Ultimaster DES Clinical Evidence

11/11/2014
Ultimaster DES
Clinical Evidence
ULTIMASTER DES
INNOVATIVE…
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bio-inspired stent design
thin-struts platform
argon-plasma surface
treatment
bioresorbable highly elastic
polymer
gradient coating technology
low dose of proven
performance drug
STENT
CHARACTERISTICS
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PLATFORM
CoCr; strut thickness 80µm
COATING
abluminal, gradient
POLYMER
bioresorbable (3-4 months)
Poly (PLLA-CL) copolymer
DRUG
Sirolimus; 3.9µg/mm stent
length
DESIGNED FOR…
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enhanced
conformability
reliable deliverability
optimized drug release
preserved endothelial
function
long term safety and
vessel patency
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11/11/2014
Ultimaster DES concept supported by
Comprehensive Clinical Program
More than 20.000pts worldwide
Undergoing or planned in studies with
Ultimaster DES
TCD10023PK
CENTURY
CENTURY II
MASTER
DISCOVERY
1TO3
Small
Vessels
Global
Registry
20 pts
105 pts
1123 pts
500 pts
60 pts
80 pts
20.000 pts
Single arm
Single arm
Randomized
Randomized
Single arm
Single arm
Single arm
1:1 vs
Xience
3:1 vs BMS
STEMI
OFDI strut
coverage
2.25 and
2.5 mm
stents
All-comers
Primary
Endpoint
TLF @9M
Ongoing
Ongoing
ongoing
Planned
Pharmacokinetics
Primary
Endpoint
LL @6M
PCR
2013
PCR
2013
PCR
2014
ULTIMASTER-PK Study
PHARMOKINETIC STUDY
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11/11/2014
Very low concentration of drug in
peripheral circulation
Data from TCD-10023PK study – Stojkovic et al. J Fund and Clin Pharm, 2014
Preserved endothelial function
in stented human coronary arteries
2,7
2,6
Distal Segment
Reference
2,5
mm
2,4
2,3
2,2
2,1
2
Baseline
Max Pacing
Nitrate
N=15
Vasomotor pattern of target and reference vessels at baseline, maximal
atrial pacing and after nitrates given, in the vessel segment distal to the
study stent at 6 months.
S. Stojkovic at al. . J Fund and Clin Pharm, 2014
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11/11/2014
Conclusions – ULTIMASTER PK Study
Sirolimus concentration in peripheral blood was very
low
Angiographic late loss at 6-month was 0.10 mm
Endothelial function, at 6 months, was fully
preserved, both proximally and distally to the
implanted Ultimaster DES
CENTURY Trial
CLINICAL EVALUATION OF NEW TERUMO DRUG ELUTING CORONARY STENT SYSTEM IN
THE TREATMENT OF PATIENTS WITH CORONARY ARTERY DISEASE
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11/11/2014
CENTURY – Study design
Prospective, multicentre, single arm clinical trial
Hypothesis: superiority vs. historical control of Kaname bare metal stent
platform for late loss at 6m
PI: W. Wijns
8 sites in Europe
Ultimaster
n= 105
Clinical Follow-up
0d
30d
6mo
12mo
2yr
3yr
4yr
5yr
Angio /IVUS/OCT
Angio/IVUS
Primary endpoint LATE LOSS at 6 months
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•
Main Inclusion Criteria
– Up to two de-novo lesions located in two epicardial vessels
Main Exclusion Criteria
– Left main CAD , CTO, ostial, bifurcation, SVG lesions
– Prior PCI with stenting (within 1 month before enrolment)
– STEMI <72h before procedure
CENTURY – Primary Endpoint
