Moins de 6 mois d’antiagrégants
après DES ?
High Tech - Marseille
25 au 27 janvier 2011
Marie-Claude MORICE, MD, FESC, FACC
Massy, France
Pas de conflit d’interet
Was optimal duration of DAPT
already established for BMS?
1 year vs. 30 days of DAPT
Acute coronary syndromes
Stable&unstable angina
median DAPT duration
8 months
No difference in bleeding
:
2,116 pts
Slight increase in bleeding (P=0.07)
Are DES particularly vulnerable to
thrombosis?
From autopsies of 23 patients treated with DES >30 days and 25 matched
BMS-treated autopsies
100
BMS
Endothelisation (%)
90
80
70
60
50
40
DES
30
20
10
0
1
2
3
4
5
6
7
8
9
11
15
16
17
20
>40
Duration (months)
Joner et al, JACC 2006
Are DES particularly vulnerable ?
PES
SES
BMS
Stettler et al. Lancet 2007
Everolimus-eluting stents vs.
non-everolimus-eluting stents
Baber et al. JACC in press
1 Year ST Rate (ARC Def/Prob)
Overall Population
Early (< 30 Days)
Late (30 Days - 1 Year)
3%
3.0%
ST (ARC Def/Prob) (%)
0.9%
2.5%
p=
0.002
2.0%
1.5%
0.84%
0.7%
1.0%
0.5%
XIENCE V
0.39%
0.4%
0.44%
0.0%
1
2%
0.2%
XIENCE V
TAXUS
XIENCE V USA
Kedhi E. et al Lancet. 2010; 375 (9710): 174-6.
COMPARE1
6
BioMatrix FlexTM
• Biolimus is a semi-synthetic sirolimus
analogue with 10x higher lipophilicity and
similar potency as sirolimus.
• Biolimus is immersed at a concentration of
15.6 g/mm into a biodegradable polymer,
polylactic acid, and applied solely to the
abluminal stent surface by a fully automated
process.
• Biolimus is co-released with polylactic acid
and completely desolves into carbon dioxide
and water after a 6-9 months period.
• The stainless steel stent platform has a strut
thickness of 120 m with a quadrature link
design.
NOBORI – DAT Study
Nobori DES components
O
O
O
O
N
O
O
HO
O
BMS Platform
PLA Biodegradable Polymer
O
OH
O
O
O
Biolimus A9™ (rapamycin
derivative)
Excellent Flexibility and
Scaffolding
Abluminal Coating
Controlled Biodegradability
A Potent New “Limus” Designed
for Stent Applications
Optimal Side Branch Access
Precise Drug Release Kinetics
Powerful Anti-proliferative and
Anti-inflammatory properties
Innovative Delivery System with
Hydrophilic M-coating
Simultaneous Polymer
Degradation and Drug Release
Highly Lipophilic with Optimal
Local Tissue Uptake
O
LEADERS: Definite ST in Complex Patients
STEMI
High SYNTAX SCORE (>16)
BES
SES
10.0
3-year HR
0.45 [0.16 to 1.31]
P = 0.14*
5.0
8.0
6.0
Δ 5.1%
4.0
8.1%
8.1%
Δ 4.3%
Δ 4.3%
3.8%
3.8%
5.1%
5.1%
4.6%
4.0
Δ2.0%
%
%
8.1%
Δ3.5%
Δ3.5%
3.0
3.0%
2.6%
2.0
2.0
0
3-year HR
0.50 [0.18 to 1.34]
P = 0.16*
6.0
2.6%
2.6%
1.0
0
0
6
12
18
Months
24
Bifurcation
6.0
30
%
Δ0.5%
2.0
Δ2.3%
36
30
3-year HR
0.28 [0.08 to 1.03]
P = 0.04*
5.2%
4.0
Δ1.8%
24
5.0
5.2%
3.4%
%
3.0
18
Multi Vessel
3.8%
2.5%
12
6.0
4.3%
4.0
6
Months
3-year HR
0.46 [0.16 to 1.35]
P = 0.15*
5.0
0
36
3.0
Δ1.9%
Δ3.7%
Δ3.7%
1.5%
1.5%
2.0
2.0%
2.0%
2.0%
1.0
1.5%
1.0
0
0
0
6
12
18
24
30
36
Months
*P values for superiority
Windecker, S., oral presentation ,TCT 2010
0
6
12
18
Months
24
30
36
Overall
Population
LEADERS :Effect of DAPT
Discontinuation Patient who d/c
DAPT
%
P = 0.12*
P = 0.24*
N=19/857
