財団季報

Vol.8

2019.12月号

5Articles

Dual antiplatelet therapy using cilostazol for secondary
prevention in patients with high-risk ischaemic stroke inJapan: a multicentre, open-label, randomised controlled trial
Kazunori Toyoda, Shinichiro Uchiyama, Takenori Yamaguchi, J Donald Easton, Kazumi Kimura, Haruhiko Hoshino, Nobuyuki Sakai,
Yasushi Okada, Kortaro Tanaka, Hideki Origasa, Hiroaki Naritomi, Kiyohiro Houkin, Keiji Yamaguchi, Masanori Isobe, Kazuo Minematsu, on behalfof the CSPS.com Trial Investigators

Summary

Background Although dual antiplatelet therapy with aspirin and clopidogrel reduces early recurrence of ischaemic
stroke, with long-term use this type of therapy is no longer effective and the risk of bleeding increases. Given thatcilostazol prevents stroke recurrence without increasing the incidence of serious bleeding compared with aspirin, we
aimed to establish whether dual antiplatelet therapy involving cilostazol is safe and appropriate for long-term use.
Methods In a multicentre, open-label, randomised controlled trial across 292 hospitals in Japan, patients with highrisk non-cardioembolic ischaemic stroke identified on MRI were randomly assigned to two groups in a 1:1 ratio toreceive monotherapy with either oral aspirin (81 or 100 mg, once per day) or clopidogrel (50 or 75 mg, once per day)alone, or a combination of cilostazol (100 mg, twice per day) with aspirin or clopidogrel. Randomisation was done
centrally (using block randomisation with a block size of six per each participating hospital) through a web-based
registration system and was done by EPS Corporation. The patients were required to have at least 50% stenosis of amajor intracranial or extracranial artery or two or more of the vascular risk factors. Trial medication was continued forhalf a year or longer, for a maximum of 3·5 years. The primary efficacy outcome was the rate of first recurrence ofsymptomatic ischaemic stroke. Safety outcomes were severe or life-threatening bleeding; any adverse events; serious
adverse events; and any bleeding events. Efficacy analyses were done in the intention-to-treat population and safety
analyses were done in the as-treated population. This trial was registered with ClinicalTrials.gov (number
NCT01995370) and UMIN Clinical Trials Registry (number 000012180).
Findings Participants were recruited from Dec 13, 2013, to March 31, 2017. 932 patients assigned to the dual therapy
group and 947 patients assigned to the monotherapy group were included in the intention-to-treat analysis. The trial
was stopped after the enrolment of 1884 patients of an anticipated 4000 patients because of the delay in recruitment.
Ischaemic stroke recurred in 29 (3%) of 932 patients (annualised rate 2·2%) on dual therapy including cilostazol and64 (7%) of 947 patients (annualised rate 4·5%) on monotherapy during a median 1·4 years follow-up (hazard ratio[HR] 0·49, 95% CI 0·31–0·76, p=0·0010). Severe or life-threatening bleeding occurred in eight patients (annualised
rate 0·6%) on dual therapy and 13 patients (annualised rate 0·9%) on monotherapy (HR 0·66, 95% CI 0·27–1·60,
p=0·35). Occurrence of any type of adverse event was similar between the groups (255 [28%] of 910 patients in the
dual therapy group vs 219 [24%] of 921 patients in the monotherapy group); as was occurrence of serious adverse
events (87 [10%] vs 142 [15%]) and bleeding events (38 [4%] vs 33 [4%]). Gastrointestinal bleeding, which affectednine (<1%) of 910 patients in the monotherapy group and nine (<1%) of 921 patients in the dual therapy group, wasthe most common type of bleeding.
Interpretation The combination of cilostazol with aspirin or clopidogrel had a reduced incidence of ischaemic strokerecurrence and a similar risk of severe or life-threatening bleeding compared with treatment with aspirin or
clopidogrel alone in patients at high risk for recurrent ischaemic stroke.
Funding Otsuka Pharmaceutical.
Copyright © 2019 Elsevier Ltd. All rights reserved.

Introduction
Patients with non-cardioembolic ischaemic stroke have ahigher risk of recurrence when they have carotid steno­
sis,1 intracranial arterial stenosis,2 or multiple vascularrisk factors than when they do not have these com­plications.3,4 For such patients, comprehensive pre­ventive
therapy, including antiplatelet medication, has beenwww.thelancet.com/neurology Vol 18 June 2019

proven beneficial. However, newer antiplatelet agentsthat are promising for patients with coronary arterydisease and have been in commercial use for around10 years, such as ticagrelor and prasugrel, did not show
advantages over conventional antiplatelet agents forpatients with stroke in randomised controlled trials(RCTs).5,6

Lancet Neurol 2019; 18: 539–48
See Comment page 515
Department of Cerebrovascular
Medicine, National Cerebral andCardiovascular Centre, Osaka,
Japan (K Toyoda MD,
T Yamaguchi MD); ClinicalResearch Centre for Medicine,International University of
Health and Welfare, Tokyo,
Japan (S Uchiyama MD); Centre
for Brain and Cerebral Vessels,
Sanno Hospital and Sanno
Medical Centre, Tokyo, Japan(S Uchiyama); Department of
Neurology, University ofCalifornia, San Francisco, CA,
USA (J D Easton MD);
Department of Neurological
Science, Graduate School of
Medicine, Nippon Medical
School, Tokyo, Japan(K Kimura MD); Department of
Neurology, Tokyo SaiseikaiCentral Hospital, Tokyo, Japan(H Hoshino MD); Department of
Neurosurgery, Kobe City
Medical Centre General
Hospital, Kobe, Japan(N Sakai MD); Clinical ResearchInstitute and Department of
Cerebrovascular Medicine and
Neurology, National Hospital
Organisation Kyushu Medical
Centre, Fukuoka, Japan(Y Okada MD); Department of
Neurology (K Tanaka MD) andDivision of Biostatistics andClinical Epidemiology(H Origasa PhD), University of
Toyama, Toyama, Japan;
Department of Neurology, Senri
Chuo Hospital, Toyonaka, Japan(H Naritomi MD); Department of
Neurosurgery, Hokkaido
University Graduate School of
Medicine, Sapporo, Japan(K Houkin MD); Department of
Neurology, Ichinomiya Nishi
Hospital, Ichinomiya, Japan(K Yamaguchi MD); Departmentof Neurosurgery, Kushiro Rosai
Hospital, Kushiro, Japan(M Isobe MD); and Headquartersof the Iseikai Medical
Corporation, Osaka, Japan(K Minematsu MD)

539

Articles

Correspondence to:
Dr Kazunori Toyoda, Department
of Cerebrovascular Medicine,National Cerebral andCardiovascular Centre,
Osaka 565-8565, Japan
totyoda@ncvc.go.jp

Research in context
Evidence before this study
We searched PubMed on Dec 31, 2018, for relevant articles
in English published since Jan 1, 1999, using the searchterms “antiplatelet therapy”, “aspirin”, “cilostazol”,“clopidogrel”, “stroke”, “cerebral ischaemia”, and “cerebral
infarction”. We also manually searched references fromoriginal articles and pertinent reviews. Searches wererestricted to completed trials in humans with abstracts or fulltexts published.

receiving placebo. A meta-analysis of data from randomised
controlled trials of long-term aspirin plus dipyridamole versus
aspirin alone in patients with ischaemic stroke and transientischaemic attack, including the ESPS2, ESPRIT, JASAP, and other
trials, showed greater reduction of the risk of recurrent
ischaemic stroke with combination therapy 12 weeks after
randomisation. The risk of bleeding of the combination was
higher than clopidogrel monotherapy based on the results ofthe ESPS2 and PRoFESS trials.

