Download **** 1 - Clinical Trial Results

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
S
eoul N
Seoul
National
ationalU
University
niversityH
Hospital
ospital
C
ardiovascular
C
enter
Cardiovascular Center
Disclosure Statement
of Financial Interest
Within the past 12 months, I or my spouse/partner have had a financial
interest/arrangement or affiliation with the organization(s) listed below.
Affiliation/Financial Relationship
•
•
•
•
Grant
Research Support
Consulting Fees
Honoraria
Seoul National University Hospital
Cardiovascular Center
Company
•
•
•
•
•
•
•
•
Abbott Vascular
Boston Scientific
Medtronic
Cordis
Astra Zeneca,
Daichi Sankyo,
Eli Lily,
Sanofi Aventis
Background
Everolimus-Eluting Stent
Sirolimus-Eluting Stent
• EES has been shown to be superior
to PES with regard to angiographic
and clinical endpoints.
• SES has been known to be the most
efficacious DES regarding inhibition
of neointima and LL
Everolimus is the 40-o-(2-hydroxyethyl) derivative of sirolimus targeting mTOR
• Thinner fluoropolymer (7.8 μm)
• EVA:BMA copolymers (13.7 μm)
• Thinner strut thickness (81 μm)
• strut thickness (140 μm)
• Cobalt–chromium alloy platform
• Stainless steel
Head-to-head comparison of angiographic & clinical outcomes,
has not been performed at RCT basis
Seoul National University Hospital
Cardiovascular Center
Objective
To evaluate the safety
Hypothesis
and long-term efficacy
EES is non-inferior to SES in
of Xience/Promus
• inhibiting neointimal growth
compared with the
at 9 months angiography
Cypher select
Seoul National University Hospital
Cardiovascular Center
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
Seoul National University Hospital
Cardiovascular Center
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
DAT 6 mo
DAT 12 mo
N=515
N=514
Randomization
3:1
Sirolimus-Eluting Stent
2x2
factorial design
DAT 6 mo
DAT 12 mo
N=171
N=172
N=343
Percutaneous Coronary Intervention
Secondary clinical
endpoint evaluation
Clinical
1mo
Angiographic
Seoul National University Hospital
Cardiovascular Center
3mo
9mo
12mo
2yr
Primary endpoint:
In-segment LL
Am Heart J 2009 May;157:811-817.e1.
3yr
4yr
5yr
Study Endpoints
• Primary Endpoint: In-segment late luminal loss (LL) at 9 months
(for comparison of stenting with EES vs. SES)
• Secondary Endpoints:











All Death, Cardiac death
Myocardial infarction (Q-wave and non-Q wave)
Target vessel revascularization (TVR) (all and ID)
Target lesion revascularization (TLR) (all and ID)
Stent thrombosis, Bleeding, CVA
Acute success (device, lesion, and clinical)
In-stent LL, and Angiographic pattern of restenosis at 9-month
In-stent and in-segment % diameter stenosis (%DS) at 9 months
In-stent % volume obstruction (%VO) at 9 months
Incomplete stent apposition post index procedure
Persisting incomplete stent apposition, late-acquired incomplete stent apposition, aneurysm,
thrombosis, and persisting dissection at 9 months
Seoul National University Hospital
Cardiovascular Center
Statistical Assumption
Primary Endpoint
In-segment late luminal loss (LL) at 9 months
• LL of EES: 0.2±0.41 mm (assumed)
• LL of SES: 0.2±0.48 mm (SIRIUS, E-SIRIUS, C-SIRIUS, SIRTAX, SPIRIT II, III)
• Non-inferiority margin: 0.1 mm
(type I error: 0.05; statistical power: 90%; attrition: 20%)
Seoul National University Hospital
Cardiovascular Center
Independence in Trial Coordination
