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Cilostazol as an alternative to aspirin after ischaemic stroke: a randomised, double-blind, pilot study
Yining Huang, Yan Cheng, Jiang Wu, Yansheng Li, En Xu, Zhen Hong, Zhengyi Li, Weiwei Zhang, Meiping Ding, Xuguang Gao, Dongsheng Fan, Jinsheng Zeng, Kasing Wong, Chuanzhen Lu, Jiangxi Xiao, Chen Yao, on behalf of the cilostazol versus aspirin for secondary ischaemic stroke prevention (CASISP) cooperation investigators

Summary
Lancet Neurol 2008; 7: 49499 Published Online May 5, 2008 DOI:10.1016/S14744422(08)70094-2 See Reection and Reaction page 469 Peking University First Hospital, Beijing, China (Y Huang MD, J Xiao MD, C Yao MD); Tianjin Medical University Aliated Hospital, Tianjin, China (Y Cheng MD); Jilin University First Hospital, Changchun, China (J Wu MD); Shanghai Jiao Tong University, School of Medicine Aliated Renji Hospital, Shanghai, China (Y Li MD); Guangzhou Medical College the Second Aliated Hospital, Guangzhou, China (E Xu MD); Fudan University Huashan Hospital, Shanghai, China (Z Hong MD, C Lu MD); Xian Jiaotong University First Hospital, Xian, China (Z Li MD); Beijing Military Branch General Hospital, Beijing, China (W Zhang MD); Zhejiang University Second Hospital, Hangzhou, China (M Ding MD); Peking University Peoples Hospital, Beijing, China (X Gao MD); Peking University Third Hospital, Beijing, China (D Fan MD); First Aliated Hospital, Sun Yat-Sen University, Guangzhou, China (J Zeng MD); and Prince of Wales Hospital, Hong Kong, China (K Wong MD) Correspondence to: Y Huang, Department of Neurology, Peking University First Hospital, Beijing 100034, China yiningh@yahoo.com

Background Most patients who have had a stroke are given aspirin; however, aspirin-related cerebral haemorrhage is a complication that is currently of concern, particularly in China where there is a high incidence of cerebral haemorrhage in secondary prevention programmes and within the community. Cilostazol, a phosphodiesterase 3 (PDE3) inhibitor, is an alternative to aspirin that works through a dierent mechanism. This trial aimed to compare the ecacy and safety of cilostazol with that of aspirin for the long-term prevention of the recurrence of ischaemic stroke. Methods 720 patients (mean age 602 years, SD 986) who had had an ischaemic stroke within the previous 16 months were enrolled consecutively in a prospective, multicentre, double-blind, randomised trial. 360 patients were randomly assigned to receive cilostazol and 360 patients to receive aspirin. Analysis was by intention to treat. Patients in both groups took the medication for 1218 months. The primary endpoint was any recurrence of stroke (ischaemic stroke, haemorrhagic stroke, or subarachnoid haemorrhage) during the trial period. All patients had MRI with T1 MRI, T2 MRI, diusion-weighted imaging (DWI), T2 uid-attenuated inversion recovery (FLAIR), and T2 gradient echo imaging (T2*) at the beginning and the end of the study. This trial is registered with ClinicalTrials.gov, number NCT00202020. Findings The average duration of treatment was 740 person-years, and 719 patients were analysed (360 in the cilostazol group and 359 in the aspirin group). The primary endpoint was reported in 12 patients in the cilostazol group and in 20 patients in the aspirin group. The estimated hazard ratio, calculated with KaplanMeier curves (risk of primary endpoint in cilostazol group vs aspirin group), was 062 (95% CI 030126; p=0185). Symptomatic cerebral haemorrhage was reported in six patients: one in the cilostazol group and ve in the aspirin group. Asymptomatic cerebral haematoma was found in four patients in the aspirin group and one patient in the cilostazol group. Brain bleeding events were signicantly more common in the aspirin group than in the cilostazol group (7 vs 1, p=0034). All of the six patients with symptomatic haemorrhage had previous cerebral microbleeds in the area where the haematoma was located. Interpretation The results of this pilot study showed no signicant dierence in the rate of recurrence of stroke between patients with ischaemic stroke who were randomly assigned to take either cilostazol or aspirin. The lower rates of ischaemic and haemorrhagic stroke in the cilostazol group suggest that cilostazol might be a more eective and safer alternative to aspirin for Chinese patients with ischaemic stroke; however, a larger phase III trial is required to conrm this. Funding National Health Ministry of the Peoples Republic of China; Otsuka Pharmaceutical.

