Transcript Preliminary Analysis of 분지병변 관상동맥 중재술 등록 연구

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
Samsung Medical Center
Sungkyunkwan University
School of Medicine
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
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.
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
Samsung Medical Center
Sungkyunkwan University
School of Medicine
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
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
Prospective, open label, two-arm, randomized multi-center trial
1443 Patients Matching
Enrollment Criteria
DAT 6 months
DAT 12 months
N=722
N=721
2x2
factorial design
EES
SES
EES
SES
N=540
N=182
N=539
N=182
Percutaneous Coronary Intervention
Primary clinical
endpoint evaluation
Clinical
1mo
Angiographic
Samsung Medical Center
Sungkyunkwan University
School of Medicine
3mo
9mo
12mo
2yr
Co-primary angiographic
endpoint evaluation
Am Heart J 2009 May;157:811-817.e1
www.clinicaltrials. gov (NCT00698607).
3yr
4yr
5yr
Presented at LBCT session in TCT 2010 by Dr. HS Kim
• 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.
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
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)
DSMB
MRCC
CEAC
Data Safety
Monitoring Board
Trial
Coordinating Center
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
Samsung Medical Center
Sungkyunkwan University
School of Medicine
The companies were not
involved with the protocol
development or the study
process, including site
selection, management, and
data collection and analysis.
19 Hospitals in Republic of Korea
• Seoul National University Hospital
• Gangnam Severance Hospital
• Yonsei University Severance Hospital
• NHIC Ilsan Hospital
• Samsung Medical Center
• Inje University Sanggye Paik Hospital
• Seoul National University Bundang Hospital • Korea University Anan Hospital
• Gachon University Gil Medical Center
• Pusan National University Hospital
• Yonsei University Wonju Christian Hospital
• Boramae Medical Center
• Hallym University Sacred Heart Hospital
• Kangnam Sacred Heart Hospital
• Kandgong Sacred Heart Hospital
• Uijeongbu St. Mary’s Hospital
• Chonam National University Hospital
• Keimyung University Dongsan Hospital
• Ewha Womans University Mokdong Hospital
Samsung Medical Center
Sungkyunkwan University
School of Medicine
Enrolled and Randomized
(n=1,443)
Intention-totreatment
Analysis
Allocated to 6-mo DAT
(n=722)
Allocated to 12-mo DAT
(n=721)
Follow-up loss within 395 days n=6
Follow-up loss within 395 days n=9
12-mo event
Analysis
6-mo DAT with 12-mo FU
(n=716)
Samsung Medical Center
Sungkyunkwan University
School of Medicine
12-mo DAT with 12-mo FU
(n=712)
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
Variables ― no. (%)
0.560
Clinical diagnosis
Silent ischemia/ stable angina
353 (48.9)
346 (48)
Unstable angina/NSTEMI
350 (48.5)
349 (48.4)
19 (2.6)
26 (3.6)
272 (37.7)
278 (38.6)
0.729
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
Peripheral vascular disease
47 (6.5)
48 (6.7)
0.910
9 (1.2)
10 (1.4)
0.815
61.0±9.6
61.6±9.4
0.297
STEMI
Diabetes mellitus
Chronic renal failure
LV ejection fraction (%)*
* Mean±SD
Samsung Medical Center
Sungkyunkwan University
School of Medicine
Variables ― no. (%)
6-mo DAT
(N=722)
12-mo DAT
(N=721)
Angiographic disease extent
p-value
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
227 (31.4)
247 (34.3)
1.40.6
1.590.96
12 (1.7%)
315 (43.6)
1.30.6
1.640.94
12 (1.7%)
312 (43.3)
0.255
0.173
0.398
0.997
0.892
Bifurcation lesion
No. of lesion treated per patient
No. of stents per patient
Use of GP IIb/IIIa inhibitor
Use of IVUS
Samsung Medical Center
Sungkyunkwan University
School of Medicine
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
Variables ― no. (%)
Samsung Medical Center
Sungkyunkwan University
School of Medicine