In 2013, Lee and colleagues reported the results of ameta-analysis of data from seven randomised controlled trialsof long-term dual-antiplatelet and single-antiplatelet therapy
in patients with ischaemic stroke and transient ischaemic
attack. The seven trials assessed the following antiplatelet
regimens: aspirin plus clopidogrel versus aspirin monotherapy
in the CHARISMA and SPS3 trials; aspirin plus dipyridamole,a phosphodiesterase inhibitor, versus aspirin monotherapy in
the ESPRIT and JASAP trials; aspirin plus clopidogrel versus
clopidogrel monotherapy in the MATCH trial; aspirin plus
dipyridamole versus clopidogrel monotherapy in the PRoFESS
trial; and aspirin plus ticlopidine versus ticlopidine
monotherapy in the TOPALS trial. Recurrent stroke risk did not
differ between patients receiving dual-antiplatelet therapy andthose receiving monotherapy with any choice of antiplatelet
agents. Risk for intracranial haemorrhage did not differ
between patients receiving dual-antiplatelet therapy and thosereceiving aspirin monotherapy but it was greater in patients
receiving dual-antiplatelet therapy than in those receiving
clopidogrel monotherapy.

A combination of cilostazol, a phosphodiesterase-3 inhibitor,
and aspirin did not increase bleeding compared with aspirinalone or aspirin plus clopidogrel in small trials in patients withstroke and intracranial arterial stenosis in the TOSS, TOSS-2,
and CATHARSIS trials. In the CATHARSIS trial, the mean annual
incidence of all vascular events, stroke, and ischaemic stroke
tended to be lower in patients receiving dual therapy than inthose receiving aspirin monotherapy.

ESPS2 is another randomised controlled trial of long-term
aspirin, dipyridamole, their combined use, and placebo inpatients with ischaemic stroke and transient ischaemic attack.
Risk reduction of recurrent stroke was greater with the
combination therapy than with each monotherapy. Severe or
fatal bleeding events were around twice as common in patients
receiving aspirin monotherapy and those receiving dual therapy
as those receiving dipyridamole monotherapy and those

Given that antiplatelet agents act through a range of
mechanisms, including platelet inhibition of throm­boxane A2 production, inhibition of cyclic adenosine
3’,5’-monophosphate production, and inhibition of P2Y12
receptors, a combination of agents can produce more
effective stroke prevention than single agents. The com­bination of dual antiplatelet therapy with aspirin andclopidogrel decreases the risk of early stroke recurrence inpatients with minor ischaemic stroke or high-risk
transient ischaemic attack compared with aspirinmonotherapy.7,8 Several weeks or months later, however,risk reduction of stroke with aspirin combined withclopidogrel was attenuated and dual therapy was harmful
in such patients because of the higher risk of major
bleeding than with monotherapy.9–12
540

To the best of our knowledge, no randomised controlled trial ofdual therapy with cilostazol plus thienopyridines for stroke has
been done.
Added value of this study
The results of our Cilostazol Stroke Prevention Study for
Antiplatelet Combination indicate that recurrence of ischaemic
stroke was less common with long-term dual therapy with the
combination of cilostazol with aspirin or clopidogrel than withlong-term monotherapy with aspirin or clopidogrel alone inpatients who developed non-cardioembolic ischaemic strokewith major cephalocervical artery stenosis or multiple vascularrisk factors. There was no evidence of a higher risk of severe or
life-threatening bleeding with dual therapy than withmonotherapy.
Implications of all the available evidence
The combination of cilostazol with aspirin or clopidogrel seems
to be a pharmacotherapeutic approach that could berecommended in the chronic stage of high-risk,
non-cardioembolic, ischaemic stroke.

Cilostazol, a phosphodiesterase 3 inhibitor, has anti­
platelet and vasodilatory properties as well as antiinflam­
matory and antiproliferative effects,13 and causes bleeding
complications less frequently than other antiplatelet agentsbased in animal and human studies.14,15 In RCTs, cilostazol
decreased recurrent stroke in patients with non-cardio­
embolic ischaemic stroke, with a similar risk of ser­ious bleeding compared with placebo and with half therisk of serious bleeding compared with aspirin.16,17 In ameta-analysis involving patients with stroke and otheratherothrombotic diseases, cilostazol was associated withsignificantly lower incidences of total vascular events andof cerebrovascular events than was placebo.18 In anothermeta-analysis of secondary stroke prevention, cilostazol
was associated with significantly less haemorrhagic
www.thelancet.com/neurology Vol 18 June 2019

Articles

stroke, a reduced risk of the combined endpoint of stroke,
myocardial in­
farction, and vascular death, and fewer
bleeding events than aspirin.19 Cilostazol monotherapy isrecommended as first-line antiplatelet therapy for second­ary prevention of non-cardioembolic ischaemic stroke inJapanese guidelines.20
A combination of aspirin and dipyridamole, anotherphosphodiesterase inhibitor, showed a greater reductionof the risk of recurrent ischaemic stroke than aspirinalone only in the chronic stage 12 weeks after random
assignment to treatment in patients with ischaemic stroke
and transient ischaemic attack.21 However, dipyridamoleincreased major bleeding when added to aspirin.
By contrast, a combination of cilostazol and aspirin did
not increase bleeding compared with aspirin alone or
aspirin plus clopidogrel in small trials in stroke patientswith intracranial arterial stenosis.22–24 Triple medication
with the addition of cilostazol did not increase bleed­ing compared with dual medication with aspirin andclopidogrel in a meta-analysis of patients with a drugeluting coronary stent.25 Thus, the addition of cilostazol
might enhance the preventive effects of classic anti­
platelet agents in patients with chronic stroke without
increasing bleeding risk.
The Cilostazol Stroke Prevention Study for Antiplatelet
Combination (CSPS.com) was designed to test the
hypothesis that a combination of cilostazol with aspirin
or clopidogrel reduces recurrence of ischaemic stroke inthe chronic stage without increasing the bleeding risk
compared with aspirin or clopidogrel alone.