Introduction
Stroke is the second leading cause of mortality in China, with about 7 million people aected countrywide.1 Aspirin is eective for the prevention of secondary stroke and has been used in up to 89% of patients in China (REACH registry, unpublished data). However, although recurrent stroke is controlled by this treatment, the incidence of cerebral haemorrhage and other bleeding events is higher in China than in high-income countries.2 To overcome the risk of haemorrhage, combinations of antiplatelet drugs that act on dierent pathways have been used; these compounds were used eectively and safely in patients with unstable coronary heart disease, with the most benets seen during the

rst few weeks of treatment.3 The results of recent studies have shown that the combination of two antiplatelet drugs failed to improve stroke prevention rates owing to the increased risk of bleeding events associated with their long-term use.4,5 Bleeding due to antiplatelet drugs is an important clinical problem in primary6 and secondary stroke prevention, particularly in the Chinese population, which has a higher incidence of cerebral haemorrhage than other ethnic groups.7,8 Cilostazol, a selective inhibitor of phosphodiesterase 3 (PDE3), prevents inactivation of the intracellular second messenger cyclic AMP and irreversibly inhibits platelet aggregation and vasodilation. In addition, cilostazol delays the onset of atherosclerosis,9 protects the vessel
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endothelium, inhibits the proliferation of arterial smoothmuscle cells,10,11 and has shown ecacy in the prevention of ischaemic stroke in a group of patients from Japan.12 However, no studies have compared the ecacy of cilostazol with that of aspirin, which continues to be widely used to prevent secondary ischaemic stroke. We report the results of a trial to assess the ecacy and safety of cilostazol compared with aspirin in the prevention of secondary stroke in a small sample of patients, which could be a pilot study for a large phase III trial.

Methods
Participants
720 patients (495 male and 225 female, mean age 602 years) were enrolled consecutively between May 1, 2004, and Dec 31, 2004. Follow-up was concluded on Dec 31, 2005. Patients were eligible for inclusion if they had had an ischaemic stroke within the preceding 1 to 6 months, their diagnosis had been conrmed with neuroimaging, and they had a modied Rankin scale score of less than 4 at enrolment. Exclusion criteria were one or more from a history of intracranial or subarachnoid haemorrhage, cardiogenic embolism, severe disability, uncontrolled severe comorbidities, contraindications to antiplatelet treatment, or the use of other antiplatelet drugs during the trial period. All patients with hypertension or high lipid concentrations were given antihypertensive drugs or statins, respectively, and were seen by doctors every month during the follow-up period. Liver and kidney function, electrocardiogram, and lipid proles were monitored in all patients every 3 months. Informed written consent was obtained from all patients and ethics approval was obtained at each centre.

patient enrolment and within 2 weeks of the end of the study, except for those for patients who had primary endpoints or who died. Eight radiologists from the Department of Radiology, Peking University First Hospital, who were part of the CASISP cooperation investigators and were blinded to the clinical data, manually evaluated the DICOM-formatted MRIs (82%) or lms (18%) independently. In the event of unclear or suspected lesions, a consensus diagnosis was reached by two radiologists. Microbleeds were diagnosed if the MRI T2* series showed a lesion of less than 5 mm in the brain parenchyma. Haematoma was diagnosed if there was a lesion with a diameter of 15 mm or more and the image was a black circle around a white signal seen on T2 MRI and T2 FLAIR or a high-density signal seen with T1 MRI. Lacunar infarction was dened as a lesion with a diameter that was less than 15 mm in the area of the penetrating arterioles.

