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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

Lancet Neurol 2008; 7: 494–99 Published Online May 5, 2008 DOI:10.1016/S14744422(08)70094-2 See Reflection and Reaction page 469 Peking University First Hospital, Beijing, China (Y Huang MD, J Xiao MD, C Yao MD); Tianjin Medical University Affiliated Hospital, Tianjin, China (Y Cheng MD); Jilin University First Hospital, Changchun, China (J Wu MD); Shanghai Jiao Tong University, School of Medicine Affiliated Renji Hospital, Shanghai, China (Y Li MD); Guangzhou Medical College the Second Affiliated Hospital, Guangzhou, China (E Xu MD); Fudan University Huashan Hospital, Shanghai, China (Z Hong MD, C Lu MD); Xi’an Jiaotong University First Hospital, Xi’an, 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 People’s Hospital, Beijing, China (X Gao MD); Peking University Third Hospital, Beijing, China (D Fan MD); First Affiliated 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

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 different mechanism. This trial aimed to compare the efficacy and safety of cilostazol with that of aspirin for the long-term prevention of the recurrence of ischaemic stroke. Methods 720 patients (mean age 60·2 years, SD 9·86) who had had an ischaemic stroke within the previous 1–6 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 12–18 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, diffusion-weighted imaging (DWI), T2 fluid-attenuated inversion recovery (FLAIR), and T2 gradient echo imaging (T2*) at the beginning and the end of the study. This trial is registered with, 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 Kaplan–Meier curves (risk of primary endpoint in cilostazol group vs aspirin group), was 0·62 (95% CI 0·30–1·26; p=0·185). Symptomatic cerebral haemorrhage was reported in six patients: one in the cilostazol group and five 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 significantly more common in the aspirin group than in the cilostazol group (7 vs 1, p=0·034). 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 significant difference 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 effective and safer alternative to aspirin for Chinese patients with ischaemic stroke; however, a larger phase III trial is required to confirm this. Funding National Health Ministry of the People’s Republic of China; Otsuka Pharmaceutical.

Stroke is the second leading cause of mortality in China, with about 7 million people affected countrywide.1 Aspirin is effective 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 different pathways have been used; these compounds were used effectively and safely in patients with unstable coronary heart disease, with the most benefits seen during the

