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Samsung Medical Center Sungkyunkwan University School of Medicine Hyeon-Cheol Gwon, Joo Yong Hahn, Young Bin Song, Kyung Woo Park, Yang Soo Jang, Hyo-Soo.

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Presentation on theme: "Samsung Medical Center Sungkyunkwan University School of Medicine Hyeon-Cheol Gwon, Joo Yong Hahn, Young Bin Song, Kyung Woo Park, Yang Soo Jang, Hyo-Soo."— Presentation transcript:

1 Samsung Medical Center Sungkyunkwan University School of Medicine 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 Samsung Medical Center Sungkyunkwan University School of Medicine CONSULTING FEES/HONORARIA: Cordis, Medtronic Asia Pacific RESEARCH/RESEARCH GRANTS: Abbott Korea, Medtronic Korea Within the past 12 months, I or my spouse/partner have had a financial interest/arrangement or affiliation with the organization(s) listed below.

3 Samsung Medical Center Sungkyunkwan University School of Medicine  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 Samsung Medical Center Sungkyunkwan University School of Medicine  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 Hypothesis Six-month DAT is non-inferior to 12-month DAT in terms of target vessel failure at 12 months

5 Samsung Medical Center Sungkyunkwan University School of Medicine 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 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

6 Samsung Medical Center Sungkyunkwan University School of Medicine Prospective, open label, two-arm, randomized multi-center trial Clinical Angiographic Primary clinical endpoint evaluation Co-primary angiographic endpoint evaluation DAT 6 months N=722 DAT 12 months N= Patients Matching Enrollment Criteria EES N=540 SES N=182 EES N=539 SESN=182SESN=182 Percutaneous Coronary Intervention 2x2 factorial design Am Heart J 2009 May;157: e1 gov (NCT ).

7 Presented at LBCT session in TCT 2010 by Dr. HS Kim

8 Samsung Medical Center Sungkyunkwan University School of Medicine 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 Samsung Medical Center Sungkyunkwan University School of Medicine 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 Samsung Medical Center Sungkyunkwan University School of Medicine Executive Committee (HS Kim, MD, YS Jang, MD, JH Yoon, MD, HC Gwon, MD, IH Chae, MD, TH Ahn, MD) Steering Committee 19 study investigators DSMB Data Safety Monitoring Board MRCC Trial Coordinating Center CEAC Clinical Event Adjudication Committee 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.

11 Samsung Medical Center Sungkyunkwan University School of Medicine 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 19 Hospitals in Republic of Korea

12 Samsung Medical Center Sungkyunkwan University School of Medicine Enrolled and Randomized (n=1,443) Allocated to 6-mo DAT (n=722) 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 6-mo DAT with 12-mo FU (n=716) 12-mo DAT with 12-mo FU (n=712) 12-mo event Analysis Follow-up loss within 395 days n=9

13 Samsung Medical Center Sungkyunkwan University School of Medicine Variables ― no. (%) 6-mo DAT (N=722) 12-mo DAT (N=721) p-value Age (years)* 63.0± ± Males 470 (65.1)461 (63.9)0.646 Body mass index (kg/m2)* 24.9± ± Clinical diagnosis 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)0.646 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)62 (8.6)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 47 (6.5)48 (6.7)0.910 Peripheral vascular disease9 (1.2)10 (1.4)0.815 LV ejection fraction (%)*61.0± ± * Mean±SD

14 Samsung Medical Center Sungkyunkwan University School of Medicine Variables ― no. (%) 6-mo DAT (N=722) 12-mo DAT (N=721) p-value Angiographic disease extent 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) Lesion type B2C 406 (57.2)421 (59.1) Total occlusion 14 (2.0)11 (1.5) Thrombotic lesion 73 (10.3)70 (9.8) Ulcerative lesion 23 (3.2)16 (2.2) Bifurcation lesion 227 (31.4)247 (34.3) No. of lesion treated per patient 1.4   No. of stents per patient 1.59   Use of GP IIb/IIIa inhibitor12 (1.7%) Use of IVUS315 (43.6)312 (43.3)0.892