Executive Committee
(HS Kim, MD, YS Jang, MD,
JH Yoon, MD, IH Chae, MD,
HC Kwon, MD, TH Ahn, MD)
DSMB
MRCC
CEAC
(Data Safety
Monitoring Board)
Trial Coordinating
Center (CC)
(BJ Park, MD, PhD)
(Clinical Event
Adjudication
Committee)
Steering Committee
(19 study investigators)
Seoul National University Hospital
Cardiovascular Center
Participating Centers
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
• Korea University Anan Hospital
Hospital
• Pusan National University Hospital
• Gachon University Gil Medical Center
• Boramae Medical Center
• Yonsei University Wonju Christian
• Kangnam Sacred Heart Hospital
Hospital
• Uijeongbu St. Mary’s Hospital
• Hallym University Sacred Heart Hospital • Keimyung University Dongsan Hospital
• Kandgong Sacred Heart Hospital
• Chonam National University Hospital
Seoul National University Hospital
Cardiovascular Center
• Ewha Womans University Mokdong
Hospital
Study Flow: Angiographic F/U
Enrolled and randomized
(N=1443)
EES
N=1079
Did not receive allocated stent: 24
- DES: 17
- POBA: 1
- BMS: 2
- Not inserted: 3
- CABG: 1
Failed PCI: 1
Randomized
SES
3:1
N=364
Did not receive allocated stent : 29
- DES: 23
- POBA: 1
- BMS: 0
- Not inserted: 4
- CABG: 1
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
Seoul National University Hospital
Cardiovascular Center
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
25±3.1
25±2.9
0.885
402 (37.3)
148 (40.7)
0.248
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
99 (9.2)
30 (8.2)
0.589
Previous bypass surgery
12 (1.1)
6 (1.6)
0.419
Previous congestive heart failure
8 (0.7)
1 (0.3)
0.463
Cerebrovascular disease
Peripheral vascular disease
57 (5.3)
13 (1.2)
37 (10.2)
6 (1.6)
0.001
0.594
Body-mass index, kg/m2
Diabetes mellitus
Chronic renal failure
Seoul National University Hospital
Cardiovascular Center
Baseline Profiles
Variables ― no. (%)
Multivessel disease
Left ventricular ejection fraction, %
Clinical indication
Silent ischemia
Chronic stable angina
Unstable angina
NSTEMI
STEMI
Medications at discharge
Aspirin
Clopidogrel
Statin
ACE inhibitor
Angiotensin II-receptor antagonist
Beta-blocker
Calcium-channel blocker
Seoul National University Hospital
Cardiovascular Center
EES
(N=1,079)
SES
(N=364)
564 (52.3)
61.4±9.4
185 (50.8)
60.8±9.8
39 (3.6)
472 (43.7)
464 (43.0)
76 (7.0)
28 (2.6)
16 (4.4)
172 (47.3)
139 (38.2)
20 (5.5)
17 (4.7)
1,066 (99.3)
1,063 (99.0)
892 (83.1)
355 (33.1)
356 (33.1)
665 (61.9)
362 (33.7)
356 (98.9)
357 (99.2)
304 (84.4)
119 (33.1)
122 (33.9)
214 (59.4)
128 (35.6)
p-value
0.633
0.335
0.115
0.510
1.000
0.539
1.000
0.796
0.404
0.522
Lesion and Procedural Profiles
Variables ― no. (%)
Location
Left anterior descending
Left circumflex
Right coronary
Coronary graft
Multivessel disease**
ACC-AHA B2/C type
Total occlusion
Thrombus-containing
Bifurcation lesions
Calcification
Minimal luminal diameter, mm
Reference vessel diameter, mm
Diameter stenosis, %
Lesion length, mm
Lesion length > 20mm
EES
(N=1,458)
SES
(N=468)
0.815
722 (49.7)
319 (22)
411 (28.3)
1 (0.1)
564 (52.3)
746 (53.0)
48 (3.4)
114 (8.1)
166 (11.4)
589 (41.8)
0.87±0.48
2.87±0.49
69.67±15.34
20.32±12.05
544 (40.2)
235 (50.4)
101 (21.7)
130 (27.9)
0 (0)
185 (50.8)
245 (54.2)
18 (4)
33 (7.3)
50 (10.7)
183 (40.4)
0.88±0.5
2.88±0.52
69.64±15.39
20.48±11.51
182 (41.9)
*comparisons were performed using the generalized estimating equations (GEE).