Statistical analyses
The sample size was calculated on the basis of practical considerations, and the trial was designed to be a pilot study in accordance with the paucity of clinical data that compared cilostazol and aspirin directly. We also hoped to image asymptomatic strokes, particularly cerebral microbleeds and cerebral haemorrhage, as a complication of treatment. All case report forms were managed by an independent data management company (DMS Pharmaceutical Group, Park Ridge, IL, USA). Data were inputted by two separate operators and analysed with SAS version 6.1 (SAS, Cary, NC, USA). All primary endpoints were rechecked by the steering
720 patients enrolled and screened with MRI

Procedures
The study was designed as a multicentre, double-blind, double-dummy, randomised, aspirin-controlled trial. Patients were assigned to a treatment group at each centre by a computer-based stratied block randomisation on the basis of a pre-established scheme, which was stratied according to each site (gure 1). The aspirin and the cilostazol pills were made to look the same. The primary endpoint was dened as any occurrence of stroke, including ischaemic stroke, cerebral haemorrhage, or subarachnoid haemorrhage. The combined endpoints were dened as more than one of recurrent stroke, new myocardial infarction, transient ischaemic attack, vascular eventincluding pulmonary embolism, deep venous thrombosis, or peripheral arterial occlusion disorderdeath from vascular causes, or death from any other cause. All patients had an MRI series of T1 MRI, T2 MRI, diusion-weighted imaging (DWI), T2 uid-attenuated inversion recovery (FLAIR) MRI, and T2 gradient echo imaging (T2*) with a magnetic eld of 15 Tesla or higher for all imaging. Images were examined within 2 weeks of
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360 patients randomly assigned to cilostazol

360 patients randomly assigned to aspirin 1 patient was eliminated for not taking the assigned drug

47 patients discontinued 25 patients had adverse events 8 patients did not follow the protocol 6 patients were lost to follow up 8 patients withdrew owing to other cause 3 patients died 1 had MI 1 died suddenly of unknown cause 1 drowned

35 patients discontinued 15 patients had adverse events 3 patients had a lack of eect 7 patients did not follow the protocol 3 patients were lost to follow up 7 patients withdrew owing to other causes 5 patients died 2 had MI 1 had liver cancer 1 had pancreatitis 1 patient committed suicide

MRI screen

MRI screen

360 in intention-to-treat analysis

359 in intention-to-treat analysis

Figure 1: Trial prole

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Cilostazol (n=360) Age (years)* Male Systolic blood pressure (mm Hg) Diastolic blood pressure (mm Hg) Days after stroke intervention started Hypertension Diabetes High lipid concentrations On aspirin at baseline On cilostazol at baseline Modied Rankin scale score 0 1 2 3 NIHSS 35 (972%) 162 (45%) 98 (272%) 35 (1805%) 227 (200) 6014 (1005, 224) 241 (67%) 13541 (1670) 8287 (930) 7726 (5005) 285 (79%) 65 (18%) 98 (27%) 223 (62%) 2 (<1%)

Aspirin (n=359) 6031 (971, 219) 253 (70%) 13822 (1756) 8380 (1084) 7972 (5196) 284 (79%) 66 (18%) 113 (31%) 223 (62%) 5 (1%) 36 (10%) 166 (462%) 93 (259%) 64 (178) 245 (205)

of this article. The corresponding author had full access to all the data in the study and had nal responsibility for the decision to submit the article for publication.

Results
Treatment was given for a total of 740 person-years. The trial prole is shown in gure 1. 569 patients (79%) had vascular risk factors, including hypertension, diabetes, and high lipid concentrations. The proles of the cilostazol patients and aspirin patients were similar (table 1), although baseline systolic blood pressure was signicantly higher in the control group than in the cilostazol group (p=003) but this resolved after 1 months treatment with antihypertensive drugs. 223 patients (62%) used aspirin in both the aspirin and cilostazol groups for the 3 months before enrolment, whereas only ve patients in the cilostazol group and two patients in the aspirin group used cilostazol in the 3 months before enrolment. There were no signicant dierences in National Institutes of Health stroke scale (NIHSS) score (p=021) and modied Rankin scale score (p=099) between the treatment groups at the end of the follow up, although this was a post-hoc analysis. 301 patients in the cilostazol group and 299 patients in the aspirin group received treatment for 1218 months. 32 patients had primary endpoints: 26 patients had ischaemic stroke (11 in the cilostazol group and 15 in the aspirin group) and six patients had symptomatic haemorrhagic stroke (one in the cilostazol group and ve in the aspirin group). The stroke recurrence rate was 326 patients per year in the cilostazol group and 527 patients per year in the aspirin group (p=018). Cumulative analysis of the primary endpoints (gure 2) showed that the two curves were close during the rst 6 months of treatment, and that aspirin was more eective than cilostazol during this period. After 6 months, the curves divided in favour of cilostazol. The estimated hazard ratio (the risk of a primary endpoint in the cilostazol group vs the aspirin group) was 062 (95% CI 030126); p=0185. The 180-day and 540-day estimated recurrence rates of stroke were 267% for the cilostazol group versus 233% for the aspirin group and 362% for the cilostazol group versus 641% for the aspirin group, respectively. There was no signicant dierence in the combined endpoints between the two groups (table 2). The estimated hazard ratio for the cilostazol group versus the aspirin group was 070 (040121); p=0200. Baseline MRI screens showed infarctions in all patients, and 39% had cerebral microbleeds seen with MRI T2*. More than one infarction was seen in 238 (66%) of the cilostazol-treated patients and 247 (69%) of the aspirintreated patients. In the MRI screens at the end of study, no new large infarctions or lacunar infarctions were detected by FLAIR; however, the number of patients with cerebral microbleeds; however, ther was an increase in the umber of microbleeds in both groups (17/292, 582%
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*Data are mean (SD, number of patients under 65 years). Data are mean (SD). All other data are numbers of patients (%).

