#28-Tanahashi
ASENT 13th Annual Meeting
Mega Clinical Studies
- Lessons from CSPS2 -
Norio Tanahashi
Saitama Medical University
International Medical Center，
Japan
#28-Tanahashi
Background
 The efficacy of aspirin and other antiplatelets in
secondary prevention of cerebral infarction has
been demonstrated in various studies and metaanalyses, mostly conducted in the US and EU.
 A significant reduction in risk of recurrence of
cerebral infarction for cilostazol compared with
placebo was demonstrated in the Cilostazol
Stroke Prevention Study （CSPS）
 Cilostazol Stroke Prevention StudyⅡ （CSPSⅡ） is
the first, long-term, large-scale, phase4 clinical
trial in Japan.
#28-Tanahashi
#28-Tanahashi
Treatment strategy for
atherothrombotic cerebral infarction
Cilostazol
Improvement of endothelial
Antiplatelet
Vasodilation
function
Antiplatelet
Improvement
of
Anti-atherosclerosis
endothelial function
Vasodilation
Anti-atherosclerosis
#28-Tanahashi
Cilostazol is Superior to Aspirin for
Secondary Stroke Prevention：
Results of
CSPSⅡ
Multi-center, randomized, prospective, double-blind, active-controlled,
parallel-group comparative study
in Japan
#28-Tanahashi
Outline of study plan
 Objective：This study was designed to investigate
whether cilostazol is superior to aspirin in
secondary prevention of cerebral infarction in stroke
patients in Japan.
 Number of participants：1300 in each group,
for a total of 2600
 Number of study institutions：294
 Study period：5 years,
（December 2003 to December 2008）
#28-Tanahashi
Study design
Multi-center, randomized, double-blind, active-controlled, parallel-group,
comparative study
1300
Cilostazol 200mg
R
Duration of treatment: 1–5 years
Study period：December 2003-December 2008
Aspirin 81mg
1300
Primary endpoint：Occurrence of stroke
(cerebral infarction, cerebral hemorrhage, or subarachnoid hemorrhage)
#28-Tanahashi
Main inclusion and exclusion criteria
Main inclusion criteria
 Patients in stable condition within 182 days （26 weeks） of
occurrence of cerebral infarction
 Patients with infarct-related foci detected by x-ray CT scan or MRI
 Patients aged 20-80 years （inclusive） at time of consent
 Patients having no cardiac diseases possibly associated with
cardiogenic cerebral embolism
Main exclusion criteria






Patients with hemorrhage or bleeding tendency
Patients with ischemic heart failure
Patients with peptic ulcer
Patients with severe blood disorders
Patients with severe hepatic or renal disorders
Patients with malignant neoplasm or who have received any therapy
for malignant neoplasm within 5 years prior to study enrollment
#28-Tanahashi
Criteria for Evaluation
Primary endpoint
 Occurrence of stroke （cerebral infarction, cerebral hemorrhage, or
subarachnoid hemorrhage） during the treatment period
Secondary endpoints
 Recurrence of cerebral infarction during the treatment period
 Occurrence of ischemic cerebrovascular diseases （cerebral
infarction or TIA） during the treatment period
 Occurrence of all-cause death during the treatment period
 Occurrence of cerebral stroke, TIA, angina pectoris, myocardial