15 Samsung Medical Center Sungkyunkwan University School of Medicine Variables ― no. (%) 6-mo DAT (N=957) 12-mo DAT (N=970) p-value LAD location467 (49.1)459 (47.4)0.473 ACC/AHA B2/C type487 (52.8)505 (53.7)0.696 Long Lesion (≥ 20 mm)353 (40.2)373 (41.2)0.664 Tortuous lesion73 (7.9)59 (6.3)0.168 Total occlusion14 (1.5)11 (1.2)0.514 Ulcerated lesion23 (2.4)16 (1.6)0.240 Thrombotic lesion74 (8.0)73 (7.8)0.835 Bifurcation lesion236 (24.7)272 (28.0)0.092 Calcific lesion186 (20.2)194 (20.6)0.803

16 Samsung Medical Center Sungkyunkwan University School of Medicine Variables ― no. (%) 6-mo DAT (N=957) 12-mo DAT (N=970) p-value No. of stents per lesion 1.20   Max stent diameter 3.21   Min stent diameter 3.08   Sum of stent length 27.8   Device success 941 (99.7)963 (99.7)0.977 Lesion success 941 (99.7)964 (99.8)0.636 Procedural success 935 (99.0)956 (99.0)0.857 Pre-PCI MLD 0.86   Pre-PCI RD 2.91   Lesion length 20.0   Post-PCI Instent MLD 2.63   Post-PCI Inseg MLD 2.26   Post-PCI RD 2.95  

17 Samsung Medical Center Sungkyunkwan University School of Medicine Variables ― no. (%) 6-mo DAT (N=722) 12-mo DAT (N=721) p-value Use of aspirin at 1 year676 (99.9%)667 (99.3%) Duration of clopidogrel therapy190 [ ]375 [ ] 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 year34 (4.7%)22 (3.1%) Medications at discharge Aspirin707 (99.4)704 (99.0)0.364 Clopidogrel702 (98.7)708 (99.6)0.082 Statin604 (85.0)582 (81.9)0.117 ACE inhibitor224 (31.5)243 (34.2)0.283 ARB244 (34.3)231 (32.5)0.465 Beta blocker427 (60.1)445 (62.6)0.327 Warfarin6 (0.8)13 (1.8)0.106 Calcium channel blocker238 (33.5)249 (35.0)0.539 (*due time: 120~240 days in 6-mo DAT group, 300~420 days in 12-mo DAT group)

18 Samsung Medical Center Sungkyunkwan University School of Medicine Variables ― no. (%) 6-mo DAT (N=716) 12-mo DAT (N=712) RR (95% CI)p-value Total death4 (0.6)7 (1.0)0.57 ( )0.359 Cardiac death2 (0.3)3 (0.4)0.66 ( )0.650 MI13 (1.8)8 (1.1)1.63 ( )0.277 MI of target vessel12 (1.7)5 (1.0)1.72 ( )0.253 CVA3 (0.4)5 (0.7)0.60 ( )0.473 TLR17 (2.4)19 (2.7)0.89 ( )0.723 TVR22 (3.1)22 (3.2)0.95 ( )0.865 Any revascularization41 (5.7)43 (6.0)0.95 ( )0.802 Stent thrombosis6 (0.8)3 (0.4)2.00 ( )0.320 Any bleeding4 (0.6)10 (1.4)0.39 ( )0.105 TIMI major bleeding2 (0.3)4 (0.6)0.50 ( )0.409 Safety endpoint24 (3.4)22 (3.1)1.09 ( )0.779 TVF34 (4.7%) 31 (4.4%)1.10 ( )0.721 MACCE54 (7.5)60 (8.4)0.89 ( )0.537 Safety endpoint: death, MI, CVA, stent thrombosis, or TIMI major bleeding TVF: cardiac death, MI, or TVR MACCE: death, MI, CVA, or any revascularization (Chi-square test)

