The role of cilostazol for the treatment of

- The 14th Annual Congress of the ASVS -
Hiroshi Shigematsu, M.D., Ph.D.
Vascular Center, Sanno Medical Center
International University of Health and Welfare
The Role of Cilostazol for the Treatment of
Intermittent Claudication
1831 Boullay
1846 Brodie
1859 Charcot
1898 Erb

Clinical Features in Arteriosclerosis Obliterans
Fontaine II
III
IV I
72％
10.6％
12％
5.4％
5100 cases
（Shigematsu H: Ther Res 13:4009-4019,1992）

Inter-Society Consensus
for the Management of PAD
(2005)
Fate of the Claudicant over Five Years
Natural history of athersclerotic lower extremity PAD syndromes
PAD population (50 years and over)
Initial clinical
presentation
Other leg pain
30-40%
Typical claudication
10-35%
Critical limb ischemia
1-3%
Asymptomatic PAD
20-50%
1-year outcomes
Amputation
30%
Alive with
two limbs
45%
Mortality
25%
5-year outcomes
Functional impairment
Limb morbidity
Worsening
claudication
10-20%
Stable claudication
70-80%
Critical limb
ischemia
5-10%
Amputation
(see CLI data)
CV morbidity and mortality
Mortality
15-30%
Non-fatal cardiovascular
event (MI or stroke) 20%
Non-CV
causes
25%
CV causes
75%
(from ACC/AHA guideline)

Purpose of Medical Therapies
“The Japanese Circulation Society Guidelines for management of Peripheral Arterial Occlusive Disease”.
# To improve ischemic symptoms
# To improve patency for vascular reconstruction
and endovascular treatment
# To prevent systemic vascular event

Overall Treatment Strategy for PAD
Claudication medical therapy
Peripheral Arterial Disease
Improved symptoms
Continue
Symptoms deteriorate
Suspected proximal lesion
Localize the lesion：
-MRA or CTA
-Conventional angiography
Revascularization
-Angioplasty
-Bypass surgery
Risk factor modification：
Smoking cessation
-LDL cholesterol < 100 mg/dL
-HbA1C < 7.0%
-BP < 140/90 mmHg
-BP < 130/80 mmHg if diabetic
or renal disease
Limitation that affects quality of life：
-History of significant exercise
limitation or
-Reduced treadmill performance or
-Reduced function by questionnaire
(TASC II)
No limitation to QOL
Or reduced exercise
Capacity
-monitor patients for
Loss of function

Mean Maximal Walking Distance
using the mean percent change from baseline
Mean （±95％ confidence interval） maximal walking distance by intention-to-treat analysis, using the mean percent change from
baseline. The cilostazol-treated group was significantly different （p＜0.05） at each 4-week point, compared with either the
pentoxifylline- or placebo-treated groups. There were no significant differences at any time point between the pentoxifylline-
treated group and the placebo-treated group.
70
60
50
40
30
20
10
0
4
*
8
*
12
*
16
*
20
*
24
*
Week
Meanpercentchangefrombaseline
（Maximalwalkingdistance）
Cilostazol 100 mg bid
Penotoxifylline 400 mg tid
Placebo
Dowson DL et al: Am J Med 109 523-530 (2000)
n=227
n=232
n=239

Numbers of Patients by Treatment and Dose
in 6 Studies
Flow diagram showing numbers of patients by treatment and dose in six randomized, double-blind, placebo-controlled, Phase 3 trials in patients
treated with cilostazol （CLZ）, pantoxifylline, or placebo. QOL: quality of life. PAD : peripheral Arterial Disease.
*195 patients had no baseline questionnaire.
†151 patients had withdrawn prior to trial completion.
Randomized patients
ｎ=2,252
1 withdrawal
CLZ 50 mg bid
n=303
Intent-to-treat analysis n=1,751*
CLZ 50 mg bid
n=281
Completed trial n=1,600†
CLZ 50 mg bid
n=250
CLZ 100 mg bid
n=821
CLZ 100 mg bid
n=730
CLZ 100 mg bid
n=642
Placebo
n=822
Placebo
n=740
Placebo
n=708
150 mg CLZ bid
n=73
or
Pentoxifylline
n=232
Not included
in sub analysis
Regensteiner JG et al: J Am Geriatr Soc 50 1939-1946 (2002)

Walking Impairment Questionnaire
Score
Baseline Follow-up Absolute change
P-value†
Change
％Meters, Mean±SD
Walking distance
Placebo
29±26
32±27
35±29
43±32
6±25*
11±27* ＜.0001
21
34
Walking speed
Placebo
37±27
39±28
40±27
47±30
3±26*
8±26* ＜.0001
8
21
Stair climbing
Placebo
47±33
49±33
49±33
55±35
2±30
6±28* ＜.0017
4
12
Calf-pain severity
Placebo
38±25
41±24
47±27
55±27
9±28*
15±28* ＜.0001
24
34
*P<.05 compared with baseline value within group.
†P-values for difference in change from baseline to postbaseline in the group taking cilostazol versus the placebo group.
bid: twice a day. Regensteiner JG et al: J Am Geriatr Soc 50 1939-1946 (2002)

Medical Outcomes Study Short Form-36:
Summary Scores
Summary score
Baseline Follow-up
Absolute change P-value†
Change
％Mean±SD
Physical
Placebo
36±10
36±10
36±10
38±10
0
2±9* ＜.0001
0
5
Mental
Placebo
56±9
56±9
56±10
55±10
0
1 .2832
0
2
Note: These scores are normed based on a mean of 50 and SD of 10.
*p<.05 compared with baseline value within group.
†p-values for difference in change from baseline to postbaseline in the group taking cilostazol versus the placebo group.
bid: twice a day.