Table 1: Baseline characteristics

Primary endpoints Aspirin 30 days 90 days 180 days 360 days 540 days 028 (028) 086 (050) 233 (082) 542 (124) 641 (142) Cilostazol 085 (049) 144 (064) 267 (088) 362 (103) 362 (103)

Combined endpoints Aspirin 028 (028) 115 (057) 380 (103) 835 (151) 976 (169) Cilostazol 114 (056) 203 (076) 387 (105) 639 (135) 639(135)

Primary endpoints: ischaemic stroke, haemorrhagic stroke, and subarachnoid haemorrhage. Combined endpoints: recurrent stroke, new myocardial infarction, transient ischaemic attack, vascular event (pulmonary embolism, deep venous thrombosis, or peripheral arterial occlusion disorder), death from vascular causes, or death from any other cause. Data quoted as mean (SD) number of events estimated from Kaplan-Meier curves.

Table 2: Primary and combined endpoints

committee, and the database was locked before the data were unblinded. To evaluate ecacy, we used the primary endpoint and the combined endpoints as primary variables. In addition, secondary variables were dened as clinical symptomatic cerebral haemorrhage and asymptomatic cerebral haematoma seen with MRI. Both an intention-to-treat analysis, which was dened as taking at least one of the allocated drugs, and a perprotocol analysis were done in the statistical report, and although they produced similar results all data in this article are based on the intention-to-treat analysis because endpoint analysis was the focus. KaplanMeier curves were used for the analysis of the primary endpoints and the Cox proportional hazard regression model to calculate the relative risk (RR).

Role of the funding source

The funding sources had no role in the study design, data collection, data analysis, data interpretation, or the writing
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cilostazol vs 17/310, 548% aspirin). More asymptomatic haematomas were seen in patients in the aspirin group than in patients in the cilostazol group (four vs one); however, three of these patients (two in the aspirin group and one in the cilostazol group) also had symptomatic cerebral haemorrhage, which meant that only two new asymptomatic haematomas were reported by the radiologists in the aspirin group. The incidence of severe cerebral bleeds was signicantly higher in the aspirin group than in the cilostazol group (seven [ve symptomatic and two asymptomatic haemorrhages] vs one symptomatic haemorrhage, 195% vs 028%, RR=714 (95% CI 0875833); p=0038, and all the sites of symptomatic cerebral haemorrhage were associated with cerebral microbleeds seen on the baseline MRI T2*. All cerebral bleeds were lacunar infarctions, with the exception of one, which was a middle cerebral artery occlusion. Generally, there was no dierence in major side-eects between the two treatments, although mild adverse events, such as headache, dizziness, and tachycardia, were more common in the cilostazol group and palpitations were more common in the cilostazol group (table 3). Drug-related bleeding events were more prevalent in the aspirin-treated group: bleeding outside the brain was seen in 4% of the cilostazol-treated patients and 9% of the aspirin-treated patients (table 4).