**compared with the Chi-square t-test
Seoul National University Hospital
Cardiovascular Center
p-value*
0.633
0.632
0.583
0.567
0.728
0.628
0.678
0.641
0.955
0.812
0.562
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†
36.85±24.87
5 (1.4)
0.410
Use of GpIIb/IIIa inhibitors**
37.7±24.89
19 (1.8)
Minimal luminal diameter (in stent)
Minimal luminal diameter (in segment)
Diameter stenosis (in stent)
Diameter stenosis (in segment)
Acute gain (in stent)
Acute gain (in segment)
Use of intravascular ultrasound (IVUS)*
Lesion success
Device success
Procedure success
2.6±0.46
2.22±0.51
8.59±8.95
19.01±11.07
1.73±0.54
1.35±0.58
466 (43.2)
1444 (99.7)
1446 (99.9)
1433 (99.0)
2.6±0.49
2.24±0.53
8.3±8.3
18.37±11.19
1.72±0.53
1.35±0.57
160 (44)
460 (99.8)
457 (99.1)
457 (99.1)
0.848
0.554
0.451
0.238
0.753
0.877
0.798
0.817
0.100
0.928
*comparisons were performed using the generalized estimating equations (GEE).
**compared with the Chi-square test, and †with the independent t-test
Seoul National University Hospital
Cardiovascular Center
0.617
QCA Data(1) :all lesions
EES
(N=949)
SES
(N=267)
p-value*
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
69.57±15.14
71.02±14.83
0.178
2.60±0.45
2.59±0.48
0.796
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
1.73±0.54
1.76±0.54
0.526
1.35±0.57
1.38±0.56
0.364
Variables ― no. (%)
Before procedure
Lesion length ― mm
Diameter stenosis ― %
Immediately after procedure
Minimal luminal diameter ― mm
In stent
In segment
Diameter stenosis ― %
In stent
In segment
Acute gain ― mm
In stent
In segment
*comparisons were performed using the generalized estimating equations (GEE).
Seoul National University Hospital
Cardiovascular Center
QCA Data(1) :all lesions
Variables ― no. (%)
Follow-up at 9 months
Minimal luminal diameter ― mm
In stent
In segment
Diameter stenosis ― %
In stent
In segment
Late luminal loss ― mm
In stent
In segment
Binary restenosis ― %
In stent
In segment
Restenosis pattern** ― %
Focal
Diffuse
Proliferative
Total occlusion
EES
(N=949)
SES
(N=267)
p-value*
2.42±0.53
2.12±0.52
2.44±0.55
2.16±0.53
0.458
0.256
14.63±13.33
22.53±13.81
13.94±12.10
21.02±12.72
0.415
0.079
0.19±0.33
0.10±0.36
0.15±0.33
0.05±0.34
0.082
0.051
18 (1.9)
30 (3.2)
3 (1.1)
6 (2.3)
0.293
0.352
1.000
27 (90.0)
1 (3.3)
1 (3.3)
1 (3.3)
6 (100.0)
0 (0.0)
0 (0.0)
0 (0.0)
*comparisons were performed using the generalized estimating equations (GEE).