first 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 Vol 7 June 2008


T2 fluid-attenuated inversion recovery (FLAIR) MRI. which was stratified according to each site (figure 1). and Dec 31. double-dummy. as a complication of treatment. and the trial was designed to be a pilot study in accordance with the paucity of clinical data that compared cilostazol and aspirin directly. uncontrolled severe comorbidities. and T2 gradient echo imaging (T2*) with a magnetic field of 1·5 Tesla or higher for all Vol 7 June 2008 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 effect 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 profile 495 . USA). patient enrolment and within 2 weeks of the end of the study. Informed written consent was obtained from all patients and ethics approval was obtained at each centre. All case report forms were managed by an independent data management company (DMS Pharmaceutical Group. inhibits the proliferation of arterial smoothmuscle cells. USA). manually evaluated the DICOM-formatted MRIs (82%) or films (18%) independently. electrocardiogram. Data were inputted by two separate operators and analysed with SAS version 6. Park Ridge. Lacunar infarction was defined as a lesion with a diameter that was less than 15 mm in the area of the penetrating arterioles.1 (SAS. The aspirin and the cilostazol pills were made to look the same. NC. or death from any other cause. T2 MRI. or peripheral arterial occlusion disorder—death from vascular causes. Peking University First Hospital. Statistical analyses The sample size was calculated on the basis of practical considerations. 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. The primary endpoint was defined as any occurrence of stroke. The combined endpoints were defined as more than one of recurrent stroke.10. including ischaemic stroke. Microbleeds were diagnosed if the MRI T2* series showed a lesion of less than 5 mm in the brain parenchyma. diffusion-weighted imaging (DWI). IL. randomised. We also hoped to image asymptomatic strokes. or subarachnoid haemorrhage. mean age 60·2 years) were enrolled consecutively between May 1.thelancet. Eight radiologists from the Department of Radiology. deep venous thrombosis. contraindications to antiplatelet treatment. except for those for patients who had primary endpoints or who died. which could be a pilot study for a large phase III trial. 2005. Methods Participants 720 patients (495 male and 225 female. transient ischaemic attack. All patients had an MRI series of T1 MRI. which continues to be widely used to prevent secondary ischaemic stroke. 2004. Images were examined within 2 weeks of http://neurology. All primary endpoints were rechecked by the steering 720 patients enrolled and screened with MRI Procedures The study was designed as a multicentre. vascular event—including pulmonary embolism. no studies have compared the efficacy of cilostazol with that of aspirin. Cary. Patients were assigned to a treatment group at each centre by a computer-based stratified block randomisation on the basis of a pre-established scheme. cerebral haemorrhage. who were part of the CASISP cooperation investigators and were blinded to the clinical data. particularly cerebral microbleeds and cerebral haemorrhage. their diagnosis had been confirmed with neuroimaging. new myocardial infarction. Patients were eligible for inclusion if they had had an ischaemic stroke within the preceding 1 to 6 months. Liver and kidney function.11 and has shown efficacy in the prevention of ischaemic stroke in a group of patients from Japan. a consensus diagnosis was reached by two radiologists. aspirin-controlled trial. respectively.Articles endothelium. Follow-up was concluded on Dec 31. We report the results of a trial to assess the efficacy and safety of cilostazol compared with aspirin in the prevention of secondary stroke in a small sample of patients. and were seen by doctors every month during the follow-up period. and lipid profiles were monitored in all patients every 3 months. Exclusion criteria were one or more from a history of intracranial or subarachnoid haemorrhage. and they had a modified Rankin scale score of less than 4 at enrolment. cardiogenic embolism. or the use of other antiplatelet drugs during the trial period. double-blind. 2004.12 However. In the event of unclear or suspected lesions. severe disability. All patients with hypertension or high lipid concentrations were given antihypertensive drugs or statins.

