Pletaal (cilostazol) utk dokter.ppt (a)

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  • Naar een ets van Adam van Vianen, 1598
  • The majority (88%) of strokes are ischemic in origin; approximately 12% of all strokes are hemorrhagic. Hemorrhagic strokes are more likely than ischemic strokes to result in death within 30 days. 1 Reference 1. American Heart Association. Heart Disease and Stroke Statistics — 2005 Update . Dallas, Tex: American Heart Association; 2005 .
  • 왼쪽 : Subtype-specific, age adjusted annual ischemic stroke incidence per 100,000 persons 2. 오른쪽 : Relative, age-adjusted rate of each subtype incidence
  • SPIRIT : stroke prevention in reversible ischemia trial WARSS : Comparison of warfarin and aspirin fro prevention of recurrent ischemic stroke
  • Pharmacologic effects of cilostazol PDE III is found more predominantly in the platelets, the cardiac muscles cells, the vascular smooth muscle cells, and the fatty tissue or adipose cells. When the action of PDE III is inhibited by cilostazol, there is an increase in cAMP levels in these cells. The increase in the cAMP levels in these cells or tissues leads to ; an inhibition of platelet aggregation ( at platelets ) vasodilation and an inhibition of VSMC proliferation ( at VSMC ) an increase in heart rate and contractile force ( at heart ) an improvement in lipid metabolism ( at adipose tissues )
  • This shows the Caplan-Myer curve of primary endpoint. Relative risk reduction of cilostazol against aspirin was 25.7%.
  • This shows the Caplan-Myer curve of composite endpopint including ischemic and hemorrhagic events. The relative risk reduction was 20.1%.
  • Amazingly, the relative risk reduction of bleeding events wiht cilostazol against aspirin was 54.2%.
  • Pharmacologic Effects of Cilostazol Cilostazol has a broad spectrum of pharmacologic effects, each of which may contribute to its ability to improve blood flow to the lower extremities. Principal among these pharmacologic actions are antiplatelet and antithrombotic activities and vasodilatory effects caused by the increased cAMP in platelets and blood vessels. Mild increases in heart rate may result. In addition, cilostazol has been shown to increase blood flow and to increase HDL-C and decrease triglycerides. Cilostazol also inhibits proliferation of rat vascular smooth muscle cells in culture.
  • Pletaal (cilostazol) utk dokter.ppt (a)

    1. 1. CEREBROVSCULARDISEASES
    2. 2. stroke: global burden of diseaseestimated rank 1990 projected rank 20201 lower respiratory tract 1 ischaemic heart disease infections 2 unipolar depression2 bowel infections 3 traffic accidents3 perinatal disorders 4 cerebrovascular disease4 unipolar depression 5 chronic obstructive pulmonary dis.5 ischaemic heart disease 7 lower respiratory tract6 cerebrovascular disease infections7 tuberculosis 7 tuberculosis8 measles 8 war9 traffic accidents 9 bowel infections10 congenital malformations 10 HIV Murray et al. Lancet 1997;349:1436-42
    3. 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. 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. 5. Incidence of Ischemic Stroke vs Hemorrhagic Stroke and mortalityThe majority of strokes are ischemic Ischemic stroke Hemorrhagic stroke 40 36%-37% 30-day mortality (%) 12% 30 88% 20 8%-12% 10 0 INCIDENCE MORTALITYAmerican Heart Association Heart Disease and Stroke Statistics—2005 Update.
    6. 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. 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. 8. Medications Anticoagulation vs antiplatelet ??
    9. 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. 10. WASIDPrimary endpoints : stroke, brain hemorrhage, vascular death 22.1% in aspirin group 21.8% in warfarin group NEJM 2005;352:1305
    11. 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.
    12. 12. 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.
    13. 13. MATCH StudyPrimary end point; Primary intracranial hemorrhageStroke, MI, Vascular death,rehospitalization for acute ischemic event Diener HC et al. Lancet 2004;364:331-37
    14. 14. 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) 0.17Bhatt 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.
    15. 15. H N O Cilostazol N (CH2)4O N N H NMode of actionInhibition 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 adenosineResult:Tissue specific (ischemia) controlled (adenosine!) changes(increase) in cAMP level with subsequent cell-type specificmodulation of cAMP-mediated actions
    16. 16. H O NCilostazol N N N (CH2)4O H NCellular 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
    17. 17. 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.
    18. 18. 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.
    19. 19. Pletaal (cilostazol) Clinical Trial
    20. 20. 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
    21. 21. 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 20Cumulative 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
    22. 22. 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
    23. 23. DAPC StudyStudy of Diabetic Atherosclerosis Prevention by Cilostazol* Pletaal (100-200 mg/d) n = 145329 patients type 2 DM whohave 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
    24. 24. DAPC StudyStudy 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 rightCommon Carotid Artery compared with aspirin. *Katakami N. et al. : Circulation. 2010;121:2584-2591
    25. 25. DAPC StudyStudy 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 rightCommon Carotid Artery compared with aspirin. *Katakami N. et al. : Circulation. 2010;121:2584-2591
    26. 26. DAPC StudyStudy 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
    27. 27. Pharmacologic Effects of Pletaal inhibition ofAntiplatelet activity Pletaal vascular smooth muscle cells DecreasesAntithrombotic triglycerides activity (15%) Produces Increases vasodilation HDL-C (10%) Endothelial Increases protection blood flow

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