1884 patients enrolled

5 excluded
2 did not develop index stroke event
3 duplicate enrolment

1879 patients randomly assigned

932 assigned to receive dual
therapy
910 received at least one dose
22 never received a dose

947 assigned to receive
monotherapy
921 received at least one dose
26 never received a dose

241 excluded
26 developed major
events91 discontinued trial
drugs
73 withdrew consent
1 met exclusion criteria
50 lost to follow-up

183 excluded
49 developed major
events33 discontinued a trial
drug
14 withdrew consent
4 met exclusion criteria
83 lost to follow-up

691 were in the trial at 6 months

764 were in the trial at 6 months

932 included in primary analysis
910 included in as-treated analysis

947 included in primary analysis
921 included in as-treated analysis

Study design and participants

Figure 1: Trial profile
Major events include all vascular events, including stroke, myocardial infarction, other vascular events (eg, aortic
dissection, aortic rupture, pulmonary embolism, heart failure, angina pectoris, or peripheral artery diseaserequiring hospitalisation, and revascularisation of the coronary artery, aorta, cephalocervical artery, and peripheralarteries), transient ischaemic attack, death from any cause, and severe or life-threatening bleeding as defined in
the GUSTO classifications.

In this multicentre, open-label, parallel-group RCT,patients were recruited at 292 hospitals across Japan(appendix). Details regard­ing the trial rationale, design,and methods have been described elsewhere.26 The
protocol was approved by the ethics committee at eachparticipating site, and all patients gave written informed
consent before being randomly assigned to treatment.
A Steering Committee was responsible for the design,interpretation, and supervision of the trial (appendix).
The final trial protocol was prepared by the protocolcommittee (appendix). Any event related to the primaryand sec­
ondary outcomes was reviewed by the Event
Evalua­tion Committee who were masked to antiplatelet
medica­tions. Charges for trial drugs were covered by thehealth insurance of each patient. All investigators andcoordi­nators who were provided access to the results
were asked to sign a confidentiality agreement to ensurethat the results were not disclosed to third parties before
publication and presentation of the primary results.
Eligible patients were aged between 20 years and 85 years
and had developed a non-cardioembolic ischaemic stroke
identified on MRI between 8 days and 180 days before thestart of the protocol treatment, and were taking either
aspirin or clopidogrel alone as antiplatelet therapy whenproviding informed consent. The patients were required tomeet at least one of the following three criteria indicatinga high risk for stroke recurrence: at least 50% sten­osis of a major intra­cranial artery (to the level of A2 [thepostcommun­
icating segment of the anterior cerebral
artery], M2 [the Sylvian segment of the middle cerebral
artery], or P2 [the ambient segment of the posterior cerebral
artery]); at least 50% stenosis of an extracranial artery (thecom­mon carotid artery, internal carotid artery, vertebral
artery, brachiocephalic artery, or subclavian artery); andtwo or more risk factors derived from the Essen Stroke
Risk Score and Fukuoka Stroke Risk Score,3,4 including age
65 years or older, hypertension, diabetes mellitus, chronic
kidney disease, peripheral arterial disease, history of
ischaemic stroke other than the qualifying episode for thistrial, history of ischaemic heart disease, and current smok­
ing. Patients had to be able to visit the study centre
throughout the observa­
tion period. Major exclusion
criteria were high-risk sources of cardioembolism, useof anticoagulants, con­tra­indication to MRI examination,
matic non-traumatic intracranialand history of sympto­
haemorrhage, any other haemorrhagic disease, bleeding
predisposition, or blood clotting disorders. Additional

Methods

www.thelancet.com/neurology Vol 18 June 2019

See Online for appendix

541

Articles

information regarding the inclusion and exclusion criteria
is provided in the protocol (appendix).26
Dual therapy(n=932)

Monotherapy(n=947)Age, years

69·6 ± 9·2

69·7 ± 9·2

Female sex

295 (32%)

264 (28%)

Male sex

637 (68%)683 (72%)

Asian ethnicity*932 (100%)

947 (100%)

Body-mass index

23·9 ( 3·6)

23·7 (3·4)

Systolic

136 (126−149)

138 (126−151)

Diastolic78 (70−87)

79 (70−88)

Hypertension

781 (84%)789 (83%)

Dyslipidaemia

492 (53%)528 (56%)

Diabetes

346 (37%)355 (38%)

Chronic kidney disease

70 (8%)

49 (5%)

Peripheral arterial disease

27 (3%)

22 (2%)

History of ischaemic stroke†

125 (13%)147 (16%)

History of ischaemic heart disease48 (5%)

48 (5%)Median blood pressure, mm Hg

Medical history

Current smoking

259 (28%)275 (29%)

Two or more risk factors

843 (90%)845 (89%)

Intracranial artery stenosis

275 (30%)272 (29%)

Extracranial artery stenosis

116 (12%)137 (14%)

Modified Rankin Scale‡ score at
randomisation of 0–1

843 (90%)855 (90%)

Aspirin383 (41%)380 (40%)

Clopidogrel§549 (59%)567 (60%)

Lacunar464 (50%)461 (49%)

Atherothrombotic

389 (42%)399 (42%)

Other or undetermined

79 (8%)

87 (9%)

Supratentorial

688 (74%)698 (74%)

Infratentorial

216 (23%)214 (23%)Both

9 (1%)

14 (1%)

Unreported

19 (2%)

21 (2%)

27 (13–63)

25 (13–64)

Antiplatelet use at randomisation

Stroke subtype

Infarct location

Median time to randomisation after
index events, days

Data are n (%) of overall patients, including those with missing data, mean (SD),or median (IQR). 49 patients (23 in the dual therapy group and 26 in themonotherapy group) are missing data for body-mass index; 60 patients (28 in
the dual therapy group and 32 in the monotherapy group) for blood pressure;
41 patients (20 in the dual therapy group and 21 in the monotherapy group) for
medical history; 42 patients (20 in the dual therapy group and 22 in themonotherapy group) for current smoking; 155 patients (77 in the dual therapy
group and 78 in the monotherapy group) for intracranial artery stenosis;
254 patients (116 in the dual therapy group and 138 in the monotherapy group)for extracranial artery stenosis; and 57 patients (26 in the dual therapy group and
31 in the monotherapy group) for modified Rankin Scale score at randomisation.
*Self-reported; all are reported as Japanese. †Except the qualifying stroke for thistrial. ‡The modified Rankin Scale measures the degree of disability in the daily
activities of patients, ranging from 0 to 6, with higher scores indicating worse
functional deficits than lower scores. §36 patients in the dual therapy group and23 patients in the monotherapy group were taking clopidogrel 50 mg once perday; the other patients were taking clopidogrel 75 mg once per day.

Table 1: Baseline characteristics of patients

542

Randomisation and masking
Patients were randomly assigned to two groups in a
1:1 ratio to receive one of the following treatments: mono­
therapy with aspirin (81 mg or 100 mg) or clopidogrel(50 mg or 75 mg) once per day; or dual therapy with
Pletaal (Otsuka Pharmaceutical, Tokyo, Japan), a brand ofcilostazol (100 mg, twice per day, the recommended dosefor stroke prevention in Japan), together with either
aspirin (81 mg or 100 mg) or clopidogrel (50 mg or 75 mg),once per day. Randomisation was done centrally througha web-based registration system administered by the EPS
Corporation. A permuted block-randomisation scheme
was used with a block size of six for each participating
hospital. Placebo agents were not used because of thelimited amount of funding.

