hyeon-cheol gwon , joo yong hahn, young bin song,

Samsung Medical CenterSungkyunkwan UniversitySchool of Medicine ACC 2011 LBCT

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

http://www.accscientificsession.org/

ACC 2011 LBCTSamsung Medical CenterSungkyunkwan UniversitySchool of Medicine

Disclosure Statement of Financial Interest

• 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.


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 addi-

tion to aspirin may be associated with greater cost

and higher risk of bleeding.

Background


To test the safety and efficacy of 6-month duration

compared with 12-month duration of dual an-

tiplatelet therapy (DAT) in addition to aspirin after

the implantation of DES

Objective of Study

HypothesisSix-month DAT is non-inferior to 12-month DAT

in terms of target vessel failure at 12 months


Patient EligibilityGeneral 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


Trial DesignProspective, open label, two-arm, randomized multi-center trial

1mo 3mo 9mo 12moClinical

Angiographic3yr2yr 4yr 5yr

Primary clinical end-point evaluation

Co-primary angiographicendpoint evaluation

DAT 6 monthsN=722

DAT 12 monthsN=721

1443 Patients Matching Enroll-ment Criteria

EESN=540

SESN=182

EESN=539

SESN=182

Percutaneous Coronary Intervention

2x2 factorial design

Am Heart J 2009 May;157:811-817.e1www.clinicaltrials. gov (NCT00698607).

EXCELLENT RCT EES vs. SESPresented 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 EndpointsAll death, cardiac deathMyocardial infarction (MI)Cerebrovascular accident (CVA) Target lesion revascularization (TLR)Target vessel revascularization (TVR)Any revascularizationStent thrombosis: definite or probable stent thrombosis by ARC definitionTIMI major bleeding: a drop in Hb > 5 g/dl or in Hct > 15%Safety endpoint: death, MI, CVA, stent thrombosis, or TIMI major bleedingMajor adverse cardiocerebral event (MACCE): death, MI, CVA, or any revasc

* Definitions follow the ARC recommendations, if not described.


Sample Size CalculationPrimary 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 CoordinationExecutive Committee

(HS Kim, MD, YS Jang, MD, JH Yoon, MD,HC Gwon, MD, IH Chae, MD, TH Ahn, MD)

Steering Committee

19 study investigators

DSMBData Safety

Monitoring Board

MRCCTrial

Coordinating Center

CEACClinical Event Adjudica-

tion Committee

Grant Support1) Ministry of Health, Welfare, and Family Affairs of Korea2) Abbott Vascular Korea3) Boston Scientific Korea

The companies were not in-volved with the protocol devel-opment or the study process, including site selection, man-agement, and data collection and analysis.


Participating Centers

• 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


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

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


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) 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) 0.017Previous 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) 0.910Peripheral vascular disease 9 (1.2) 10 (1.4) 0.815LV ejection fraction (%)* 61.0±9.6 61.6±9.4 0.297

Baseline Clinical Profiles

* Mean±SD




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) 0.861Lesion type B2C 406 (57.2) 421 (59.1) 0.457Total occlusion 14 (2.0) 11 (1.5) 0.540Thrombotic lesion 73 (10.3) 70 (9.8) 0.778Ulcerative lesion 23 (3.2) 16 (2.2) 0.258Bifurcation lesion 227 (31.4) 247 (34.3) 0.255No. of lesion treated per patient 1.40.6 1.30.6 0.173No. of stents per patient 1.590.96 1.640.94 0.398Use of GP IIb/IIIa inhibitor 12 (1.7%) 12 (1.7%) 0.997Use of IVUS 315 (43.6) 312 (43.3) 0.892

Angiographic and ProceduralProfiles (per Patient)




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

Angiographic Profiles(per lesion)




No. of stents per lesion 1.200.46 1.210.46 0.429

Max stent diameter 3.210.42 3.190.42 0.315

Min stent diameter 3.080.41 3.060.43 0.287

Sum of stent length 27.813.0 28.313.7 0.362

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 0.860.49 0.880.47 0.304

Pre-PCI RD 2.910.50 2.840.50 0.005Lesion length 20.011.5 20.712.3 0.185

Post-PCI Instent MLD 2.630.46 2.580.47 0.330

Post-PCI Inseg MLD 2.260.51 2.190.51 0.003Post-PCI RD 2.950.46 2.910.46 0.025

Procedural Profiles and QCA(per lesion)




