 Further, these contributors were initially detected when the patients suffered cardioembolic
Statistical analysis
All continuous data were expressed as mean+ SD. Statistical analysis was performed with GraphPad Instat, version 3.05 (GraphPad Software Inc., La Jolla, CA, USA) and JMP Pro 10.0.2 (SAS Institute Inc., Tokyo, Japan). The data between groups were compared by the chi-squared test, unpaired t-test or Kruskal–Wallis test as appropriate. A multivariate logistic regression analysis was conducted to test the effects of various clinical parameters on the occurrence of cardioembolic stroke. A forward stepwise
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Figure 1 Stroke subtypes in each antiplatelet agent group. AS: aspirin; TIC/CLO: ticlopidine/clopidogrel; CZL: cilostazol.
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Table 1 Patient baseline characteristics
Aspirin (n5475) Age Male sex (%) Major vessel stenosis (%) Cerebral microbleeds (%) Prior stroke subtype No (primary prevention) LAA (%) SVO (%) Cardioembolic (%) Past history Coronary disease (%) ASO (%) AF (%) Hypertension (%) Diabetes mellitus (%) Hyperlipidaemia (%) Drinking history (%) Smoking (%) Laboratory data HbA1c (%) HDL cholesterol (mg/dL) LDL cholesterol (mg/dL) eGFR (mL/minute/1.73 m2) Medication ARB (%) Statin (%) Pioglitazone (%) Stroke subtype LAA (%) SVO (%) Cardioembolic (%) ICH (%)
Ticlopidine/clopidogrel (n5108)
Cilostazol (n560)
P value
77.2+ 9.7 254 (53.5) 112 (23.6) 139 (58.9)
77.3+ 9.4 65 (60.2) 25 (23.2) 29 (52.7)
75.1+ 10.5 40 (66.7) 12 (21.7) 21 (60.0)
0.2497 0.0927 0.9428 0.6828
212 (44.6) 76 (16.0) 112 (23.6) 53 (11.2)
50 (46.3) 14 (13.0) 26 (24.1) 12 (11.1)
28 (46.7) 8 (13.3) 14 (23.3) 7 (11.7)
0.9213 0.6654 0.9923 0.9926
131 (27.6) 12 (2.5) 139 (29.3) 391 (82.3) 109 (23.0) 143 (30.1) 96 (22.8) 98 (22.7)
27 (25.0) 5 (4.6) 30 (27.8) 87 (80.6) 29 (26.9) 31 (28.7) 25 (24.8) 25 (24.5)
15 (25.0) 2 (3.3) 20 (33.3) 42 (70.0) 15 (25.0) 20 (33.3) 15 (26.8) 17 (29.8)
0.8107 0.4989 0.7451 0.0731 0.6727 0.8203 0.7643 0.4871
5.54+ 0.80 54.3+ 17.1 110.8+ 33.0 51.6+ 22.3
5.73+ 0.99 52.1+ 14.2 108.7+ 31.9 53.6+ 21.7
5.88+ 1.13 53.9+ 18.1 114.0+ 36.0 58.5+ 18.9
0.0768 0.7014 0.6982 0.0099
194 (41.2) 101 (21.4) 18 (3.8)
42 (39.3) 24 (22.4) 3 (2.8)
21 (35.6) 15 (25.4) 4 (6.8)
0.6887 0.7678 0.4342
119 (26.0) 113 (24.7) 120 (26.3) 105 (23.7)
35 (32.4) 40 (37.0) 16 (14.8) 17 (16.0)
18 (31.0) 26 (44.8) 2 (3.5) 12 (21.8)
0.3416 0.0007 v0.0001 0.2328
LAA: large artery atherosclerosis; SVO: small vessel occlusion; ASO: arteriosclerosis obliterans; HBA1c: haemoglobin A1c; HDL: high-density lipoprotein; LDL: low-density lipoprotein; ICH: intracerebral haemorrhage; ARB: angiotensin II receptor blocker; eGFR: estimated glomerular filtration rate; AF: atrial fibrillation.
