Comparison of 6-month vs. 12-month Antiplatelet Therapy After Stent Implantation

1. The Randomized Comparison of 6-month vs. 12-month Duration of Dual Antiplatelet Therapy after the Implantation of Drug Eluting Stent Hyeon-Cheol Gwon, Joo Yong Hahn, Young Bin Song, Kyung Woo Park, Yang Soo Jang, Hyo-Soo Kim, On behalf of the EXCELLENT Trial Investigators Samsung Medical Center, Sungkyunkwan University School of Medicine

2. Disclosure Statement of Financial Interest Within the past 12 months, I or my spouse/partner have had a financial interest/arrangement or affiliation with the organization(s) listed below. • CONSULTING FEES/HONORARIA: • Cordis, • Medtronic Asia Pacific • RESEARCH/RESEARCH GRANTS: • Abbott Korea, • Medtronic Korea

3. Background • Current guidelines recommend at least 12 months of dual antiplatelet therapy after DES implantation • This recommendation is not based on any prospectively randomized data. • Prolonged duration of clopidogrel therapy in addition to aspirin may be associated with greater cost and higher risk of bleeding.

4. Objective of Study • To test the safety and efficacy of 6-month duration compared with 12-month duration of dual antiplatelet therapy (DAT) in addition to aspirin after the implantation of DES • Hypothesis • Six-month DAT is non-inferior to 12-month DAT • in terms of target vessel failure at 12 months

5. Patient Eligibility

6. Trial Design Prospective, open label, two-arm, randomized multi-center trial 1443 Patients Matching Enrollment Criteria DAT 6 monthsN=722 DAT 12 monthsN=721 2x2 factorial design EESN=539 SES N=182 EESN=540 SESN=182 Percutaneous Coronary Intervention Primary clinical endpoint evaluation Clinical 1mo 3mo 9mo 12mo 2yr 3yr 4yr 5yr Angiographic Co-primary angiographic endpoint evaluation Am Heart J 2009 May;157:811-817.e1 www.clinicaltrials. gov (NCT00698607).

7. EXCELLENT RCT EES vs. SES Presented at LBCT session in TCT 2010 by Dr. HS Kim

8. Study Endpoints • Primary Endpoint • 12-month target vessel failure (TVF) • a composite of cardiac death, MI, or TVR • Co-primary endpoint • In-segment late luminal loss (LL) at 9 months(for comparison of EES vs. SES) • Secondary Endpoints • All death, cardiac death • Myocardial infarction (MI) • Cerebrovascular accident (CVA) • Target lesion revascularization (TLR) • Target vessel revascularization (TVR) • Any revascularization • Stent thrombosis: definite or probable stent thrombosis by ARC definition • TIMI major bleeding: a drop in Hb > 5 g/dl or in Hct > 15% • Safety endpoint: death, MI, CVA, stent thrombosis, or TIMI major bleeding • Major adverse cardiocerebral event (MACCE): death, MI, CVA, or any revasc • * Definitions follow the ARC recommendations, if not described.

9. Sample Size Calculation • Primary Endpoint • 12-month Target Vessel Failure (TVF) • TVF in 12-month DAT group: 10% • Non-inferiority design with non-inferiority margin 4% • Type I error 0.05, type II error 0.20 • Sampling ratio 6-month:12-month = 1:1 • Estimated drop out rate 5% • Total 1,372 patients needed

10. Independence in Trial Coordination The companies were not involved with the protocol development or the study process, including site selection, management, and data collection and analysis.