infarction, cardiac failure, or hemorrhage requiring hospitalization
during the treatment period
#28-Tanahashi
Patients characteristics1
Cilostazol
（ｎ=1337）
959 （71.7）
Aspirin
（ｎ=1335）
957 （71.7）
Age* （Yr）
63.5±9.2
63.4±9.0
0.76
BMI* （kg/m2）
24.0±3.1
23.9±3.1
0.54
Male sex - n （％）
Stroke subtypes - n （％）
Atherothrombotic
Lacunar
Undetermined
Days after onset - n （％）
- 28 days
29-56 days
57-112 days
113 -< days
P value
0.98
0.57
435 （32.5）
869 （65.0）
33 （2.5）
420 （31.5）
874 （65.5）
41 （3.1）
0.35
414
354
343
226
（31.0）
（26.5）
（25.7）
（16.9）
419
338
320
258
（31.4）
（25.3）
（24.0）
（19.3）
＊ Mean±SD
#28-Tanahashi
Patients characteristics 2
Cilostazol
（n=1337）
Aspirin
（n=1335）
Severity at baseline
（Classification by Modified Rankin Scale） n （％）
Grade
Grade
Grade
Grade
Grade
Grade
0
1
2
3
4
5
207
612
406
73
39
0
（15.5）
（45.8）
（30.4）
（5.5）
（2.9）
（0.0）
P value
0.55
186
613
432
69
35
0
（13.9）
（45.9）
（32.4）
（5.2）
（2.6）
（0.0）
Smoking - n （％）
385 （28.8）
403 （30.2）
0.43
Alcohol intake - n （％）
640 （47.9）
624 （46.7）
0.56
991
18
393
599
0.10
0.47
0.19
0.62
0.12
Complications - n （％）
Hypertension
Ischemic heart disease
Diabetes mellitus
Dyslipidemia
976
11
382
560
（73.0）
（0.8）
（28.6）
（41.9）
（74.2）
（1.3）
（29.4）
（44.9）
＊ Mean±SD
#28-Tanahashi
Concomitant medications
Cilostazol
（ｎ=1337）
Antihypertensive agents
ARB
Ca antagonists
ACE inhibitors
900
617
627
111
（67.3）
（46.1）
（46.9）
（8.3）
Aspirin
（n=1335）
999
723
753
121
（74.8）
（54.2）
（56.4）
（9.1）
Lipid-lowering agents
Statins
401 （30.0）
362 （27.1）
452 （33.9）
402 （30.1）
Antidiabetic agents
271 （20.3）
278 （20.8）
Digestive agents
863 （64.5）
908 （68.0）
n （％）
#28-Tanahashi
Primary and secondary endpoint
Cilostazol
（n＝1337）
Aspirin
（n＝1335）
No of patients （％）
【Efficacy end point】
Cilostazol better
0
0.5
Primary endpoint
Stroke （Cerebral infarction, cerebral
hemorrhage, subarachnoid
hemorrhage）
Hazard ratio
（95% confidence interval）
82 （2.76）
119 （3.71）
Cerebral infarction
72 （2.43）
88 （2.75）
Ischemic cerebrovascular disorder
（Cerebral infarction, TIA）
86 （2.90）
103 （3.21）
Death from any cause
13 （0.42）
13 （0.39）
Composite secondary end point*
138 （4.66）
186 （5.81）
1
Hazard ratio
Log-rank test
P value
0.74
（0.56-0.98）
0.04
Aspirin better
1.5
2.0
2.5
Secondary end point
0.88
（0.65-1.20）
0.90
（0.68-1.19）
1.07
（0.50-2.31）
0.80
（0.64-0.99）
0.42
0.46
0.86
0.04
【Safety end point】
Bleeding events （cerebral
0.46
hemorrhage,
23 （0.77）
57 （1.78）
＜0.001
subarachnoid hemorrhage, bleeding
（0.30-0.71）
requiring hospitalization）
* Cerebral infarction, cerebral hemorrhage, subarachnoid hemorrhage, TIA, angina pectoris, myocardial infarction, cardiac failure or
hemorrhage requiring hospitalization, death
#28-Tanahashi
Primary end point：Occurrence of stroke （cerebral
infarction, cerebral hemorrhage, or subarachnoid hemorrhage）
（％）
Cumulative incidence
15
n
Estimate
No of
occurrence Incidence /year
Cilostazol
1337
82
2.76%
Aspirin
1335
119
3.71%
Aspirin
10
Cilostazol
5
P=0.0357
Log-rank test
RRR=25.7％
0
0
100
200
300
400
500
600
700
800
900 1000 1100 1200 1300 1400 1500 1600 1700
Days after randomization
No. at Risk
Cilostazol
1337 1137
1063
1031
989
941
896
864
788
