Samsung Medical Center Sungkyunkwan University School 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
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, O n behalf of the EXCELLENT Trial Investigators - PowerPoint PPT Presentation
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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
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.
ACC 2011 LBCTSamsung Medical CenterSungkyunkwan UniversitySchool 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 addi-
tion to aspirin may be associated with greater cost
and higher risk of bleeding.
Background
ACC 2011 LBCTSamsung Medical CenterSungkyunkwan UniversitySchool of Medicine
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
ACC 2011 LBCTSamsung Medical CenterSungkyunkwan UniversitySchool of Medicine
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
ACC 2011 LBCTSamsung Medical CenterSungkyunkwan UniversitySchool of Medicine
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
ACC 2011 LBCTSamsung Medical CenterSungkyunkwan UniversitySchool of Medicine
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.
ACC 2011 LBCTSamsung Medical CenterSungkyunkwan UniversitySchool of Medicine
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
ACC 2011 LBCTSamsung Medical CenterSungkyunkwan UniversitySchool of Medicine
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.
ACC 2011 LBCTSamsung Medical CenterSungkyunkwan UniversitySchool of Medicine
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
ACC 2011 LBCTSamsung Medical CenterSungkyunkwan UniversitySchool of Medicine
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
ACC 2011 LBCTSamsung Medical CenterSungkyunkwan UniversitySchool of Medicine
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
ACC 2011 LBCTSamsung Medical CenterSungkyunkwan UniversitySchool of Medicine
12-month TVF in Stent Subgroups(Kaplan-Meier Analysis)
Cumulative proportional TVF estimate at 1 year
-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
ACC 2011 LBCTSamsung Medical CenterSungkyunkwan UniversitySchool of Medicine
TVF in Stent Subgroups
Patient Number at Risks6-mo 540 531 528 524 511
12-mo 539 531 524 521 505
Everolimus-eluting Stent Sirolimus-eluting Stent
Patient Number at Risks6-mo 182 176 176 174 171
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%
ACC 2011 LBCTSamsung Medical CenterSungkyunkwan UniversitySchool of Medicine
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)
ACC 2011 LBCTSamsung Medical CenterSungkyunkwan UniversitySchool of Medicine
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%
Cumulative proportional TVF estimate at 1 year
ACC 2011 LBCTSamsung Medical CenterSungkyunkwan UniversitySchool of Medicine
Months after initial procedure
Cum
ulat
ive
inci
denc
e ra
te (%
)
Patient Number at Risks6-month 497 490 488 487 480
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%
ACC 2011 LBCTSamsung Medical CenterSungkyunkwan UniversitySchool of Medicine
12-month TVF in Stent Subgroups by Per-protocol Analysis
Cumulative proportional TVF estimate at 1 year
-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
Everolimus-eluting Stent Sirolimus-eluting Stent
Non-inferior
1.3 3.7 2.3 6.7
Pre-specified non-inferiority margin: 4.0%
Upper 1-sided97.5% CIDifference
ACC 2011 LBCTSamsung Medical CenterSungkyunkwan UniversitySchool of Medicine
TVF in Stent Subgroups by Per-protocol Analysis
Patient Number at Risks6-mo 377 373 373 371 365
12-mo 332 329 329 329 328
Everolimus-eluting Stent Sirolimus-eluting Stent
Patient Number at Risks
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%
ACC 2011 LBCTSamsung Medical CenterSungkyunkwan UniversitySchool 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.
Study Limitations
ACC 2011 LBCTSamsung Medical CenterSungkyunkwan UniversitySchool of Medicine
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.