Efficacy of Xience/Promus versus Cypher to rEduce Late Loss in stENT Hyo-Soo Kim MD, PhD on behalf of the investigators Seoul National University Hospital, Seoul, Korea

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

Trial Design Prospective, open label, two-arm, randomized multi-center trial 1372 Patients Matching Enrollment Criteria 19 centers in Korea Everolimus-Eluting Stent N=1029 Randomization 3:1 Sirolimus-Eluting Stent N=343 DAT 6 mo N=515 DAT 12 mo N=514 2x2 factorial design DAT 6 mo N=171 DAT 12 mo N=172 Percutaneous Coronary Intervention 1mo 3mo 9mo 12mo Clinical Angiographic 3yr 2yr 4yr 5yr Secondary clinical endpoint evaluation Primary endpoint: In-segment LL Am Heart J 2009 May;157:811-817.e1.

Study Flow: Angiographic F/U Enrolled and randomized (N=1443) EES N=1079 Randomized 3:1 SES N=364 Did not receive allocated stent: 24 - DES: 17 - BMS: 2 - CABG: 1 - POBA: 1 - Not inserted: 3 Failed PCI: 1 Did not receive allocated stent : 29 - DES: 23 - BMS: 0 - CABG: 1 - POBA: 1 - Not inserted: 4 Failed PCI: 0 Received EES (1054 Pts, 1388 Lesions) Received SES (335 Pts, 414 Lesions) Angiographic F/U (67.3%) 709 Pts, 949 Lesions Angiographic F/U (64.5%) 216 Pts, 267 Lesions

Baseline Profiles Variables ― no. (%) EES (N=1,079) SES (N=364) p-value Age, years ― mean±SD 62.5±10.1 63.4±9.9 0.125 Males 703 (65.2) 228 (62.6) 0.386 Body-mass index, kg/m2 25±3.1 25±2.9 0.885 Diabetes mellitus 402 (37.3) 148 (40.7) 0.248 Chronic renal failure 12 (1.1) 3 (0.8) 0.773 Hypertension 790 (73.2) 266 (73.1) 0.959 Dyslipidemia 820 (76.0) 269 (73.9) 0.422 Current smoker 278 (25.8) 106 (29.1) 0.210 Family history of CAD 99 (9.2) 28 (7.7) 0.388 Previous myocardial infarction 56 (5.2) 17 (4.7) 0.696 Previous percutaneous coronary intervention 30 (8.2) 0.589 Previous bypass surgery 6 (1.6) 0.419 Previous congestive heart failure 8 (0.7) 1 (0.3) 0.463 Cerebrovascular disease 57 (5.3) 37 (10.2) 0.001 Peripheral vascular disease 13 (1.2) 0.594 Table 1 5

Baseline Profiles Variables ― no. (%) EES (N=1,079) SES (N=364) p-value Multivessel disease 564 (52.3) 185 (50.8) 0.633 Left ventricular ejection fraction, % 61.4±9.4 60.8±9.8 0.335 Clinical indication 0.115 Silent ischemia 39 (3.6) 16 (4.4) Chronic stable angina 472 (43.7) 172 (47.3) Unstable angina 464 (43.0) 139 (38.2) NSTEMI 76 (7.0) 20 (5.5) STEMI 28 (2.6) 17 (4.7) Medications at discharge Aspirin 1,066 (99.3) 356 (98.9) 0.510 Clopidogrel 1,063 (99.0) 357 (99.2) 1.000 Statin 892 (83.1) 304 (84.4) 0.539 ACE inhibitor 355 (33.1) 119 (33.1) Angiotensin II-receptor antagonist 356 (33.1) 122 (33.9) 0.796 Beta-blocker 665 (61.9) 214 (59.4) 0.404 Calcium-channel blocker 362 (33.7) 128 (35.6) 0.522 Table 1 6