11. Participating Centers 19 Hospitals in Republic of Korea • Seoul National University Hospital • Yonsei University Severance Hospital • Samsung Medical Center • Seoul National University Bundang Hospital • Gachon University Gil Medical Center • Yonsei University Wonju Christian Hospital • Hallym University Sacred Heart Hospital • Kandgong Sacred Heart Hospital • Chonam National University Hospital • Gangnam Severance Hospital • NHIC Ilsan Hospital • Inje University Sanggye Paik Hospital • Korea University Anan Hospital • Pusan National University Hospital • Boramae Medical Center • Kangnam Sacred Heart Hospital • Uijeongbu St. Mary’s Hospital • Keimyung University Dongsan Hospital • EwhaWomans University Mokdong Hospital

12. Study flow Enrolled and Randomized (n=1,443) Allocated to 6-mo DAT (n=722) Allocated to 12-mo DAT (n=721) Intention-to-treatment Analysis Follow-up loss within 395 days n=6 Follow-up loss within 395 days n=9 6-mo DAT with 12-mo FU (n=716) 12-mo DAT with 12-mo FU (n=712) 12-mo event Analysis

13. Baseline Clinical Profiles * Mean±SD

14. Angiographic and ProceduralProfiles (per Patient)

15. Angiographic Profiles(per lesion)

16. Procedural Profiles and QCA(per lesion)

17. Medications (*due time: 120~240 days in 6-mo DAT group, 300~420 days in 12-mo DAT group)

18. 12-month Clinical Event (Chi-square test) Safety endpoint: death, MI, CVA, stent thrombosis, or TIMI major bleeding TVF: cardiac death, MI, or TVR MACCE: death, MI, CVA, or any revascularization

19. 1˚ Endpoint 12-month Target Vessel Failure (Kaplan-Meier Analysis) Cumulative proportional TVF estimate at 1 year Difference p=0.426 12-mo DAT(N=361) 4.3±0.8% Non-inferiority p=0.0031 Pre-specified non-inferiority margin 4.0% 6-mo DAT(N=1067) 5.2±0.8% Non-inferior 3.6% 0.9% Upper 1-sided 97.5% CI Difference

20. 1˚ Endpoint Target Vessel Failure 6-mo DAT 12-mo DAT P=0.507 HR = 1.17 (95% CI 0.73-1.89) 4.7% Cumulative incidence rate (%) 4.4% Months after initial procedure

21. 1˚ Endpoint Target Vessel Failure (Landmark Analysis) 6-mo DAT ~ 6 months 6 months ~ 12-mo DAT P=0.563 HR = 1.25 (95% CI 0.59-2.67) P=0.699 HR = 1.13 (95% CI 0.61-2.07)

22. Cardiac Death 6-mo DAT 12-mo DAT P=0.533 HR = 0.58 (95% CI 0.10 – 3.23) Cumulative incidence rate (%) 0.4% 0.3% Months after initial procedure

23. Myocardial Infarction 6-mo DAT 12-mo DAT P=0.280 HR = 1.62 (95% CI 0.67 – 3.93) Cumulative incidence rate (%) 1.8% 1.1% Months after initial procedure

24. Stent Thrombosis (Definite or probable stent thrombosis by ARC definition) 6-mo DAT 12-mo DAT P=0.426 HR = 1.68 (95% CI 0.47 – 6.06) Cumulative incidence rate (%) 0.8% 0.4% Months after initial procedure

25. TIMI Major Bleeding (Overt clinical bleeding with a drop of Hb > 5 g/dl or Hct > 15%) 6-mo DAT 12-mo DAT P=0.419 HR = 0.50 (95% CI 0.09 – 2.71) Cumulative incidence rate (%) 0.6% 0.3% Months after initial procedure

26. Safety Endpoint (Death, MI, stent thrombosis, CVA, or TIMI major bleeding) 6-mo DAT 12-mo DAT P=0.678 HR = 1.13 (95% CI 0.64 – 1.99) Cumulative incidence rate (%) 3.4% 3.1% Months after initial procedure

27. MACCE (Death, MI, CVA, or any revascularization) 8.4% 6-mo DAT 12-mo DAT P=0.896 HR = 0.98 (95% CI 0.68 – 1.40) 7.5% Cumulative incidence rate (%) Months after initial procedure

