The document discusses cerebrovascular diseases and stroke. Some key points: - Stroke is projected to be the 4th leading cause of death globally by 2020. - Most strokes are ischemic rather than hemorrhagic. The majority of stroke survivors suffer chronic disability, with up to 30% permanently disabled. - Prevention offers the best opportunity to reduce the burden of stroke since treatment options for acute stroke are limited. - The drug cilostazol has been shown to significantly reduce the risk of recurrent strokes compared to placebo and has a better safety profile than aspirin with fewer bleeding risks.

1. CEREBROVSCULAR
DISEASES

2. stroke: global burden of disease
estimated rank 1990 projected rank 2020
1 lower respiratory tract 1 ischaemic heart disease
infections 2 unipolar depression
2 bowel infections 3 traffic accidents
3 perinatal disorders 4 cerebrovascular disease
4 unipolar depression 5 chronic obstructive
pulmonary dis.
5 ischaemic heart disease
7 lower respiratory tract
6 cerebrovascular disease
infections
7 tuberculosis 7 tuberculosis
8 measles 8 war
9 traffic accidents 9 bowel infections
10 congenital malformations 10 HIV
Murray et al. Lancet 1997;349:1436-42

3. Chronic disability: Major burden of stroke
• Most strokes are not fatal
• Aftermath of stroke includes:
– Neurologic disability
– Dementia
– Depression
– Epilepsy
– Falls/fractures
• Up to 30% of survivors
are permanently disabled
Rothwell PM. Lancet. 2001;357:1612-1616.
American Heart Association. 2002 Heart and Stroke Statistical Update. 2001.

4. Prevention is the Key
 Despite enthusiasm for acute stroke therapies, public
health impact is small
- tPA therapy associated with 11% absolute in-
crease in good outcomes
- tPA only applied to 1%-2% of acute strokes
* Public health impact currently small
* Prevention offers best opportunity to reduce burden
of stroke

5. Incidence of Ischemic Stroke vs Hemorrhagic
Stroke and mortality
The majority of strokes are ischemic
Ischemic stroke Hemorrhagic stroke
40 36%-37%
30-day mortality (%)
12% 30
88% 20
8%-12%
10
0
INCIDENCE MORTALITY
American Heart Association Heart Disease and Stroke Statistics—2005 Update.

6. Ischemic Stroke Subtype Incidence Among White,
Blacks, and Hispanics
(Circulation 2005;111:1327-1331)
714 patients from 1993 to 1997, NOMASS
 Intracranial atherosclerotic stroke is more common in Asians,
Hispanics, and Blacks
 6 ~ 29% in Blacks
 11% in Hispanics
 22 ~ 33% in Asians

7.  Recent meta-analysis showed interesting points
associated with the prognosis of symptomatic ICAS
(Cerebrovasc Dis 2001;12:228-234)
 A higher rate of recurrent stroke in pts with
intracranial ICA disease (RR 1.09; 95% CI,
1.05-1.14) than MCA or extracranial ICA disease
 No other vascular risk factors than hypertension
(1.23;1.07-1.41) increase the risk.

8. Medications
 Anticoagulation vs antiplatelet ??

9.  Warfarin (INR 2-3) vs. ASA (1300mg/d) for preventing
recurrent stroke and vascular death
 Symptomatic stenosis of a major intracranial artery
 A total of 569 patients had been randomized and the
average length of follow-up was 1.8 years.
 The WASID trial was stopped by the NINDS on 7/18/03

10. WASID
Primary endpoints :
stroke, brain hemorrhage, vascular death
22.1% in aspirin group
21.8% in warfarin group
NEJM 2005;352:1305

11. Lessons from WASID
 Intracranial stenosis is a really high-risk disease.
 Warfarin is associated with high rate of bleeding
complication without benefit over aspirin.
 Alternative therapy using different antiplatelet regimen is
needed.

13. CAPRIE: Clopidogrel versus Aspirin in Patients at risk of Ischemic
Events
- RESULTS -
Primary endpoint by subgroup
Treatment group Events Relative risk Relative risk reduction (%)
Subgroup (patient years per year reduction p Aspirin Clopidogrel
at risk) (%) (95% CI) better better
Stroke Clopidogrel (6054) 7.15 7.3% 0.26
Aspirin (5979) 7.71 (–5.7 to 18.7)
MI Clopidogrel (5787) 5.03 –3.7% 0.66
Aspirin (5843) 4.84 (–22.1 to 12.0)
Peripheral
arterial Clopidogrel (5795) 3.71 23.8% 0.0028
disease Aspirin (5797) 4.86 (8.9 to 36.2)
All patients Clopidogrel (17,636) 5.32 8.7% 0.043
Aspirin (17,519) 5.83 (0.3 to 16.5)
–30 –20 –10 0 10 20 30 40
CAPRIE Steering Committee. Lancet 1996;348:1329–39.