N=24/850
N=0/165
*P values for superiority (Fisher Exact Test)
** KM estimates
N=4/169
N=0/540
N=2/515
Subsequent Late ST (ARC Def/Prob) (%)
Late ST Rates (30 Days - 1 Year)
After DAPT Interruption
3,0%
Overall
2,5%
2,0%
1,5%
1,0%
0,37%
0,49%
0,5%
0,26%
0%
0,0%
13/3500
No Interruption
2/435
Interruption
After 30 Days*
1/378
0/292
Interruption
Interruption
After 90 Days* After 180 Days*
*Out to 1 year
11
NOBORI 2- DAT Study
12 months data for DAT available for
2971 patients
DAT group:
Patients under DAT at 1 year
n=2303
non-DAT group:
Patients who stopped DAT earlier
n=668
Clinical Follow-Up up to 5 years
Primary Endpoint: Target Lesion Failure at 12 months
Composite of Death, MI Target vessel related and TLR
12 Months FU = 97%
NOBORI – DAT Study
Baseline Demographics
DAT
Non-DAT
N=2303
N=668
64.2±11.0
64.7±10.6
0.4
Male, %
79.2
74.4
<0.01
Previous MI, %
32.2
36.1
0.07
Prior PCI, %
33.2
28.7
0.03
Prior CABG, %
9.4
7.4
0.1
Diabetes Mellitus, %
31.2
22.8
<0.01
Insulin-dependent, %
7.3
5.6
0.1
Hyperlipidemia, %
71.0
73.9
0.2
Hypertension, %
68.2
71.8
0.08
Current smoker, %
25.4
26.0
0.8
3.16±1.79
3.18±1.66
0.6
Age, years (meanSD)
Charlson Comorbidity,
N (meanSD)
P-value
DAPT Interruption Pattern*
Temporary Interruption % (N)
5.6% (N = 243)
Number of Interruptions
1.1 ± 0.5 (N = 243)
Days to First Interruption (days)
134.3 ± 121.4 (N = 243)
Duration of Interruption (days)
20.3 ± 46.9 (N = 243)
Top 3 Reasons for Interruption
Surgical Procedure = 35.4%
Adverse Event** = 30.5%
Patient Non-compliance = 9.5%
Permanent Discontinuation % (N)
8.5% (N = 366)
Days to Discontinuation (days)
239.2 ± 140.4 (N = 366)
Top 3 Reasons for Discontinuation
Adverse Event** = 21.9%
Surgical Procedure = 10.7%
Increased Bleeding Risk = 9.6%
*Out to 1 year
**Adverse Events include all events regardless of their severity and/or relationship with drugs or device
14
NOBORI – DAT Study
Clinical outcomes at 1 year
DAT
N=2303
Non-DAT
N=668
P-value
Cardiac Death %
0.6
0.2
NS
MI %
1.7
0.6
0.04
TLR - CABG %
0.4
0.5
NS
TLR - PCI %
2.0
0.5
0.003
TVR, non TL %
1.2
0.6
NS
TLF %
3.6
1.4
0.002
MACE %
4.7
2.1
0.003
Stent Thrombosis % – Early
0.4
0.0
NS
Stent Thrombosis % – Late
0.1
0.0
NS
Stent Thrombosis % – Total
0.5
0.0
NS
TLF = Target Lesion Failure (Cardiac death, MI, clinically driven TLR);
ST = Definite/Probable according to ARC; MACE = Cardiac Death, any MI, TVR
NOBORI – DAT Study
Patients that stopped DAT before 1 year
2,0
Events during DAT
Events after stopping DAT
(%)
1,2
1,0
0,9
0,9
0,5
0,5
0,2
0,2
0,0
0,0
0,5
0,4
0,4
0,1
0,2
0,0 0,0
0,0
Cardiac
Death
MI
TVRCABG
TLR-PCI
TVR-NTL
MACE
TLF
TLF = Target Lesion Failure (Cardiac death, MI, clinically driven TLR);
ST = Definite/Probable according to ARC; MACE = Cardiac Death, any MI, TVR
ST
Conclusions
• In 3 large trials, real-world population of
respectively 3000, 1400, 5000 patients,
NOBORI, BIOSENSOR and XIENCE V
stents demonstrates very low stent
thrombosis rates for the whole population
• In a real-world experience of unanticipated
DAPT interruption, the 3 stents had an
observed near zero ST event rate
afterDAPT interruption.