Medical Outcomes Study Short Form-36:
Physical Subscales
Physical subscale
Baseline Follow-up Absolute change
p-value†
Change
％Mean±SD
Physical function
Placebo
Role limitations, physical problems
Placebo
Bodily pain
Placebo
General health perception
Placebo
51±21
54±21
53±38
54±38
56±22
56±22
58±21
58±21
53±23
59±23
51±39
57±39
56±24
60±24
57±22
58±21
2±19*
5±19*
‐2±39
3±37*
0
4±23*
‐1±15
0.1±15.0
＜.0001
.0013
.0003
.0957
2
9
6
6
0
7
2
0
*p＜.05 compared with baseline value within group.
†p-values for difference in change from baseline to post-baseline in the group taking cilostazol versus the placebo group.
bid: twice a day.

 A 3- to 6-month course to determine efficacy of
cilostazol should be first-line pharmacotherapy
for the relief of claudication symptoms, as
evidence shows both an improvement in
treadmill exercise performance and in quality of
life [A].
 Controlled data also support the efficacy of
naftidrofuryl [A].
(TASC II)
Pharmacotherapy for Symptoms of
Intermittent Claudication

(Dept. of Vasc. Surg., Tokyo Med. Univ.)
ACC/AHA
Guidelines for the Management of PAD
B. MEDICAL AND PHARMACOLOGICAL TREATMENT
FOR CLAUDICATION.-1
CILOSTAZOL.
RECOMMENDATIONS
Class I
1. Cilostazol (100 mg orally 2 times per day) is indicated as an effective
therapy to improve symptoms and increase walking distance in patients
with lower extremity PAD and intermittent claudication (in the absence
of heart failure). (Level of Evidence: A)
2. A therapeutic trial of cilostazol should be considered in all patients with
lifestyle-limiting claudication (in the absence of heart failure). (Level
of Evidence: A)
(Hirsch et al. JACC 47:1239-1312, 2006)

CASTLE
Cilostazol: A Study in Long-term Effects
Kiyomizu temple in Kyoto

Multicenter, randomized, double-blind placebo-controlled, parallel groups, with an
independent Data Monitoring Committee to monitor safety parameters
Design
Pletal
Placebo
Treatment Period
Approximately 3 years
Follow-up period
14 days
Termination
of Drug
Day -30
(Screening)
Placebo
Washout Period
Randomization
to Drug
Day 0
CASTLE
Patient Number: 1439

CASTLE
(Cilostazol: A Study in Long-term Effects)
Objective Evaluate the long-term safety of cilostazol compared
with placebo in patients with IC secondary to PAD
Primary EP All-cause mortality throughout study
Secondary EP Cardiovascular mortality:
-fatal MI, fatal stroke and sudden death
Cardiovascular morbidity:
-coronary, cerebrovascular and peripheral vascular
Study
Population
Randomized 1435 males and females with claudication
Followed 3 years (2 years enrollment)
Exclusion of CHF patients
Estimated 185 deaths in 3 years (annual rate 4.5%)
Actual deaths = 101, study stopped prior to reaching desired
number of events

Concomitant Aspirin and Clopidogrel
Number
Cilostazol
717
Placebo
718
Total
1435
Aspirin
Ave 234 mg (80-650 mg)
527
(73.1%)
503
(70.1%)
1030
(71.6%)
Clopidogrel
Ave 83 mg (38-300 mg)
195
(27.0%)
198
(27.6%)
393
(27.3%)
No interaction between cilostazol and concomitant
use of either aspirin or clopidogrel on bleeding risk

Baseline Demographics
Cilostazol Placebo
Number 717 718
Age 67 66
Male 66% 66%
Smoker 29% 31%
Diabetes 38% 36%
MI 29% 29%
Stroke 10% 11%

Mortality
Cilostazol Placebo
Total deaths 49 52
CV death 14 (1.9%) 14 (1.9%)
MI 6 (0.8%) 5 (0.7%)
Stroke 1 (0.1%) 4 (0.7%)
Sudden 3 (0.2%) 5 (0.3%)
Other 39 (5.4%) 38 (5.4%)
Includes all patients on and off treatment

CASTLE Sub-analysis
CV Events from Investigator Reports
VascularEventRate/year
Cerebrovascular
Events
Cardiac Events
Total Vascular
Events
Placebo （718）Cilostazol （717）
% % %
2.63
4.32
8.56
9.08
10.97
13.40
RRR 40.1%
5
2.5
0
10
5
0
15
7.5
0
p = 0.034 p = 0.605 p = 0.101