Procedures
Choice of the antiplatelet agent at randomisation, either
aspirin or clopidogrel administered orally, was estab­lished by the decision of each physician in charge.
Clopidogrel 50 mg once per day is officially approved inJapan for patients who are older (eg, aged ≥75 years) or
those with low weight (≤50 kg), although 75 mg once per
day is mainly used in clinical practice for patients who
are older or those with low weight. Trial medication was
continued for 6 months or longer, for a maximum of
3·5 years. To prevent adverse drug reactions such as
headache and tachycardia, cilostazol treatment could bestarted at 100 mg once per day and increased to 100 mg
twice per day within 15 days. Changes in these threeanti­
platelet medications were not permitted after in­formed consent was obtained. Patients who stopped
taking the trial drugs for longer than 4 weeks were with­drawn from the trial. Follow-up intervals were at 1 month,
3 months, 6 months, and every 6 months thereafter, withmodified Rankin Scale, blood pressure, compliance tothe study drug, and adverse events being assessed ateach visit.

Outcomes
The primary efficacy outcome was the first recurrence ofsymptomatic ischaemic stroke. The secondary efficacy
outcomes were as follows: any stroke (ischaemic or
haemorrhagic); haemorrhagic stroke (intracerebral or
subarachnoid haemorrhage, symptomatic); ischaemic
stroke or transient ischaemic attack; death from any
cause; a composite of stroke, myocardial infarction, andvascular death; and all vascular events, including stroke,
myocardial infarction, and other vascular events (eg,aortic dissection; aortic rupture; pulmonary embolism;
heart failure, angina pectoris, or peripheral artery dis­ease requiring hospital admission; revascularisationof a coronary artery, aorta, cephalocervical artery, andperipheral arteries).
www.thelancet.com/neurology Vol 18 June 2019

Articles

Safety outcomes were as follows: severe or lifethreatening bleeding as defined in the Global Utilizationof Streptokinase and Tissue Plasminogen Activator for
Occluded Coronary Arteries classification, which includes
symptomatic intracranial haemorrhage (haemorrhagic
stroke and subdural or epidural haemorrhage) and bleed­
ing resulting in substantial haemodynamic com­promise
requiring treatment;27 symptomatic intracranial haem­
orrhage; any adverse events; serious adverse events; andany bleeding events.
Investigators at each participating site were aware of thestudy allocation used. The efficacy and safety outcomes
were always evaluated by the Independent Data Monitoring
Committee and the Event Evaluation Committee, in which
all members were masked to treatment allocation. Investi­
gators at each participating site needed to submit additional
clinical data upon request from the committees.

Statistical analysis
Details are provided in the statistical analysis plan, whichis available with the protocol (appendix). Briefly, the plan
was to enrol 4000 patients and follow them for a
maximum of 3·5 years, to detect a 30% relative rate
reduction in the dual therapy group with 80% power, on
the basis of an estimated rate of occurrence of the primary
outcome of 4% per year in the monotherapy group.
Efficacy analyses were done in the intention-to-treat
population, focused only upon time to first event. Safety
analyses were done with patients who had received at least
one dose of a trial regimen. The treatment groups werecompared using the log-rank test. Cox proportional hazard
models were used to calculate hazard ratios (HRs) and
95% CIs for the dual therapy group compared with themonotherapy group. Patients who did not develop eventswere treated as censored at the last observational date. The
assumption of proportional hazards was confirmed when
performing each analysis. The treat­ment groups areshown by Kaplan-Meier plots and compared using the logrank test. A CI for the number needed to treat was obtainedby taking reciprocals of the values defining the CI for thehazard ratio. Subgroup analyses were done following
stratification by age, sex, body-mass index, medical history,
current smok­ing status, stenosis of intracranial arteries,
stenosis of extracranial arteries, modified Rankin Scalescore at randomisation, antiplatelet agents (aspirin or
clopidogrel), and subtype of ischaemic stroke. All thesecomponents were prespecified in the protocol. Tests forinteraction between the treatment groups and subgroups
were done using the Cox proportional hazards model. A
secondary as-treated (per-protocol) analysis of the primary
outcome that included patients who had received at least
one dose of a trial regimen, with data censored 1 day after
permanent discontinuation of trial medication, was also
performed. As a post-hoc analysis, we calculated meanvalues of change in systolic blood pressure from thebaseline value and analysed the difference between groups
using a Wilcoxon rank sum test.
www.thelancet.com/neurology Vol 18 June 2019

Adverse event

Number of patients inthe dual therapy group(n=91)

Number of patients inthe monotherapy group(n=33)

66 (73%)

12 (36%)

Palpitations or tachycardia

28* (31%)0

Headache

9* (10%)0Skin adverse event

8 (9%)

3 (9%)

Minor bleeding

7 (8%)

2 (6%)

Cancer7 (8%)

2 (6%)

Gastrointestinal adverse event

4 (4%)

3 (9%)

Other adverse event

7 (8%)

2 (6%)

11 (12%)14 (42%)

Initiation of prohibited concomitant medications

3 (3%)

9 (27%)Development of non-severe ischaemia

4 (4%)

1 (3%)

Interruption of medication before or after surgicalprocedure

1 (1%)

3 (9%)

Medical judgment to stop, add, or change
antithrombotics

Other reason

3 (3%)

1 (3%)

Other physician-determined reason

14 (15%)5 (15%)

Change to generic cilostazol products

9 (10%)

0

By mistake

4 (4%)

4 (12%)

Other reason

1 (1%)

1 (3%)0

2 (6%)

Discontinuation by patient’s decision*Four patients with simultaneous palpitations and headache were listed twice in this table.

Table 2: Reasons for discontinuation of trial drugs

Missing data were not imputed, as baseline data wereavailable for all intention-to-treat patients. Data with a
missing value for included variables in the Cox regression
model were excluded from the analysis. The statisticalanalysis committee prepared and finalised the statist­
ical analysis plan. The Independent Data Monitoring
Committee monitored the trial. Statistical analysis
was delegated to a contract research organisation (EPS
Corporation, Tokyo, Japan). All statistical analyses weredone using SAS software version 9.4. The CSPS.com trial
is registered with ClinicalTrials.gov (number NCT01995370)
and UMIN Clinical Trials Registry (number 000012180).

Role of the funding source
The funder had no role in study design, data collection,
data analysis, data interpretation, or writing of the report.
The corresponding author had full access to all the datain the study and had final responsibility for the decision
to submit for publication.