stroke. In our study, 21.9% of the patients with no history of AF or cardiac disease suffered cardioembolic stroke while undergoing antiplatelet therapy. Thus, AF was initially detected when cardiogenic stroke occurred in most patients. Randomised trials and meta-analyses demonstrated the efficacy of cilostazol to prevent secondary ischaemic stroke compared to aspirin.7 To the best of our knowledge, this is the first study to provide evidence that the patients undergoing antiplatelet therapy with cilostazol present lower risk of suffering cardioembolic stroke. Originally, the occurrence and persistence of AF is primarily promoted by electrical and structural remodelling, characterised by atrial dilatation, shortening of the atrial effective refractory period, and inhomogeneous and prolonged dispersion of electrical conduction.14 Notably, a recent study demonstrated that cilostazol decreased total atrial conduction time (TACT), indicative of the electro-anatomical substrate for AF. It was concluded that cilostazol could prevent the development and/ or recurrence of AF in patients with PAD.11 Moreover, the results of a basic animal study supported this hypothesis and showed that primary and secondary prevention of AF is improved via reduction of
TACT duration or its prevention.15 Another study reported that cilostazol was effective in the treatment of arrhythmias by affecting the automaticity of the heart and increasing the heart rate.16 These effects result in an improvement of bradyarrhythmias, including bradycardic AF, atrioventricular block, sick sinus syndrome and ventricular arrhythmias. Recent reports indicated that cilostazol lowered the incidence of cardiovascular death and major cardiovascular events in patients with cardiac disease or PAD.17 Moreover, preclinical studies have demonstrated other vascular protective effects of cilostazol, beyond its antiplatelet and vasodilatory actions, in different disease models, including anti-inflammation, antioxidation, inhibition of matrix metalloproteinases (MMPs), antiatherosclerosis and endothelial protection, which are all relevant to the pathophysiology of AF and atrial electrical functions.18–21 Especially on the basis of the current evidence, it is likely that inflammation is involved in electrophysiologic and structural atrial remodelling, processes that are integral to the development and perpetuation of AF and that may link the antiinflammatory effect of cilostazol directly or indirectly to the incidence of AF.22
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Table 2 Univariate analysis for risk factors for cardioembolic stroke in patients undergoing antiplatelet therapy P value
Odds ratio
Age 0.0003 1.07 Male sex 0.2872 0.81 Systolic blood pressure 0.1732 0.99 Diastolic blood pressure 0.3033 1.00 Aspirin v0.0001 2.81 Ticlopidine 0.0894 0.43 Clopidogrel 0.345 0.70 Cilostazol v0.0001 0.11 ARB 0.7696 1.06 Statin 0.2982 0.75 Pioglitazone 0.4673 1.37 Hypertension 0.6292 0.90 Diabetes mellitus 0.5004 1.16 Hyperlipidaemia 0.7546 1.07 Drinking history 0.3909 1.24 Smoking 0.0211 1.72 HbA1c 0.3547 0.89 HDL cholesterol 0.6064 0.99 LDL cholesterol 0.4909 0.99 Platelets 0.192 1.01 Total cholesterol 0.4143 1.01 BUN 0.3449 1.01 Serum creatinine 0.0108 1.02 eGFR 0.0039 0.99 Primary or secondary stroke 0.2734 1.27 TIA 1.0000 1.02 Asymptomatic infarction 0.2504 0.74 Coronary disease 0.0505 0.63 AF 0.2466 0.77
95% CI 1.03–1.12 0.56–1.18 0.98–1.01 0.98–1.03 1.67–4.73 0.17–1.11 0.36–1.39 0.03–0.47 0.72–1.55 0.47–1.21 0.56–3.36 0.56–1.43 0.75–1.79 0.71–1.61 0.77–1.97 1.10–2.68 0.59–1.30 0.97–1.02 0.96–1.01 0.95–1.06 0.99–1.04 0.96–1.05 0.80–1.29 0.97–1.01 0.86–1.87 0.43–2.43 0.46–1.20 0.40–0.99 0.50–1.18
ARB: angiotensin II receptor blocker; HDL: high-density lipoprotein; LDL: low-density lipoprotein; BUN: blood urea nitrogen; eGFR: estimated glomerular filtration rate; AF: atrial fibrillation; TIA: transient ischaemic attack.
Table 3 Multivariate analysis for risk factors for cardioembolic stroke in patients undergoing antiplatelet therapy Variable
Odds ratio
Age Serum creatinine Aspirin Cilostazol Smoking
1.03 1.17 1.75 0.19 1.86
95% CI
P value
1.01–1.06 1.03–1.34 1.00–3.22 0.03–0.73 1.16–2.94
0.0029 0.0198 0.0486 0.0125 0.0102
prevent cardioembolic stroke by affecting cardiac remodelling. Longitudinal course of electrophysiological cardiac function and its contribution to the embolus formation is necessary to confirm this hypothesis. Nevertheless, we herein provide evidence that the patients undergoing antiplatelet therapy with cilostazol present lower risk of suffering cardioembolic stroke, in contrast with earlier findings of prevention of secondary thrombus formation. Therefore, we believe this finding to be quite novel. Confirmation by prospective multicenter trials is necessary.