28. Subgroup Analysis *ACS = unstable angina, NSTEMI, or STEMI Favors 6-mo DAT Favors 12-mo DAT

29. 12-month TVF in Stent Subgroups (Kaplan-Meier Analysis) Cumulative proportional TVF estimate at 1 year 12-mo DAT(N=182) 2.2±1.1% 12-mo DAT(N=539) 5.1±1.0% 6-mo DAT(N=182) 5.0±1.6% 6-mo DAT(N=540) 5.2±1.0% Non-inferiority p=0.0029 Non-inferiority p=0.268 Everolimus-eluting Stent Sirolimus-eluting Stent 97.5% 2.9% 6.6% 0.1% 2.2% Upper 1-sided 97.5% CI Pre-specified non-inferiority margin: 4.0% Difference

30. TVF in Stent Subgroups Everolimus-eluting Stent Sirolimus-eluting Stent 6-mo DAT 12-mo DAT p=0.914 HR = 1.03 (0.61-1.75) p=0.168 HR = 2.29 (0.71-7.43) 5.0% 4.9% 4.6% 2.2%

31. Study flow: Per-protocol analysis Enrolled and Randomized (n=1,443) Allocated to 6-mo DAT (n=722) Allocated to 12-mo DAT (n=721) Intention-to-treatment Analysis • Follow-up loss within 395 days (n=6) • Clopidogrel duration less than due time (n=14) • Clopidogrel duration more than due time (n=192) • No information about clopidogrel (n=13) • Follow-up loss within 395 days (n=9) • Clopidogrel duration less than due time (n=41) • Clopidogrel duration more than due time (n=219) • No information about clopidogrel (n=13) DAT 6-mo with 12-mo FU (n=497, 68.8%) DAT 12-mo with 12-mo FU (n=439, 60.9%) Per-protocol Analysis (*due time: 120~240 days in 6-mo DAT group, 300~420 days in 12-mo DAT group)

32. 12-month Target Vessel Failureby Per-protocol Analysis Cumulative proportional TVF estimate at 1 year Difference p=0.158 12-mo DAT(N=439) 4.3±0.8% Non-inferiority p=0.0093 Pre-specified non-inferiority margin 4.0% 6-mo DAT(N=497) 3.6±0.8% Non-inferior 3.6% 1.5% Upper 1-sided 97.5% CI Difference

33. Target Vessel Failureby Per-protocol Analysis 6-mo DAT 12-mo DAT P=0.203 HR = 1.66 (95% CI 0.76 – 3.59) Cumulative incidence rate (%) 3.2% 2.1% Months after initial procedure

34. 12-month TVF in Stent Subgroups by Per-protocol Analysis Cumulative proportional TVF estimate at 1 year 12-mo DAT(N=107) 1.9±1.3% 12-mo DAT(N=332) 2.1±0.8% 6-mo DAT(N=120) 4.2±1.8% 6-mo DAT(N=377) 4.4±0.9% Non-inferiority p=0.222 Non-inferiority p=0.013 Everolimus-eluting Stent Sirolimus-eluting Stent 3.7 6.7 1.3 2.3 Non-inferior Upper 1-sided 97.5% CI Pre-specified non-inferiority margin: 4.0% Difference

35. TVF in Stent Subgroups by Per-protocol Analysis Everolimus-eluting Stent Sirolimus-eluting Stent p=0.286 HR=1.65 (0.66-4.13) p=0.332 HR=2.25 (0.44-1.6) 4.2% 2.9% 1.9% 2.1%

36. Study Limitations • The incidence of primary endpoint was lower than expected. • Underpowered to test hard endpoints of death, MI, or stent thrombosis. • Significant proportion of the patients crossed over to shorter or longer duration of clopidogrel therapy. • Longer term duration of follow-up is to be done.

37. Conclusions • Six-month DAT is non-inferior to 12-month DAT with regard to the risk of target vessel failure at 12 months after DES implantation. • In particular, the EES subgroup showed very similar event rates between the 6-month and 12-month DAT groups. • A larger-scale randomized controlled trial is required to test the impact of shorter duration of clopidogrel therapy on the hard endpoints of death, MI, or stent thrombosis.