Results
Participants were recruited from Dec 13, 2013, to
March 31, 2017 (initially planned to March 31, 2016); thesteering committee extended the period of enrolment for
1 year to increase the number of anticipated patients.
However, the number of enrolled patients (1884 patients)
did not reach half the estimated number needed to reacha power of 80% (figure 1). The steering committee judgedthat the complete enrolment of 4000 patients was543Articles

Dual therapy
Number ofpatients

Monotherapy
Annual event
rate

Number ofpatients

HR (95% CI)

p value

4·5

0·49 (0·31–0·76)

0·0010

Annual event
rate

Primary efficacy outcome

n=932

Ischaemic stroke*

29 (3%)

Secondary efficacy outcomes

n=932

Any stroke

34 (4%)

2·6

71 (7%)

5·0

0·51 (0·34–0·77)

0·0012

Haemorrhagic stroke*

5 (1%)

0·4

7 (1%)

0·5

0·77 (0·24–2·42)

0·65

Ischaemic stroke or transient ischaemic attack

32 (3%)

2·4

69 (7%)

4·9

0·50 (0·33–0·76)

0·00091

Death from any cause

6 (1%)

0·5

7 (1%)

0·5

0·92 (0·31–2·73)

0·88

Composite of stroke, myocardial infarction,and vascular death38 (4%)

2·9

78 (8%)

5·5

0·52 (0·35–0·77)

0·00079

All vascular events

47 (5%)

3·6

90 (10%)6·4

0·56 (0·39–0·80)

0·0011

Safety outcomes

n=910

0·35

n=947
2·2

64 (7%)
n=947

n=921

Severe or life-threatening bleeding

8 (1%)

0·6

13 (1%)

0·9

0·66 (0·27–1·60)

Intracranial haemorrhage

8 (1%)

0·6

13 (1%)

0·9

0·66 (0·27–1·60)

0·35

Haemorrhagic adverse events

38 (4%)

2·9

33 (4%)

2·4

1·23 (0·77–1·96)

0·38

Annual event rate indicates the number of events per 100 person-years. HR=hazard ratio. *Two patients who developed ischaemic stroke (one in each of the two treatmentgroups) and two patients who developed haemorrhagic stroke (one in each of the two treatment groups) had fatal outcomes.

Table 3: Efficacy and safety outcomes

unlikely by the further extension within the limit offunding, and therefore finally decided to stop enrolment
on March 31, 2017. Final observations were done on
March 31, 2018. No interim analysis was done giventhat enrolment did not reach 2000 patients. Of
the 1884 patients who consented to participate in the
study between Dec 13, 2013, and March 31, 2017,
1879 (>99%) were randomly assigned to treatment;
two patients (<1%) did not develop ischaemic stroke as
an index event and three patients (<1%) were registered
twice. Thus, 932 patients assigned to the dual therapy
group and 947 patients assigned to the monotherapy
group were included in the intention-to-treat analysis.
Regarding conditions indicating a high risk of strokerecurrence, 547 (29%) of 1879 patients had at least
50% stenosis of a major intracranial artery, 253 (13%) of1879 patients had at least 50% stenosis of an extracranialartery, and 1698 (90%) of 1879 patients had two or morerisk factors (table 1). At randomisation and before
enrolment into the study, clopidogrel was being taken by1116 (59%) of 1879 patients; 59 (5%) of these 1116 patientswere taking clopidogrel 50 mg once per day, and theremaining 1057 (95%) were taking clopidogrel 75 mg
once per day (table 1; appendix). Characteristics atbaseline are shown in table 1. The median time fromthe qualifying stroke to randomisation was 26 days
(IQR 13–62).
The median duration of follow-up was 1·4 years over­all (IQR 0·6–2·2), resulting in 2724·1 patient-years offollow-up. The median duration of follow-up in the dual
therapy group was 1·4 years (IQR 0·8–2·2), resulting in
1316·4 patient-years of follow-up, and the median durationof follow-up in the monotherapy group was 1·4 years (IQR
0·5–2·2), resulting in 1408·1 patient-years of follow-up.
544

Discontinuation of follow-up within 6 months for rea­sons other than development of major events occurredin 215 (23%) of 932 patients in the dual therapy groupand 134 (14%) of 947 patients in the monother­apy group (figure 1). These 349 patients were older (mean70·5 years, SD 8·9, vs 69·4 years, SD 9·2), and lesscommonly had dyslipidaemia (43% vs 57%) and two or
more risk factors (82% vs 92%) than the remaining
1530 patients. Of these, 91 patients in the dual therapy
group and 33 patients in the monotherapy group dis­continued trial drugs. Reasons for the discontinuation of
trial drugs are shown in table 2. Palpitations or tachycardia(24 patients), headache (five patients), and both palpitations
or tachycardia and headache (four patients) were common
reasons for the discontinuation of trial drugs, events
that were only recorded in the dual therapy group(33 [4%] of 932).
Systolic blood pressure (SBP) is shown in the appendix.
The dual therapy group had SBP levels that were
2–4 mm Hg lower than the monotherapy group through­out the follow-up period (p=0·29).
The primary efficacy outcome of ischaemic stroke
occurred in 29 (3%) of 932 patients (2·2 events per
100 person-years) during follow-up in the dual therapy
group and in 64 (7%) of 947 patients (4·5 events per
100 person-years) in the monotherapy group (HR 0·49;
95% CI 0·31–0·76; p=0·0010; table 3 and figure 2A).
The numbers needed to prevent ischaemic stroke were43 (95% CI 27–103). The secondary efficacy outcome ofany stroke was lower in the dual therapy group (34 [4%] of
932 patients than in the monotherapy group (71 [7%] of
947 patients; table 3). Haemorrhagic stroke occurred infive (1%) of 932 patients in the dual therapy group andin seven (1%) of 947 patients in the monotherapy groupwww.thelancet.com/neurology Vol 18 June 2019

ArticlesA

Patients with event (%)

25

Monotherapy

15
11·4
10
4·7

5

0

183

366

548

731

913

1096

1278

1461

932
(226)
947
(150)

691
(109)
764
(124)

576
(159)
628
(193)

411
(134)
426
(138)

276
(121)
283
(129)

154
(79)
152
(70)

75
(50)
79
(57)

25
(25)
22
(22)

0
(0)
0
(0)

B
HR 0·52 (95% CI 0·35–0·77)
p=0·0008

25

15
10
6·2
5
0

Number at risk
(number censored)
Dual therapy
Monotherapy

0

183

366

548

731

913

1096

1278

1461

932
(220)
947
(146)

691
(109)
764
(121)

576
(158)
628
(190)

411
(132)
426
(136)

276
(121)
283
(128)

154
(79)
152
(70)

75
(50)
79
(56)

25
(25)
22
(22)

0
(0)
0
(0)

25
Patients with event (%)

C

In this multicentre RCT of secondary stroke prevention
in patients with high-risk non-cardioembolic ischaemic
stroke, the recurrence of ischaemic stroke was lesscommon with long-term dual therapy with cilostazol plus
aspirin or clopidogrel than with long-term monotherapy
with aspirin or clopidogrel alone. We found no evidenceof a higher risk of severe or life-threatening bleeding withdual antiplatelet therapy than with monotherapy.
Addition of cilostazol to single antiplatelet therapy
almost halved the incidence rates of recurrent ischaemic
stroke, any stroke, ischaemic stroke or transient ischaemic
attack, a composite of stroke, myocardial infarction, andvascular death, and all vascular events. Given that the rate
reduction was strong compared with our estimate (30%),26
positive effects of dual therapy on efficacy outcomes wereshown despite the smaller-than-planned sample size. The
majority of the enrolled patients (59%) were taking
clopidogrel, and the addition of cilostazol to clopidogrel
reduced the rate of recurrent ischaemic stroke by 55% inthis cohort. Such a beneficial effect for patients receiving