Lesion and Procedural Profiles Variables ― no. (%) EES (N=1,458) SES (N=468) p-value* Location 0.815 Left anterior descending 722 (49.7) 235 (50.4) Left circumflex 319 (22) 101 (21.7) Right coronary 411 (28.3) 130 (27.9) Coronary graft 1 (0.1) 0 (0) Multivessel disease** 564 (52.3) 185 (50.8) 0.633 ACC-AHA B2/C type 746 (53.0) 245 (54.2) 0.632 Total occlusion 48 (3.4) 18 (4) 0.583 Thrombus-containing 114 (8.1) 33 (7.3) 0.567 Bifurcation lesions 166 (11.4) 50 (10.7) 0.728 Calcification 589 (41.8) 183 (40.4) 0.628 Minimal luminal diameter, mm 0.87±0.48 0.88±0.5 0.678 Reference vessel diameter, mm 2.87±0.49 2.88±0.52 0.641 Diameter stenosis, % 69.67±15.34 69.64±15.39 0.955 Lesion length, mm 20.32±12.05 20.48±11.51 0.812 Lesion length > 20mm 544 (40.2) 182 (41.9) 0.562 Table 2 *comparisons were performed using the generalized estimating equations (GEE). **compared with the Chi-square t-test 7

Lesion and Procedural Profiles Variables ― no. (%) EES (N=1,458) SES (N=468) p-value* No. of stents per lesion 1.21±0.47 1.19±0.42 0.311 No. of stents per patient† 1.64±0.97 1.53±0.87 0.049 Total stent length per lesion ― mm 27.86±13.42 28.55±13.22 0.375 Total stent length per patient† 37.7±24.89 36.85±24.87 0.410 Use of GpIIb/IIIa inhibitors** 19 (1.8) 5 (1.4) 0.617 Minimal luminal diameter (in stent) 2.6±0.46 2.6±0.49 0.848 Minimal luminal diameter (in segment) 2.22±0.51 2.24±0.53 0.554 Diameter stenosis (in stent) 8.59±8.95 8.3±8.3 0.451 Diameter stenosis (in segment) 19.01±11.07 18.37±11.19 0.238 Acute gain (in stent) 1.73±0.54 1.72±0.53 0.753 Acute gain (in segment) 1.35±0.58 1.35±0.57 0.877 Use of intravascular ultrasound (IVUS)* 466 (43.2) 160 (44) 0.798 Lesion success 1444 (99.7) 460 (99.8) 0.817 Device success 1446 (99.9) 457 (99.1) 0.100 Procedure success 1433 (99.0) 0.928 Table 2 *comparisons were performed using the generalized estimating equations (GEE). **compared with the Chi-square test, and †with the independent t-test 8

QCA Data(1) :all lesions Variables ― no. (%) EES (N=949) SES (N=267) p-value* Before procedure Lesion length ― mm 20.34±11.80 20.89±11.44 0.512 Reference vessel diameter ― mm 2.86±0.49 2.86±0.52 0.937 Minimal luminal diameter― mm 0.87±0.47 0.83±0.47 0.278 Diameter stenosis ― % 69.57±15.14 71.02±14.83 0.178 Immediately after procedure Minimal luminal diameter ― mm In stent 2.60±0.45 2.59±0.48 0.796 In segment 2.22±0.51 2.21±0.52 0.968 8.57±8.94 8.30±8.63 0.577 19.13±11.30 18.42±10.82 0.322 Acute gain ― mm 1.73±0.54 1.76±0.54 0.526 1.35±0.57 1.38±0.56 0.364 Table 3-1 *comparisons were performed using the generalized estimating equations (GEE). 9

QCA Data(1) :all lesions Variables ― no. (%) EES (N=949) SES (N=267) p-value* Follow-up at 9 months Minimal luminal diameter ― mm In stent 2.42±0.53 2.44±0.55 0.458 In segment 2.12±0.52 2.16±0.53 0.256 Diameter stenosis ― % 14.63±13.33 13.94±12.10 0.415 22.53±13.81 21.02±12.72 0.079 Late luminal loss ― mm 0.19±0.33 0.15±0.33 0.082 0.10±0.36 0.05±0.34 0.051 Binary restenosis ― % 18 (1.9) 3 (1.1) 0.293 30 (3.2) 6 (2.3) 0.352 Restenosis pattern** ― % 1.000 Focal 27 (90.0) 6 (100.0) Diffuse 1 (3.3) 0 (0.0) Proliferative Total occlusion Table 3-1 *comparisons were performed using the generalized estimating equations (GEE). **compared with the Fishcer’s exact test 10

Non-inferiority p-value 1˚ Endpoint In-segment late LL EES (N=935) 0.10±0.36 mm SES (N=266) 0.05±0.34 mm Mean ΔLL: 0.051 mm Upper 1-sided 95% CI: 0.091 mm Non-inferiority p-value 0.023 Prespecified non-inferiority margin: 0.1 mm Non-inferior Table 4: PP, all lesions -0.01 0.00 0.01 0.02 0.03 0.04 0.05 0.06 0.07 0.08 0.09 0.10 0.11 mm Upper 1-sided 95% CI 11

