The Randomized Comparison of 6-month vs 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

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

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.

Objective of Study Hypothesis 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

General Exclusion Criteria Angiographic Exclusion Criteria Patient Eligibility Inclusion Criteria > 50% stenosis by visual estimation Evidence of myocardial ischemia Stable angina Unstable angina Recent infarction, silent ischemia + functional study or reversible changes in the ECG c/w ischemia Target lesion must be located in a native coronary artery 2.25mm ≤ RVD ≤ 4.25mm Lesion length: no limitation Multiple stenting: no limitation General Exclusion Criteria GI or GU bleeding ≤3 months, major surgery ≤ 2 months Hb<10 g/dL, PLT<100K Elective surgical procedure planned ≤ 12 months LVEF < 25%, or in shock MI ≤ 72 hours Creatinine level ≥ 3.0mg/dL or dependence on dialysis Severe hepatic dysfunction (AST, ALT ≥ x3 UNL) Patients who have received any stent implantation in the target vessel prior to enrollment Angiographic Exclusion Criteria Patients with significant LM stenosis BMS or DES ISR CTO True bifurcation lesions requiring two stents

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

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

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.

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

Independence in Trial Coordination Executive Committee (HS Kim, MD, YS Jang, MD, JH Yoon, MD, HC Gwon, MD, IH Chae, MD, TH Ahn, MD) DSMB Data Safety Monitoring Board MRCC Trial Coordinating Center CEAC Clinical Event Adjudication Committee Steering Committee 19 study investigators Grant Support 1) Ministry of Health, Welfare, and Family Affairs of Korea 2) Abbott Vascular Korea 3) Boston Scientific Korea The companies were not involved with the protocol development or the study process, including site selection, management, and data collection and analysis.

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 Ewha Womans University Mokdong Hospital

Study flow Enrolled and Randomized (n=1,443) Allocated to 6-mo DAT 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

Baseline Clinical Profiles Variables ― no. (%) 6-mo DAT (N=722) 12-mo DAT (N=721) p-value Age (years)* 63.0±9.6 62.4±10.4 0.209 Males 470 (65.1) 461 (63.9) 0.646 Body mass index (kg/m2)* 24.9±3.1 25.1±3.0 0.324 Clinical diagnosis 0.560 Silent ischemia/ stable angina 353 (48.9) 346 (48) Unstable angina/NSTEMI 350 (48.5) 349 (48.4) STEMI 19 (2.6) 26 (3.6) Diabetes mellitus 272 (37.7) 278 (38.6) 0.729 Chronic renal failure 6 (0.8) 9 (1.2) 0.435 Hypertension 525 (72.7) 532 (73.8) Dyslipidemia 543 (75.2) 550 (76.3) 0.634 Current smoker 198 (27.4) 186 (25.8) 0.485 Family history of CAD 62 (8.6) 65 (9.0) 0.774 Previous myocardial infarction 47 (6.5) 27 (3.7) 0.017 Previous PCI 67 (9.3) 0.650 Previous CABG 11 (1.5) 7 (1.0) 0.344 Previous congestive heart failure 4 (0.6) 5 (0.7) 0.753 Cerebrovascular disease 48 (6.7) 0.910 Peripheral vascular disease 10 (1.4) 0.815 LV ejection fraction (%)* 61.0±9.6 61.6±9.4 0.297 Table 1 * Mean±SD