010 009 008 007 006 005 004 003 002 001 0 0 Number at risk Cilostazol 360 Aspirin 359

Cilostazol Aspirin 0061% vs 0036% RRR 381% (030126), p=018

Probability of primary endpoints

100

200

300 Days

400

500

600

322 339

313 328

303 309

177 183

30 24

Figure 2: Kaplan-Meier curves for the accumulation of primary endpoints

Cilostazol N Headache Dizziness Tachycardia Palpitation 49 32 22 5 Frequency 49 35 22 5 % 1361 889 611 139

Aspirin N 19 17 7 35 Frequency 20 17 7 39 % 528 472 194 972

Discussion
Cilostazol has similar eects to those of aspirin in the prevention of recurrent ischemic stroke during the rst 6 months after starting treatment. By contrast, after 6 months, cilostazol was more eective than aspirin, and at the end of the study there was a 381% reduction in the relative risk of a primary endpoint in the cilostazol group compared with the aspirin group. However, this did not reach statistical signicance, which, we feel, is due to the small sample size and the short follow-up period. 25% (5/20) of all primary endpoints in the aspirin group were due to haemorrhagic stroke but only 8% (1/12) in the cilostazol group were, which is an important distinction between the two drug treatments. Protection of the endothelium during inammation is a therapeutic advantage in the treatment of atherosclerosis and the prevention of stroke and other vascular events.13,14 Unlike aspirin, cilostazol has a substantial antiplatelet eect and therefore confers protection on the endothelium,15,16 increases the concentration of highdensity lipoprotein, and reduces triglyceride concentrations.17,18 Cilostazol also inhibits the proliferation of blood-vessel smooth muscle,19 and Kwon and colleagues20 reported that cilostazol improved intracranial stenosis after 6 months treatment. These actions might have an important role in the prevention of secondary stroke. We speculate that these eects explain the dierent distribution of the KaplanMeier curves after 6 to 7 months treatment.
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N=number of patients with event. Frequency=total number of events. %=percentage of patients with event in each group.

Table 3: Incidence and frequency of mild adverse events

Cilostazol Total bleeding events Rhinorrhagia Sclera bleed Faecal occult blood MIC urine Haemoptisis Cerebral Upper GI Lower GI Urine Gingiva Vaginal Haemorrhoids Purpura 16 (4%) 1 (<1%) 0 (0%) 5 (1%) 2 (<1%) 0 (0%) 1 (<1%) 2 (<1%) 2 (<1%) 3 (<1%) 0 0 2 (<1%) 2 (<1%)

Aspirin 32 (9%) 6 (2%) 1 (<1%) 8 (2%) 2 (<1%) 1 (<1%) 5 (1%) 1 (<1%) 0 (0%) 0 (0%) 3 (<1%) 1 (<1%) 0 (0%) 3 (<1%)

Data are actual number of bleeding events (%).