19 Samsung Medical Center Sungkyunkwan University School of Medicine Non-inferior % 6-mo DAT (N=1067) 5.2±0.8% 5.2±0.8% 12-mo DAT (N=361) 4.3±0.8% 4.3±0.8% Differencep=0.426 Non-inferiorityp=0.0031Non-inferiorityp= ˚ Endpoint (Kaplan-Meier Analysis) Cumulative proportional TVF estimate at 1 year 0.9% 3.6% Pre-specified non-inferiority margin 4.0% Upper 1-sided 97.5% CI Difference

20 Samsung Medical Center Sungkyunkwan University School of Medicine Months after initial procedure Cumulative incidence rate (%) Patient Number at Risks 6-month month ˚ Endpoint P=0.507 HR = 1.17 (95% CI ) 4.7% 4.4% 6-mo DAT 12-mo DAT

21 Samsung Medical Center Sungkyunkwan University School of Medicine 1˚ Endpoint (Landmark Analysis) Patient Number at Risks 6-month month ~ 6 months 6 months ~ Patient Number at Risks P=0.563 HR = 1.25 (95% CI ) P=0.699 HR = 1.13 (95% CI ) 6-mo DAT 12-mo DAT

22 Samsung Medical Center Sungkyunkwan University School of Medicine Months after initial procedure Cumulative incidence rate (%) Patient Number at Risks 6-month month P=0.533 HR = 0.58 (95% CI 0.10 – 3.23) 0.3% 0.4% 6-mo DAT 12-mo DAT

23 Samsung Medical Center Sungkyunkwan University School of Medicine Months after initial procedure Cumulative incidence rate (%) Patient Number at Risks 6-month month P=0.280 HR = 1.62 (95% CI 0.67 – 3.93) 6-mo DAT 12-mo DAT 1.8% 1.1%

24 Samsung Medical Center Sungkyunkwan University School of Medicine (Definite or probable stent thrombosis by ARC definition) Months after initial procedure Cumulative incidence rate (%) Patient Number at Risks 6-month month P=0.426 HR = 1.68 (95% CI 0.47 – 6.06) 6-mo DAT 12-mo DAT 0.8% 0.4%

25 Samsung Medical Center Sungkyunkwan University School of Medicine (Overt clinical bleeding with a drop of Hb > 5 g/dl or Hct > 15%) Months after initial procedure Cumulative incidence rate (%) Patient Number at Risks 6-month month P=0.419 HR = 0.50 (95% CI 0.09 – 2.71) 6-mo DAT 12-mo DAT 0.3% 0.6%

26 Samsung Medical Center Sungkyunkwan University School of Medicine (Death, MI, stent thrombosis, CVA, or TIMI major bleeding) Months after initial procedure Cumulative incidence rate (%) Patient Number at Risks 6-month month P=0.678 HR = 1.13 (95% CI 0.64 – 1.99) 6-mo DAT 12-mo DAT 3.4% 3.1%

27 Samsung Medical Center Sungkyunkwan University School of Medicine (Death, MI, CVA, or any revascularization) P=0.896 HR = 0.98 (95% CI 0.68 – 1.40) Months after initial procedure Cumulative incidence rate (%) Patient Number at Risks 6-month month mo DAT 12-mo DAT 7.5% 8.4%

28 Samsung Medical Center Sungkyunkwan University School of Medicine N 6-mo DAT 12-mo DAT Χ 2 p-value Cox HR Cox p-value P for interaction Age< (5.0%)12 (3.2%)  (4.5%)19 (5.7%) ACS*No69421 (6.9%)14 (4.1%) Yes73413 (3.6%)17 (4.6%) DiabetesNo88410 (2.2%)23 (5.3%) Yes54424 (8.9%)8 (2.9%) LVEF< 50%1233 (3.0%)4 (7.1%)  50% (4.8%)25 (4.6%) BifurcationNo95923 (4.7%)20 (4.3%) Yes46911 (4.9%)11 (4.5%) StentEES (4.7%)27 (5.1%) SES3619 (5.0%)4 (2.2%) Multi-stentNo85414 (3.2%)12 (2.9%) Yes56320 (7.5%)19 (6.4%) Favors 6-mo DATFavors 12-mo DAT *ACS = unstable angina, NSTEMI, or STEMI