Cardiac or
Cerebrovascular
Cardiac
Cerebrovascular
p = 0.018
p = 0.086
p = 0.038
0 21
Cilostazol Better Placebo Better
CASTLE CV Events
Diabetes Subgroup
Hazard ratio （Cilostazol : Placebo） and 95％ confidence interval are
from a Cox proportional hazards model. P-value is from a log-rank test.
Placebo （242）Cilostazol （273）

Adverse and Serious Adverse Events
AE’s Cilostazol Placebo
Palpitations 38 (5.3%) 18 (2.5%)
Diarrhea 78 (10.9%) 48 (6.7%)
Headache
Bleeds
75 (10.5%)
57 (7.9%)
35 (4.9%)
80 (11.1%)
SAE’s
Cerebral
Bleeds
7 (1.0%)
18 (2.5%)
15 (2.1%)
22 (3.1%)

Conclusion of CASTLE Study
• Approximately 1400 (700 cilostazol) patients with
claudication were treated in this controlled trial for 12
months or longer, followed up to 3 years
• CASTLE reconfirms for the safety of the long-term
treatment of IC patients with cilostazol
– No increased risk of cardiovascular morbidity or
mortality
– No increased risk for bleeding, either alone or with
concomitant antiplatelet therapy
– Castle data suggest a risk reduction benefit in
stroke population similar to CSPS

Cilostazol group （n=102）
Non-Cilostazol group（n=102）
log-rank test
P=0.0010
0 10 20 30 40 50 60
Follow-up （months）
Average follow-up period 28±24 months
Primary patency rate of hemodialysis patient after limb PTA
(adjusted by baseline characteristics)
Cilostazol Improves Primary Patency Rate after PTA
in Hemodialysis Patient with PAD
1.0
0.8
0.6
0.4
0.2
0.0
Patencyrate
372 consecutive lesions of 193 hemodialysis patients with PAD after successful PTA. Patients were stratified either to cilostazol group (130
lesions of 71 patients) and non-cilostazol group (242 lesions of 122 patients), and followed for 5 years using Doppler ultrasound or
angiography. To minimize the selection bias for cilostazol administration, a propensity-matched analysis was performed, adjusted by patient
characteristics such as gender (men), age, diabetes, critical limb ischemia (CLI), TASC type for C or D, femoropopliteal lesion and stenting.
Ishii, H., Kumada, Y. et al. : Clin. J. Am. Soc. Nephrol., 3(4), 1034-1040, 2008

Non-Cilostazol group Cilostazol group
COX regression model
Revascularization Limb amputation All cause Death Cardiovascular death
P=0.013
P=0.014 P=0.014 P=0.039
(n=102)(n=102 ) (n=102)(n=102) (n=52) (n=54) (n=52) (n=54)
55.3
34.3
20.7
3.7
37.5
23.7
36.9
8.3
0
20
40
60
80
100
(%) 5-year outcome
Ishii, H., Kumada, Y. et al. : Clin. J. Am. Soc. Nephrol., 3(4), 1034-1040, 2008
Cilostazol Improves Long-Term Prognosis after PTA
in Hemodialysis Patient with PAD
372 consecutive lesions of 193 hemodialysis patients with PAD after successful PTA. Patients were stratified either to cilostazol group (130
lesions of 71 patients) and non-cilostazol group (242 lesions of 122 patients), and followed for 5 years using Doppler ultrasound or
angiography. To minimize the selection bias for cilostazol administration, a propensity-matched analysis was performed, adjusted by patient
characteristics such as gender (men), age, diabetes, critical limb ischemia (CLI), TASC type for C or D, femoropopliteal lesion and stenting.

Cilostazol
Ticlopidine
Months
P=0.013
Log-rank test
0
10
20
30
40
50
60
70
80
90
100
0 12 24 36 48
Patency(%)
64
63
42
54
40
51
32
45
Ticlopidine
Cilostazol
Cilostazol reduces restenosis after envovascular therapy
in patients with femoropopliteal lesions
This study was designed as a prospective,randomized,open-label,blinded end point study in a single institution.Between
March 2004 and June 2005,we randomized 127 patients who were successfully treated with EVT for de novo femoropopliteal
lesions to receive cilostazol(200mg/d,n=63) or ticlopidine(200mg/d,n=64) in addition to aspirin(100mg/d).Antiplatelet
madications were started at least 1 week before EVT and were continued until the end of follow-up.Patency was defined by
duplex ultrasound imaging with peak systolic velocity ratio ＞2.4.
Iida.O. et al.: J. Vasc. Surg., 48(1), 144-149, 2008
All-eventfreesurvival(%)
0
10
20
30
40
50
60
70
80
90
100
P=0.031
Log-rank test
0 12 24 36 48
Months
Cilostazol
Ticlopidine
64
63
39
49
32
45
26
37
87%
65%
82%
60%
73%
51%
77%
60%
72%
50%
60%
41%