14. MATCH Study
Primary end point; Primary intracranial hemorrhage
Stroke, MI, Vascular death,
rehospitalization for acute ischemic event Diener HC et al. Lancet 2004;364:331-37

15. CHARISMA study
Overall Population: Primary Efficacy
Outcome (MI, Stroke, or CVPlacebo + ASA*†
Death)
8 7.3%
Clopidogrel + ASA*
Cumulative event rate (%)
6.8%
6
4
RRR: 7.1% [95% CI: -4.5%, 17.5%] Overall Population: Safety Results
2 p=0.22
0
Clopidogrel Placebo
0 6 12 18 24 30 + ASA + ASA
Months since randomization Safety Outcome* - N (%) (n=7802) (n=7801) RR (95% CI) p value
† FirstOccurrence of MI (fatal or non-fatal), stroke (fatal or non-fatal), or cardiovascular death
*All patients received ASA 75-162 mg/day GUSTO Severe Bleeding 130 (1.7) 104 (1.3) 1.25 (0.97, 1.61) 0.09
§The number of patients followed beyond 30 months decreases rapidly to
zero and there are only 21 primary efficacy events that occurred beyond
this time (13 clopidogrel and 8 placebo) Fatal Bleeding 26 (0.3) 17 (0.2) 1.53 (0.83, 2.82) 0.17
Bhatt DL, Fox KA, Hacke W, et al. NEJM 2006.
Primary ICH 26 (0.3) 27 (0.3) 0.96 (0.56, 1.65) 0.89
GUSTO Moderate Bleeding 164 (2.1) 101 (1.3) 1.62 (1.27, 2.08) <0.001
*Adjudicated outcomes by intention to treat analysis
ICH= Intracranial Hemorrhage
GUSTO =Global utilization of streptokinase and tissue
plasminogen activator for occluded coronary arteries
Bhatt DL, Fox KA, Hacke W, et al. NEJM 2006.

16. H
N O
Cilostazol N (CH2)4O
N N H
N
Mode of action
Inhibition of PDE IIIA (IC50: 0.2 – 0.4 µM)
Multiple interactions with adenosine: inhibition of uptake
(IC50: 5-10 µM), synergistic (platelets, SMC) and antagonistic
(cardiocytes) modulation of effects by adenosine
Result:
Tissue specific (ischemia) controlled (adenosine!) changes
(increase) in cAMP level with subsequent cell-type specific
modulation of cAMP-mediated actions

17. H O
N
Cilostazol N
N
N
(CH2)4O
H
N
Cellular targets
Targets cAMP actions (selected)
• Inhibition of aggregation
• Inhibition of expression of
5’AMP
platelet adhesion molecules
PDE IIIA • Inhibition of expression of
adhesion molecules
endothelial cell
• Stimulation of angiogenesis
cAMP
• Vasodilation
A2 • Inhibition of proliferation,
Adenosine smooth muscle cell
A1
ATP • Antiischemic /
antiinflammatory /
neuroprotective effects
neuronal cell • Inhibition of apoptosis

18. Guideline Stroke Perdossi 2011.
Bab VIII. Pencegahan Sekunder Stroke Iskemik
E. Riwayat TIA atau Stroke
Halaman 117-118
• Pletaal (100 mg) 2 x sehari menunjukkan efek penurunan yang signifikan terhadap
kejadian stroke berulang dibandingkan placebo: 41,7% p=0,0150 (event rate per
year Pletaal 3,37% sedangkan pada placebo 5,78%) dan efektif untuk mencegah
lakunar infark pada differential analysis. ( Class I, Level of Evidence A).
• Ratio terjadinya stroke serta ratio terjadinya perdarahan pada cilostazol secara
signifikan lebih rendah dibandingkan aspirin. Penurunan risiko relatif terjadinya
stroke, Cilostazol vs aspirin : 25,7% p=0,0357 (yearly rate of cerebral infarction
cilostazol 2,76% vs aspirin 3,71%). Penurunan risiko relatif terjadinya perdarahan
pada cilostazol terhadap aspirin sebesar 54,2% (p=0,0004). Insiden perdarahan
pertahun untuk cilostazol 0,77%, sedangkan aspirin 1,78%. (Class I, Level of
Evidence A).
*Guideline Stroke 2011. Kelompok Studi Stroke. Perhimpunan Dokter Spesialis Saraf Indonesia PERDOSSI.

19. Guideline Stroke Perdossi 2011.
Bab VIII. Pencegahan Sekunder Stroke Iskemik
E. Riwayat TIA atau Stroke
Halaman 117-118
• Pada penelitian review (Jepang dan China) sebanyak 3477 pasien, yang
membandingkan cilostazol dengan aspirin pada kejadian vascular events setelah
stroke (stroke, infark miokard, atau kematian akibat gangguan vaskular),
didapatkan cilostazol menurunkan risiko vascular events dengan risiko relatif 0,72;
95% CI 0,57-0,91, bedasarkan tipe stroke (iskemik atau perdarahan) adalah 33%;
95% CI 14-48%, sedangkan kejadian stroke perdarahan lebih rendah dengan
penurunan risiko sebesar 74%; 95% CI 45-87%.
*Guideline Stroke 2011. Kelompok Studi Stroke. Perhimpunan Dokter Spesialis Saraf Indonesia PERDOSSI.