Angiographic and Procedural Profiles (per Patient) Variables ― no. (%) 6-mo DAT (N=722) 12-mo DAT (N=721) p-value Angiographic disease extent 0.904 1-vessel disease 347 (48.1) 346 (48.0) 2-vessel disease 226 (31.3) 232 (32.2) 3-vessel disease 149 (20.6) 143 (19.8) LAD location 442 (61.6) 440 (61.2) 0.861 Lesion type B2C 406 (57.2) 421 (59.1) 0.457 Total occlusion 14 (2.0) 11 (1.5) 0.540 Thrombotic lesion 73 (10.3) 70 (9.8) 0.778 Ulcerative lesion 23 (3.2) 16 (2.2) 0.258 Bifurcation lesion 227 (31.4) 247 (34.3) 0.255 No. of lesion treated per patient 1.40.6 1.30.6 0.173 No. of stents per patient 1.590.96 1.640.94 0.398 Use of GP IIb/IIIa inhibitor 12 (1.7%) 0.997 Use of IVUS 315 (43.6) 312 (43.3) 0.892 Table 1

Angiographic Profiles (per lesion) Variables ― no. (%) 6-mo DAT (N=957) 12-mo DAT (N=970) p-value LAD location 467 (49.1) 459 (47.4) 0.473 ACC/AHA B2/C type 487 (52.8) 505 (53.7) 0.696 Long Lesion (≥ 20 mm) 353 (40.2) 373 (41.2) 0.664 Tortuous lesion 73 (7.9) 59 (6.3) 0.168 Total occlusion 14 (1.5) 11 (1.2) 0.514 Ulcerated lesion 23 (2.4) 16 (1.6) 0.240 Thrombotic lesion 74 (8.0) 73 (7.8) 0.835 Bifurcation lesion 236 (24.7) 272 (28.0) 0.092 Calcific lesion 186 (20.2) 194 (20.6) 0.803 Table 1

Procedural Profiles and QCA (per lesion) Variables ― no. (%) 6-mo DAT (N=957) 12-mo DAT (N=970) p-value No. of stents per lesion 1.200.46 1.210.46 0.429 Max stent diameter   3.210.42 3.190.42 0.315 Min stent diameter 3.080.41 3.060.43 0.287 Sum of stent length 27.813.0 28.313.7 0.362 Device success 941 (99.7) 963 (99.7) 0.977 Lesion success 964 (99.8) 0.636 Procedural success 935 (99.0) 956 (99.0) 0.857 Pre-PCI MLD 0.860.49 0.880.47 0.304 Pre-PCI RD 2.910.50 2.840.50 0.005 Lesion length 20.011.5 20.712.3 0.185 Post-PCI Instent MLD 2.630.46 2.580.47 0.330 Post-PCI Inseg MLD 2.260.51 2.190.51 0.003 Post-PCI RD 2.950.46 2.910.46 0.025 Table 1

Medications Variables ― no. (%) 6-mo DAT (N=722) 12-mo DAT (N=721) p-value Use of aspirin at 1 year 676 (99.9%) 667 (99.3%) Duration of clopidogrel therapy 190 [181-260] 375 [364-395] Clopidogrel duration Less than due time* Within due time* More than due time* No information 16 (2.2%) 501 (69.4%) 192 (26.6%) 13 (1.8%) 45 (6.2%) 442 (61.3%) 219 (30.4%) 15 (2.1%) Clopidogrel restart within 1 year 34 (4.7%) 22 (3.1%) Medications at discharge Aspirin 707 (99.4) 704 (99.0) 0.364 Clopidogrel 702 (98.7) 708 (99.6) 0.082 Statin 604 (85.0) 582 (81.9) 0.117 ACE inhibitor 224 (31.5) 243 (34.2) 0.283 ARB 244 (34.3) 231 (32.5) 0.465 Beta blocker 427 (60.1) 445 (62.6) 0.327 Warfarin 6 (0.8) 13 (1.8) 0.106 Calcium channel blocker 238 (33.5) 249 (35.0) 0.539 Table 2 (*due time: 120~240 days in 6-mo DAT group, 300~420 days in 12-mo DAT group)