Sufficient Treatment Of Peripheral Intervention by Cilostazol（STOP-IC）
STOP-IC
The Sufficient Treatment of Peripheral Intervention by Cilostazol

12-month follow up
Angiography or duplex
n=75
12-month follow up
Angiography or duplex
n=77
A total of 200 patients were enrolled in this study. Nine were excluded before receiving PTA with provisionalnitinol stenting (cilostazol n=7, non-cilostazol n=2
P=0.17), leaving 191 evaluable patients (cilostazol n=93, non-cilostazol n=98). 28 more patients were lost to 12 months follow-up angiography and the remaining 152
patients (80%) completed 12-month angiographic follow-up.
Randomization according to inclusion/exclusion criteria
n=200
12 months Angiography follow-up chart
Cilostazol group
Baseline n=100
Non-Cilostazol group
Baseline n=100
7 patients 2 patients
No indication for endovascular therapy
after angiography assessment (n=9)
Death before 12 months follow-up
(n=11)
- Pneumonia 2
- Sepsis 1
- Lung cancer 1
- Myocardial infarction 2
- Unknown 1
- Pneumonia 2
- Myocardial infarction 1
- Multiple organ failure 1
Lost to 12 months follow-up angiography
(n=28)
Study flow chart
Iida, O. et al.: Circulation, 127(23), 2307-2315, 2013

The angiographic restenosis rate was significantly lower in the cilostazol group than in the non-cilostazol group. Restenosis was
evaluated by angiography (≥50% stenosis). The angiographic restenosis rate was 24% at 12 months in the cilostazol group and 49% in
the non-cilostazol group by ITT analysis (p=0.0001).
Non-Cilostazol Cilostazol
0
20
40
60
80
100
Restenosisrate(%)
OR: 0.26
(95%CI: 0.13, 0.53)
P=0.0001
49%
(38/77)
20%
(18/75)
Twelve-month angiographic restenosis rates following PTA with provisional nitinol stenting for
symptomatic de novo femoropopliteal lesions in the cilostazol group and the non-cilostazol group
(Primary endpoint, ITT analysis)

Restenosis was defined as a peak systolic velocity ratio >2.0. According to ITT analysis, restenosis rates were similar between the
cilostazol and non-cilostazol groups at 3 and 6 months, whereas the restenosis rate was significantly lower in the cilostazol group
at 12 months.
3Mo
0
10
20
30
50
60
Restenosisrate(%)
P=0.006
7%
(6/85)
11%
(9/82)
40
6Mo 12Mo
18%
(15/85)
18%
(15/82)
45%
(38/85)
22%
(18/82)
P=1.00
P=0.73
Non-Cilostazol
Cilostazol
The 12-month restenosis rate evaluated by duplex ultrasound following PTA with provisional nitinol stenting for
symptomatic de novo femoropopliteal lesions in the cilostazol group and the non-cilostazol group
(Secondary endpoint, ITT analysis)

At 12 months, event-free survival was significantly higher in the cilostazol group than in the non-cilostazol group (83% versus 71%; p=0.02).
0 3 6 9 12
Months
0
20
40
60
80
100
Event-FreeSurvival(%)
93
98
90
93
86
85
82
74
60
47
Cilostazol
Non-Cilostazol
Log-rank test p=0.02
Event-free survival (ITT analysis)

PAD Patients Are at
Increased Risk for CV Ischemic Events
PAD* (≥50 years old)
5-year Outcomes
Limb Morbidity
70%–80%
Stable claudication
10%–20%
Worsening claudication
1%–2%
Critical limb ischemia
CV Morbidity
20%
Nonfatal CV event
(MI or stroke)
Mortality
15% to 30%
▪ 75% from CV
causes
* Patients with an initial clinical presentation of asymptomatic PAD, atypical leg pain, or claudication.
Adapted from Hirsch AT et al. Available at: www.acc.org. Accessed March 22, 2006.
Up to 1/3 of PAD patients will
die in 5 years, 75% from CV causes

(2005)
Survival of patients with PAD
100
80
60
40
20
0
Survival(%)
0 5 10 15
Follow up (years)
CLI
IC
Control
(from TASC II)

39.4％
36.9%
14.2%
9.5%
CVD
CAD
PAD
Wattanakit K.,et al., JACC, 45(suppl A), 417A, 2005
－REACH Registry－
Atherothrombosis patients more than
68,00 patients has been registered
Overlap in Vascular Disease Affecting
Different Territories

Polyvascular disease
CAD: 24.8% (22.0% 2 locations; 2.8% 3 locations)
CVD: 40.2% (34.3% 2 locations; 5.9% 3 locations)
PAD: 61.5% (48.0% 2 locations; 13.5% 3 locations)
1
2
3
1
2
3
1
2
3
CAD CVD PAD

One Year Outcome of REACH Registry
0
2
8
10
CV death Non-fatal MI Non-fatal stroke CV death /
MI / stroke
4
6
Symptomatic Disease Locations, No.
None (Multiple Risk Factors Only) (n = 11 587)
1 Location (n = 42 716)
2 Locations (n = 9542)
3 Locations (n = 1132)
One-Year CV Event Rates as a Function
of Number of Symptomatic Disease Locations
Patients,%
All P values <.001. CV indicates cardiovascular; MI, myocardial infarction.
Patients with at least 3 factors but no symptoms are counted as 0, even in the presence of asymptomatic carotid plaque
or reduced ankle brachial index. Error bars represent 95% confidence intervals.
Steg PG et al, JAMA 2007;297(11): 1197-1206.