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 dischargeAspirin 707 (99.4) 704 (99.0) 0.364Clopidogrel 702 (98.7) 708 (99.6) 0.082Statin 604 (85.0) 582 (81.9) 0.117ACE inhibitor 224 (31.5) 243 (34.2) 0.283ARB 244 (34.3) 231 (32.5) 0.465Beta blocker 427 (60.1) 445 (62.6) 0.327Warfarin 6 (0.8) 13 (1.8) 0.106Calcium channel blocker 238 (33.5) 249 (35.0) 0.539

Medications

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


Variables ― no. (%)

6-mo DAT(N=716)

12-mo DAT(N=712) RR (95% CI) p-value

Total death 4 (0.6) 7 (1.0) 0.57 (0.17-1.94) 0.359Cardiac death 2 (0.3) 3 (0.4) 0.66 (0.11-3.97) 0.650MI 13 (1.8) 8 (1.1) 1.63 (0.67-3.95) 0.277MI of target vessel 12 (1.7) 5 (1.0) 1.72 (0.67-4.39) 0.253CVA 3 (0.4) 5 (0.7) 0.60 (0.14-2.50) 0.473TLR 17 (2.4) 19 (2.7) 0.89 (0.46-1.72) 0.723TVR 22 (3.1) 22 (3.2) 0.95 (0.52-1.72) 0.865Any revascularization 41 (5.7) 43 (6.0) 0.95 (0.61-1.47) 0.802Stent thrombosis 6 (0.8) 3 (0.4) 2.00 (0.50-8.02) 0.320Any bleeding 4 (0.6) 10 (1.4) 0.39 (0.12-1.26) 0.105TIMI major bleeding 2 (0.3) 4 (0.6) 0.50 (0.09-2.72) 0.409Safety endpoint 24 (3.4) 22 (3.1) 1.09 (0.60-1.96) 0.779TVF 34 (4.7%) 31 (4.4%) 1.10 (0.67-1.80) 0.721MACCE 54 (7.5) 60 (8.4) 0.89 (0.60-1.30) 0.537

12-month Clinical Event

Safety endpoint: death, MI, CVA, stent thrombosis, or TIMI major bleedingTVF: cardiac death, MI, or TVRMACCE: death, MI, CVA, or any revascularization

(Chi-square test)


Non-inferior

-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 %

6-mo DAT(N=1067)5.2±0.8%

12-mo DAT(N=361)

4.3±0.8%

Difference

p=0.426

Non-inferiority

p=0.0031

1˚ Endpoint

12-month Target Vessel Failure(Kaplan-Meier Analysis)

Cumulative proportional TVF estimate at 1 year

0.9% 3.6%

Pre-specified non-inferiority

margin4.0%

Upper 1-sided 97.5% CIDifference


Months after initial procedure

Cum

ulat

ive

inci

denc

e ra

te (%

)

Patient Number at Risks6-month 722 707 701 697 681

12-month 721 710 699 698 680

Target Vessel Failure1˚ Endpoint

P=0.507HR = 1.17 (95% CI 0.73-1.89)

4.7%

4.4%

6-mo DAT12-mo DAT


Target Vessel Failure1˚ Endpoint

(Landmark Analysis)

Patient Number at Risks

6-month 722 707 701

12-month 721 710 699

~ 6 months 6 months ~


701 697 681

699 698 680

P=0.563HR = 1.25 (95% CI 0.59-2.67)

P=0.699HR = 1.13 (95% CI 0.61-2.07)

6-mo DAT12-mo DAT


Cardiac Death


Cum

ulat

ive

inci

denc

e ra

te (%

)


12-month 721 710 699 698 680

P=0.533HR = 0.58 (95% CI 0.10 – 3.23)

0.3%

0.4%

6-mo DAT12-mo DAT


Myocardial Infarction


Cum

ulat

ive

inci

denc

e ra

te (%

)


12-month 721 710 699 698 680

P=0.280HR = 1.62 (95% CI 0.67 – 3.93)

6-mo DAT12-mo DAT

1.8%

1.1%


Stent Thrombosis(Definite or probable stent thrombosis by ARC definition)


Cum

ulat

ive

inci

denc

e ra

te (%

)


12-month 721 710 699 698 680

P=0.426HR = 1.68 (95% CI 0.47 – 6.06)

6-mo DAT12-mo DAT

0.8%

0.4%


TIMI Major Bleeding(Overt clinical bleeding with a drop of Hb > 5 g/dl or Hct > 15%)


Cum

ulat

ive

inci

denc

e ra

te (%

)


12-month 721 710 699 698 680

P=0.419HR = 0.50 (95% CI 0.09 – 2.71)

6-mo DAT12-mo DAT

0.3%

0.6%


Safety Endpoint(Death, MI, stent thrombosis, CVA, or TIMI major bleeding)


Cum

ulat

ive

inci

denc

e ra

te (%

)