Acknowledgements RESTATE Study Group includes the following institutions: Nagasaki University (Nobutaka Horie, Akira Tsujino, Izumi Nagata), Sasebo General Hospital (Makio Kaminogo), Ishizaka Hospital (Tomohito Hirao), Yasunaga Hospital (Masaaki Fukushima), Izaki Hospital (Akira Izaki), Miyazaki Hospital (Katsuharu Mori), Ebisumachi Hospital (Akira Shibayama), Nagasaki Saiseikai Hospital (Wataru Haraguchi), Jyuzenkai Hospital (Kiyoshi Shirakawa), Kawatana Medical Centre (Makoto Hirose), Nagasaki Medical Centre (Hideaki Takahata), Shimabara General Hospital (Gohei So), Nagasaki Rousai Hospital (Tsuyoshi Izumo) and Kenpo Ishahaya Hospital (Kunihiko Nagasato).
Disclaimer Statements Contributors Nobutka Horie: design, data analysis and manuscript preparation. Makio Kaminogo, Tsuyoshi Izumo, Kentaro Hayashi and Akira Tsujino: data collection. Izumi Nagata: supervised the study. Funding This work was supported in part by a grant-inaid for scientific research to Isumi Nagata (24592134). Conflicts of interest There is no conflict of interest with regard to the submitted manuscripts. Ethics approval This paper has received ethical approval from Nagasaki University.
Several limitations of this study should be discussed. First, this is a retrospective analysis of consecutive patients from the RESTATE database. Second, the patients taking cilostazol had a significantly higher incidence of small vessel stroke, including BAD, probably owing to a higher percentage of males or elevated haemoglobin A1c23 in that group, although the efficacy of cilostazol on non-cardioembolic stroke has been established in a randomised control trial.7 Third, data of follow-up echocardiography or electrocardiography evaluations were not collected over time in the context of this study, and this study did not confirm the hypothesis that cilostazol may decrease the incidence of AF. Moreover, we did not fully clarify the evidence that cilostazol could
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References 1 Hankey GJ, Eikelboom JW. Antithrombotic drugs for patients with ischaemic stroke and transient ischaemic attack to prevent recurrent major vascular events. Lancet Neurol. 2010;9:273–84. 2 Committee CS. A randomised, blinded, trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE). CAPRIE Steering Committee. Lancet. 1996;348: 1329–39. 3 Minami N, Suzuki Y, Yamamoto M, Kihira H, Imai E, Wada H, et al. Inhibition of shear stress–induced platelet aggregation by cilostazol, a specific inhibitor of cGMP–inhibited phosphodiesterase, in vitro and ex vivo. Life Sci. 1997;61: L383–9. 4 Ikeda Y. Antiplatelet therapy using cilostazol, a specific PDE3 inhibitor. Thromb Haemost. 1999;82:435–8. 5 Stone WM, Demaerschalk BM, Fowl RJ, Money SR. Type 3 phosphodiesterase inhibitors may be protective against cerebrovascular events in patients with claudication. J Stroke Cerebrovasc Dis. 2008;17:129–33.
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6 Hiatt WR, Money SR, Brass EP. Long–term safety of cilostazol in patients with peripheral artery disease: the CASTLE study (cilostazol: a study in long–term effects). J Vasc Surg. 2008;47:330–6. 7 Shinohara Y, Katayama Y, Uchiyama S, Yamaguchi T, Handa S, Matsuoka K, et al. Cilostazol for prevention of secondary stroke (CSPS 2): an aspirin–controlled, double–blind, randomised non–inferiority trial. Lancet Neurol. 2010;9:959–68. 8 Toyoda K, Yasaka M, Iwade K, Nagata K, Koretsune Y, Sakamoto T, et al. Dual antithrombotic therapy increases severe bleeding events in patients with stroke and cardiovascular disease: a prospective, multicenter, observational study. Stroke. 2008;39:1740–5. 9 Wang Y, Wang Y, Zhao X, Liu L, Wang D, Wang C, et al. Clopidogrel with aspirin in acute minor stroke or transient ischemic attack. N Engl J Med. 2013;369:11–19. 10 Johnston SC, Easton JD, Farrant M, Barsan W, Battenhouse H, Conwit R, et al. Platelet–oriented inhibition in new TIA and minor ischemic stroke (POINT) trial: rationale and design. Int J Stroke. 2013;8:479–83. 11 Alizade E, Sahin M, Sims¸ek Z, Ac¸ar G, Bulut M, Gu¨ler A, et al. Cilostazol decreases total atrial conduction time in patients with peripheral artery disease. Perfusion. 2014;29(3):265–71. 12 Adams HP Jr, Bendixen BH, Kappelle LJ, Biller J, Love BB, Gordon DL, et al. Classification of subtype of acute ischemic stroke. Definitions for use in a multicenter clinical trial. TOAST. Trial of Org 10172 in Acute Stroke Treatment. Stroke. 1993;24:35–41. 13 Wolf PA, Kannel WB, McNamara PM, McNamara PM, Gordon T. The role of impaired cardiac function in atherothrombotic brain infarction: the Framingham study. Am J Public Health. 1973;63:52–8. 14 Allessie MA, Boyden PA, Camm AJ, Kle´ber AG, Lab MJ, Legato MJ, et al. Pathophysiology and prevention of atrial fibrillation. Circulation. 2001;103:769–77.
