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1 Gyeongsang National University Hospital, Jinju, Korea. 2 Asan Medical Center, Seoul, Korea.

Adding Cilostazol to Dual Antiplatelet Therapy Achieves Greater Platelet Inhibition Compared with High Maintenance Dose Clopidogrel in Patients with Acute Myocardial Infarction ACCEL-AMI study.

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1 Gyeongsang National University Hospital, Jinju, Korea. 2 Asan Medical Center, Seoul, Korea.

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  1. Adding Cilostazol to Dual Antiplatelet Therapy Achieves Greater Platelet Inhibition Compared with High Maintenance Dose Clopidogrel in Patients with Acute Myocardial InfarctionACCEL-AMI study Circulation Cardiovascular Intervention 2010;1:17-26. Young-Hoon Jeong,1Jin-Yong Hwang,1 In-Suk Kim,1 Yongwhi Park,1 Seok-Jae Hwang,1 Seung-Whan Lee,2Choong Hwan Kwak,1 Seong-Wook Park2 1 Gyeongsang National University Hospital, Jinju, Korea. 2 Asan Medical Center, Seoul, Korea.

  2. Background • Enhanced platelet reactivitymay mainly underlie the risk of adverse cardiovascular disease in the early phase of AMI. • High post-clopidogrel platelet reactivity (HPPR) in patients with AMI has been associated with ischemic clinical events including stent thrombosis.

  3. Efficacy and Safety Correlated with IPA ASA+prasugrel ASA+ticagrelor ASA+clopidogrel BLEEDING= Non-CABG Major ASA Relative Rate EFFICACY= Death/MI/Stroke Placebo ASA+prasugrel ASA ASA+clopidogrel ASA+ticagrelor % IPA Antithrombotic Trialists’ Collaboration. BMJ. 2002;324:71 Yusuf et al. N Engl J Med. 2001;345:494 Wiviott et al. N Engl J Med 2007;357:2001-2015 Wallentin et al. N Engl J Med 2009;361:1-13 *IPA = inhibition of platelet aggregation

  4. The impact of adjunctive cilostazol in STEMI patients 26% Chen KY et al. Circulation 2009:119:3207-14.

  5. Mechanism of Cilostazol: Inhibition of phosphodiesterase 3 H O N (CH2)4O N N N H N Targets cAMP actions (selected) Cilostazol 5’AMP • Inhibition of aggregation • Inhibition of expression of • adhesion molecules PDE3A platelet • Inhibition of expression of • adhesion molecules • Angiogenesis cAMP endothelial cell A2 Adenosine • Vasodilatory action • Inhibition of proliferation, • migration and matrix synthesis • Headache A1 ATP smooth muscle cell • Palpitation • Tachycardia Elevation of cAMP and adenosine in diverse cardiovascular system cardiocyte

  6. Role of cAMP / Protein Kinase A PKA catalytic subunit phosphorylates CREB* and activates transcription a AC b g ATP GTP 2Pi Altered Protein Function Inactive protein kinase A (PKA) cAMP P ADP Nucleus ATP ATP ADP P Free PKA catalytic subunit migrates to nucleus Regulatory subunit of PKA binds cAMP dissociates from the catalytic subunit Altered Gene Expression  PKA can phosphorylate many different proteins depending on tissue type and status  PKA can activate enzymes or gene regulatory proteins

  7. Pleiotropic Effects of Cilostazol • Inhibition of Oxidative Stress • Restoration from Endothelial Senescence • Reduction of Adhesion molecule • Reduced leukocyte adhesiveness • Inhibition of Vascular Smooth Muscle Cell growth • Reduction of ischemia-reperfusion injury • Enhanced angiogenesis • Inhibition of adenosine uptake • Platelet inhibition and anti-thrombosis

  8. Postulated Modulation of P2Y12 Receptor Signalling Angiolillo DJ et al. Eur Heart J 2008; 29:2202.

  9. Purpose of Study • It has not been established whether the benefit of adjunctive cilostazol to dual antiplatelet therapy (“triple antiplatelet therapy”: TAPT) may be related with greater inhibition of ADP-induced platelet aggregation in AMI patients. • We compared the degree of platelet inhibition by adjunctive cilostazol (100mg twice a day)vs.high-MD clopidogrel (150 mg/d) in AMI patients undergoing coronary stenting.

  10. Study Population • Enrollment - ≥ 18 years of age - AMI patients undergoing uneventful coronary stenting • Exclusion criteria - a history of active bleeding and bleeding diatheses - oral anticoagulation therapy with coumadin - contraindication to antiplatelet therapy - LV ejection fraction < 30% - leukocyte < 3,000/mm3 and/or platelet < 100,000/mm3 - AST or ALT level ≥ 3 times upper normal - serum creatinine level ≥ 2.5 mg/dl - non-cardiac disease with a life expectancy < 1 year

  11. Patients undergoing coronary stenting for AMI (n = 120) Clopidogrel 600mg loading  75 mg/d before randomization Exclusion criteria (n = 25)Low LV ejection faction anticoagulation etc. Refusal (n = 5) Randomization after pre-discharge platelet reactivity assessment: 3-5 days after coronary stenting (n = 90) High MD clopidogrel 150 mg/d (n = 30) Standard MD clopidogrel 75 mg/d (n = 30) Adjunctive cilostazol 100 mg twice daily (n = 30) Platelet reactivity at 30-day follow-up (n = 30) Platelet reactivity at 30-day follow-up (n = 30) Platelet reactivity at 30-day follow-up (n = 30)