686
570
450
331
227
135
68
29
8
Aspirin
1335 1227
1148
1089
1046
1005
967
926
837
750
628
509
377
255
152
75
33
7
#28-Tanahashi
Occurrence of cerebral stroke, TIA, angina pectoris,
myocardial infarction, cardiac failure, or hemorrhage
requiring hospitalization
（％）
25
Cumulative incidence
Estimate
No of
occurrences Incidence /year
n
Cilostazol
1337
138
4.66%
Aspirin
1335
186
5.81%
20
Aspirin
15
Cilostazol
10
P=0.0437
Log-rank test
RRR=20.1％
5
0
0
100
200
300
400
500
600
700
800
900 1000 1100 1200 1300 1400 1500 1600 1700
Days after randomization
No. at Risk
Cilostazol
1337 1136
1062
1031
987
941
896
863
787
686
569
449
331
227
135
68
29
8
Aspirin
1335 1226
1145
1087
1045
1005
966
923
836
750
628
508
376
255
152
75
33
7
#28-Tanahashi
Occurrence of bleeding events （cerebral hemorrhage,
subarachnoid hemorrhage, bleeding requiring
hospitalization）
（％）
Cumulative incidence
10
Estimate
No of
occurrences Incidence /year
n
Cilostazol
1337
23
0.77%
Aspirin
1335
57
1.78%
P=0.0004
Log-rank 検定
RRR=54.2％
Aspirin
5
0
Cilostazol
0
100
200
300
400
500
600
700
800
900 1000 1100 1200 1300 1400 1500 1600 1700
Days after randomization
No. at Risk
Cilostazol
1337 1137
1063
1032
990
942
896
864
788
686
570
451
331
227
135
68
29
8
Aspirin
1335 1227
1149
1090
1047
1006
967
927
836
751
628
509
377
255
152
75
33
7
#28-Tanahashi
Summary of adverse events
Cilostazol
（ｎ=1337）
Aspirin
（ｎ=1335）
P value*
313 （23.4）
217 （16.3）
＜0.001
Diarrhea
164 （12.3）
85 （6.4）
＜0.001
Palpitations
156 （11.7）
71 （5.3）
＜0.001
Dizziness
129 （9.6）
97 （7.3）
0.03
Tachycardia
89 （6.7）
21 （1.6）
＜0.001
Hypertension
120 （9.0）
185 （13.9）
＜0.001
Constipation
110 （8.2）
155 （11.6）
0.003
n （％）
Headache
*：Fisherの正確検定
#28-Tanahashi
Results
• Cilostazol significantly reduced occurrence of stroke
（cerebral infarction, cerebral hemorrhage, or
subarachnoid hemorrhage） compared with aspirin.
（P=0.0357,RRR=25.7％ ）。
• Cilostazol significantly reduced occurrence of cerebral
stroke, TIA, angina pectoris, myocardial infarction,
cardiac failure, or hemorrhage requiring hospitalization
compared with aspirin. （P=0.0437、RRR=20.1％ ）
• Cilostazol significantly reduced occurrence of bleeding
events （cerebral hemorrhage, subarachnoid hemorrhage,
bleeding requiring hospitalization）（P=0.0004、
RRR=54.2％）
#28-Tanahashi
Conclusions
• Cilostazol demonstrated efficacy in
preventing recurrent stroke in patients with
cerebral infarction, with less bleeding
compared to aspirin for the first time.
• Cilostazol is a suitable first option for the
prevention of recurrent stroke.
Occurrence of Stroke
#28-Tanahashi
-CSPS2 Sub analysis（％/person・year）
4.5
4.0
3.5
3.0
4.07
RRR
32%
3.03
2.5
2.0
RRR
25%
Cilostazol
Aspirin
3.06
2.08
1.5
1.0
0.5
0
（n=435）
（n=420）
Atherothrombotic
（n=869）
（n=874）
Lacunar
#28-Tanahashi
Occurrence of Cerebral Infarction
-CSPS2 Sub analysis（％/person・year）
3.5
3.0
2.5
Cilostazol
Aspirin
RRR
28%
2.88
2.69
2.45
2.0
1.5
RRR
7%
1.77
1.0
0.5
0
（n=435）
（n=420）
Atherothrombotic
（n=869）
（n=874）
Lacunar
#28-Tanahashi
Incidence of Hemorrhagic Stroke among Ischemic Stroke Subtypes
CSPS2 sub-analysis
（％/person・year）
1.4
1.2
p=0.0030