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15 Matsuyama N, Tsutsumi T, Kubota N, Nakajima T, Suzuki H, Takeyama Y. Direct action of an angiotensin II receptor blocker on angiotensin II–induced left atrial conduction delay in spontaneously hypertensive rats. Hypertens Res. 2009;32: 721–6. 16 Kanlop N, Chattipakorn S, Chattipakorn N. Effects of cilostazol in the heart. J Cardiovasc Med. 2011;12:88–95. 17 Ahn Y, Jeong MH, Jeong JW, Kim KH, Ahn TH, Kang WC, et al. Randomized comparison of cilostazol vs clopidogrel after drug–eluting stenting in diabetic patients – clilostazol for diabetic patients in drug–eluting stent (CIDES) trial. Circ J. 2008;72:35–9. 18 Agrawal NK, Maiti R, Dash D, Pandey BL. Cilostazol reduces inflammatory burden and oxidative stress in hypertensive type 2 diabetes mellitus patients. Pharmacol Res. 2007;56: 118–23. 19 Inoue T, Uchida T, Sakuma M, Imoto Y, Ozeki Y, Ozaki Y, et al. Cilostazol inhibits leukocyte integrin Mac–1, leading to a potential reduction in restenosis after coronary stent implantation. J Am Coll Cardiol. 2004;44:1408–14. 20 Omi H, Okayama N, Shimizu M, Fukutomi T, Nakamura A, Imaeda K, et al. Cilostazol inhibits high glucose–mediated endothelial–neutrophil adhesion by decreasing adhesion molecule expression via NO production. Microvasc Res. 2004;68: 119–25. 21 Toda Y, Katsura K, Saito M, Inaba T, Sakurazawa M, Katayama Y. The effect of cilostazol and aspirin pre–treatment against subsequent transient focal cerebral ischemia in rat. Neurol Res. 2014;36:1011–9. 22 Galea R, Cardillo MT, Caroli A, Marini MG, Sonnino C, Narducci ML, et al. Inflammation and C–reactive protein in atrial fibrillation: cause or effect? Tex Heart Inst J. 2014;41:461–8. 23 Nakase T, Yoshioka S, Sasaki M, Suzuki A. Clinical evaluation of lacunar infarction and branch atheromatous disease. J Stroke Cerebrovasc Dis. 2013;22:406–12.