20. Pletaal (cilostazol)
Clinical Trial

21. Pletaal Lebih Superior Dibandingkan Aspirin Untuk Mencegah Stroke Berulang
(CSPS 2)
*Multi-center, randomized, prospective, double-blind, active-controlled, parallel-group
comparative study.
Primary Endpoint : Occurrence of stroke, cerebral infarction, cerebral
hemorrhage, or subarachnoid hemorrhage.
%
15 No of Estimate
n
occurrence Incidence /year
Pletaal 1,337 82 2.76% Aspirin
Cumulative incidence
Aspirin 1,335 119 3.71%
10 Time from start of drug admin to stroke
Longer in Pletaal group.
Pletaal
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
AHA/ASA International Stroke Conference 2010 Plenary Session II: Late Breaking Science, CSPS2 Abstracts, San Antonio, Texas, February 26, 2010

22. Secondary Endpoint : Occurrence of cerebral stroke, TIA, angina
pectoris, myocardial infarction, cardiac failure, or hemorrhage
requiring hospitalization
% No of Estimate
n
25 occurrences Incidence /year
Pletaal 1337 138 4.66%
Aspirin
20
Cumulative incidence
Aspirin 1335 186 5.81%
15
Pletaal
10
p = 0.0437
Log-rank test
5 RRR= 20.1
0
0 100 200 300 400 500 600 700 800 900 1000 1100 1200 1300 1400 1500 1600 1700
Days after randomization
AHA/ASA International Stroke Conference 2010 Plenary Session II: Late Breaking Science, CSPS2 Abstracts, San Antonio, Texas, February 26, 2010

23. Occurrence of bleeding events, cerebral hemorrhage, subarachnoid
hemorrhage, bleeding requiring hospitalization.
%
No of Estimate
10 n
occurrences Incidence /year
Pletaal 1,337 23 0.77%
p = 0.0004
Aspirin 1,335 57 1.78%
Cumulative incidence
Log-rank test
Aspirin RRR=54.2
5
Pletaal
0
0 100 200 300 400 500 600 700 800 900 1000 1100 1200 1300 1400 1500 1600 1700
Days after randomization
AHA/ASA International Stroke Conference 2010 Plenary Session II: Late Breaking Science, CSPS2 Abstracts, San Antonio, Texas, February 26, 2010

24. DAPC Study
Study of Diabetic Atherosclerosis Prevention by Cilostazol*
Pletaal (100-200 mg/d)
n = 145
329 patients type 2 DM who
have ASO Carotid Artery Ultrasonographic
R Scans
1 Year 2 Years
n = 152
Aspirin (81-100 mg/d)
• Subjects :
• Patients with type 2 diabetes and arteriosclerosis obliterans.
• Age : 40 - 85 years.
• Clinical findings suggestive of arteriosclerosis obliterans (ASO).
• Study Design : Multi Center, Randomized, Open-Blind, Active Control.
• Primary Endpoints : The changes in maximum IMT (Intima Media Thickness) of the right and left
common carotid arteries (maximum CCA-IMT) and mean CCA-IMT from baseline.
*Katakami N. et al. : Circulation. 2010;121:2584-2591

25. DAPC Study
Study of Diabetic Atherosclerosis Prevention by Cilostazol*
Primary Endpoints : Changes in max IMT
Δ LCCA-max IMT Δ RCCA-max IMT
Pletaal (n=145) Pletaal (n=145)
Pletaal significantly inhibited the progression of maximum IMT of left and right
Common Carotid Artery compared with aspirin.
*Katakami N. et al. : Circulation. 2010;121:2584-2591

26. DAPC Study
Study of Diabetic Atherosclerosis Prevention by Cilostazol*
Primary Endpoints : Changes in mean IMT
Δ LCCA-mean IMT Δ RCCA-mean IMT
Pletaal (n=144) Pletaal (n=144)
Pletaal significantly inhibited the progression of mean IMT of left and right
Common Carotid Artery compared with aspirin.
*Katakami N. et al. : Circulation. 2010;121:2584-2591

27. DAPC Study
Study of Diabetic Atherosclerosis Prevention by Cilostazol*
Changes from baseline to year 2 in Total cholesterol, LDL-
cholesterol, HDL-cholesterol and Triglyceride
Change of Total Cholesterol Change of HDL-Cholesterol
Pletaal
Pletaal (n=144)
Change of LDL-Cholesterol Change of Triglycerides
Pletaal
Pletaal (n=144)
Pletaal significantly improves serum lipid levels compared with aspirin.
*Katakami N. et al. : Circulation. 2010;121:2584-2591

28. Pharmacologic Effects of
Pletaal
inhibition of
Antiplatelet
activity
Pletaal vascular smooth
muscle cells
Decreases
Antithrombotic
triglycerides
activity
(15%)
Produces Increases
vasodilation HDL-C (10%)
Endothelial Increases
protection blood flow