Cilostazol
Aspirin
1.20
1.0
0.8
0.6
0.59
0.4
0.2
0
0.31
（n=435）
（n=420）
Atherothrombotic
0.36
（n=869）
（n=874）
Lacunar
#28-Tanahashi
Occurrence of
Intracranial Hemorrhage
Cilostazol group
(%)
Aspirin group
(%)
6
6
P=0.114, log-rank test
Cumulative incidence
Cumulative incidence
P=0.829, log-rank test
4
2
Lacunar infarction
Lacunar infarction
4
2
Atherothrombotic infarction
Atherothrombotic infarction
00
100
200
300
400
500
600
700
800
900
1000 1100 1200 1300 1400
1500 1600 1700
0
1800
0
100
Days after randomization
Stroke subtype
200
300
400
500
600
700
800
900
1000 1100 1200 1300 1400
1500 1600 1700 1800
Days after randomization
Stroke subtype
0
100
200 300 400 500 600 700 800 900 1000 1100 1200 1300 1400 1500 1600 1700 1800
Lacunar
869 741 694 674 648 608 578 558 508 443 373
298
215
151
93
42
15
3
0
Lacunar
874
804
753 710 689 658 632 610 545 488 410
326
242
162
92
46
19
4
0
Atherothrombotic
435 367 341 331 317 310 296 286 262 225 182
141
105
71
41
25
13
4
0
Atherothrombotic
420
389
365 348 328 318 306 290 265 239 197
166
125
87
56
27
13
3
0
No. at risk
0
100 200 300 400 500 600 700 800 900 1000 1100 1200 1300 1400 1500 1600 1700 1800
No. at risk
#28-Tanahashi
Design of S-ACCESS
● Multi-center, double-blind, randomized study conducted in Japan
● Subject : Ischemic stroke patients
Sarpogrelate 100mgTID (n=750)
n=1507
R
1.59 years – mean follow up
Aspirin 81mg / day (n=757)
-Primary Endpoint: Cerebral infarction
-Secondary Endpoint: Clusters of serious vascular events (stroke,
acute coronary syndrome, or vascular event-related death)
Shinohara Y, et al. Stroke 2008; 39: 1827-1833.
#28-Tanahashi
Results of S-ACCESS
(%/person-year)
(%/person-year)
P=0.19
7
1.2
6.1
1.0
6
1
4.9
Incidence
5
0.8
4
0.6
0.6
3
0.4
2
0.2
1
0
0
SPG
ASA
Primary endpoint
Cerebral
infarction
SPG
ASA
Intracranial hemorrhage
Intracranial
hemorrhage
#28-Tanahashi
Design of CAPRIE
● Multi-center, double-blind, randomized study
● Subject : Patients with ischemic stroke, MI, or symptomatic PAD
Clopidogrel 75mg/day 3 (n=9599)
n=19185
R
1.91 years – mean follow up
Aspirin 325mg/day (n=9586)
-Primary Endpoint:
Composite of ischemic stroke, MI, or vascular
death
-Secondary Endpoint: Amputation, vascular death
CAPRIE Steering Committee. Lancet 1996; 348: 1329-1339.
#28-Tanahashi
Results of CAPRIE
P=0.043
(%/person-year)
5.8
6
(%/person-year)
0.5
5.3
5
Incidence
0.4
4
0.3
0.3
3
0.2
0.2
2
0.1
1
0
CLO
ASA
Primary endpoint
Ischemic stroke, MI,
or vascular death
0
CLO
ASA
Intracranial hemorrhage
Intracranial
hemorrhage
#28-Tanahashi
Design of CHARISMA
● Multi-center, double-blind, randomized study
● Subject : Patients with clinically evident vascular disease or
multiple risk factors
n=15603
Clopidogrel 75mg/day + Aspirin 75 162mg/day (n=7802)
R
28 months - median follow up
Aspirin 75 - 162mg/day (n=7801)
-Primary Endpoint:
Composite of MI, stroke or deaths from
cordiovascular causes
-Secondary Endpoint: Composite of MI, stroke, death from
cardiovascular causes, or hospitalization for unstable angina, TIA,
or a revascularization procedure
Bhatt DL, et al. N Engl J Med 2006; 354: 1706-1717.
