Pletaal (cilostazol) utk dokter.ppt (a)

CEREBROVSCULAR CEREBROVSCULAR DISEASESDISEASES

stroke: global burden of stroke: global burden of diseasedisease

11 lower respiratory tract lower respiratory tract infections infections

22 bowel infectionsbowel infections33 perinatal disordersperinatal disorders44 unipolar depressionunipolar depression55 ischaemic heart diseaseischaemic heart disease66 cerebrovascular diseasecerebrovascular disease77 tuberculosistuberculosis88 measles measles 99 traffic accidents traffic accidents 1010 congenital congenital

malformationsmalformations

Murray et al. Lancet 1997;349:1436-42

estimatedestimated rank 1990 rank 1990 projectedprojected rank 2020 rank 20201 1 ischaemic heart diseaseischaemic heart disease2 unipolar depression2 unipolar depression3 traffic accidents3 traffic accidents4 cerebrovascular disease4 cerebrovascular disease55 chronic obstructive chronic obstructive pulmonary dis.pulmonary dis.66 lower respiratory tract lower respiratory tract infectionsinfections7 tuberculosis7 tuberculosis8 war8 war9 bowel infections 9 bowel infections 10 HIV 10 HIV

Chronic disability: Major burden of stroke

Rothwell PM. Lancet. 2001;357:1612-1616.American Heart Association. 2002 Heart and Stroke Statistical Update. 2001.

Most strokes are not fatal

Aftermath of stroke includes: – Neurologic disability – Dementia – Depression – Epilepsy – Falls/fractures

Up to 30% of survivors are permanently disabled

Prevention is the KeyPrevention is the Key

Despite enthusiasm for acute stroke Despite enthusiasm for acute stroke therapies, public health impact is smalltherapies, public health impact is small

- tPA therapy associated with 11% absolute - tPA therapy associated with 11% absolute in- in-

crease in good outcomescrease in good outcomes

- tPA only applied to 1%-2% of acute - tPA only applied to 1%-2% of acute strokesstrokes

* Public health impact currently small* Public health impact currently small

* Prevention offers best opportunity to * Prevention offers best opportunity to reduce burden of stroke reduce burden of stroke

INCIDENCE

Hemorrhagic stroke

88%

12%

8%-12%

36%-37%

0

10

20

30

40

30-d

ay m

ort

alit

y (%

)

MORTALITY

Incidence of Ischemic Stroke vs Incidence of Ischemic Stroke vs Hemorrhagic Stroke and mortalityHemorrhagic Stroke and mortality

American Heart Association Heart Disease and Stroke Statistics—2005 Update.

The majority of strokes are ischemic

Ischemic stroke

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 Intracranial atherosclerotic stroke is more

common in common in Asians, Hispanics, and BlacksAsians, Hispanics, and Blacks 6 ~ 29% in Blacks6 ~ 29% in Blacks

11% in Hispanics11% in Hispanics

22 ~ 33% in Asians22 ~ 33% in Asians

Recent meta-analysis showed interesting Recent meta-analysis showed interesting

points associated with thepoints associated with the prognosis prognosis of of

symptomatic ICAS symptomatic ICAS

(Cerebrovasc Dis 2001;12:228-234)(Cerebrovasc Dis 2001;12:228-234)

A higher rate of recurrent stroke in pts A higher rate of recurrent stroke in pts

with intracranial ICA disease (RR 1.09; with intracranial ICA disease (RR 1.09;

95% CI, 1.05-1.14) than MCA or 95% CI, 1.05-1.14) than MCA or

extracranial ICA diseaseextracranial ICA disease

No other vascular risk factors than No other vascular risk factors than

hypertension (1.23;1.07-1.41) increase hypertension (1.23;1.07-1.41) increase

the risk.the risk.

MedicationsMedications

Anticoagulation vs antiplatelet Anticoagulation vs antiplatelet ????

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

WASIDWASID

Primary endpoints : stroke, brain hemorrhage, vascular death 22.1% in aspirin group 21.8% in warfarin group

NEJM 2005;352:1305

Lessons from WASIDLessons from WASID

Intracranial stenosis is a really Intracranial stenosis is a really high-riskhigh-risk disease. disease.

