CILON-T Late Breaking Trial : Randomized prospective trial of dual vs. triple antiplatelet therapy after DES implantatio

1. CILON-T Late Breaking Trial :Randomized prospective trial of dual vs. triple antiplatelet therapy after DES implantation ACC & i2 summit, March 15th 2010, Atlanta, Georgia Hyo-Soo Kim, MD, PhD Seoul National University Hospital Seoul, Korea

2. Nothing to disclose

3. CILON-T trial • CILostazol-based triple anti-platelet therapy ON Ischemic Complication after drug-eluting stenT implantation • Multicenter, prospective, randomized trial • PROBE (Prospective Randomized Open-label Blinded Evaluation) • Principal investigator • Hyo-Soo Kim, MD, PhD • Clinical trials identifier • NCT00776828

4. CILON-T trial : participating centers

5. Backgroundof the CILON-T trial Accumulating evidences suggest the relationship between clopidogrel resistance & clinical events. Recent studies reported the value of using VerifyNow (PRU) in predicting clinical events. Efficacy of adding cilostazol in reducing clinical events has been reported in the registry or small randomized controlled study of specific subpopulation.

6. Backgroundof the CILON-T trial • Efficacy of adding cilostazol on DAT in reducing • clinical events or PRU valuehas not been tested • in the real-world all-comer patients with DES implantation • at the level of large randomized controlled study.

7. CILON-T Clinical Trial Design • Comparison of two anti-platelet regimens with random assignment of statin type (atorva-20 & rosuva-10) • 960 patients randomized (Sep 2006~June 2009) TAT group (477) versus DAT group (483) • Five centers in Korea • Follow-up requirements • P2Y12 reaction unit (VerifyNow TM P2Y12) at discharge & 6 mo • Clinical F/U at 1, 3 and 6 mo • Angiographic F/U (recommended)

8. Assessed for eligibility (n=976) Randomization (n=960) DAT (n=483) TAT (n=477) Atorvastatin (n=241) Rosuvastatin (n=236) Atorvastatin (n=242) Rosuvastatin (n=241) 3 Withdrawal at patient request 14 Withdrawal at clinician’s judgment 3 Failed PCI 2 Withdrawal at patient request 19 Withdrawal at clinician’s judgment 4 Failed PCI TAT (n=457) DAT (n=458) 915 patients with successful PCI & follow-up • ** Primary endpoint : at 6 month • Cardiovascular death, nonfatal MI, ischemic stroke, TLR • Platelet (P2Y12) reaction unit

9. CILON-T Trial Endpoints • Primary Endpoint • Composite of clinical outcomes within six months (cardiac death, MI, ischemic stroke & TLR) • Secondary endpoint • PRU level measured at discharge & 6 mo after the index procedure • All cause of death, stent thrombosis, and each component of primary endpoint at six months • Safety Endpoint • Bleeding complications according to TIMI criteria • The incidence of drug discontinuation • Heart rate

10. Key participation criteria • Inclusion criteria • Age 18~80yrs • All-comers : patients with native coronary artery lesions for which DES implantation was feasible • Exclusion criteria • Hepatic dysfunction (GOT/GPT >*3 UNL) • Renal dysfunction (Scr>2.0mg/dl or on dialysis) • LV dysfunction (EF <30%) • Uncontrolled hematological disease • Patients taking warfarin or other antiplatelet agents • Allergy to study medications

11. RESULTS

12. Clinical profiles of patients

13. Profiles of Medication at Discharge

14. Angiographic profiles of patients

15. Procedural profiles of patients

16. Results: P2Y12 reaction unit (PRU): TAT vs DAT PRU p < 0.001 p < 0.001

17. Results: Change of PRU for 6 months : TAT vs DAT TAT DAT P2Y12 reaction unit (PRU) p< 0.001 p =0.23 At discharge 6 mo At discharge 6 mo

18. Results: Clinical outcomes depending on PRU value Composite of CD, nonfatal MI, ischemic stroke & TLR Composite of CD, nonfatal MI & ischemic stroke TLR p=0.077 p=0.486 p=0.037

19. Results: Clinical outcomes depending on anti-plt regimen

20. Results: Clinical outcomes depending on anti-plt regimen Double anti-PLT regimen Triple anti-PLT regimen Composite of CD, nonfatal MI, ischemic stroke & TLR Composite of CD, nonfatal MI & ischemic stroke TLR p=0.818 for log-rank test p=0.701 for log-rank test p=0.742 for log-rank test 9.2% 7.2% 8.5% 6.6% 2.0% 2.0%

21. Distribution of PRU in pts with MACCE

22. PRU value versus Anti-PLT regimen to predict MACCE Composite of CD, nonfatal MI, ischemic stroke & TLR Composite of CD, nonfatal MI & ischemic stroke TLR

23. Subgroup analysis : TAT vs DAT Baseline characteristics HR 95% CI Diabetes 0.37-1.60 0.78 Yes 1.02 0.57-1.83 No Age ≥ 65 yr 1.34 0.69-2.58 0.64 0.32-1.29 <65 yr Sex 0.66 0.39-1.13 Male 3.41 1.12-10.4 Female Lesion length 0.79 0.34-1.84 ≥ 28mm 0.70 0.38-1.31 <28mm Reference vessel diameter <2.75mm 0.80 0.38-1.69 ≥2.75mm 0.85 0.45-1.60 0 1 2 TAT better DATbetter

24. Results: Safety outcomes : TAT vs DAT

25. Results: Independent predictors for MACCE (Cox-regression analysis)

26. Study limitations • Open-label study, but blinded evaluation • Platelet reactivity measured by single method • Not powered to verify the effect of cilostazol on the hard endpoint, such as CD, nonfatal MI or stent thrombosis

27. Summary of CILON-T randomized controlled trial • TAT achieved lower PPR (post-treatment platelet reactivity) than DAT. • But it did not necessarily reduce MACCE within six months after DES implantation, • because there were substantial numbers of hypo-responders even to TAT. • The importance of PPR is reflected by the finding that the patients with low PPR (PRU < 210 unit) did not develop any thrombotic event (CD, MI, or ischemic stroke) irrespective of anti-platelet regimen.

28. Conclusion of CILON-T randomized controlled trial • Tailored decision on the adjunctive use of cilostazol according to PPR (post-treatment platelet reactivity) can be helpful to reduce adverse clinical outcomes in patients who undergo DES implantation.