12-month 721 710 699 698 680

P=0.678HR = 1.13 (95% CI 0.64 – 1.99)

6-mo DAT12-mo DAT

3.4%

3.1%


MACCE(Death, MI, CVA, or any revascularization)

P=0.896HR = 0.98 (95% CI 0.68 – 1.40)


Cum

ulat

ive

inci

denc

e ra

te (%

)


12-month 721 710 699 698 680

6-mo DAT12-mo DAT

7.5%

8.4%


N 6-moDAT

12-moDAT

Χ2 p-value Cox HR Cox

p-valueP for

interactionAge < 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 0.1880.301

Yes 734 13 (3.6%) 17 (4.6%) 0.474 0.728

Diabetes No 884 10 (2.2%) 23 (5.3%) 0.018 0.0550.001

Yes 544 24 (8.9%) 8 (2.9%) 0.003 0.006

LVEF < 50% 123 3 (3.0%) 4 (7.1%) 0.286 0.5030.330

50% 1086 26 (4.8%) 25 (4.6%) 0.833 0.607

Bifurcation No 959 23 (4.7%) 20 (4.3%) 0.769 0.6080.957

Yes 469 11 (4.9%) 11 (4.5%) 0.830 0.668

Stent EES 1067 25 (4.7%) 27 (5.1%) 0.739 0.9140.305

SES 361 9 (5.0%) 4 (2.2%) 0.149 0.168

Multi-stent No 854 14 (3.2%) 12 (2.9%) 0.819 0.8940.597

Yes 563 20 (7.5%) 19 (6.4%) 0.601 0.311

Subgroup Analysis

0 1 2 3Favors 6-mo DAT Favors 12-mo DAT

*ACS = unstable angina, NSTEMI, or STEMI


12-month TVF in Stent Subgroups(Kaplan-Meier Analysis)


-1 0 1 2 3 4 5 6

6-mo DAT(N=182)

5.0±1.6%

12-mo DAT(N=182)

2.2±1.1%

Non-inferior-ity

p=0.268

97.5%

-1 0 1 2 3 4 5 6

6-mo DAT(N=540)

5.2±1.0%

12-mo DAT(N=539)

5.1±1.0%

Non-inferior-ity

p=0.0029

Everolimus-eluting Stent Sirolimus-eluting Stent

0.1% 2.9% 2.2% 6.6%

Pre-specified non-inferiority margin: 4.0%

Upper 1-sided97.5% CIDifference


TVF in Stent Subgroups

Patient Number at Risks6-mo 540 531 528 524 511

12-mo 539 531 524 521 505



12-mo 182 179 179 178 176

p=0.914HR = 1.03 (0.61-1.75)

p=0.168HR = 2.29 (0.71-7.43)

6-mo DAT12-mo DAT

4.6%

5.0%4.9%

2.2%


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

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)

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


Non-inferior

-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 %

12-month Target Vessel Failure by Per-protocol Analysis

1.5% 3.6%

Upper 1-sided 97.5% CIDifference

6-mo DAT(N=497)

3.6±0.8%

12-mo DAT(N=439)

4.3±0.8%

Difference

p=0.158

Non-inferiority

p=0.0093

Pre-specified non-inferiority

margin4.0%




Cum

ulat

ive

inci

denc

e ra

te (%

)


12-month 439 435 435 435 433

Target Vessel Failure by Per-protocol Analysis

P=0.203HR = 1.66 (95% CI 0.76 – 3.59)

6-mo DAT12-mo DAT

3.2%

2.1%


12-month TVF in Stent Subgroups by Per-protocol Analysis


-1 0 1 2 3 4 5 6

6-mo DAT(N=120)

4.2±1.8%

12-mo DAT(N=107)

1.9±1.3%

Non-inferior-ity

p=0.222

-1 0 1 2 3 4 5 6

6-mo DAT(N=377)

4.4±0.9%

12-mo DAT(N=332)

2.1±0.8%

Non-inferior-ity

p=0.013


Non-inferior

1.3 3.7 2.3 6.7

Pre-specified non-inferiority margin: 4.0%

Upper 1-sided97.5% CIDifference


TVF in Stent Subgroups by Per-protocol Analysis


12-mo 332 329 329 329 328



120 117 117 116 115

107 106 106 106 105

p=0.286HR=1.65 (0.66-4.13)

p=0.332HR=2.25 (0.44-1.6)

2.9%

2.1%

4.2%

1.9%


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.

Study Limitations


Six-month DAT is non-inferior to 12-month DAT with re-gard 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.

Conclusions

hyeon-cheol gwon , joo yong hahn, young bin song,

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