Minimal Luminal Diameters 1˚ Endpoint In-Sement Minimal Luminal Diameters 20 40 60 80 100 Before Procedure EES SES 9-month F/U EES SES After Procedure EES SES % of Lesions 0.0 1.0 2.0 3.0 4.0 Minimal Luminal Diameter (mm)

In-segment & in-stent LL : long lesion or DM subgroup Variables EES SES Total Mean ΔLL (EES-SES) Upper 1-sided 95% CI p-value 1˚Endpoint: In-segment LLL 935 266 1,201 0.0507 0.0912 0.023 Long lesion (≥ 20mm) 369 111 480 0.0344 0.0962 0.041 DM 359 109 468 0.1105 0.1746 0.620 Post-hoc: in-stent LLL 0.0431 0.0811 0.007 0.0328 0.0920 0.031 0.1230 0.1824 0.765 Table 4 13

Cumulative incidence rate (%) Months after initial procedure 2˚ Endpoint Hard Endpoints : Composite of cardiac death, or MI 0.0 2.0 4.0 1.0 3.0 Log-Rank p-value=0.561 Cumulative incidence rate (%) SES: 1.9% EES: 1.5% 3 6 9 12 Months after initial procedure Patient Number at Risks EES 1078 1066 1064 1055 1052 SES 363 356 355 354

Cumulative incidence rate (%) Months after initial procedure 2˚ Endpoint Soft Endpoints TLR 0.0 2.0 4.0 1.0 3.0 5.0 Log-Rank p-value=0.400 EES: 2.4% Cumulative incidence rate (%) SES: 1.7% 3 6 9 12 Months after initial procedure Patient Number at Risks EES 1078 1066 1060 1043 1029 SES 363 356 355 351 350

Cumulative incidence rate (%) Months after initial procedure 2˚ Endpoint Target Lesion Failure : Composite of cardiac death, MI, or ID-TLR 0.0 2.0 4.0 1.0 3.0 5.0 Log-Rank p-value=0.552 EES: 3.7% Cumulative incidence rate (%) SES: 3.0% 3 6 9 12 Months after initial procedure Patient Number at Risks EES 1078 1066 1060 1043 1029 SES 363 356 355 351 350

: Composite of cardiac death, MI, or ID-TLR 2˚ Endpoint Target Lesion Failure : Composite of cardiac death, MI, or ID-TLR Subgroups Pt No. Relative Risk (95% CI) Int P DM Yes (N=542) 0.423 No (N=874) Age ≥ 70 (N=371) 0.952 < 70 (N=1045) Lesion length (mm) > 20 (N=622) 0.552 ≤ 20 (N=794) CCR (mg/dL) ≥ 60 (N=243) 0.699 < 60 (N=1173) Multivessel ds (N=735) 0.985 (N=681) ACS (N=728) 0.049 (N=688) Overall (N=1416) 0.527 0.25 0.5 1 2 4 8 Favors EES Favors SES

Cumulative incidence rate (%) Months after initial procedure 2˚ Endpoint Stent Thrombosis : Definite/Probable ST by ARC definition 0.0 0.4 0.8 0.2 0.6 1.0 SES: 0.8% Log-Rank p-value=0.281 Cumulative incidence rate (%) EES: 0.4% 3 6 9 12 Months after initial procedure Patient Number at Risks EES 1078 1077 1071 1057 1043 SES 363 361 360 356 355

Myocardial Infarction 2˚ Endpoint Myocardial Infarction MI, total p=1.000 MI, peri-procedural p=0.741 MI, spontaneous p=0.379 EES N=1,057 SES N=359 EES N=1,057 SES N=359 EES N=1,057 SES N=359

Summary : EXCELLENT-RCT The efficacy of EES was non-inferior to SES in inhibiting late loss at 9 months & clinical events at 12 months. The incidence of ST was not different between EES and SES although numerically lower in EES. Tendency of higher late-loss in EES than SES may lead to the intriguing reciprocal trend between soft versus hard endpoints : higher incidence of TLR but lower incidence of death, MI, or ST.  should be confirmed in the larger study in the future Long term follow up will tell us whether Xience/Promus will offer similar efficacy along with better long term safety compared with the best 1st generation DES, Cypher.