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Department of Neurosurgery, Nagasaki University School of Medicine, Japan, 2Retrospective Study of Stroke Risk in Antithrombotic Therapy (RESTATE) Group, Nagasaki, Japan, 3Department of Neurology and Strokology, Nagasaki University School of Medicine, Japan Objectives: Randomised trials have shown the efficacy of antiplatelet therapy with cilostazol to prevent secondary ischaemic stroke. Recently, cilostazol has been reported to prevent the development and/or recurrence of atrial fibrillation (AF), which can potentially prevent cardioembolic stroke in patients undergoing antiplatelet therapy. Herein, we examined the impact of prior antiplatelet therapy with cilostazol on the incidence of cardioembolic stroke, which had not been fully investigated. Methods: Using the multicenter retrospective study of stroke risk in antithrombotic therapy (RESTATE) database, we analysed consecutive patients with primary or secondary stroke under single antiplatelet therapy. We evaluated the characteristics of ischaemic stroke based on the type of antiplatelet agent used: aspirin, ticlopidine/clopidogrel or cilostazol. Results: Of 1069 consecutive patients with primary or secondary stroke during antithrombotic therapy from January to December 2012, 615 patients received single antiplatelet therapy (293 and 322 cases of primary and secondary strokes, respectively). Interestingly, the percentage of cardioembolic infarction was significantly lower in patients taking cilostazol compared with other agents. Multivariate regression analysis found that age (OR: 1.03, 95% CI: 1.01–1.06, P50.0029), serum creatinine (OR: 1.17, 95% CI: 1.03–1.34, P50.0198), aspirin (OR: 1.75, 95% CI: 1.00–3.22, P50.0486), cilostazol (OR: 0.19, 95% CI: 0.03–0.73, P50.0125), and smoking (OR: 1.86, 95% CI: 1.16–2.94, P50.0102) were independently associated with cardioembolic stroke. Conclusions: Cilostazol may prevent cardioembolic stroke in patients undergoing antiplatelet therapy. This could be a novel strategy for cardioembolic stroke prevention potentially by affecting cardiac remodelling, in contrast to secondary anticoagulant therapy.
Keywords: Cardioembolic stroke, Antiplatelet therapy, Cilostazol, Atrial fibrillation, Recurrence
Introduction Antiplatelet therapy is indicated for both the management of acute ischaemic stroke and for its prevention.1 Aspirin has been widely used for the prevention of recurrent stroke in patients with transient ischaemic attack (TIA) and ischaemic stroke of arterial origin because it is effective and inexpensive. Evidence from recent randomised trials indicates that other antiplatelet agents can reduce the risk of ischaemic stroke.2 Cilostazol is an antiplatelet drug that inhibits phosphodiesterase 3, increases cyclic adenosine monophosphate concentrations, and consequently inhibits platelet aggregation. Cilostazol also has vasodilatory activity, inhibits vascular smooth muscle proliferation and protects the
Correspondence to: Nobutaka Horie, Department of Neurosurgery, Nagasaki University School of Medicine, 1-7-1 Sakamoto, Nagasaki 8528501, Japan. Email: [email protected]
ß W. S. Maney and Son Ltd 2015 DOI 10.1179/1743132815Y.0000000021
vascular wall and endothelium in vivo and in vitro.3,4 The cilostazol: a study in long-term effects (CASTLE) study results showed that treatment with cilostazol reduced the risk of cerebrovascular events from 6.1 to 3.2%, and the absolute risk reduction was 3% compared with placebo without affecting cardiovascular mortality or bleeding.5,6 Cilostazol for prevention of secondary stroke (CSPS 2) group also reported noninferiority, and possible superiority, of cilostazol to aspirin for stroke prevention after an ischaemic stroke with fewer haemorrhagic complications.7 Efficacy of dual antiplatelet therapy (DAPT) to prevent recurrent stroke and haemorrhagic complications is controversial8; thus, DAPT is under study in ongoing randomised trials.9,10 Nevertheless, selection of antiplatelet agents according to stroke subtypes seems relevant to optimise antiplatelet therapy. Whether to use single antiplatelet or DAPT is also a topic of debate.
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Interestingly, a recent study reported that cilostazol could prevent the development and/or recurrence of atrial fibrillation (AF) in patients with peripheral artery disease (PAD),11 which translates into potential cardioembolic stroke prevention in patients undergoing antiplatelet therapy. We aimed to clarify the impact of prior antiplatelet therapy with cilostazol on the incidence of cardioembolic stroke, which has not been fully investigated.
Methods Patient selection This was a substudy of the multicentre retrospective study of stroke risk in antithrombotic therapy (RESTATE), including 14 participating stroke centres in Nagasaki, Japan. Consecutive patients with primary or secondary stroke during antithrombotic therapy were enrolled. Patients taking a single antiplatelet agent, including aspirin, ticlopidine/clopidogrel or cilostazol were analysed. Inclusion criteria were ischaemic stroke owing to large artery atherosclerosis, small vessel occlusion including branch atheromatous disease (BAD), cardioembolic stroke and haemorrhagic stroke undergoing single antiplatelet therapy for more than 6 months. Cardioembolic stroke was defined as the presence of AF or a highrisk source of embolism identified on echocardiography or electrocardiography without any atherosclerosis-related stenosis or occlusion, according to Trial of ORG 10172 in Acute Stroke Treatment (TOAST) classification.12 Cryptogenic stroke was excluded in this study. Primary stroke was defined as the first stroke episode in patients undergoing antiplatelet therapy for primary stroke prevention, coronary disease or arteriosclerosis obliterans, without history of intracranial diseases. Secondary stroke was defined as chronically recurrent stroke in patients undergoing antiplatelet therapy for secondary prevention. Patients taking anticoagulants, including warfarin, and dual or triple antiplatelet agents were excluded. Data retrieved per patient included age, sex, presentation subtype, past history, laboratory data, medication, magnetic resonance imaging findings and antiplatelet agent used.
model-building procedure was performed for the parameters with Pv0.05 achieved in univariate analysis. The level of significance was set at Pv0.05.