WarfarinWarfarin is associated with is associated with high rate of bleedinghigh rate of bleeding

complication without benefit over aspirin.complication without benefit over aspirin.

Alternative therapy using different Alternative therapy using different antiplatelet antiplatelet

regimenregimen is needed. is needed.

CAPRIE: Clopidogrel versus Aspirin in Patients at risk of Ischemic CAPRIE: Clopidogrel versus Aspirin in Patients at risk of Ischemic EventsEvents

- RESULTS -- RESULTS -

Stroke Clopidogrel (6054)Aspirin (5979)

MI Clopidogrel (5787)Aspirin (5843)

Peripheral arterialdisease

Clopidogrel (5795)Aspirin (5797)

All patients Clopidogrel (17,636)Aspirin (17,519)

7.157.71

5.034.84

3.714.86

5.325.83

0.26

0.66

0.0028

0.043

Relative risk reduction (%)

7.3%(–5.7 to 18.7)

–3.7%(–22.1 to 12.0)

23.8%(8.9 to 36.2)

8.7%(0.3 to 16.5)

SubgroupTreatment group(patient years at risk)

Eventsper year(%)

pRelative riskreduction (95% CI)

Primary endpoint by subgroup

Aspirinbetter

Clopidogrelbetter

0–10–20 10 20 30 40–30

CAPRIE Steering Committee. Lancet 1996;348 :1329–39.

MATCH StudyMATCH Study

Primary end point; Primary end point; Stroke, MI, Vascular death, Stroke, MI, Vascular death, rehospitalization for acute ischemic eventrehospitalization for acute ischemic event

Primary intracranial hemorrhagePrimary intracranial hemorrhage

Diener HC et al. Lancet 2004;364:331-37Diener HC et al. Lancet 2004;364:331-37

Overall Population: Primary Efficacy Outcome (MI, Stroke, or CV Death)†

† First Occurrence of MI (fatal or non-fatal), stroke (fatal or non-fatal), or cardiovascular death*All patients received ASA 75-162 mg/day§The number of patients followed beyond 30 months decreases rapidly tozero and there are only 21 primary efficacy events that occurred beyond this time (13 clopidogrel and 8 placebo)

Bhatt DL, Fox KA, Hacke W, et al. NEJM 2006.

Cum

ulat

ive

even

t rat

e (%

)

0

2

4

6

8

Months since randomization

0 6 12 18 24 30

Placebo + ASA*7.3%

Clopidogrel + ASA*6.8%

RRR: 7.1% [95% CI: -4.5%, 17.5%]p=0.22

Overall Population: Safety Results

Clopidogrel Placebo+ ASA + ASA

Safety Outcome* - N (%) (n=7802) (n=7801) RR (95% CI) p value

GUSTO Severe Bleeding 130 (1.7) 104 (1.3) 1.25 (0.97, 1.61) 0.09

Fatal Bleeding 26 (0.3) 17 (0.2) 1.53 (0.83, 2.82) 0.17

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 analysisICH= Intracranial HemorrhageGUSTO =Global utilization of streptokinase and tissue

plasminogen activator for occluded coronary arteries

Bhatt DL, Fox KA, Hacke W, et al. NEJM 2006.

CHARISMA study

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

CilostazolCilostazolMode of action

Result:

Tissue specific (ischemia) controlled (adenosine!) changes

(increase) in cAMP level with subsequent cell-type specific

modulation of cAMP-mediated actions

ONH

(CH2)4ONN

NN H

ATP

5’AMP

• Vasodilation• Inhibition of proliferation,

• Inhibition of aggregation

• Inhibition of expression of adhesion molecules

cAMP actions (selected)Targets

• Inhibition of expression of adhesion molecules

• Stimulation of angiogenesisendothelial cellcAMP

platelet

smooth muscle cell

CilostazolCellular targets

PDE IIIA

AdenosineA2

A1

ONH

(CH2)4ONN

NN H

neuronal cell

• Antiischemic / antiinflammatory / neuroprotective effects• Inhibition of apoptosis

Guideline Stroke Perdossi 2011.