Cardiovascular deaths（Vascular deaths including CAD, CVD, PAD）
Non fatal myocardial infarction
Non fatal stroke
5.0
4.0
2.0
0
1.44%
1.38%
2.05%
0.99%
3.70%
2.51%
1.29%
1.92%1.93%
n=38,602 n=18,013 n=8,581
3.0
1.0
One-Year CV Event Rates for the Total Population and Main Subsets, Adjusted for Sex and Age
Steg, G. et al.: JAMA, 297, 1197-1206, 2007 ( made from Table 3)
REACH REGISTRY : Reduction of Atherothrombosis for Continued Health
Incidenceofcardiovasculareventin1year,%
Patients with CAD Patients with CVD Patients with PAD
Incidence of Cardiovascular Event in 1 year
in Global Patients (44 countries) with Atherothrombosis
― REACH Registry ―

REACH REGISTRY
Cardiovascular deaths（Vascular deaths including CAD, CVD, PAD）
Non fatal myocardial infarction
Non fatal stroke
S Uchiyama：Jpn J Stroke, 29, 767-770, 2007 (made from Table 2）
Patients with CAD Patients with CVD Patients with PAD
0.84%
1.15%
0.97%
0.46%
2.60%
0.66% 0.66%
2.32%
0.58%
n=2,252 n=1,962 n=603
Incidence of Cardiovascular Event in 1 year
in Japanese Patients with Atherothrombosis ― REACH Registry ―
2.5
2.0
1.0
0
1.5
0.5
Incidenceofcardiovasculareventin1year,%
REACH REGISTRY : Reduction of Atherothrombosis for Continued Health

Effects of Cilostazol on Stroke Prevention
Japanese patients with cerebral infarction
Cilostazol n=526
Placebo n=526
Endpoint: Ischemic stroke
CSPS
J Stroke and Cerebrovasc Dis,. 2000
500
（days）
100
（％）
95
90
85
80
Eventfreerate
Cilostazol
Placebo
Log-rank test：p=0.0150
RRR=41.7%
12000
Cerebral hemorrhage
Cilostazol n=4
Placebo n=7
THE LANCET Neurology. 2008
0.08
0.10
Probabilityofprimaryendpoints
0 300 600
（days）
0.06
0.04
0.02
0.00
Cilostazol
RRR=38.1%
Aspirin
p=0.18
Chinise patients with cerebral infarction
Cilostazol n=360
Aspirin n=360
Endpoint: Stroke
CASISP
Cerebral hemorrhage
Cilostazol n=1
Aspirin n=7

(2005)
 All symptomatic patients with or without a history of other
cardiovascular disease should be prescribed an antiplatelet drug
long term to reduce the risk of cardiovascular morbidity and
mortality [A].
 Aspirin is effective in patients with PAD who also have clinical
evidence of other forms of cardiovascular disease (coronary or
carotid) [A].
 The use of aspirin in patients PAD who do not have clinical
evidence of other forms of cardiovascular disease can be
considered [C].
 Clopidogrel is effective in reducing cardiovascular events in a
subgroup of patients with symptomatic PAD, with or without other
clinical evidence of cardiovascular disease [B]
Antiplatelet Therapy in Peripheral Arterial Disease

Pharmacologic Treatment
for Claudication Symptoms
Cardiovascular Risk Reduction
Cardiovascular Risk Reduction vs
Treatment for Claudication Symptoms
Separate
Management
Strategies
Cilostazol: Indicated to reduce
symptoms of intermittent
claudication, as indicated by an
increased walking distance
Clopidogrel: Indicated to reduce
the risk of atherothrombotic events
(recent MI, recent ischemic stroke,
or vascular death) in individuals
with established PAD

PAD no / unknown
asymptomatic PAD
symptomatic PAD
1.0
0.9
0.8
0.7
0.6
0.5
Event-freesuvival
0 1 2 3 4 5
Time after baseline (years)
Persons
atrisk
5392
836
593
5303
810
561
5192
776
515
5085
742
484
5017
722
463
4935
700
433
4464
612
357
4004
528
301
3953
520
286
3885
493
276
3850
484
268
Diehm C. et al； Circulation. 2009;120:2053-2061.
Event-free survival by PAD status at 5 years
(all-cause mortality or severe vascular events*)
* Myocardial infarction, coronary revascularization, stroke, carotid
revascularization, peripheral revascularization, or amputation