Monotherapy

HR 0·66 (95% CI 0·27–1·60)
p=0·3539

20
15
10
5
0

Number at risk
(number censored)
Dual therapy

21·4

20

Discussion

www.thelancet.com/neurology Vol 18 June 2019

Dual therapy
Monotherapy
HR 0·49 (95% CI 0·31–0·76)
p=0·0010

200Number at risk
(number censored)
Dual therapy

Patients with event (%)(table 3). A composite of stroke, myocardial infarction,and vascular death occurred in 38 (4%) of 932 patients inthe dual therapy group and in 78 (8%) of 947 patientsin the monotherapy group (table 3 and figure 2B). Other
secondary outcomes are reported in table 3. We observed
no significant treatment-by-subgroup interactions among
the prespecified subgroups (appendix).
In the as-treated (per-protocol) analysis, ischaemic stroke
occurred in 28 (3%) of 910 patients (annualised rate 2·1%)
in the dual therapy group and in 62 (7%) of 921 patients(annualised rate 4·4%) in the monotherapy group(HR 0·49, 95% CI 0·31–0·76, p=0·0010; appendix).
Severe or life-threatening bleeding occurred ineight (1%) of 910 patients (annualised rate 0·6%) duringfollow-up in the dual therapy group and in 13 (1%) of
921 patients (0·9 events per 100-person years) in themonotherapy group (table 3 and figure 2C). All of these
21 events were intracranial haemorrhage events.
Any type of adverse event occurred in 255 (28%) of
910 patients during follow-up in the dual therapy groupand in 219 (24%) of 921 patients in the monotherapy group.
Non-serious adverse events were also recorded, althoughthese events occurred only in the dual therapy group;
26 patients developed headache, 33 developed palpitations,and 26 developed tachycardia (table 4 and appendix).
Serious adverse events occurred in 87 (10%) of 910 patientsin the dual therapy group and in 142 (15%) of 921 patientsin the monotherapy group (p=0·00017; appendix). Bleed­ing events occurred in 38 (4%) of 910 patients in the dual
therapy group and in 33 (4%) of 921 patients in themonotherapy group (p=0·55; appendix). Gastrointestinal
bleed­ing, which affected nine (<1%) of 910 patients in themonotherapy group and nine (<1%) of 921 patients inthe dual therapy group, was the most common type of
bleeding.

2·7
2·0
0

183

366

548

731

913

1096

1278

1461

75
(50)
79
(57)

25
(25)
22
(22)

0
(0)
0
(0)

Days since start of observations
932
(235)
947
(178)

691
(115)
764
(134)

576
(164)
628
(200)

411
(135)
426
(141)

276
(122)
283
(129)

154
(78)
152
(73)

Figure 2: Kaplan-Meier analysis of outcomes
The Kaplan-Meier curves for the time to the first event of the primary efficacy outcome, defined as ischaemic stroke(A), that of the secondary efficacy outcome of a composite of stroke, myocardial infarction, and vascular death (B),and that of the safety outcome of severe or life-threatening bleeding (C) are shown. Data are from theintention-to-treat analysis. HR=hazard ratio.

545

Articles

Number of patients in dual therapy group (n=910)

Number of patients in monotherapy group (n=921)

MildModerate

SevereMild

Moderate

SevereTotal

138 (15%)83 (9%)

34 (4%)

86 (9%)103 (11%)30 (3%)

Nervous system disorders

41 (5%)

36 (4%)

6 (1%)

39 (4%)

42 (5%)

10 (1%)

Cerebral infarction

15 (2%)

18 (2%)

3 (<1%)

28 (3%)

30 (3%)

5 (1%)Headache16 (2%)

9 (1%)

1 (<1%)

0

0

0

Transient ischaemic attack

1 (<1%)

2 (<1%)

0

3 (<1%)

3 (<1%)

056 (6%)

12 (1%)

10 (1%)

5 (1%)

6 (1%)

6 (1%)

Palpitations

27 (3%)

4 (<1%)

2 (<1%)

000Tachycardia

22 (2%)

4 (<1%)

0

0

0

0

21 (2%)

6 (1%)0

8 (1%)

12 (1%)

1 (<1%)

10 (1%)

2 (<1%)

0

0

0

0

Infections and infestations

7 (1%)

4 (<1%)

5 (1%)

7 (1%)

9 (1%)

4 (<1%)

Injury, poisoning, and procedural complications

4 (<1%)

3 (<1%)

6 (1%)

7 (1%)

9 (1%)

1 (<1%)

Benign, malignant, and unspecified neoplasms(including cysts and polyps)

1 (<1%)

10 (1%)

5 (1%)

3 (<1%)

5 (1%)

4 (<1%)

Skin and subcutaneous tissue disorders

13 (1%)

2 (<1%)0

7 (1%)

5 (1%)

0

Cardiac disorders

Gastrointestinal disorders
Diarrhoea

Only adverse events with greater than 1% incidence are presented. Severity of adverse events are classified into three levels: mild, causing discomfort but no interference withdaily activities; moderate, causing discomfort that is sufficient to restrict or affect daily activities; and severe, cannot perform work or daily activities.

Table 4: Adverse events according to severity

clopidogrel seemed to provide more substantial rate
reduction in patients overall.
The efficacy outcomes for ischaemic events weregenerally identical between monotherapy and dual
therapy during the initial 100 days, and they showedintergroup differences thereafter. The comparably favour­
able effect of monotherapy in the early days partly
coincides with pooled data from randomised trials
showing that the absolute risk of recurrent ischaemic
stroke decreased gradually, with no reduction after
12 weeks with aspirin alone compared with the control.21
As a pleiotropic effect, other than its antiplatelet effect,cilostazol combined with aspirin prevented stenosis
progression after ischaemic stroke with intracranialarterial atherosclerosis and reduced restenosis after
coronary stenting compared with aspirin alone,22,28
although the change in arterial stenosis during the followup period was not assessed in this trial. Cilostazol has
been reported to reduce the intima-media thickness anddecrease lipid and necrotic components in the carotid
plaque.29 The divergence of the efficacy event curves
during the long-term chronic stage after stroke also
appeared in the European and Australasian Stroke Pre­vention in Reversible Ischaemia Trial,30 an RCT thatcompared the combination of dipyridamole plus aspirinwith aspirin monotherapy for the secondary prevention of
stroke of presumed arterial origin. A meta-analysis
including this trial showed that adding dipyridamole toaspirin reduced the risk of recurrent ischaemic stroke
only after 12 weeks.21 Additionally, the combination of
dipyridamole plus aspirin for patients with stroke showeda somewhat lower risk of recurrent stroke than clopidogrelmonotherapy after around 3 years of treatment in thePrevention Regimen for Effectively Avoiding Second
546