Results Of 1069 consecutive patients with primary or secondary stroke during antithrombotic therapy from January to December 2012, 615 patients were undergoing single antiplatelet therapy (293 and 322 cases of primary and secondary stroke, respectively). Regarding the relationship between prior antiplatelet agent and stroke subtype, there were no relevant differences in prior stroke subtype and comorbidities among the groups. However, the percentage of cardioembolic stroke was significantly lower in patients taking cilostazol compared with other agents both in primary and secondary stroke presentation (Fig. 1, Table 1). Effects of various factors on cardioembolic stroke are shown in Table 2. Univariate analysis showed that age (P50.0003), aspirin (Pv0.0001), cilostazol (Pv0.0001), smoking (P50.0211), serum creatinine (P50.0108) and estimated glomerular filtration rate (P50.0039) significantly affected cardiogenic stroke incidence (Table 2). Multivariate logistic regression analysis indicated that age (OR: 1.03, 95% CI: 1.01–1.06, P50.0029), serum creatinine (OR: 1.17, 95% CI: 1.03–1.34, P50.0198), aspirin (OR: 1.75, 95% CI: 1.00–3.22, P50.0486), cilostazol (OR: 0.19, 95% CI: 0.03–0.73, P50.0125) and smoking (OR: 1.86, 95% CI: 1.16–2.94, P50.0102) were independently associated with cardioembolic stroke (Table 3).
Discussion Cardiac diseases and impaired cardiac function are predisposing factors for stroke. Atrial fibrillation is a common heart condition and an important risk factor for cardioembolic stroke, which has high mortality and morbidity. Notably, the prevalence of AF increased with age as well as cardiac failure, coronary heart disease and hypertension in the Framingham study.13 Further, these contributors were initially detected when the patients suffered cardioembolic
Statistical analysis
All continuous data were expressed as mean+ SD. Statistical analysis was performed with GraphPad Instat, version 3.05 (GraphPad Software Inc., La Jolla, CA, USA) and JMP Pro 10.0.2 (SAS Institute Inc., Tokyo, Japan). The data between groups were compared by the chi-squared test, unpaired t-test or Kruskal–Wallis test as appropriate. A multivariate logistic regression analysis was conducted to test the effects of various clinical parameters on the occurrence of cardioembolic stroke. A forward stepwise
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Figure 1 Stroke subtypes in each antiplatelet agent group. AS: aspirin; TIC/CLO: ticlopidine/clopidogrel; CZL: cilostazol.
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Table 1 Patient baseline characteristics
Aspirin (n5475) Age Male sex (%) Major vessel stenosis (%) Cerebral microbleeds (%) Prior stroke subtype No (primary prevention) LAA (%) SVO (%) Cardioembolic (%) Past history Coronary disease (%) ASO (%) AF (%) Hypertension (%) Diabetes mellitus (%) Hyperlipidaemia (%) Drinking history (%) Smoking (%) Laboratory data HbA1c (%) HDL cholesterol (mg/dL) LDL cholesterol (mg/dL) eGFR (mL/minute/1.73 m2) Medication ARB (%) Statin (%) Pioglitazone (%) Stroke subtype LAA (%) SVO (%) Cardioembolic (%) ICH (%)
Ticlopidine/clopidogrel (n5108)
Cilostazol (n560)
P value
77.2+ 9.7 254 (53.5) 112 (23.6) 139 (58.9)
77.3+ 9.4 65 (60.2) 25 (23.2) 29 (52.7)
75.1+ 10.5 40 (66.7) 12 (21.7) 21 (60.0)
0.2497 0.0927 0.9428 0.6828
212 (44.6) 76 (16.0) 112 (23.6) 53 (11.2)
50 (46.3) 14 (13.0) 26 (24.1) 12 (11.1)
28 (46.7) 8 (13.3) 14 (23.3) 7 (11.7)
0.9213 0.6654 0.9923 0.9926
131 (27.6) 12 (2.5) 139 (29.3) 391 (82.3) 109 (23.0) 143 (30.1) 96 (22.8) 98 (22.7)
27 (25.0) 5 (4.6) 30 (27.8) 87 (80.6) 29 (26.9) 31 (28.7) 25 (24.8) 25 (24.5)
15 (25.0) 2 (3.3) 20 (33.3) 42 (70.0) 15 (25.0) 20 (33.3) 15 (26.8) 17 (29.8)
0.8107 0.4989 0.7451 0.0731 0.6727 0.8203 0.7643 0.4871