The corresponding author had full access to all the data in the study and had final responsibility for the decision to submit the article for publication. and the database was locked before the data were unblinded. haemorrhagic stroke. although baseline systolic blood pressure was significantly higher in the control group than in the cilostazol group (p=0·03) but this resolved after 1 month’s treatment with antihypertensive Vol 7 June 2008 *Data are mean (SD. p=0·200. and that aspirin was more effective than cilostazol during this period. The trial profile is shown in figure 1. including hypertension. Kaplan–Meier curves were used for the analysis of the primary endpoints and the Cox proportional hazard regression model to calculate the relative risk (RR). 224) 241 (67%) 135·41 (16·70) 82·87 (9·30) 77·26 (50·05) 285 (79%) 65 (18%) 98 (27%) 223 (62%) 2 (<1%) Aspirin (n=359) 60·31 (9·71. or the writing 496 . 5·82% http://neurology. The estimated hazard ratio (the risk of a primary endpoint in the cilostazol group vs the aspirin group) was 0·62 (95% CI 0·30–1·26). The 180-day and 540-day estimated recurrence rates of stroke were 2·67% for the cilostazol group versus 2·33% for the aspirin group and 3·62% for the cilostazol group versus 6·41% for the aspirin group. data analysis. p=0·185. death from vascular causes. Cumulative analysis of the primary endpoints (figure 2) showed that the two curves were close during the first 6 months of treatment. and 39% had cerebral microbleeds seen with MRI T2*. 301 patients in the cilostazol group and 299 patients in the aspirin group received treatment for 12–18 months. which was defined as taking at least one of the allocated drugs. 569 patients (79%) had vascular risk factors. and a perprotocol analysis were done in the statistical report. however. or death from any other cause. Role of the funding source The funding sources had no role in the study design. †Data are mean (SD). deep venous thrombosis. the curves divided in favour of cilostazol. Combined endpoints: recurrent stroke. 219) 253 (70%) 138·22 (17·56) 83·80 (10·84) 79·72 (51·96) 284 (79%) 66 (18%) 113 (31%) 223 (62%) 5 (1%) 36 (10%) 166 (46·2%) 93 (25·9%) 64 (17·8) 2·45 (2·05) of this article. Both an intention-to-treat analysis. respectively. The stroke recurrence rate was 3·26 patients per year in the cilostazol group and 5·27 patients per year in the aspirin group (p=0·18). data interpretation. The profiles of the cilostazol patients and aspirin patients were similar (table 1). 223 patients (62%) used aspirin in both the aspirin and cilostazol groups for the 3 months before enrolment. The estimated hazard ratio for the cilostazol group versus the aspirin group was 0·70 (0·40–1·21). however. All other data are numbers of patients (%). although this was a post-hoc analysis. vascular event (pulmonary embolism. Data quoted as mean (SD) number of events estimated from Kaplan-Meier curves. number of patients under 65 years). 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 five in the aspirin group).thelancet. There were no significant differences in National Institutes of Health stroke scale (NIHSS) score (p=0·21) and modified Rankin scale score (p=0·99) between the treatment groups at the end of the follow up. 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. new myocardial infarction.Articles 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 Modified Rankin scale score 0 1 2 3 NIHSS† 35 (9·72%) 162 (45%) 98 (27·2%) 35 (18·05%) 2·27 (2·00) 60·14 (10·05. To evaluate efficacy. transient ischaemic attack. ther was an increase in the umber of microbleeds in both groups (17/292. and subarachnoid haemorrhage. After 6 months. There was no significant difference in the combined endpoints between the two groups (table 2). secondary variables were defined as clinical symptomatic cerebral haemorrhage and asymptomatic cerebral haematoma seen with MRI. More than one infarction was seen in 238 (66%) of the cilostazol-treated patients and 247 (69%) of the aspirintreated patients. Baseline MRI screens showed infarctions in all patients. or peripheral arterial occlusion disorder). and high lipid concentrations. data collection. Table 1: Baseline characteristics Primary endpoints Aspirin 30 days 90 days 180 days 360 days 540 days 0·28 (0·28) 0·86 (0·50) 2·33 (0·82) 5·42 (1·24) 6·41 (1·42) Cilostazol 0·85 (0·49) 1·44 (0·64) 2·67 (0·88) 3·62 (1·03) 3·62 (1·03) Combined endpoints Aspirin 0·28 (0·28) 1·15 (0·57) 3·80 (1·03) 8·35 (1·51) 9·76 (1·69) Cilostazol 1·14 (0·56) 2·03 (0·76) 3·87 (1·05) 6·39 (1·35) 6·39(1·35) Primary endpoints: ischaemic stroke. no new large infarctions or lacunar infarctions were detected by FLAIR. In the MRI screens at the end of study. In addition. Results Treatment was given for a total of 740 person-years. whereas only five patients in the cilostazol group and two patients in the aspirin group used cilostazol in the 3 months before enrolment. the number of patients with cerebral microbleeds. diabetes. we used the primary endpoint and the combined endpoints as primary variables. Table 2: Primary and combined endpoints committee.