  12. Study Measurement • Method 1. Conventional aggregometry with 5 and 20 μM ADP- maximal aggregation (Aggmax) and late aggregation at 5 minutes (Agglate)2. VerifyNow P2Y12 assay- P2Y12 reaction units (PRU) and % inhibition • Parameters IPA (inhibition of platelet aggregation, %)= [(Aggbase – AggFU)/(Aggbase)] X100Percent change of PRU (%)= [(PRUbase – PRUFU)/(PRUbase)] X100Rate of HPPR (%) = 5 or 20 μM ADP-induced Aggmax > 50%

  13. AggRAM aggregometer ADP (5 μM) Arachidonic acid (1.6 mM) ADP (20 μM) ADP+PGE1

  14. VerifyNowTM (Ultegra rapid platelet function assay) • Turbidimetric based optical detection system – to measure PLT induced aggregation as an increase in light transmission • Simple, rapid report, not require specialized technician • “Point-of-care system”

  15. Baseline Characteristics (I)

  16. Baseline Characteristics (II)

  17. Baseline Characteristics (III)

  18. Platelet Reactivity by Conventional Aggregometry * p < 0.001 for Triple group vs. High-MD group † p = 0.001 for Triple group vs. High-MD group

  19. Platelet Reactivity by VerifyNow P2Y12 assay * p = 0.085 for Triple group vs. High MD group †p = 0.034 for Triple group vs. High MD group

  20. Inhibition of Maximal Platelet Aggregation (%) p < 0.001 by ANOVA p < 0.001 by ANOVA p < 0.001 p < 0.001 p < 0.001 p < 0.001 49±20 42±21 p = 0.002 p = 0.003 24±20 19±19 7±21 6±13 5 μM ADP 20 μM ADP

  21. Inhibition of Late Platelet Aggregation (%) p < 0.001 p < 0.001 p < 0.001 p < 0.001 p < 0.001 p = 0.006 71±26 66±34 p = 0.018 p = 0.008 40±31 38±42 17±43 11±36 5 μM ADP 20 μM ADP

  22. Change of P2Y12 reaction unit (%) p < 0.001 by ANOVA p < 0.001 p = 0.071 43±24 p = 0.003 31±28 11±23

  23. Rate of HPPR (5 μM ADP-induced Aggmax > 50%) (%) p = 0.602 by ANOVA p = 0.003 by ANOVA p = 0.795 p = 1.000 p = 0.601 p = 0.003 p = 0.021 p = 0.532 Pre-discharge 30-day follow-up

  24. Rate of HPPR (20 μM ADP-induced Aggmax > 50%) (%) p < 0.001 p = 0.737 by ANOVA p = 0.001 p = 0.170 p = 0.003 by ANOVA Pre-discharge 30-day follow-up

  25. Achieving Balance: efficacy vs. bleeding • Superiority of Ticagrelor to Prasugrel in terms of cardiovascular mortality - ↓ myocardial infarction > ↑ major bleeding - elevated level of adenosine: inhibition of adenosine reuptake by red blood cells • No increase of major bleeding by TAPT 1) Endothelium-targeted antithrombotic therapy: Cilostazol reduces the number of partially activated platelets by interacting with activated endothelial cells. 2) Adjunctive cilostazol to aspirin or clopidogrel does not prolong bleeding time. 3) Cilostazol has the relatively short recovery time of platelet function.

  26. Beneficial role of Cilostazol in AMI patients • Additive platelet inhibition irrespective of CYP2C19 genotyping - Carrier of CYP2C19 mutant allele: East Asian 55-60% vs. Caucasian 25-30% - Hepatic metabolism of Cilostazol: mainly CYP3A system • Elevated level of adenosine • Activation of RISK (PI3/Akt) pathway - Reduction of ischemia-reperfusion injury • Control of diverse pathway of atherothrombosis - oxidative stress - endothelial dysfunction - expression of adhesion molecule - inflammation cascade - cholesterol oxidation

  27. Juggling Antiplatelets • Choice of intensified antiplatelet regimens (TAPT vs. prasugrel vs. ticagrelor)- efficacy - bleeding risk - tolerability - cost - duration - additional pleiotropic effect ex) control of neointimal hyperplasia • “Head to head comparison”is needed.

  28. Efficacy and Safety Correlated with IPA ASA+prasugrel TAPT ASA+ticagrelor ASA+clopidogrel Adjunctive Cilostazol: Pleiotropic effects on diverse cardiovascular system BLEEDING= Non-CABG Major ASA Relative Rate EFFICACY= Death/MI/Stroke Placebo ASA+prasugrel TAPT ASA ASA+clopidogrel ASA+ticagrelor % IPA Antithrombotic Trialists’ Collaboration. BMJ. 2002;324:71 Yusuf et al. N Engl J Med. 2001;345:494 Wiviott et al. N Engl J Med 2007;357:2001-2015 Wallentin et al. N Engl J Med 2009;361:1-13 *IPA = inhibition of platelet aggregation

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