0.7 ≤ABI <0.9
0.5 ≤ABI <0.7
ABI <0.5 or (a)
1.0
0.9
0.8
0.7
0.6
0.5
Event-freesuvival
0 1 2 3 4 5
Time after baseline (years)
Persons
atrisk
2172
3414
800
2137
3351
773
2092
3274
742
2046
3204
710
2026
3152
696
1997
3092
678
1811
2788
589
1626
2499
511
1609
2461
500
1579
2420
478
1568
2392
469
Event-free survival by ABI category
(all-cause mortality or severe vascular events*)
* Myocardial infarction, coronary revascularization, stroke, carotid
revascularization, peripheral revascularization, or amputation
214
213
206
199
191
177
178
166
166
156
153
142
127
112
103
90
100
85
93
80
91
78
1.1 ≤ABI ≤1.5
0.9 ≤ABI <1.1
(a) previous peripheral revascularisation or amputation due to PAD

0.0
0.5
1.0
1.5
2.0
2.5
3.0
StrokeM ICV deathFatal strokeAll Death
HazardRatio(vs.no/unknownPAD)
Asymptomatic PAD
SymptomaticPAD
Event Rates of Symptomatic or Asymptomatic PAD
in the Elderly People over 65 years

2011 ACCF/AHA Focused Update of the Guideline for the
Management of Patients With Peripheral Artery Disease
(Updating the 2005 Guideline)
Circulation November 1, 2011

Recommendations for
Ankle-Brachial Index, Toe-Brachial Index,
and Segmental Pressure Examination
The resting ABI should be used to establish the lower extremity
PAD diagnosis in patients with suspected lower extremity PAD,
defined as individuals with 1 or more of the following:
# Exertional leg symptoms,
# Nonhealing wounds,
# Age 65 years and older or
# 50 years and older
with a history of smoking or diabetes.
(Level of Evidence: B)
( Circulation November 1, 2011)

ABI results should be uniformly reported with
noncompressible values defined as greater than 1.40,
# Normal values 1.00 to 1.40,
# Borderline 0.91 to 0.99 and
# Abnormal 0.90 or less
(Level of Evidence: B)
( Circulation November 1, 2011)

2010 2020
Japan 23.0% 28.6%
Korea 11.1 15.5
Taiwan 10.7 16.1
Singapore 9.0 13.9
Thailand 8.9 13.0
China 8.4 11.7
Vietnam 6.5 8.2
Indonesia 5.0 6.3
Malaysia 4.8 6.9
Philippine 3.7 4.9
Elderly People >65 years in Asian Countries
Data from United Nations 2012

2010 284,160,000
2020 400,940,000
Increasing Number of Elderly People
> 65 years In Asia
Data from United Nations 2012

How to make a diagnosis of
asymptomatic PAD patients ?

The Japanese Association
for
Cardiovascular disease Prevention

Results of the ABI measurement
(2011-2012)
Number of Pts
PAD
(ABI<=0.9)
Borderline
(ABI 0.91-0.99)
4,099 116 257
100% 2.8% 6.3%

Memorial Day for cardiovascular Disease Prevention
“Prevent PAD - Green IVY movement -”

Symbol Mark
A leaf of the Ivy looks like heart
A vine of the Ivy looks like artery
Green color means youthfulness
and hope

Extend the Movement to Asian Countries

In Conclusion
Cilostazol
- increase walking distances in patients with
intermittent claudication
- reduces target lesion revascularization
- improves long-term patency
after PPI in the femoropopliteal artery
Cilostazol
- does not increase risk of mortality or bleeding
- reduces cardiovascular events in diabetes patients

Thank you for your attention !

Diagnosis of claudication and systemic risk treatment
＊It is not yet proven that treatment of diabetes mellitus will significantly reduce peripheral arterial disease (PAD)-specific (limb ischemic) endpoits. Primary
treatment of diabetes mellitus should be continued according to established guidelines. †The benefit of angiotensin-converting enzyme (ACE)-ingibition in
individuals without claudication has not been specifically documented in prospective clinical trials, but has been extrapolated from orher “at risk” populations.
ABI=ankle-brachial index; HgbA1C=hemoglobin A; JNC-7=Seventh Report of the Joint National Committee on the Prevention, Detection, Ecaluation, and
Treatment of High Blood Pressure; LOE=level of evidence; NCEP ATP-III=National Cholesterol Education Program Adult Treatment Panel III.
Classic Claudication Symptoms:
Muscle fatigue, cramping, or pain that reproducibly begins during exercise and that promptly resolves with rest
ABI greater than 0.90
Exercise ABI
(TBI, segmental pressure, or duplex
ultrasound examination)
Pharmacological Risk Reduction:
Anti-platelet therapy
(ACE-inhibition;†Class IIa, LOE B)
Chart document the history of walking impairment (pain-free and total walking distance) and specific lifestyle limitations
Go to Figure 6, Treatment of Claudication
Document pulse examination
ABI
ABI less than or equal to 0.90
Confirmed PAD Diagnosis
Risk factor normalization: Immediate smoking cessation
Treat Hypertension: JNC-7 guidelines
Treat lipides: NCEP ATP-III guidelines
Treat diabetes mellitus: HgbA1C less than 7%‡
Abnormal
Results
Normal
Results
No PAD or consider arterial
entrapment syndromes
(Hirsch et al. JACC 47:1239-1312, 2006)