**compared with the Fishcer’s exact test
Seoul National University Hospital
Cardiovascular Center
In-segment late LL
EES
(N=935)
SES
(N=266)
0.10±0.36 mm
0.05±0.34 mm
Mean ΔLL: 0.051 mm
Non-inferiority
p-value
Upper 1-sided 95% CI: 0.091 mm
0.023
Prespecified non-inferiority
margin: 0.1 mm
Non-inferior
-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
Seoul National University Hospital
Cardiovascular Center
In-Sement
Minimal Luminal Diameters
100
Before Procedure
EES
SES
% of Lesions
80
9-month F/U
EES
SES
60
After Procedure
EES
SES
40
20
0
0.0
1.0
2.0
Minimal Luminal Diameter (mm)
Seoul National University Hospital
Cardiovascular Center
3.0
4.0
In-stent late LL
EES
(N=935)
SES
(N=266)
0.19±0.33 mm
0.15±0.33 mm
Mean ΔLL: 0.043 mm
Non-inferiority
p-value
Upper 1-sided 95% CI: 0.082 mm
0.007
Prespecified non-inferiority
margin: 0.1 mm
Non-inferior
-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
Seoul National University Hospital
Cardiovascular Center
In-Stent
Minimal Luminal Diameters
100
Before Procedure
EES
SES
% of Lesions
80
9-month F/U
EES
SES
60
After Procedure
EES
SES
40
20
0
0.0
1.0
2.0
Minimal Luminal Diameter (mm)
Seoul National University Hospital
Cardiovascular Center
3.0
4.0
Hard Endpoints
Cumulative incidence rate (%)
: Composite of cardiac death, or MI
4.0
Log-Rank p-value=0.561
3.0
2.0
SES: 1.9%
1.0
EES: 1.5%
0.0
0
3
6
9
12
Months after initial procedure
Patient Number at Risks
EES
1078
1066
1064
1055
1052
SES
363
356
355
354
354
Seoul National University Hospital
Cardiovascular Center
Cumulative incidence rate (%)
Soft Endpoints
TLR
5.0
Log-Rank p-value=0.400
4.0
3.0
EES: 2.4%
2.0
1.0
SES: 1.7%
0.0
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
Seoul National University Hospital
Cardiovascular Center
Cumulative incidence rate (%)
Target Lesion Failure
: Composite of cardiac death, MI, or ID-TLR
5.0
Log-Rank p-value=0.552
4.0
EES: 3.7%
3.0
SES: 3.0%
2.0
1.0
0.0
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
Seoul National University Hospital
Cardiovascular Center
Target Lesion Failure
: Composite of cardiac death, MI, or ID-TLR
Subgroups
DM
Pt No.
Yes
No
Age
≥ 70
< 70
Lesion length (mm) > 20
≤ 20
CCR (mg/dL)
≥ 60
< 60
Multivessel ds
Yes
No
ACS
Yes
No
(N=542)
(N=874)
(N=371)
(N=1045)
(N=622)
(N=794)
(N=243)
(N=1173)
(N=735)
(N=681)
(N=728)
(N=688)
Overall
(N=1416)
Relative Risk (95% CI)
0.423
0.952
0.552
0.699
0.985
0.049
0.527
0.25
0.5
Favors EES
Seoul National University Hospital
Cardiovascular Center
Int P
1
2
4
Favors SES
8
Cumulative incidence rate (%)
Stent Thrombosis
: Definite/Probable ST by ARC definition
1.0
SES: 0.8%
0.8
Log-Rank p-value=0.281
0.6
EES: 0.4%
0.4
0.2
0.0
0
3
6
9
12
Months after initial procedure
Patient Number at Risks
EES
1078
1077
1071
1057
1043
SES
363
361
360
356
355
Seoul National University Hospital
Cardiovascular Center
Myocardial Infarction
MI, total
p=1.000
1.3%
1.4%
MI,
peri-procedural
MI,
spontaneous
p=0.741
p=0.379
1.0%
0.8%
0.6%
0.4%
EES
SES
EES
SES
EES
SES
N=1,057
N=359
N=1,057
N=359
N=1,057
N=359
Seoul National University Hospital
Cardiovascular Center
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.
Seoul National University Hospital
Cardiovascular Center
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
S
eoul N
Seoul
National
ationalU
University
niversityH
Hospital
ospital
C
ardiovascular
C
enter
Cardiovascular Center