5.54+ 0.80 54.3+ 17.1 110.8+ 33.0 51.6+ 22.3
5.73+ 0.99 52.1+ 14.2 108.7+ 31.9 53.6+ 21.7
5.88+ 1.13 53.9+ 18.1 114.0+ 36.0 58.5+ 18.9
0.0768 0.7014 0.6982 0.0099
194 (41.2) 101 (21.4) 18 (3.8)
42 (39.3) 24 (22.4) 3 (2.8)
21 (35.6) 15 (25.4) 4 (6.8)
0.6887 0.7678 0.4342
119 (26.0) 113 (24.7) 120 (26.3) 105 (23.7)
35 (32.4) 40 (37.0) 16 (14.8) 17 (16.0)
18 (31.0) 26 (44.8) 2 (3.5) 12 (21.8)
0.3416 0.0007 v0.0001 0.2328
LAA: large artery atherosclerosis; SVO: small vessel occlusion; ASO: arteriosclerosis obliterans; HBA1c: haemoglobin A1c; HDL: high-density lipoprotein; LDL: low-density lipoprotein; ICH: intracerebral haemorrhage; ARB: angiotensin II receptor blocker; eGFR: estimated glomerular filtration rate; AF: atrial fibrillation.
stroke. In our study, 21.9% of the patients with no history of AF or cardiac disease suffered cardioembolic stroke while undergoing antiplatelet therapy. Thus, AF was initially detected when cardiogenic stroke occurred in most patients. Randomised trials and meta-analyses demonstrated the efficacy of cilostazol to prevent secondary ischaemic stroke compared to aspirin.7 To the best of our knowledge, this is the first study to provide evidence that the patients undergoing antiplatelet therapy with cilostazol present lower risk of suffering cardioembolic stroke. Originally, the occurrence and persistence of AF is primarily promoted by electrical and structural remodelling, characterised by atrial dilatation, shortening of the atrial effective refractory period, and inhomogeneous and prolonged dispersion of electrical conduction.14 Notably, a recent study demonstrated that cilostazol decreased total atrial conduction time (TACT), indicative of the electro-anatomical substrate for AF. It was concluded that cilostazol could prevent the development and/ or recurrence of AF in patients with PAD.11 Moreover, the results of a basic animal study supported this hypothesis and showed that primary and secondary prevention of AF is improved via reduction of
TACT duration or its prevention.15 Another study reported that cilostazol was effective in the treatment of arrhythmias by affecting the automaticity of the heart and increasing the heart rate.16 These effects result in an improvement of bradyarrhythmias, including bradycardic AF, atrioventricular block, sick sinus syndrome and ventricular arrhythmias. Recent reports indicated that cilostazol lowered the incidence of cardiovascular death and major cardiovascular events in patients with cardiac disease or PAD.17 Moreover, preclinical studies have demonstrated other vascular protective effects of cilostazol, beyond its antiplatelet and vasodilatory actions, in different disease models, including anti-inflammation, antioxidation, inhibition of matrix metalloproteinases (MMPs), antiatherosclerosis and endothelial protection, which are all relevant to the pathophysiology of AF and atrial electrical functions.18–21 Especially on the basis of the current evidence, it is likely that inflammation is involved in electrophysiologic and structural atrial remodelling, processes that are integral to the development and perpetuation of AF and that may link the antiinflammatory effect of cilostazol directly or indirectly to the incidence of AF.22
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Table 2 Univariate analysis for risk factors for cardioembolic stroke in patients undergoing antiplatelet therapy P value
Odds ratio