Treatment of claudication
＊Inflow disease should be suspected in individuals with gluteal or thigh claudicatio and femoral pulse diminution or bruit and should be confirmend by
noninvasive vascular laboratory diagnostic evidence of aortoiliac stenoses. †Outflow disease represents femoropopliteal and infrapopliteal stenoses (the
presence of occlusive lesions in the lower extremity arterial tree below the inguinal ligament from the common femoral artery to the pedal vessels).
PAD=peripheral arterial disease.
Confirmed PAD Diagnosis
Clinical improvement:
Follow-up visits
at least annually
Evaluation for additional endovascular
or surgical revascularization
No significant functional disability Lifestyle-limiting symptoms Lifestyle-limiting symptoms with
evidence of inflow disease*
Further anatomic definition by
more extensive noninvasive or
angiographic diagnostic techniques
Endovascular therapy
(or surgical bypass per anatomy)
Pharmacological therapy:
Cilostazol (Pentoxifylline)
Three-month trial
Supervised
exercise program
Three-month trial
Preprogram and
postprogram exercise
testing for efficacy
No claudication treatment
required.
Follow-up visits at least
annually to monitor for
development of leg, coronary.
or cerebrovascular ischemic
symptoms.
Significant disability:
despite medical therapy and/or
inflow endovascular therapy
with documentation of outflow†
PAD, with favorable procedural
anatomy and procedural
risk benefit ratio
(Hirsch et al. JACC 47:1239-1312, 2006)

Cilostazol
group, n=93
Non-Cilostazol
group, n=98
P value
Age-yrs
Male gender-no. (%)
Body mass index
Hypertension-no. (%)
Dislipidemia-no. (%)
Statin treatment-no. (%)
Diabetes mellitus-no. (%)
Glycosylated hemoglobin at baseline-%
History of Smoking-no. (%)
End stage renal disease on dialysis-no. (%)
Coronary artery disease-no. (%)
Cerebrovascular disease-no. (%)
Rutherford classification-no. (%)
2
3
4
Baseline ankle brachial index ABPI
72±9
64 (69)
22±3
75 (81)
41 (44)
30 (32)
52 (56)
6.4±1.7
41 (44)
15 (16)
35 (38)
22 (24)
23 (25)
61 (65)
9 (10)
0.71±0.15
73±8
67 (68)
22±3
80 (82)
49 (50)
38 (39)
55 (56)
6.2±1.1
47 (48)
15 (15)
39 (40)
19 (19)
28 (29)
59 (60)
11 (11)
0.66±0.14
0.51
1.0
0.83
1.0
0.47
0.37
1.0
0.43
0.56
1.0
0.77
0.48
0.74
0.03
Baseline Clinical Characteristics of the Patients

Cilostazol group, n=93 Non-Cilostazol group, n=98 P value
TASC II classification-no (%)
A
B
C
D
Occlusion-no of patients (%)
Length of target lesion-mm
Lesion calcification-%
Number of below the knee run-off (%)
0
1
2
3
Reference vessel diameter of target lesion-mm
Proximal
Distal
Stent implantation-no. (%)
Number of stent implantation-no. (%)
1
2
3
Diameter of stent-mm, no. (%)
6
7
8
Diameter of post dilation balloon-mm, no. (%)
4
5
6
Degree of stenosis before and after intervention-%
Minimum lumen diameter (MLD) before and after intervention-mm
Procedure related complication -no. (%)
Distal embolization-no. (%)
Puncture site complication-no. (%)
34 (37)
18 (19)
24 (26)
17 (18)
37 (40)
132±90
37 (40)
4 (4)
29 (31)
38 (41)
22 (24)
5.4±1.4
4.9±1.0
82 (88)
36 (44)
20 (24)
26 (32)
38 (46)
16 (20)
28 (34)
15 (16)
46 (50)
32 (34)
81±21/22±15
0.8±0.9/3.8±0.9
2 (2)
1 (1)
1 (1)
33 (34)
23 (23)
26 (27)
16 (16)
38 (39)
125±82
45 (46)
1 (1)
31 (32)
38 (39)
28 (28)
5.3±1.4
5.0±1.0
88 (90)
36 (41)
34 (39)
18 (20)
42 (48)
19 (20)
27 (31)
10 (10)
60 (61)
28 (29)
82±20/21±14
0.9±1.0/3.9±1.0
3 (3)
1 (1)
2 (2)
0.95
1.0
0.55
0.46
0.48
0.90
0.51
0.82
0.09
0.87
0.22
1.0/0.76
0.66/0.47
1.0
1.0
1.0
Baseline angiographic characteristics of lesions and
intervention procedure

Cilostazol group Non-Cilostazol P value
Degree of stenosis at 12 month-%
Occlusion within 12 months-n. %
Minimum lumen diameter (MLD) at
12 months-mm
Late lumen loss (LLL)-mm
Stent fracture at 12 months-%
Target lesion revascularization within
12 months-no. (%)
Amputation within 12 months-no. (%)
Death within 12 months-no. (%)
39±23
4 (5)
3.1±1.5
1.1±0.6
12 (17)
14/82 (17)
0 (0)
7 (8)
52±22
7 (9)
2.2±1.1
1.4±0.7
10 (20)
34/85 (40)
2 (2)
4 (4)
0.0006
0.53
<0.0001
0.03
0.64
0.001
0.50
0.36
Outcomes at 12 months

