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Dominick J. Angiolillo, MD , PhD Director of Cardiovascular Research Assistant Professor of Medicine

CRT 2008 Wednesday February 13 th , 2008.

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Dominick J. Angiolillo, MD , PhD Director of Cardiovascular Research Assistant Professor of Medicine

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  1. CRT 2008 Wednesday February 13th, 2008 A Randomized Study Assessing the Impact of Cilostazol on Platelet Function Profiles in Patients with Diabetes Mellitus and Coronary Artery Disease on Dual Antiplatelet Therapy: Results of the OPTIMUS-2(Optimizing anti-Platelet Therapy In diabetes MellitUS)Study Dominick J. Angiolillo, MD, PhD Director of Cardiovascular Research Assistant Professor of Medicine University of Florida College of Medicine – Jacksonville, Fl

  2. Presenter Disclosure Information Name: Dominick J Angiolillo Within the past 12 months, the presenter or their spouse/partner have had a financial interest/arrangement or affiliation with the organization listed below. Company Name: Relationship: Bristol Myers Squibb Consultant/Speaker bureau Sanofi-Aventis Consultant/Speaker bureau Eli Lilly Consultant/Speaker bureau Daiichi Sankyo Consultant/Speaker bureau Portola Consultant GSK Educational Grant OPTIMUS 2 was an investigator-initiated study. Dr Angiolillo was recipient of the 2006 GSK International Competitive Educational Grant to perform the study. Otsuka pharmaceuticals provided study medication.

  3. Ischemic Risk (including stent thrombosis) Individual response variability to dual antiplatelet therapy OPTIMUS-2 20 15 10 Number of patients 5 0 2.5 12.5 22.5 32.5 42.5 52.5 62.5 72.5 82.5 92.5 7.5 17.5 27.5 37.5 47.5 57.5 67.5 77.5 87.5 97.5 % Platelet aggregation (LTA-ADP 20mM) Angiolillo DJ et al. Am J Cardiol 2006; 97: 38-43

  4. OPTIMUS-2 Non responders (Platelet inhibition 10%) Low responders (Platelet inhibition 10-29%) Responders (Platelet inhibition >30%) 80 p=0.002 p<0.0001 60 8% 38% 14% Platelet aggregation (%) 56% 40 78% 6% 20 0 DM No-DM DM No-DM ADP 20M ADP 6M Influence of Diabetes Mellitus on Clopidogrel-induced Antiplatelet Effects Acute phase of treatment Long-term phase of treatment No-DM DM p=0.04 24 hrs post 300 mg LD Angiolillo DJ et al. Diabetes 2005; 54:2430-5 Angiolillo DJ et al. J Am Coll Cardiol 2006; 48: 298-304

  5. OCH3 CH3 O O O C N HOOC N * HS Cl S 15% active metabolite Cl Gi cAMP PDE-III Gs cAMP AC Upregulation of P2Y12 receptor signaling in type 2 diabetes mellitus Clopidogrel ATP ADP P2X1 P2Y1 Gastro-intestinal absorption Gq G12 “Rho” Ca2+ flux Shape change PIP2 P2Y12 PLCβ Shape change + DAG IP3 Hepatic CYP Biotransformation PKC αi βγ Ca2+ mobilization MLCK-P AC PI3K 85% inactive metabolites (Esterases in blood) GP IIb/IIIa receptor activation Granule secretion PKB/Akt Rap1b Cilostazol GP IIb/IIIa receptor activation Initiation of Platelet Aggregation Stabilization of Platelet Aggregation VASP VASP-P PGE1 GP IIb/IIIa receptor activation adapted from Angiolillo DJ et al JACC 2007

  6. OPTIMUS-2 Objectives To evaluate platelet function profiles obtained with the adjunct of cilostazol in patients with type 2 diabetes mellitus and coronary artery disease while on standard dual (aspirin and clopidogrel) antiplatelet therapy.