Strokes trial.31 These findings suggest that phospho­
diesterase inhibitors, including cilostazol and dipyrida­mole, prevented stroke via long-lasting mechanisms, suchas vasoprotection and anti-atherogenic activity.
The mild reduction of systolic blood pressure duringfollow-up on dual therapy might be protective against
stroke recurrence. Vasodilation, suppression of angio­
tensin 2-induced hypertensive endothelial dysfunction,and other effects of cilostazol might influence bloodpressure.32
The incidence of severe or life-threatening bleeding as acore safety outcome was almost the same over 1 year
between the two groups, although their low incidences
might weaken statistical power. This finding is com­patible
with previous reports on mono, dual, or triple antiplatelet
therapy involving cilostazol, showing that cilostazol did
not increase bleeding compared to pharma­
cotherapy
without cilostazol.18,19,22–25 Thus, dual medication involving
cilostazol is effective and safe during the chronic stage of
non-cardioembolic ischaemic stroke or transient ischaemic
attack; during this stage, guidelines do not recommend
taking the combination of aspirin and clopidogrel.
A strength of this trial is that MRI with angiography
was routinely done to identify infarct distribution and for
intracranial vascular imaging. The widespread presenceof MRI devices in Japan enabled us to set its performanceas an indispensable inclusion criterion without missing
many patients. The second strength was the combina­
tion of a thienopyridine with cilostazol compared withthienopyridine monotherapy in an RCT in a large popu­
lation for the first time, to our knowledge. Care should
be taken in interpreting this comparison because thiswas a prespecified subgroup analysis without significant
treatment-by-subgroup interactions.
www.thelancet.com/neurology Vol 18 June 2019

Articles

The limitations of this trial include that the number ofenrolled patients was only 47% of the planned number.
Use of health insurance to cover the costs of trial drugs
instead of free-of-charge provision from a manufacturer,
in addition to prohibiting the use of generic cilostazol
products that were much cheaper than the brand-namedrug, was a possible reason for the delay in recruiting
patients, which might weaken statistical power for theprespecified subgroups. This cost issue could also be themain reason for the high numbers of consent withdrawals
in the dual therapy group.
Another limitation was that patients developing the
primary efficacy outcomes were few (93 patients), giventhat the trial was stopped before reaching half of theplanned sample size, although the annual event rate (5%)
was similar to the estimated event rate (4%). The few
primary efficacy events could reduce statistical accuracy.
Additionally, the trial treatment was not masked. Thus, thetrial investigators were aware of the study drug allocation.
Generalisability of the present findings to other coun­tries is uncertain because the ethnicity was limited toJapanese people within this trial, although differences in
the pharmacokinetics of cilostazol among ethnicities
have not been suggested.
Furthermore, discontinuation of trial medication within
6 months occurred in the dual therapy group three times
as frequently as in the monotherapy group. Occurrenceof headache and palpitations, which are known early sideeffects of cilostazol,13 was partly the cause of the difference.
Discontinuation of cilostazol because of headache,
palpitations, or tachycardia (3·5%) was less than half as
common in patients assigned to receive cilostazol in the
CSPS2 trial.17 Optional choice of cilostazol 100 mg once
per day during the initial 15 days in the present trial
seemed to decrease early side-effects.
In conclusion, for secondary prevention in patientswith stroke at high-risk for stroke recurrence, long-term
treatment with a combination of cilostazol with aspirin or
clopidogrel had a lower rate of ischaemic stroke and otherefficacy endpoints, including stroke or vascular events,
and a similar risk of severe or life-threatening bleed­ing
than long-term treatment with aspirin or clopidogrel
alone. Addition of cilostazol to aspirin or clopidogrel
seems to be a pharmacotherapeutic regimen that could
be recommended in the chronic stage of high-risk
non-cardioembolic ischaemic stroke for patients who
can tolerate the early side-effects of cilostazol, such as
palpitations and headache.
Contributors
All authors, except JDE, were involved in the design and execution of the
Cilostazol Stroke Prevention Study for Antiplatelet Combination(CSPS.com) trial. KaT wrote the first draft of the manuscript andprovided tables, figures, and references. SU had a central role in revising
the first draft of the manuscript. TY supervised the trial. All otherauthors edited the manuscript and approved the final draft.
Declaration of interests
The CSPS.com trial was conducted under a trial contract between theconsignee, Japan Cardiovascular Research Foundation, and the

www.thelancet.com/neurology Vol 18 June 2019consignor, Otsuka Pharmaceutical. The Japan Cardiovascular Research
Foundation received funding for trial implementation and managementfrom Otsuka Pharmaceutical. Participating members, including theauthors and each committee member, received scientific consultancy
fees for trial design and management, depending on their roles.
KaT reports personal fees from Otsuka Pharmaceutical and Bayer
Yakuhin outside the submitted work. SU reports grants and personal
fees from Bayer, Boehringer Ingelheim, Daiichi Sankyo, Sanofi, Otsuka,
Takeda, AstraZeneca, Dainippon Sumitomo, Mitsubishi Tanabe,
Shionogi, Astellas Amgen, Bristol-Myers Squibb, and the Japan
Cardiovascular Foundation outside the submitted work. JDE reports
grants from the US National Institutes of Health (National Institutes of
Health and National Institute of Neurological Disorders and Stroke) andpersonal fees from Boehringer Ingelheim outside the submitted work.
KK reports personal fees from Bayer Yakuhin outside the submitted
work. HH reports personal fees from Otsuka Pharmacertical outside
the submitted work and speaker’s fees from Nippon Boehringer
Ingelheim, Bayer Yakuhin, Bristol-Meyers Squibb, Daichi Sankyo,
Pfizer Japan, and Sanofi KK. NK reports personal fees from Otsuka
Pharmaceutical outside the submitted work and personal fees
(honoraria for lecture presentations) from Bayer Yakuhin and Daiichi
Sankyo. YO reports personal fees (honoraria for lecture presentations)from Otsuka, Daiichi Sankyo, Pfizer, Bristol Myers-Squibb, Bayer, andBoehringer Ingelheim, outside the submitted work. KM reports
personal fees from Otsuka Pharmaceutical outside the submitted work,and personal fees (honoraria for seminar presentations) and other fees
(advisory board) from Bayer Yakuhin. All other authors declare nocompeting interests.
Data sharing
Deidentified individual participant data and the study protocol areavailable upon request to koubo@jcvrf.jp, only if the request is intended
to contribute to the improvement of people’s health and welfare.
Researchers can request data disclosure between 18 months and
36 months following the publication of the Article. Only the researchers
who requested disclosure are entitled to use the data and only in a way
consistent with the principle of safeguarding study participants’ privacy
and the provisions of informed consent.
References
Rothwell PM, Eliasziw M, Gutnikov SA, et al. Analysis of pooled1data from the randomised controlled trials of endarterectomy for
symptomatic carotid stenosis. Lancet 2003; 361: 107–16.
2
Derdeyn CP, Chimowitz MI, Lynn MJ, et al. Aggressive medical
treatment with or without stenting in high-risk patients withintracranial artery stenosis (SAMMPRIS): the final results of arandomised trial. Lancet 2014; 383: 333–41.
3Diener HC, Ringleb PA, Savi P. Clopidogrel for the secondary
prevention of stroke. Expert Opin Pharmacother 2005; 6: 755–64.
4
Kamouchi M, Kumagai N, Okada Y, Origasa H, Yamaguchi T,
Kitazono T. Risk score for predicting recurrence in patients withischemic stroke: the Fukuoka stroke risk score for Japanese.
Cerebrovasc Dis 2012; 34: 351–57.
5
Johnston SC, Amarenco P, Albers GW, et al. Ticagrelor versus
aspirin in acute stroke or transient ischemic attack. N Engl J Med
2016; 375: 35–43.
6
Ogawa A, Toyoda K, Kitagawa K, et al. Comparison of prasugrel andclopidogrel in patients with non-cardioembolic ischaemic stroke:
the PRASTRO-I randomised trial. Lancet Neurol 2019; 18: 238–47.
7Wang Y, Wang Y, Zhao X, et al. Clopidogrel with aspirin in acuteminor stroke or transient ischemic attack. N Engl J Med 2013;
369: 11–19.
8
Johnston SC, Easton JD, Farrant M, et al. Clopidogrel and aspirin in
acute ischemic stroke and high-risk TIA. N Engl J Med 2018;
379: 215–25.
9Diener HC, Bogousslavsky J, Brass LM, et al. Aspirin andclopidogrel compared with clopidogrel alone after recent ischaemic
stroke or transient ischaemic attack in high-risk patients(MATCH): randomised, double-blind, placebo-controlled trial.
Lancet 2004; 364: 331–37.
10 Bhatt DL, Fox KA, Hacke W, et al. Clopidogrel and aspirin versus
aspirin alone for the prevention of atherothrombotic events.
N Engl J Med 2006; 354: 1706–17.