Age 0.0003 1.07 Male sex 0.2872 0.81 Systolic blood pressure 0.1732 0.99 Diastolic blood pressure 0.3033 1.00 Aspirin v0.0001 2.81 Ticlopidine 0.0894 0.43 Clopidogrel 0.345 0.70 Cilostazol v0.0001 0.11 ARB 0.7696 1.06 Statin 0.2982 0.75 Pioglitazone 0.4673 1.37 Hypertension 0.6292 0.90 Diabetes mellitus 0.5004 1.16 Hyperlipidaemia 0.7546 1.07 Drinking history 0.3909 1.24 Smoking 0.0211 1.72 HbA1c 0.3547 0.89 HDL cholesterol 0.6064 0.99 LDL cholesterol 0.4909 0.99 Platelets 0.192 1.01 Total cholesterol 0.4143 1.01 BUN 0.3449 1.01 Serum creatinine 0.0108 1.02 eGFR 0.0039 0.99 Primary or secondary stroke 0.2734 1.27 TIA 1.0000 1.02 Asymptomatic infarction 0.2504 0.74 Coronary disease 0.0505 0.63 AF 0.2466 0.77
95% CI 1.03–1.12 0.56–1.18 0.98–1.01 0.98–1.03 1.67–4.73 0.17–1.11 0.36–1.39 0.03–0.47 0.72–1.55 0.47–1.21 0.56–3.36 0.56–1.43 0.75–1.79 0.71–1.61 0.77–1.97 1.10–2.68 0.59–1.30 0.97–1.02 0.96–1.01 0.95–1.06 0.99–1.04 0.96–1.05 0.80–1.29 0.97–1.01 0.86–1.87 0.43–2.43 0.46–1.20 0.40–0.99 0.50–1.18
ARB: angiotensin II receptor blocker; HDL: high-density lipoprotein; LDL: low-density lipoprotein; BUN: blood urea nitrogen; eGFR: estimated glomerular filtration rate; AF: atrial fibrillation; TIA: transient ischaemic attack.
Table 3 Multivariate analysis for risk factors for cardioembolic stroke in patients undergoing antiplatelet therapy Variable
Odds ratio
Age Serum creatinine Aspirin Cilostazol Smoking
1.03 1.17 1.75 0.19 1.86
95% CI
P value
1.01–1.06 1.03–1.34 1.00–3.22 0.03–0.73 1.16–2.94
0.0029 0.0198 0.0486 0.0125 0.0102
prevent cardioembolic stroke by affecting cardiac remodelling. Longitudinal course of electrophysiological cardiac function and its contribution to the embolus formation is necessary to confirm this hypothesis. Nevertheless, we herein provide evidence that the patients undergoing antiplatelet therapy with cilostazol present lower risk of suffering cardioembolic stroke, in contrast with earlier findings of prevention of secondary thrombus formation. Therefore, we believe this finding to be quite novel. Confirmation by prospective multicenter trials is necessary.
Acknowledgements RESTATE Study Group includes the following institutions: Nagasaki University (Nobutaka Horie, Akira Tsujino, Izumi Nagata), Sasebo General Hospital (Makio Kaminogo), Ishizaka Hospital (Tomohito Hirao), Yasunaga Hospital (Masaaki Fukushima), Izaki Hospital (Akira Izaki), Miyazaki Hospital (Katsuharu Mori), Ebisumachi Hospital (Akira Shibayama), Nagasaki Saiseikai Hospital (Wataru Haraguchi), Jyuzenkai Hospital (Kiyoshi Shirakawa), Kawatana Medical Centre (Makoto Hirose), Nagasaki Medical Centre (Hideaki Takahata), Shimabara General Hospital (Gohei So), Nagasaki Rousai Hospital (Tsuyoshi Izumo) and Kenpo Ishahaya Hospital (Kunihiko Nagasato).
Disclaimer Statements Contributors Nobutka Horie: design, data analysis and manuscript preparation. Makio Kaminogo, Tsuyoshi Izumo, Kentaro Hayashi and Akira Tsujino: data collection. Izumi Nagata: supervised the study. Funding This work was supported in part by a grant-inaid for scientific research to Isumi Nagata (24592134). Conflicts of interest There is no conflict of interest with regard to the submitted manuscripts. Ethics approval This paper has received ethical approval from Nagasaki University.
Several limitations of this study should be discussed. First, this is a retrospective analysis of consecutive patients from the RESTATE database. Second, the patients taking cilostazol had a significantly higher incidence of small vessel stroke, including BAD, probably owing to a higher percentage of males or elevated haemoglobin A1c23 in that group, although the efficacy of cilostazol on non-cardioembolic stroke has been established in a randomised control trial.7 Third, data of follow-up echocardiography or electrocardiography evaluations were not collected over time in the context of this study, and this study did not confirm the hypothesis that cilostazol may decrease the incidence of AF. Moreover, we did not fully clarify the evidence that cilostazol could
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