  7. OPTIMUS-2 Cilostazol 100 mg b.i.d. for 2 weeks Cilostazol 100 mg b.i.d. for 2 weeks Randomization Placebo b.i.d. for 2 weeks Placebo b.i.d. for 2 weeks 2 weeks Visit 2 4 weeks Visit 3 Baseline Visit 1 Study Design Prospective, randomized, double-blind, placebo controlled, cross-over design Type 2 Diabetes Mellitus patients with coronary artery disease on aspirin (81 mg) + clopidogrel (75 mg) therapy for ≥ one month Inclusion Criteria

  8. OPTIMUS-2 PGE1 ADP VASP VASP-P Activated or resting platelets Inhibited platelets Endpoints Primary: P2Y12 reactivity index (PRI) Secondary: - VASP-P - VerifyNow P2Y12 (%inhibition and PRU) - Light Transmittance Aggregometry (LTA) Aggmax and Agglate following 5 and 20 mmol/L ADP stimuli w/wo 5nM PGE1 (post treatment platelet reactivity, IPA, platelet disaggregation) Power Calculation: Cilostazol will lead to a 15 ± 16% decrease in PRI; a minimum of 17 patients required to achieve a power of 95% ( two-sided = 0.05)

  9. OPTIMUS-2 Placebo N=12 Cilostazol N=13 Withdrawal due to side effects N=4 (migraine, GI symptoms, tachycardia) Withdrawal due to side effects N=1 (GI symptoms) Crossover Placebo N=9 Cilostazol N=11 20 patients Flow diagram Randomized N=25 Side effects not leading to withdrawal of study medication: cilostazol (N=3) and placebo (N=1)

  10. OPTIMUS-2 Demographics

  11. OPTIMUS-2 Absolute Change in PRI from Baseline (%) p=0.0002 CILOSTAZOL PLACEBO

  12. OPTIMUS-2 Primary Endpoint (%) p=0.0002 P2Y12 reactivity index (PRI) CILOSTAZOL PLACEBO

  13. OPTIMUS-2 VASP-P (MFI ADP + PGE1) 25 Absolute Change Content p=0.0001 p=0.0002 20 15 10 5 0 CILOSTAZOL PLACEBO CILOSTAZOL PLACEBO

  14. OPTIMUS-2 VerifyNow P2Y12 Assay PRU P2Y12 inhibtion p=0.002 p=0.0001 CILOSTAZOL PLACEBO CILOSTAZOL PLACEBO

  15. OPTIMUS-2 Light Transmittance Aggregometry No changes in Placebo vs Baseline LTA parameters (p=ns for all assessments); Cilostazol vs Baseline: (p<0.001 for all ADP + PGE1; p=ns for ADP)

  16. OPTIMUS-2 Inhibition of Platelet Aggregation (%) (%) IPA Late ADP 20mmol/L + PGE1 IPA Max ADP 20mmol/L + PGE1 p<0.0001 p<0.0001 CILOSTAZOL PLACEBO CILOSTAZOL PLACEBO IPA (%) = (intensity of aggregation at baseline) – (intensity of aggregation post cilostazol/placebo)/ (intensity of aggregation at baseline)

  17. OPTIMUS-2 (%) ADP 20mmol/L + PGE1 p<0.0001 CILOSTAZOL PLACEBO Disaggregation Platelet disaggregation (%) = 100 x (1- Aggmax / Agglate)

  18. OPTIMUS-2 Conclusions • In patients with T2DM on chronic standard dual antiplatelet therapy, treatment with cilostazol is associated with enhanced suppression of P2Y12 receptor signaling. • Enhanced P2Y12 inhibition achieved with cilostazol in adjunct to standard antiplatelet treatment regimens may explain why lower ischemic event rates, including stent thombosis, are achieved with triple oral antiplatelet therapy compared to dual therapy. • However, side effects are common with cilostazol therapy which frequently lead to drug withdrawal. • Need for further improvement in antiplatelet strategies…..awaiting more outcome data with novel and potent drugs currently under advanced clinical investigation.

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