and reduces triglyceride concentrations. dizziness. RR=7·14 (95% CI 0·87–58·33). three of these patients (two in the aspirin group and one in the cilostazol group) also had symptomatic cerebral haemorrhage.15. Frequency=total number of events. p=0·038. and all the sites of symptomatic cerebral haemorrhage were associated with cerebral microbleeds seen on the baseline MRI T2*.Articles cilostazol vs 17/310. 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 (%). however. Table 4: Bleeding events 497 . and at the end of the study there was a 38·1% reduction in the relative risk of a primary endpoint in the cilostazol group compared with the aspirin group. after 6 months. p=0·18 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 % 13·61 8·89 6·11 1·39 Aspirin N 19 17 7 35 Frequency 20 17 7 39 % 5·28 4·72 1·94 9·72 Discussion Cilostazol has similar effects to those of aspirin in the prevention of recurrent ischemic stroke during the first 6 months after starting treatment. although mild adverse events. which was a middle cerebral artery occlusion.17. were more common in the cilostazol group and palpitations were more common in the cilostazol group (table 3). Protection of the endothelium during inflammation is a therapeutic advantage in the treatment of atherosclerosis and the prevention of stroke and other vascular events. %=percentage of patients with event in each group.18 Cilostazol also inhibits the proliferation of blood-vessel smooth muscle. Generally. These actions might have an important role in the prevention of secondary stroke.13. and tachycardia. The incidence of severe cerebral bleeds was significantly higher in the aspirin group than in the cilostazol group (seven [five symptomatic and two asymptomatic haemorrhages] vs one symptomatic haemorrhage. cilostazol was more effective than aspirin. 5·48% aspirin). More asymptomatic haematomas were seen in patients in the aspirin group than in patients in the cilostazol group (four vs one). 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 Vol 7 June 2008 N=number of patients with event. 0·10 0·09 0·08 0·07 0·06 0·05 0·04 0·03 0·02 0·01 0 0 Number at risk Cilostazol 360 Aspirin 359 Cilostazol Aspirin 0·061% vs 0·036% RRR 38·1% (0·30–1·26). cilostazol has a substantial antiplatelet effect and therefore confers protection on the endothelium. All cerebral bleeds were lacunar infarctions. 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). 1·95% vs 0·28%. we feel. http://neurology. which meant that only two new asymptomatic haematomas were reported by the radiologists in the aspirin group. with the exception of one.14 Unlike aspirin.19 and Kwon and colleagues20 reported that cilostazol improved intracranial stenosis after 6 months’ treatment. which is an important distinction between the two drug treatments. such as headache. We speculate that these effects explain the different distribution of the Kaplan–Meier curves after 6 to 7 months’ treatment.thelancet. which. By contrast. there was no difference in major side-effects between the two treatments. However. this did not reach statistical significance.16 increases the concentration of highdensity lipoprotein. is due to the small sample size and the short follow-up period.