547

Articles

11
12

13

14

15

16
17

18

19
20
21

548

The SPS 3 Investigators. Effects of clopidogrel added to aspirin inpatients with recent lacunar stroke. N Engl J Med 2012; 367: 817–25.
Lee M, Saver JL, Hong KS, Rao NM, Wu YL, Ovbiagele B.
Risk-benefit profile of long-term dual- versus single-antiplatelet
therapy among patients with ischemic stroke: a systematic review
and meta-analysis. Ann Intern Med 2013; 159: 463–70.
Eikelboom JW, Hirsh J, Spencer FA, Baglin TP, Weitz JI.
Antiplatelet drugs: antithrombotic therapy and prevention ofthrombosis, 9th ed: American College of Chest Physicians
evidence-based clinical practice guidelines. Chest 2012;
141 (suppl 2): e89S–119S.
Kasahara Y, Nakagomi T, Matsuyama T, Stern D, Taguchi A.
Cilostazol reduces the risk of hemorrhagic infarction afteradministration of tissue-type plasminogen activator in a murine
stroke model. Stroke 2012; 43: 499–506.
Wilhite DB, Comerota AJ, Schmieder FA, Throm RC, Gaughan JP,
Rao AK. Managing PAD with multiple platelet inhibitors: the effectof combination therapy on bleeding time. J Vasc Surg 2003;
38: 710–13.
Gotoh F, Tohgi H, Hirai S, et al. Cilostazol stroke prevention study:a placebo-controlled double-blind trial for secondary prevention of
cerebral infarction. J Stroke Cerebrovasc Dis 2000; 9: 147–57.
Shinohara Y, Katayama Y, Uchiyama S, 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.
Uchiyama S, Demaerschalk BM, Goto S, et al. Stroke prevention bycilostazol in patients with atherothrombosis: meta-analysis ofplacebo-controlled randomized trials. J Stroke Cerebrovasc Dis 2009;
18: 482–90.
Dinicolantonio JJ, Lavie CJ, Fares H, et al. Meta-analysis ofcilostazol versus aspirin for the secondary prevention of stroke.
Am J Cardiol 2013; 112: 1230–34.
Working Group from the Japan Stroke Society. Japanese Guidelines
for the Management of Stroke 2015, update 2017. Tokyo; Kyowa
Kikaku, 2017 (in Japanese).
Rothwell PM, Algra A, Chen Z, Diener HC, Norrving B, Mehta Z.
Effects of aspirin on risk and severity of early recurrent stroke after
transient ischaemic attack and ischaemic stroke: time-course
analysis of randomised trials. Lancet 2016; 388: 365–75.

22

23
24
25

26

27
28
29
30

31
32

Kwon SU, Cho YJ, Koo JS, et al. Cilostazol prevents the progressionof the symptomatic intracranial arterial stenosis: the multicenter
double-blind placebo-controlled trial of cilostazol in symptomatic
intracranial arterial stenosis. Stroke 2005; 36: 782–86.
Kwon SU, Hong KS, Kang DW, et al. Efficacy and safety of
combination antiplatelet therapies in patients with symptomatic
intracranial atherosclerotic stenosis. Stroke 2011; 42: 2883–90.
Uchiyama S, Sakai N, Toi S, et al. Final results of Cilostazol-Aspirin
Therapy against Recurrent Stroke with Intracranial Artery Stenosis(CATHARSIS). Cerebrovasc Dis Extra 2015; 5: 1–13.
Sakurai R, Koo BK, Kaneda H, Bonneau HN, Nagai R.
Cilostazol added to aspirin and clopidogrel reduces
revascularization without increases in major adverse events inpatients with drug-eluting stents: a meta-analysis of randomized
controlled trials. Int J Cardiol 2013; 167: 2250–58.
Toyoda K, Uchiyama S, Hoshino H, et al. Protocol for Cilostazol
Stroke Prevention Study for Antiplatelet Combination (CSPS.com):a randomized, open-label, parallel-group trial. Int J Stroke 2015;
10: 253–58.
The GUSTO investigators. An international randomized trial
comparing four thrombolytic strategies for acute myocardial
infarction. N Engl J Med 1993; 329: 673–82.
Douglas JS Jr, Holmes DR Jr, Kereiakes DJ, et al. Coronary stentrestenosis in patients treated with cilostazol. Circulation 2005;
112: 2826–32.
Yamaguchi Oura M, Sasaki M, et al. Carotid plaque characteristics
on magnetic resonance plaque imaging following long-term
cilostazol therapy. J Stroke Cerebrovasc Dis 2014; 23: 2425–30.
ESPRIT Study Group, Halkes PH, van Gijn J, Kappelle LJ,
Koudstaal PJ, Algra A. Aspirin plus dipyridamole versus aspirinalone after cerebral ischaemia of arterial origin (ESPRIT):
randomised controlled trial. Lancet 2006; 367: 1665–73.
Sacco RL, Diener HC, Yusuf S, et al. Aspirin and extended-release
dipyridamole versus clopidogrel for recurrent stroke. N Engl J Med
2008; 359: 1238–51.
Shi MQ, Su FF, Xu X, et al. Cilostazol suppresses angiotensin
II-induced apoptosis in endothelial cells. Mol Med Rep 2016;
13: 2597–605.

www.thelancet.com/neurology Vol 18 June 2019