12-month Clinical Event (Chi-square test) Variables ― no. (%) 6-mo DAT RR (95% CI) p-value Total death 4 (0.6) 7 (1.0) 0.57 (0.17-1.94) 0.359 Cardiac death 2 (0.3) 3 (0.4) 0.66 (0.11-3.97) 0.650 MI 13 (1.8) 8 (1.1) 1.63 (0.67-3.95) 0.277 MI of target vessel 12 (1.7) 5 (1.0) 1.72 (0.67-4.39) 0.253 CVA 5 (0.7) 0.60 (0.14-2.50) 0.473 TLR 17 (2.4) 19 (2.7) 0.89 (0.46-1.72) 0.723 TVR 22 (3.1) 22 (3.2) 0.95 (0.52-1.72) 0.865 Any revascularization 41 (5.7) 43 (6.0) 0.95 (0.61-1.47) 0.802 Stent thrombosis 6 (0.8) 2.00 (0.50-8.02) 0.320 Any bleeding 10 (1.4) 0.39 (0.12-1.26) 0.105 TIMI major bleeding 0.50 (0.09-2.72) 0.409 Safety endpoint 24 (3.4) 1.09 (0.60-1.96) 0.779 TVF 34 (4.7%) 31 (4.4%) 1.10 (0.67-1.80) 0.721 MACCE 54 (7.5) 60 (8.4) 0.89 (0.60-1.30) 0.537 Table 2 Safety endpoint: death, MI, CVA, stent thrombosis, or TIMI major bleeding TVF: cardiac death, MI, or TVR MACCE: death, MI, CVA, or any revascularization

12-month Target Vessel Failure 1˚ Endpoint 12-month Target Vessel Failure (Kaplan-Meier Analysis) Cumulative proportional TVF estimate at 1 year 6-mo DAT (N=1067) 5.2±0.8% 12-mo DAT (N=361) 4.3±0.8% Pre-specified non-inferiority margin 4.0% Difference p=0.426 Non-inferiority p=0.0031 Upper 1-sided 97.5% CI Difference Table 4: PP, all lesions Non-inferior 0.9% 3.6% -1.5 -1.0 -0.5 0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.0 4.5 %

Cumulative incidence rate (%) Months after initial procedure 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 Patient Number at Risks 6-month 722 707 701 697 681 12-month 721 710 699 698 680

Target Vessel Failure (Landmark Analysis) ~ 6 months 6 months ~ 1˚ Endpoint Target Vessel Failure (Landmark Analysis) 6-mo DAT 12-mo DAT ~ 6 months 6 months ~ P=0.563 HR = 1.25 (95% CI 0.59-2.67) P=0.699 HR = 1.13 (95% CI 0.61-2.07) Patient Number at Risks 6-month 722 707 701 12-month 721 710 699 Patient Number at Risks 701 697 681 699 698 680

Cumulative incidence rate (%) Months after initial procedure 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 Patient Number at Risks 6-month 722 707 701 697 681 12-month 721 710 699 698 680

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 Patient Number at Risks 6-month 722 707 701 697 681 12-month 721 710 699 698 680

Cumulative incidence rate (%) Months after initial procedure 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 Patient Number at Risks 6-month 722 707 701 697 681 12-month 721 710 699 698 680

Cumulative incidence rate (%) Months after initial procedure 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 Patient Number at Risks 6-month 722 707 701 697 681 12-month 721 710 699 698 680

Cumulative incidence rate (%) Months after initial procedure 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 Patient Number at Risks 6-month 722 707 701 697 681 12-month 721 710 699 698 680

Cumulative incidence rate (%) Months after initial procedure MACCE (Death, MI, CVA, or any revascularization) 8.4% P=0.896 HR = 0.98 (95% CI 0.68 – 1.40) 7.5% Cumulative incidence rate (%) 6-mo DAT 12-mo DAT Months after initial procedure Patient Number at Risks 6-month 722 707 701 697 681 12-month 721 710 699 698 680