ABI was assessed at six times: pre and postprocedure, and at 1, 3, 6, and 12 months. Although preprocedural ABI was significantly
higher in the cilostazol group than in the non-cilostazol group, there were no other significant differences between the groups. At
12 months, ABI was not statistically different between groups (p=0.20).
Baseline
0.0
0.2
0.4
0.6
1.0
Ankle-BrachialIndex
0.8
P=0.03
Post
P=0.81
1Mo
P=0.98
3Mo
P=0.99
6Mo
P=0.99
12Mo
P=0.20
Changes in ABI (ITT analysis)

Restenosis was defined as a peak systolic velocity ratio >2.0. According to PPS analysis, restenosis rates were similar between the
cilostazol and non-cilostazol groups at 3 and 6 months, whereas the restenosis rate was significantly lower in the cilostazol group
at 12 months.
3Mo
0
10
20
30
50
60
Restenosisrate(%)
P=0.005
7%
(6/83)
10%
(8/77)
40
6Mo 12Mo
18%
(15/83)
17%
(13/77)
46%
(38/83)
22%
(17/77)
P=1.00
P=0.87
Non-Cilostazol
Cilostazol
The 12-month restenosis rate evaluated by duplex ultrasound following PTA with provisional nitinol stenting
for symptomatic de novo femoropopliteal lesions in the cilostazol group and the non-cilostazol group
(Secondary endpoint, PPS analysis)

The angiographic restenosis rate was significantly lower in the cilostazol group than in the non-cilostazol group. By PPS analysis,
the patency rate was 21% and 50%, respectively (p=0.0003) .
0
20
40
60
80
100
Restenosisrate(%)
OR: 0.27
(95%CI: 0.13, 0.55)
P=0.0003
50%
(38/76)
21%
(15/71)
Twelve-month angiographic restenosis rates following PTA with provisional nitinol stenting for symptomatic
de novo femoropopliteal lesions in the cilostazol group and the non-cilostazol group
(Primary endpoint, PPS analysis )

Odds ratios for 12-month restenosis in selected patient subgroups are shown. The p-values for interaction indicate that none of the variables had a
significant interaction with treatment.
0.01 0.1 0.5 1.0 2.0 4.0
Cilostazol better Non-Cilostazol better
Overall
Sex
Female 10/28 (36)
Male
Diabetes mellitus
NO
YES
End stage renal disease on dialysis
NO
YES
Rutherford classification
2-3
4
TASC II classification
A-B
C-D
Length of target lesion
<150
≥150
Reference vessel diameter
<5
≥5
Chronic total occlusion
NO
YES
Poor BKT run off
0-1
2-3
Number of stents
1
2-3
Stent implantation
NO
YES
18/82 (22)
16/29 (55)
8/54 (15)
5/36 (14)
13/46 (28)
15/70 (21)
3/12 (25)
16/75 (21)
2/ 7 (29)
9/32 (28)
9/50 (18)
9/52 (17)
9/30 (30)
9/28 (32)
9/54 (17)
11/51 (22)
7/31 (23)
11/52 (21)
7/30 (23)
11/39 (28)
6/35 (17)
1/ 8 (13)
17/74 (23)
38/85 (45)
0.14
22/56 (39)
15/36 (42)
23/49 (47)
33/72 (46)
5/13 (38)
31/74 (42)
7/11 (64)
18/35 (51)
20/50 (40)
21/51 (41)
17/34 (50)
14/32 (41)
24/53 (45)
22/52 (42)
16/33 (48)
22/53 (42)
16/32 (50)
21/45 (47)
13/29 (45)
4/11 (36)
34/74 (46)
0.002
0.004
0.009
0.06
0.002
0.47
0.007
0.15
0.05
0.02
0.01
0.10
0.36
0.001
0.02
0.03
0.02
0.03
0.08
0.02
0.24
0.003
0.47
0.35
0.60
0.65
0.87
0.61
0.19
0.79
0.76
0.45
0.79
Cilostazol Non-Cilostazol P P for interactionOdds ratio (95%CI)
# of Restenosis/Total # (%)
Subgroup analysis of the influence of cilostazol on 12-month
angiographic restenosis (ITT analysis)

Rutherford classification was assessed at five times: preprocedure, and at 1, 3, 6, and 12 months. There were no other significant
differences between groups preprocedure, and at 1, 3, and 6 months. At 12 months, it was significantly lower in the cilostazol
group than in the non-cilostazol group (p=0.03).
0
1
2
4
MeanRutherfordClassification
3
Baseline
P=0.68
1Mo
P=1.00
3Mo
P=0.13
6Mo
P=0.51
12Mo
P=0.03
Changes in Rutherford classification
(ITT analysis)

The role of cilostazol for the treatment of

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