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
941 (99.7)
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
Variables ― no. (%)
Samsung Medical Center
Sungkyunkwan University
School of Medicine
Variables ― no. (%)
Use of aspirin at 1 year
Duration of clopidogrel therapy
Clopidogrel duration
Less than due time*
Within due time*
More than due time*
No information
Clopidogrel restart within 1 year
Medications at discharge
Aspirin
Clopidogrel
Statin
ACE inhibitor
ARB
Beta blocker
Warfarin
Calcium channel blocker
6-mo DAT
(N=722)
12-mo DAT
(N=721)
676 (99.9%)
190 [181-260]
667 (99.3%)
375 [364-395]
16 (2.2%)
501 (69.4%)
192 (26.6%)
13 (1.8%)
34 (4.7%)
45 (6.2%)
442 (61.3%)
219 (30.4%)
15 (2.1%)
22 (3.1%)
707 (99.4)
702 (98.7)
604 (85.0)
224 (31.5)
244 (34.3)
427 (60.1)
6 (0.8)
238 (33.5)
704 (99.0)
708 (99.6)
582 (81.9)
243 (34.2)
231 (32.5)
445 (62.6)
13 (1.8)
249 (35.0)
p-value
0.364
0.082
0.117
0.283
0.465
0.327
0.106
0.539
(*due time: 120~240 days in 6-mo DAT group, 300~420 days in 12-mo DAT group)
Samsung Medical Center
Sungkyunkwan University
School of Medicine
(Chi-square test)
Variables ― no. 6-mo DAT 12-mo DAT
(%)
(N=716)
(N=712)
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
3 (0.4)
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)
3 (0.4)
2.00 (0.50-8.02)
0.320
Any bleeding
4 (0.6)
10 (1.4)
0.39 (0.12-1.26)
0.105
TIMI major bleeding
2 (0.3)
4 (0.6)
0.50 (0.09-2.72)
0.409
Safety endpoint
24 (3.4)
22 (3.1)
1.09 (0.60-1.96)
0.779
34 (4.7%)
31 (4.4%)
1.10 (0.67-1.80)
0.721
54 (7.5)
60 (8.4)
0.89 (0.60-1.30)
0.537
TVF
MACCE
Safety endpoint: death, MI, CVA, stent thrombosis, or TIMI major bleeding
TVF: cardiac death, MI, or TVR
MACCE: death, MI, CVA, or any revascularization
Samsung Medical Center
Sungkyunkwan University
School of Medicine
(Kaplan-Meier Analysis)
Cumulative proportional TVF estimate at 1 year
6-mo DAT
(N=1067)
12-mo DAT
(N=361)
5.2±0.8%
4.3±0.8%
Pre-specified
non-inferiority
margin
4.0%
Difference
Non-inferiority
p=0.426
p=0.0031
Upper 1-sided 97.5% CI
Difference
Non-inferior
3.6%
0.9%
-1.5
-1.0
-0.5
Samsung Medical Center
Sungkyunkwan University
School of Medicine
0.0
0.5
1.0
1.5
2.0
2.5
3.0
3.5
4.0
4.5 %
Cumulative incidence rate (%)
6-mo DAT
12-mo DAT
P=0.507
HR = 1.17 (95% CI 0.73-1.89)
4.7%
4.4%
Months after initial procedure
Patient Number at Risks
6-month
722
707
701
697
681
12-month
721
710
699
698
680
Samsung Medical Center
Sungkyunkwan University
School of Medicine
6-mo DAT
12-mo DAT
(Landmark Analysis)
~ 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
Patient Number at Risks
6-month
722
707
701
701
697
681
12-month
721
710
699
699
698
680
Samsung Medical Center
Sungkyunkwan University
School of Medicine
Cumulative incidence rate (%)
P=0.533
HR = 0.58 (95% CI 0.10 – 3.23)
6-mo DAT
12-mo DAT
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
Samsung Medical Center
Sungkyunkwan University
School of Medicine
Cumulative incidence rate (%)
P=0.280
HR = 1.62 (95% CI 0.67 – 3.93)
6-mo DAT
12-mo DAT
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
Samsung Medical Center
Sungkyunkwan University
School of Medicine
Cumulative incidence rate (%)
(Definite or probable stent thrombosis by ARC definition)
P=0.426
HR = 1.68 (95% CI 0.47 – 6.06)
6-mo DAT
12-mo DAT
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
Samsung Medical Center
Sungkyunkwan University
School of Medicine
Cumulative incidence rate (%)
(Overt clinical bleeding with a drop of Hb > 5 g/dl or Hct > 15%)
P=0.419
HR = 0.50 (95% CI 0.09 – 2.71)
6-mo DAT
12-mo DAT
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
Samsung Medical Center
Sungkyunkwan University
School of Medicine
Cumulative incidence rate (%)
(Death, MI, stent thrombosis, CVA, or TIMI major bleeding)
P=0.678
HR = 1.13 (95% CI 0.64 – 1.99)
6-mo DAT
12-mo DAT
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
Samsung Medical Center