Subgroup Analysis N 6-mo DAT 12-mo Χ2 p-value Cox HR Cox P for interaction Age < 65 761 19 (5.0%) 12 (3.2%) 0.202 0.115 0.127  65 667 15 (4.5%) 19 (5.7%) 0.465 0.588 ACS* No 694 21 (6.9%) 14 (4.1%) 0.252 0.188 0.301 Yes 734 13 (3.6%) 17 (4.6%) 0.474 0.728 Diabetes 884 10 (2.2%) 23 (5.3%) 0.018 0.055 0.001 544 24 (8.9%) 8 (2.9%) 0.003 0.006 LVEF < 50% 123 3 (3.0%) 4 (7.1%) 0.286 0.503 0.330  50% 1086 26 (4.8%) 25 (4.6%) 0.833 0.607 Bifurcation 959 23 (4.7%) 20 (4.3%) 0.769 0.608 0.957 469 11 (4.9%) 11 (4.5%) 0.830 0.668 Stent EES 1067 25 (4.7%) 27 (5.1%) 0.739 0.914 0.305 SES 361 9 (5.0%) 4 (2.2%) 0.149 0.168 Multi-stent 854 14 (3.2%) 12 (2.9%) 0.819 0.894 0.597 563 20 (7.5%) 19 (6.4%) 0.601 0.311 *ACS = unstable angina, NSTEMI, or STEMI 1 2 3 Favors 6-mo DAT Favors 12-mo DAT

12-month TVF in Stent Subgroups (Kaplan-Meier Analysis) Cumulative proportional TVF estimate at 1 year Everolimus-eluting Stent Sirolimus-eluting Stent 97.5% 6-mo DAT (N=540) 5.2±1.0% 12-mo DAT (N=539) 5.1±1.0% Non-inferiority p=0.0029 6-mo DAT (N=182) 5.0±1.6% 12-mo DAT (N=182) 2.2±1.1% Non-inferiority p=0.268 Pre-specified non-inferiority margin: 4.0% Upper 1-sided 97.5% CI Difference Table 4: PP, all lesions 0.1% 2.9% 2.2% 6.6% -1 1 2 3 4 5 6 -1 1 2 3 4 5 6

Everolimus-eluting Stent Sirolimus-eluting Stent TVF in Stent Subgroups 6-mo DAT 12-mo DAT Everolimus-eluting Stent Sirolimus-eluting Stent 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% Patient Number at Risks 6-mo 540 531 528 524 511 12-mo 539 521 505 Patient Number at Risks 6-mo 182 176 174 171 12-mo 179 178

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)

12-month Target Vessel Failure by Per-protocol Analysis Cumulative proportional TVF estimate at 1 year 6-mo DAT (N=497) 3.6±0.8% 12-mo DAT (N=439) 4.3±0.8% Pre-specified non-inferiority margin 4.0% Difference p=0.158 Non-inferiority p=0.0093 Upper 1-sided 97.5% CI Difference Table 4: PP, all lesions Non-inferior 1.5% 3.6% -1.5 -1.0 -0.5 0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.0 4.5 %

Target Vessel Failure by 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 Patient Number at Risks 6-month 497 490 488 487 480 12-month 439 435 433

12-month TVF in Stent Subgroups by Per-protocol Analysis Cumulative proportional TVF estimate at 1 year Everolimus-eluting Stent Sirolimus-eluting Stent 6-mo DAT (N=377) 4.4±0.9% 12-mo DAT (N=332) 2.1±0.8% Non-inferiority p=0.013 6-mo DAT (N=120) 4.2±1.8% 12-mo DAT (N=107) 1.9±1.3% Non-inferiority p=0.222 Pre-specified non-inferiority margin: 4.0% Upper 1-sided 97.5% CI Difference Table 4: PP, all lesions 1.3 3.7 2.3 6.7 Non-inferior -1 1 2 3 4 5 6 -1 1 2 3 4 5 6

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% Patient Number at Risks 6-mo 377 373 371 365 12-mo 332 329 328 Patient Number at Risks 120 117 116 115 107 106 105

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.

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.