17
Conclusions
• Shorter dual antiplatelet treatment is
vital for some patients,
• If confirmed by prospective
comparative studies ( 3 or 6 months
compared to 1 year), these new
generation of stent will fullfill our
expectations
18
•And even less than 3 months?
.- the ZEUS trial (PI Marco Valgimigli) who
is randomizing patients at risk of bleeding
to Endeavor or BMS with a minimum
length of DAPT of 1 month.
- The Leaders free trial
BioFreedom™
Selectively micro-structured surface holds drug in
abluminal surface structures
Hypothesis: Polymer-free drug
release via porous-eluting stents
may reduce late events caused by
polymer stent coatings.
Potential advantage
Proprietary Highly Lipophilic Limus drug
•
Avoid long term late adverse
effects that might be attributable
to the polymer
•
Improved surface integrity since
there is no polymer to be sheared
or peeled away from the stent
struts
•
Possible shorter need of dual
antiplatelet therapy
Pre-Clinical Safety Evaluation
Tada et al., Circ Cardiovasc Interv 2010;3;174-183
2nd Cohort PRIMARY ENDPOINT
In-Stent LLL at 12 Months FU
P = 0.001* (p=0.11**)
(mm)
P = 0.21* (p=0.55**)
N = 31
N = 35
*Non-inferiority tests. **Superiority tests.
Grube E., oral presentation, TCT 2010
N = 31
A PROSPECTIVE RANDOMIZED COMPARISON OF THE
BIOFREEDOMTM BIOLIMUS A9TM DRUG COATED STENT
VERSUS THE GAZELLE™ BARE METAL STENT IN
PATIENTS AT HIGH RISK FOR BLEEDING
LEADERS FREE PROTOCOL
Title:
LEADERS FREE
Devices Used:
- Biosensors BioFreedom™ BA9 Drug
Coated Coronary Stent
- Biosensors Gazelle™ Bare Metal
Coronary Stent
Antiplatelet Therapy:
ASA once a day for one month
(indefinitely at the discretion of the
investigator) AND Clopidogrel or
P2Y12 inhibitor (choice of the
investigator) for one month
LEADERS FREE:PROTOCOL
Design:
multi center, multi-national out of US
double blinded, randomized, trial designed to
enroll 2500 patients at up to sixty centers
worldwide. Patients will be randomized at 1:1
ratio to the stent treatment. All patients will be
followed for two years.
Organisation:
PI: P Urban, I Meredith, A Abizaid
Sponsor/ BIOSENSORS
CRO: CERC
PROTOCOL
Objectives:
(BMS)
Safety:
1) To demonstrate in symptomatic CAD patients who are unsuitable
for >1 month treatment with dual antiplatelet therapy (DAPT) that the
Biosensors BioFreedom™ Drug Coated Stent (DCS) followed by one
month DAPT is non-inferior to the Gazelle™ Bare Metal Stent
followed by one month DAPT as measured by the composite primary
endpoint of cardiac death, myocardial infarction, stent thrombosis and
urgent target lesion revascularization (TLR) at one year.
Efficacy:
2) To demonstrate in symptomatic CAD patients who are unsuitable
for >1 month treatment with DAPT that the Biosensors BioFreedom™
DCS followed by one month DAPT then followed by aspirin only
indefinitely is superior to the Gazelle™ BMS followed by one month
DAPT as measured by the incidence of clinically driven TLR at one
year.
LEADERS FREE/ INCLUSION CRITERIA
Any indication for PCI-S in patients Deemed at high risk for bleeding and candidates for 1 month
DAPT
1- Adjunctive oral anticoagulation treatment planned to continue after PCI
2- Age ≥ 75 years old
3- Baseline Hgb <11 g/dl (or anemia requiring transfusion during the 4 weeks prior to
randomization)
4- Any prior intracerebral bleed
5- Any past <=1 year stroke
6- Hospital admission for bleeding during the prior 12 months
7- Cancer diagnosed or treated <= 3 years
8- Planned daily NSAID (other than aspirin) or steroids for >=30 days after PCI
9- Planned major surgery (within 1 year)
10- Expected non-compliance to prolonged DAPT for other reasons
Alors, les BMS…… au musée?
Thank you for your attention