29 Samsung Medical Center Sungkyunkwan University School of Medicine (Kaplan-Meier Analysis) Cumulative proportional TVF estimate at 1 year mo DAT (N=182) 5.0±1.6% 5.0±1.6% 12-mo DAT (N=182) 2.2±1.1% 2.2±1.1% Non- inferiority p=0.268 p= % mo DAT (N=540) 5.2±1.0% 5.2±1.0% 12-mo DAT (N=539) 5.1±1.0% 5.1±1.0% Non- inferiority p= p= Everolimus-eluting Stent Sirolimus-eluting Stent 0.1% 2.9% 2.2% 6.6% Pre-specified non-inferiority margin: 4.0% Upper 1-sided 97.5% CI Difference

30 Samsung Medical Center Sungkyunkwan University School of Medicine Patient Number at Risks 6-mo mo Everolimus-eluting Stent Sirolimus-eluting Stent Patient Number at Risks 6-mo mo p=0.914 HR = 1.03 ( ) p=0.168 HR = 2.29 ( ) 6-mo DAT 12-mo DAT 4.6% 5.0% 4.9% 2.2%

31 Samsung Medical Center Sungkyunkwan University School of Medicine Enrolled and Randomized (n=1,443) Allocated to 6-mo DAT (n=722) Allocated to 6-mo DAT (n=722) Allocated to 12-mo DAT (n=721) Intention-to- treatment Analysis 1.Follow-up loss within 395 days (n=6) 2.Clopidogrel duration less than due time (n=14) 3.Clopidogrel duration more than due time (n=192) 4.No information about clopidogrel (n=13) 1.Follow-up loss within 395 days (n=6) 2.Clopidogrel duration less than due time (n=14) 3.Clopidogrel duration more than due time (n=192) 4.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 1.Follow-up loss within 395 days (n=9) 2.Clopidogrel duration less than due time (n=41) 3.Clopidogrel duration more than due time (n=219) 4.No information about clopidogrel (n=13) 1.Follow-up loss within 395 days (n=9) 2.Clopidogrel duration less than due time (n=41) 3.Clopidogrel duration more than due time (n=219) 4.No information about clopidogrel (n=13) (*due time: 120~240 days in 6-mo DAT group, 300~420 days in 12-mo DAT group)

32 Samsung Medical Center Sungkyunkwan University School of Medicine Non-inferior % 1.5% 3.6% Upper 1-sided 97.5% CI Difference 6-mo DAT (N=497) 3.6±0.8% 3.6±0.8% 12-mo DAT (N=439) 4.3±0.8% 4.3±0.8% Differencep=0.158 Non-inferiorityp=0.0093Non-inferiorityp= Pre-specified non-inferiority margin 4.0% Cumulative proportional TVF estimate at 1 year

33 Samsung Medical Center Sungkyunkwan University School of Medicine Months after initial procedure Cumulative incidence rate (%) Patient Number at Risks 6-month month P=0.203 HR = 1.66 (95% CI 0.76 – 3.59) 6-mo DAT 12-mo DAT 3.2% 2.1%

34 Samsung Medical Center Sungkyunkwan University School of Medicine Cumulative proportional TVF estimate at 1 year mo DAT (N=120) 4.2±1.8% 4.2±1.8% 12-mo DAT (N=107) 1.9±1.3% 1.9±1.3% Non- inferiority p=0.222 p= mo DAT (N=377) 4.4±0.9% 4.4±0.9% 12-mo DAT (N=332) 2.1±0.8% 2.1±0.8% Non- inferiority p=0.013 p=0.013 Everolimus-eluting Stent Sirolimus-eluting Stent Non-inferior Pre-specified non-inferiority margin: 4.0% Upper 1-sided 97.5% CI Difference

35 Samsung Medical Center Sungkyunkwan University School of Medicine Patient Number at Risks 6-mo mo Everolimus-eluting Stent Sirolimus-eluting Stent Patient Number at Risks p=0.286 HR=1.65 ( ) p=0.332 HR=2.25 ( ) 2.9% 2.1% 4.2% 1.9%

36 Samsung Medical Center Sungkyunkwan University School of Medicine  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 Samsung Medical Center Sungkyunkwan University School of Medicine  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.


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