Bab VIII. Pencegahan Sekunder Stroke IskemikBab VIII. Pencegahan Sekunder Stroke IskemikE. Riwayat TIA atau StrokeE. Riwayat TIA atau Stroke

Halaman 117-118Halaman 117-118

l.l. Pletaal (100 mg) 2 x sehari menunjukkan efek penurunan yang Pletaal (100 mg) 2 x sehari menunjukkan efek penurunan yang signifikan terhadap kejadian stroke berulang dibandingkan placebo: signifikan terhadap kejadian stroke berulang dibandingkan placebo: 41,7% p=0,0150 (event rate per year Pletaal 3,37% sedangkan pada 41,7% p=0,0150 (event rate per year Pletaal 3,37% sedangkan pada placebo 5,78%) dan efektif untuk mencegah lakunar infark pada placebo 5,78%) dan efektif untuk mencegah lakunar infark pada differential analysis. differential analysis. ( ( Class I, Level of Evidence AClass I, Level of Evidence A).).

m.m. Ratio terjadinya stroke serta ratio terjadinya perdarahan pada cilostazol Ratio terjadinya stroke serta ratio terjadinya perdarahan pada cilostazol secara signifikan lebih rendah dibandingkan aspirin. Penurunan risiko secara signifikan lebih rendah dibandingkan aspirin. Penurunan risiko relatif terjadinya stroke, Cilostazol vs aspirin : 25,7% p=0,0357 (yearly relatif terjadinya stroke, Cilostazol vs aspirin : 25,7% p=0,0357 (yearly rate of cerebral infarction cilostazol 2,76% vs aspirin 3,71%). Penurunan rate of cerebral infarction cilostazol 2,76% vs aspirin 3,71%). Penurunan risiko relatif terjadinya perdarahan pada cilostazol terhadap aspirin risiko relatif terjadinya perdarahan pada cilostazol terhadap aspirin sebesar 54,2% (p=0,0004). sebesar 54,2% (p=0,0004). Insiden perdarahan pertahun untuk Insiden perdarahan pertahun untuk cilostazol 0,77%, sedangkan aspirin 1,78%.cilostazol 0,77%, sedangkan aspirin 1,78%. ((Class I, Level of Evidence Class I, Level of Evidence AA).).

*Guideline Stroke 2011. Kelompok Studi Stroke. Perhimpunan Dokter Spesialis Saraf Indonesia PERDOSSI.

Guideline Stroke Perdossi 2011.

Bab VIII. Pencegahan Sekunder Stroke IskemikBab VIII. Pencegahan Sekunder Stroke IskemikE. Riwayat TIA atau StrokeE. Riwayat TIA atau Stroke

Halaman 117-118Halaman 117-118

n.n. Pada penelitian review (Jepang dan China) sebanyak 3477 pasien, yang Pada penelitian review (Jepang dan China) sebanyak 3477 pasien, yang membandingkan cilostazol dengan aspirin pada kejadian vascular membandingkan cilostazol dengan aspirin pada kejadian vascular events setelah stroke (stroke, infark miokard, atau kematian akibat events setelah stroke (stroke, infark miokard, atau kematian akibat gangguan vaskular), didapatkan cilostazol menurunkan risiko vascular gangguan vaskular), didapatkan cilostazol menurunkan risiko vascular events dengan risiko relatif 0,72; 95% CI 0,57-0,91, bedasarkan tipe events dengan risiko relatif 0,72; 95% CI 0,57-0,91, bedasarkan tipe stroke (iskemik atau perdarahan) adalah 33%; 95% CI 14-48%, stroke (iskemik atau perdarahan) adalah 33%; 95% CI 14-48%, sedangkan kejadian stroke perdarahan lebih rendah dengan penurunan sedangkan kejadian stroke perdarahan lebih rendah dengan penurunan risiko sebesar 74%; 95% CI 45-87%.risiko sebesar 74%; 95% CI 45-87%.

*Guideline Stroke 2011. Kelompok Studi Stroke. Perhimpunan Dokter Spesialis Saraf Indonesia PERDOSSI.