Based upon estimated Kaname Late Loss
0.90±0.50 mm
0.50 mm improvement considered as clinically significant
Late loss of 0.40 mm (0.90-0.50 mm) is considered upper limit for
Ultimaster DES
[-0.02 , 0.11]
0 0.04
Ultimaster DES
Late Loss result
Kaname
: 0.75±0.43 mm
Ultimaster
: 0.04±0.35 mm
[0.70 , 0.81]
0.40
0.75
LL (mm)
Kaname BMS
Result:
Ultimaster=SUPERIOR P<0.0001
Barbato E. et al. EuroInterv. 2014
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11/11/2014
OCT Representative Images – 6 months
Mean strut coverage (mm)
% Covered Struts at 6 months
0.080.04
Malapposed struts, %
96.25.4
Malapposition volume, mm3
1.66
1.86 ± 6.58
Homogeneous
neointima
Homogeneous
neointima
Courtesy H. Garcia Garcia
Clinical outcome - 1 and 2 years
Total %:
0.0
3.8
2.9
2.9
5.7
6.7
0.9
%
MI=myocardial infarction; CD-TLR = clinically driven target lesion
revascularization, TVR= target vessel revascularization, TLF=target lesion
failure, TVF=target vessel failure
ST= 1 acute stent thrombosis due to a long untreated dissection
Barbato E. et al. EuroInterv. 2014
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11/11/2014
Conclusion
Ultimaster DES showed an excellent antiproliferative profile and superior efficacy versus
its bare metal stent platform
The rate of adverse events up to 2 years was low,
with no late or very late stent thrombosis
Those findings represent initial confirmation of
the design concept of the Ultimaster DES
Comprehensive network meta-analysis
BMS
PES
‘CoCr-EES has the lowest rate of stent thrombosis,
……..also compared to BMS’
PC-ZES
SES
Lancet Editorial (Ormiston
& Webster) ‘ CoCr-EES should
CoCr -EES
be regarded as the standard against future design
improvements are compared’
Re-ZES
PtCr-EES
Palmerini et al. Lancet March 23, 2012
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11/11/2014
CENTURY II Trial
CLINICAL EVALUATION OF NEW TERUMO DRUG ELUTING CORONARY
STENT SYSTEM IN THE TREATMENT OF PATIENTS WITH CORONARY ARTERY
DISEASE
CENTURY II – study design and patient flow
ITT = Intention To Treat
PP = Per Protocol
1123 patients randomised between February
2012 and January 2013
Eligibility criteria met according
to Japanese requirements
Total Population
n=1119 ITT
n=1101 PP
Ultimaster
n=562 ITT
n=551 PP
Randomization
1:1
Cohort JR
n=722 ITT
n=715 PP
Xience
n=557 ITT
n=550 PP
Ultimaster
n=366 ITT
n= 362 PP
Xience
n=552 ITT
n=545 PP
Ultimaster
n=362 ITT
n=358 PP
Total Population
Ultimaster
n= 558 ITT
n=547 PP
9M FU
99.2%
Randomization
1:1
Xience
n=356 ITT
n=353 PP
Cohort JR
9M FU
99.3%
Xience
n=355 ITT
n=352 PP
PI: William Wijns & Shigeru Saito
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11/11/2014
Study organisation
Coordinating W. Wijns, Aalst, Belgium
Investigators S. Saito, Kanagawa, Japan
S. Saito, Japan, W. Wijns, Belgium, R. Kornowski, Israel, S.
Steering James, Sweden, E. Eltchaninoff, France, M. Valdes, Spain, G.
Committee Richardts, Germany; E. Barbato, Belgium; Medical advisors: K.
Nakamura, Japan, G.B. Danzi, Italy; B. Chevalier (CERC), France
Clinical Event R. Violini (chairperson), Italy; Dr. Y. Hamazaki, Japan; K.
Miyauchi, Japan ; E. Teiger, France; J. Ramón Rumoroso, Spain;
Committee N. Löffelhardt, Germany; G. Stankovic, Serbia.