we identified two patients with asymptomatic haematoma that did not show up in the original MRI. Z Hong. H Zhang). Sun Yat-Sen University. Contributors YH designed the study and drafted the paper. The mechanism of cerebral microbleeds is still unknown. Although the incidence of cerebral haemorrhage in our study is still within the accepted range of the relative risk for aspirinrelated cerebral haemorrhages (1·08–4·09). J Fu).10 Therefore. China (M Ding. although this study is underpowered to confirm the efficacy of cilostazol over aspirin. W Li). Jilin University First Hospital. Asymptomatic cerebral haemorrhage occurred in our series at so-called silent areas. In a hospital-based study. G Zeng ). neither cilostazol nor aspirin modifies the number of cerebral microbleeds. Shanghai Jiao Tong University. Fudan University Huashan Hospital. KW was responsible for auditing the study. or cerebellar regions. China (Y Li. five of the six patients had lacunar infarction but only 498 one patient had occlusion of the middle cerebral artery. Haematomas are different from microbleeds: the former are bigger. with newer MRI techniques (eg. is taken into consideration. such as dipyramidole or cilostazol. China (J Zeng. five patients had cerebral haematomas and two patients had asymptomatic haematomas. China (D Fan. Y Wei). CL has received consultancy fees from Otsuka. Peking University Third Hospital. Zhejiang University Second Hospital. there was a significant difference in the occurrence of cerebral haemorrhage or asymptomatic cerebral haemorrhage between the two treatment groups.Articles There is a higher incidence of cerebral haemorrhage in the Chinese population than in other ethnic groups. which means that the haematomas occurred during the study. W Lin).24 The limitations of the small sample and short duration of follow-up in the present study prevent us from concluding definitively that there are major differences between aspirin and cilostazol in the prevention of ischaemic stroke. Z Wang. which is consistent with the findings of Wardlaw and co-authors22 who suspected atherosclerosis as the cause. however. whereas the latter are small. MRI T2*) the residue of cerebral haemorrhage can be seen throughout life. In our series. ovoid. complete protection against bleeding with antithrombotic therapy is impossible. can be thought of as candidate drugs to supplement or replace aspirin in these high-risk patients. J Qiao). and isolated. Q Xu). reported reduced cerebral haemorrhage with the combination than with aspirin alone. Focal dephasing of the MRI signal due to haemosiderin leads to the appearance of dark areas on MRI T2* sequences. J Xiao). Acknowledgments This study was funded by the National Ministry of Health of the People’s Republic of China and Otsuka Pharmaceutical Co Ltd. Statistical design and analysis was done by Chen Yao. Guangzhou Medical College. China (E Xu. and widely distributed.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. and in all cases the sites of the haematomas were close to those of previous cerebral microbleeds. in which aspirin was combined with dipyramidole (another phosphodiesterase inhibitor). and in patients in the community the proportion with cerebral haemorrhage is as high as 25–50% of all strokes. China (Y Huang.22 Phosphodiesterase inhibitors reduce the incidence of cerebral haemorrhage: the authors of the European/Australasian stroke prevention in reversible ischaemia trial (ESPRIT) study. The Second Affiliated Hospital.thelancet. Beijing Military Branch General Hospital (W Zhang. and in making revisions and corrections to the paper. However. However.21 the reduction of the incidence of this side-effect is a vital goal when the poorer outcome of patients with cerebral haemorrhage. Hong Kong. All authors were involved in the conduct of the study. School of Medicine Affiliated Renji Hospital. and result in a higher incidence of morbidity and disability in patients on this treatment compared with those on cilostazol. it might serve as a pilot for a definitive large phase III trial. 24% of patients had stroke due to cerebral haemorrhage. Tianjin Medical University Affiliate Hospital. S Wang). Six patients with symptomatic cerebral haemorrhage during the follow-up had associated cerebral microbleeds. whereas only one patient had cerebral haemorrhage in the cilostazol group. Chnia (J Wu. Cerebral haemorrhage and ischaemic stroke are two different aspects to consider in stroke prevention regimens. China (Y Cheng. Peking University Affiliate People’s Hospital (X Gao. Phosphodiesterase inhibitors. in our series most of the cerebral microbleeds were localised at the basal ganglia. China (Z Li. To reduce drugrelated cerebral haemorrhage. China (C Ln. The other authors have no conflicts of interest. Prince of Wales Hospital. however. Y Tao). brainstem. Investigators for the CASISP study group Peking University First Hospital. particularly in patients with microbleeds at many sites. Vol 7 June 2008 . Cerebral haemorrhage associated with lacunar infarction has been reported by other researchers. Conflicts of interest YH has received lecture fees from Otsuka. which implies that the cerebral haemorrhages and haematomas are aspirinrelated. prevention of cerebral haemorrhage is crucial in the prevention of stroke. the interpretation of the results. M He. 39% of patients with ischaemic stroke had cerebral microbleeds that were seen at baseline with MRI T2*. http://neurology. Our study did show that even with such a small sample and over a short follow-up. such as the external capsule. therefore. screening for cerebral microbleeds might be helpful before long-term antiplatelet therapy is started and aspirin should be selected cautiously. First Affiliated Hospital. China (K Wong). G Zhou). All authors read and approved the final version of the manuscript. Xi’an Jiaotong University First Hospital. After followup of 12–18 months. the number of new cerebral microbleeds increased to 5·48% in the aspirin group and 5·82% in the cilostazol group. CL worked as consultant. In the aspirin group. round. although most researchers agree that amyloid-based angiopathy is a possible cause. particularly in the Chinese population.

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