Sungkyunkwan University
School of Medicine
(Death, MI, CVA, or any revascularization)
Cumulative incidence rate (%)
8.4%
P=0.896
HR = 0.98 (95% CI 0.68 – 1.40)
7.5%
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
Samsung Medical Center
Sungkyunkwan University
School of Medicine
Age
ACS*
N
6-mo
DAT
12-mo
DAT
Χ2
p-value
< 65
761
19 (5.0%)
12 (3.2%)
0.202
0.115
 65
667
15 (4.5%)
19 (5.7%)
0.465
0.588
No
694
21 (6.9%)
14 (4.1%)
0.252
0.188
Yes
734
13 (3.6%)
17 (4.6%)
0.474
0.728
No
884
10 (2.2%)
23 (5.3%)
0.018
0.055
Yes
544
24 (8.9%)
8 (2.9%)
0.003
0.006
< 50%
123
3 (3.0%)
4 (7.1%)
0.286
0.503
 50%
1086
26 (4.8%)
25 (4.6%)
0.833
0.607
No
959
23 (4.7%)
20 (4.3%)
0.769
0.608
Yes
469
11 (4.9%)
11 (4.5%)
0.830
0.668
EES
1067
25 (4.7%)
27 (5.1%)
0.739
0.914
SES
361
9 (5.0%)
4 (2.2%)
0.149
0.168
No
854
14 (3.2%)
12 (2.9%)
0.819
0.894
Yes
563
20 (7.5%)
19 (6.4%)
0.601
0.311
Cox
p-value
Cox HR
P for
interaction
0.127
0.301
Diabetes
LVEF
Bifurcation
0.001
0.330
0.957
Stent
0.305
Multi-stent
*ACS = unstable angina, NSTEMI, or STEMI
0
Favors 6-mo DAT
Samsung Medical Center
Sungkyunkwan University
School of Medicine
1
2
3
Favors 12-mo DAT
0.597
(Kaplan-Meier Analysis)
Cumulative proportional TVF estimate at 1 year
Everolimus-eluting Stent
Sirolimus-eluting Stent
6-mo DAT
(N=540)
12-mo DAT
(N=539)
Noninferiority
6-mo DAT
(N=182)
12-mo DAT
(N=182)
Noninferiority
5.2±1.0%
5.1±1.0%
p=0.0029
5.0±1.6%
2.2±1.1%
p=0.268
Upper 1-sided
97.5% CI
Difference
9
7.
5
%
2.9%
0.1%
-1
0
1
Samsung Medical Center
Sungkyunkwan University
School of Medicine
Pre-specified non-inferiority
margin: 4.0%
2
3
6.6%
2.2%
4
5
6
-1
0
1
2
3
4
5
6
6-mo DAT
12-mo DAT
Everolimus-eluting Stent
p=0.914
HR = 1.03 (0.61-1.75)
Sirolimus-eluting Stent
p=0.168
HR = 2.29 (0.71-7.43)
5.0%
4.9%
4.6%
2.2%
Patient Number at Risks
Patient Number at Risks
6-mo
540
531
528
524
511
6-mo
182
176
176
174
171
12-mo
539
531
524
521
505
12-mo
182
179
179
178
176
Samsung Medical Center
Sungkyunkwan University
School of Medicine
Enrolled and Randomized
(n=1,443)
Intention-totreatment
Analysis
Allocated to 6-mo DAT
(n=722)
1.
2.
3.
4.
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)
1.
2.
3.
4.
Per-protocol
Analysis
Allocated to 12-mo DAT
(n=721)
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%)
(*due time: 120~240 days in 6-mo DAT group, 300~420 days in 12-mo DAT group)
Samsung Medical Center
Sungkyunkwan University
School of Medicine
Cumulative proportional TVF estimate at 1 year
6-mo DAT
(N=497)
12-mo DAT
(N=439)
3.6±0.8%
4.3±0.8%
Pre-specified
non-inferiority
margin
4.0%
Difference
Non-inferiority
p=0.158
p=0.0093
Upper 1-sided 97.5% CI
Difference
Non-inferior
3.6%
1.5%
-1.5
-1.0
-0.5
Samsung Medical Center
Sungkyunkwan University
School of Medicine
0.0
0.5
1.0
1.5
2.0
2.5
3.0
3.5
4.0
4.5 %
Cumulative incidence rate (%)
6-mo DAT
12-mo DAT
P=0.203
HR = 1.66 (95% CI 0.76 – 3.59)
3.2%
2.1%
Months after initial procedure
Patient Number at Risks
6-month
497
490
488
487
480
12-month
439
435
435
435
433
Samsung Medical Center
Sungkyunkwan University
School of Medicine
Cumulative proportional TVF estimate at 1 year
Everolimus-eluting Stent
Sirolimus-eluting Stent
6-mo DAT
(N=377)
12-mo DAT
(N=332)
Noninferiority
6-mo DAT
(N=120)
12-mo DAT
(N=107)
Noninferiority
4.4±0.9%
2.1±0.8%
p=0.013
4.2±1.8%
1.9±1.3%
p=0.222
Upper 1-sided
97.5% CI
Difference
Pre-specified non-inferiority
margin: 4.0%
3.7
1.3
6.7
2.3
Non-inferior
-1
0
1
Samsung Medical Center
Sungkyunkwan University
School of Medicine
2
3
4
5
6
-1
0
1
2
3
4
5
6
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
Patient Number at Risks
6-mo
377
373
373
371
365
120
117
117
116
115
12-mo
332
329
329
329
328
107
106
106
106
105
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.
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.
Samsung Medical Center
Sungkyunkwan University
School of Medicine