C. Hamm, Germany, J.G.P. Tijssen, The Netherlands and, K.
Data Monitoring
Tanabe, Japan;
Committee
Management of DMC and CEC – CERC - France
Core Laboratories K.I.C. co LtD, Kanagawa, Japan
Sponsor Terumo
EPS, Japan, SBD Analytics, Belgium
CENTURY II – study devices
Platform
Drug Carrier
Coating
Drug
Ultimaster DES
Xience DES
Thin-strut (80µm) Co-Cr
Open cell design
Thin-strut (81µm) Co-Cr
PDLLA-PCL copolymer
resorbed within 3-4m
PVDF-HFP non-erodable
fluorinated copolymer
Abluminal gradient
coating technology
Circumferential
coating
sirolimus
70 µg/cm²
everolimus
100 µg/cm²
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11/11/2014
Patient eligibility
Inclusion criteria
Age ≥ 18 years (≥20 years Japan)
Suitable for treatment with DES
RVD matching stents 2.5-4.0 mm
Diameter stenosis >50%
Eligible for DAPT
Main exclusion criteria - general
EF<25%
Renal failure
Cardiogenic shock
Planned staged procedure
Additional exclusion criteria
Cohort JR
AMI < 48h
Target lesion located in left-main
trunk
Bifurcation lesion that needs
stenting of main and side branch
Ostial lesions
Lesion in venous or arterial graft
Previous (<1month) PCI with
stenting
Previous stenting in target lesion
Sample size calculation
Assumptions
TLF event free rate
Cohort JR
Total
Population
94%
90%
Non-inferiority margin
5.5%
Power
90%
Type I error (one-sided)
0.05
Sample Size
Based on the results of SPIRIT III (TVF rate of 7.2% in simple patient population) estimated
TLF free rate for Ultimaster in CENTURY II trial was set at 90%
Considering 1:1 sampling ratio (Ultimaster : Xience) and 10% drop out rate, a sample size
was calculated at 560 patients in each group for the TP (total of 1120 patients).
In agreement with Pharmaceuticals and Medical Devices Agency (PMDA) in Japan, the TLF
event free rate for Ultimaster in Cohort JR was estimated at 94% implying that 345 patients
should be included in each group (total of 690 patients).
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11/11/2014
Baseline clinical characteristics
Total population
Ultimaster
Xience
(N=551)
(N=550)
P
65 ± 11
65 ± 11
0.61
Gender, Males (%)
78.58
82.36
0.11
Diabetes (%)
31.94
30.91
0.71
IDDM (%)
16.48
14.71
0.65
Hypertension (%)
73.31
67.82
0.05
Dyslipidemia (%)
70.30
69.56
0.79
High risk ACS (%)
22.50
24.73
0.39
NSTEMI (%)
17.24
19.09
0.43
STEMI (%)
5.26
5.64
0.79
History of CAD (%)
30.75
32.06
0.66
Current smoker (%)
22.16
23.89
0.50
Previous PCI (%)
37.21
35.04
0.45
Age, N
Previous CABG (%)
4.54
3.65
0.46
Previous MI (%)
28.31
27.64
0.80
Baseline lesion characteristics
Ultimaster
Xience
(N=711)
(N=716)
1.29 ± 0.57
1.30 ± 0.57
B2
48.33
52.97
C
33.67
27.93
None/mild
78.52
82.34
Moderate/severe
21.48
17.66
Thrombus present (%)
3.92
4.05
0.90
Bifurcation (%)
13.78
14.39
0.74
9.3 ± 7.0
9.3 ± 6.4
0.36
Total population
Lesions treated (mean±SD)
ACC/AHA classification (%)
P
0.62
0.13
Calcification (%)
Syntax Score (mean±SD)
0.70
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11/11/2014
Baseline procedural characteristics
Ultimaster
Xience
(N = 551)
(N = 550)
Femoral
26.68
25.64
Radial
71.69
73.09
Brachial
1.63
1.27
Pre-dilation (%)
77.36
77.37
0.99
Post-dilation (%)
53.53
54.71
0.66
N° of stents implanted/pt
(mean SD)
1.51 ± 0.78
1.55 ± 0.86
0.94
N° of stents implanted/lesion
(mean SD)
1.18 ± 0.43
1.20 ± 0.44
0.32
Delivery success (%)
99.05
99.53
0.23
Procedure success (%)
98.00
98.18
0.83
Total population
P
Access site (%)
0.55
Primary endpoint
Freedom from TLF – 9 months
Total population
Per protocol
population
Ultimaster
N=551
Freedom from TLF
[95% CI]
N=550
95.64%
95.09%
0.55%
(527/551)
(523/550)
[-2.07%;3.18%]
P
<0.0001
Total Population
Intention to treat
population
Ultimaster
Freedom from TLF
1101 patients
Difference
Xience
1119 patients