Pletaal (cilostazol)Clinical Trial

00 17001600150014001300120011001000900800700600500400300200100

15%

5

10

Aspirin

Pletaal

p =0.0357Log-rank testRRR= 25.7

Primary Endpoint : Occurrence of stroke, cerebral infarction, Primary Endpoint : Occurrence of stroke, cerebral infarction, cerebral hemorrhage, or subarachnoid hemorrhage.cerebral hemorrhage, or subarachnoid hemorrhage.

nn No of No of occurrence occurrence

Estimate Estimate Incidence Incidence /year/year

PletaalPletaal 1,3371,337 8282 2.76%2.76%

AspirinAspirin 1,3351,335 119119 3.71%3.71%

Cum

ula

tive in

cid

en

ce

Days after randomization

Pletaal Lebih Superior Dibandingkan Aspirin Untuk Mencegah Stroke Berulang (CSPS 2)

*Multi-center, randomized, prospective, double-blind, active-controlled, parallel-group comparative study.

AHA/ASA International Stroke Conference 2010 Plenary Session II: Late Breaking Science, CSPS2 Abstracts, San Antonio, Texas, February 26, 2010

Time from start of drug admin to strokeLonger in Pletaal group.

0

25

0 17001600150014001300120011001000900800700600500400300200100

5

15

10

20

p = 0.0437Log-rank testRRR= 20.1

Secondary Endpoint : Occurrence of cerebral stroke, TIA, Secondary Endpoint : Occurrence of cerebral stroke, TIA, angina pectoris, myocardial infarction, cardiac failure, or angina pectoris, myocardial infarction, cardiac failure, or

hemorrhage requiring hospitalizationhemorrhage requiring hospitalization

%nn No of No of

occurrences occurrences Estimate Estimate

Incidence Incidence /year/year

PletaalPletaal 13371337 138138 4.66%4.66%

AspirinAspirin 13351335 186186 5.81%5.81%Aspirin

Pletaal



Cum

ula

tive in

cid

en

ce

0

10

0 17001600150014001300120011001000900800700600500400300200100

Occurrence of bleeding events, cerebral hemorrhage, Occurrence of bleeding events, cerebral hemorrhage, subarachnoid hemorrhage, bleeding requiring hospitalization.subarachnoid hemorrhage, bleeding requiring hospitalization.

5

p = 0.0004Log-rank testRRR=54.2

%

nnNo of No of

occurrenceoccurrences s

Estimate Estimate Incidence Incidence /year/year

PletaalPletaal 1,3371,337 2323 0.77%0.77%

AspirinAspirin 1,3351,335 5757 1.78%1.78%

Aspirin

Pletaal

Cum

ula

tive in

cid

en

ce



329 patients type 2 DM who have ASO

Pletaal (100-200 mg/d)

Aspirin (81-100 mg/d)

R

n = 145

n = 152

2 Years

• Subjects :

1. Patients with type 2 diabetes and arteriosclerosis obliterans.

2. Age : 40 - 85 years.

3. 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.

DAPC StudyDAPC StudyStudy of Diabetic Atherosclerosis Prevention Study of Diabetic Atherosclerosis Prevention

by Cilostazol*by Cilostazol*

1 Year

Carotid Artery Ultrasonographic Scans

*Katakami N. et al. : Circulation. 2010;121:2584-2591

Primary Endpoints : Changes in 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.

Δ LCCA-max IMT Δ RCCA-max IMT

Primary Endpoints : Changes in 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.

Δ RCCA-mean IMTΔ LCCA-mean IMT

Changes from baseline to year 2 in Total cholesterol, LDL-cholesterol, HDL-cholesterol and Triglyceride




Pletaal (n=144)

Pletaal significantly improves serum lipid levels compared with aspirin.

Pletaal

Pletaal (n=144)

Pletaal

Change of Total Cholesterol Change of HDL-Cholesterol

Change of LDL-Cholesterol Change of Triglycerides

AntiplateleAntiplatelett

activityactivity

AntithrombAntithromboticotic

activityactivity

ProducesProducesvasodilatiovasodilatio

nn

Endothelial Endothelial protectionprotection

IncreasesIncreasesblood flowblood flow

IncreasesIncreasesHDL-C HDL-C (10%)(10%)

DecreasesDecreasestriglyceridetriglyceride

s (15%)s (15%)

inhibition of inhibition of vascular vascular smooth smooth

muscle cellsmuscle cells

Pharmacologic Effects of Pharmacologic Effects of PletaalPletaal

Pletaal

Health & Medicine

Pletaal (cilostazol) utk dokter.ppt (a)