#28-Tanahashi
Results of CHARISMA
Incidence
(%/person-year)
(%/person-year)
5
0.5
4
0.4
2.9
3.1
3
0.3
2
0.2
0.1
1
0.1
0
0
CLO+ASA
ASA
Primary endpoint
MI, stroke or deaths from
cordiovascular causes
CLO+ASA
0.1
ASA
Intracranial hemorrhage
Intracranial
hemorrhage
#28-Tanahashi
Design of ESPRIT
● Multi-center, double-blind, randomized study
● Subject : TIA or minor stroke
Aspirin 30-325mg/day + Dipyridamole 200mg
BID (n=1363)
n=2739
R
3.5 years – mean follow up
Aspirin 30-325mg/day (n=1376)
-Primary Endpoint:
Composite of death from all vascular causes,
non-fatal stroke, non-fatal MI, or major bleeding
complication
-Secondary Endpoint: Death from all causes, death from all vascular
Causes, death from all vascular causes and non-fatal stroke, all major
ischemic events, all vascular events
The ESPRIT Study Group. Lancet 2006; 367: 1665-1673.
#28-Tanahashi
Results of ESPRIT
(%/person-year)
(%/person-year)
0.5
5
4.5
Incidence
4
0.4
0.4
3.6
0.3
3
0.3
2
0.2
1
0.1
0
ASA+DIP
ASA
Primary endpoint
Death from all vascular causes, non-fatal stroke,
non-fatal MI, or major bleeding complication
0
ASA+DIP
ASA
Intracranial hemorrhage
Intracranial
hemorrhage
#28-Tanahashi
Incidence of Intracranial Hemorrhage
― Western vs. Japan trials －
Trials in Western Population
Trials in Japanese Population
(%/person-year)
(%/person-year)
1.2
1.2
1
1
0.8
0.8
Incidence
1.0
0.9
0.6
0.6
0.6
0.4
0.3
0.4
0.4
0.3
0.3
0.2
0.1
0.1
0.2
0.2
0
0
CLO
ASA
CAPRIE
CLO+ASA
ASA
CHARISMA
ASA+DIP
ESPRIT
ASA
SGT
ASA
S-ACCESS
CLZ
ASA
CSPS 2
Anti Thrombotic Therapy – 2010 Recurrent stroke prevention considering risk/benefit
#28-Tanahashi
Annual incidence of cerebral hemorrhage
in general population
Hisayamacho, Japan
Male
Hisayamacho, Japan
Female
Shibata, Japan
East Asian
Changsha, China
Beijing, China
Shanghai, China
Hispanic
New Mexico, USA
Giessen, Germany
Caucasian
Framingham, USA
Rochester, USA
0
20
40
60
80
100 120 140
Annual incidence of cerebral hemorrhage (/100,000 person)
Modified from Toyoda K.: Drugs, 69, 633-647, 2009
Kazunori Toyoda：Nikkei Medical on-line http://medical.nikkeibp.co.jp/inc/mem/pub/special/att/hcp/rensai/201008/516371.html （as of October 2010)
Ethnic variation in adverse cardiovascular outcomes and bleeding
complications in the Clopidogrel for High Atherothrombotic Risk and
Ischemic Stabilization, Management, and Avoidance (CHARISMA)
study.
Multivariable analysis for bleeding complication: Moderate Bleeding
Ethnic Group
Adjusted HR (95% CI) $
p#
Asians
3.15 (1.09-9.11)
0.034
Blacks
3.78 (1.35-10.60)
0.012
Whites
1.46 (0.63-3.36)
0.377
Hispanics
#: 2-sided log-rank test
$: Cox proportional hazards model
1.00 Referent
NA
Mark KH et al.: Am Heart J. Apr;157(4),658-665,2009
#28-Tanahashi
Mechanism of Cilostazol on less bleeding
Protective Effects of Cilostazol
on Barrier Function of Vasculature
● Inhibition of MMP-9 expression which degrade
peri-vascular matrix
●Improvement of Endothelial Barrier function
PLoS ONE 1 December 2010 , Volume 5 e15178
Pharmacological Research 55 (2007) 104–110
#28-Tanahashi
Summary
• Intracranial hemorrhage was more frequent in S-ACCESS and
CSPS2 compared with the trials conducted in western in the
aspirin group
• Cilostazol decrease Incidence of intracranial hemorrhage
Compared with Aspirin
• In CSPS2, more intracranial hemorrhage was observed in
patients with lacunar infarction compared with those with
atherothrombotic infarction.
• High bleeding tendency in Japanese population might be
attributable to high rate of lacunar patients (＞60%) enrolled
in these trials.
#28-Tanahashi
Conclusion
Japanese population are considered to have
higher bleeding tendency
That ‘s reason why Lacuna infarcton is higher
rate in japanese population
Thus results of western trials may not be
applicable to Japanese population.

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