Table 4: Bleeding events

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There is a higher incidence of cerebral haemorrhage in the Chinese population than in other ethnic groups. In a hospital-based study, 24% of patients had stroke due to cerebral haemorrhage, and in patients in the community the proportion with cerebral haemorrhage is as high as 2550% of all strokes.10 Therefore, prevention of cerebral haemorrhage is crucial in the prevention of stroke. Cerebral haemorrhage and ischaemic stroke are two dierent aspects to consider in stroke prevention regimens; however, complete protection against bleeding with antithrombotic therapy is impossible. Although the incidence of cerebral haemorrhage in our study is still within the accepted range of the relative risk for aspirinrelated cerebral haemorrhages (108409),21 the reduction of the incidence of this side-eect is a vital goal when the poorer outcome of patients with cerebral haemorrhage, particularly in the Chinese population, is taken into consideration. Asymptomatic cerebral haemorrhage occurred in our series at so-called silent areas, such as the external capsule. However, with newer MRI techniques (eg, MRI T2*) the residue of cerebral haemorrhage can be seen throughout life. Focal dephasing of the MRI signal due to haemosiderin leads to the appearance of dark areas on MRI T2* sequences. In our series, we identied two patients with asymptomatic haematoma that did not show up in the original MRI, which means that the haematomas occurred during the study. Haematomas are dierent from microbleeds: the former are bigger, ovoid, and isolated, whereas the latter are small, round, and widely distributed. In the aspirin group, ve patients had cerebral haematomas and two patients had asymptomatic haematomas, whereas only one patient had cerebral haemorrhage in the cilostazol group, which implies that the cerebral haemorrhages and haematomas are aspirinrelated, and result in a higher incidence of morbidity and disability in patients on this treatment compared with those on cilostazol. 39% of patients with ischaemic stroke had cerebral microbleeds that were seen at baseline with MRI T2*. The mechanism of cerebral microbleeds is still unknown, although most researchers agree that amyloid-based angiopathy is a possible cause. However, in our series most of the cerebral microbleeds were localised at the basal ganglia, brainstem, or cerebellar regions, which is consistent with the ndings of Wardlaw and co-authors22 who suspected atherosclerosis as the cause. After followup of 1218 months, the number of new cerebral microbleeds increased to 548% in the aspirin group and 582% in the cilostazol group; therefore, neither cilostazol nor aspirin modies the number of cerebral microbleeds. Six patients with symptomatic cerebral haemorrhage during the follow-up had associated cerebral microbleeds, and in all cases the sites of the haematomas were close to those of previous cerebral microbleeds. Furthermore, ve of the six patients had lacunar infarction but only
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one patient had occlusion of the middle cerebral artery. Cerebral haemorrhage associated with lacunar infarction has been reported by other researchers.22 Phosphodiesterase inhibitors reduce the incidence of cerebral haemorrhage: the authors of the European/Australasian stroke prevention in reversible ischaemia trial (ESPRIT) study, in which aspirin was combined with dipyramidole (another phosphodiesterase inhibitor), reported reduced cerebral haemorrhage with the combination than with aspirin alone.23 We and others suggest that an important mechanism through which cilostazol reduces symptomatic and asymptomatic haematoma is protection of the endothelium and prevention of small-artery disease in the brain white matter.24 The limitations of the small sample and short duration of follow-up in the present study prevent us from concluding denitively that there are major dierences between aspirin and cilostazol in the prevention of ischaemic stroke; however, although this study is underpowered to conrm the ecacy of cilostazol over aspirin, it might serve as a pilot for a denitive large phase III trial. Our study did show that even with such a small sample and over a short follow-up, there was a signicant dierence in the occurrence of cerebral haemorrhage or asymptomatic cerebral haemorrhage between the two treatment groups. To reduce drugrelated cerebral haemorrhage, screening for cerebral microbleeds might be helpful before long-term antiplatelet therapy is started and aspirin should be selected cautiously, particularly in patients with microbleeds at many sites. Phosphodiesterase inhibitors, such as dipyramidole or cilostazol, can be thought of as candidate drugs to supplement or replace aspirin in these high-risk patients.
Investigators for the CASISP study group Peking University First Hospital, China (Y Huang, Z Wang, M He, J Xiao); Fudan University Huashan Hospital, China (C Ln, Z Hong, J Fu); Beijing Military Branch General Hospital (W Zhang, Y Wei); Zhejiang University Second Hospital, China (M Ding, S Wang); Tianjin Medical University Aliate Hospital, China (Y Cheng, G Zhou); Xian Jiaotong University First Hospital, China (Z Li, J Qiao); First Aliated Hospital, Sun Yat-Sen University, China (J Zeng, Y Tao); Shanghai Jiao Tong University, School of Medicine Aliated Renji Hospital, China (Y Li, Q Xu); Peking University Aliate Peoples Hospital (X Gao, W Li); Guangzhou Medical College, The Second Aliated Hospital, China (E Xu, G Zeng ); Peking University Third Hospital, China (D Fan, H Zhang); Jilin University First Hospital, Chnia (J Wu, W Lin); Prince of Wales Hospital, Hong Kong, China (K Wong). Contributors YH designed the study and drafted the paper. All authors were involved in the conduct of the study, the interpretation of the results, and in making revisions and corrections to the paper. Statistical design and analysis was done by Chen Yao. KW was responsible for auditing the study. CL worked as consultant. All authors read and approved the nal version of the manuscript. Conicts of interest YH has received lecture fees from Otsuka. CL has received consultancy fees from Otsuka. The other authors have no conicts of interest. Acknowledgments This study was funded by the National Ministry of Health of the Peoples Republic of China and Otsuka Pharmaceutical Co Ltd.

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