Difference
Xience
N=562
N=557
[95% CI]
95.37%
94.97%
0.40%
(536/562)
(529/557)
[-2.22%;3.02%]
P
0.0001
Saito S. et al. EHJ 2014
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11/11/2014
Target lesion failure – K-M-estimate
Total population
Xience
5.27
%
[3.69% ; 7.50%]
Ultimaster
4.36
%
[2.94% ; 6.43%]
Data up to 300 days
Saito S. et al. EHJ 2014
Stent thrombosis – 9 months
Total Population
(%)
Ultimaster
(N = 551)
Xience
(N = 550)
Overall
0.91
0.91*
Definite
0.91
0.91
Probable
0.00
0.00
Possible
0.00
0.00
Acute (0-48h)
0.00
0.00
Subacute (48h-30d)
0.54
0.36
Late (>30d-9m)
0.36
0.54
P=NS
* 1 patient had 2 definite ST at 83 and 94 days in 2 separate lesions treated
at baseline
Saito S. et al. EHJ 2014
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11/11/2014
TLF – 9 months – subgroup analyses
P = 0,88
P = 0,21
P = 0,32
P = 0,32
P = 0,28
P = 0,67
P = 0,76
TLF – Target Lesion Failure: Composite of cardiac death, MI not clearly attributable to the non-target vessel and
clinically driven TLR
ACS – Acute Coronary Syndrome; DM – Diabetes Mellitus; MVD – Multivessel Disease; LL – Long Lesions; SV – Small
Vessels
Saito S. et al. EHJ 2014
TLF – 9 months – subgroup analyses
Saito S. et al. EHJ 2014
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11/11/2014
Complex populations – cardiac death
at 9 months
Unpublished data from CENTURY II
10.0
%
8.0
Ultimaster
Xience
6.0
4.0
2.0
2.0
1.7 1.7
1.5 1.5
Diabetes
Multivessel disease
0.7
0.0
0.0
0.0
ACS
Bifurcation
Complex populations – myocardial infarction
at 9 months
Unpublished data from CENTURY II
10.0
%
Ultimaster
8.0
Xience
6.0
3.6
4.0
2.0
3.6
3.3 3.5
2.2
1.6
2.6
2.9
0.0
ACS
Diabetes
Multivessel
Small vessels
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11/11/2014
Complex populations – TLR
at 9 months
Unpublished data from CENTURY II
10.0
%
Ultimaster
8.0
Xience
6.0
4.8
3.7
4.0
2.0
3.0
2.9
2.0
1.1
1.0
1.1
Diabetes
DM MVD
0.0
Bifurcation
Long lesions
Complex populations – stent thrombosis
at 9 months
Unpublished data from CENTURY II
5.0
%
4.0
Ultimaster
Xience
3.0
2.0
1.7
0.0
1.2
1.0
1.0
1.2
0.6
0.0
Bifurcation
0.7
0.0
Long lesions
Diabetes
Small vessels
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11/11/2014
Complex populations – TLF at 9 months
Unpublished data from CENTURY II
14.0
%
12.0
Ultimaster
Xience
10.0
8.6
8.0
7.6
7.1
6.9
6.3
6.0
5.0
4.4
4.0
2.1
2.0
0.0
Bifurcation
Multivessel
Diabetes
Long lesions
Complex populations – Diabetes mellitus and
multivessel disease at 9 months
Unpublished data from CENTURY II
20.0
%
18.0
Ultimaster
Xience
16.0
14.0
13.1
11.9
12.0
10.3
10.0
8.0
6.0
7.2
6.0
6.0
5.2
4.1
3.6
4.0
3.6
2.4
2.0
1.0
1.0
0.0
0.0
MI
TLR-PCI TLR-CABG
TVR
TLF
TVF
ST
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11/11/2014
Conclusions – CENTURY II
CENTURY II study reached its primary endpoint
The Ultimaster DES with bioresorbable polymer was
found to be as safe and as effective as Xience DES
with permanent polymer in this relatively complex
patient population
Both stents showed excellent performance and low
rate of adverse events
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11/11/2014
ESC/EACTS 2014 DES recommendation
Ultimaster is amongst the 8 DES with highest level of clinical evidence
Conclusions – Ultimaster DES
Clinical Evidence
Ultimaster DES has been extensively studied in
several clinical trials
Clinical safety and efficacy were equally good in low
to moderate and in complex lesions/patients
Based on available clinical evidence Ultimaster DES is
included in the latest ESC/EACTS guidelines for
myocardial revascularization
Thin struts, abluminal gradient coating and
bioresorbable polymer are promissing feature of this
newest DES
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