High Tech - Marseille 25 au 27 janvier 2011 Marie-Claude MORICE, MD, FESC, FACC Massy, France

High Tech - Marseille25 au 27 janvier 2011Marie-Claude MORICE, MD, FESC, FACC Massy, France

Pas de conflit d’interet

Moins de 6 mois d’antiagrégants après DES ?

Was optimal duration of DAPT already established for BMS?

Stable&unstable angina

2,116 ptsmedian DAPT duration8 months

Acute coronary syndromes

1 year vs. 30 days of DAPT

No difference in bleeding Slight increase in bleeding (P=0.07)

:

Are DES particularly vulnerable to thrombosis?

100

90

80

70

60

50

40

30

20

10

0 1 2 3 4 5 6 7 8 9 11 15 16 17 20 >40

Duration (months)

En

doth

elis

atio

n (%

)

BMS

DES

From autopsies of 23 patients treated with DES >30 days and 25 matched BMS-treated autopsies

Joner et al, JACC 2006

Are DES particularly vulnerable ?

PES

SESBMS

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

0.44%0.2%

2%

0.39%0.4%

0.9%

0.0%

0.5%

1.0%

1.5%

2.0%

2.5%

3.0%

ST

(A

RC

Def

/Pro

b) (

%)

Early (< 30 Days) Late (30 Days - 1 Year)

6

1 Kedhi E. et al Lancet. 2010; 375 (9710): 174-6.

COMPARE1

XIENCE V USA

XIENCE V

TAXUSXIENCE V

0.84%0.7%

3%

p = 0.002

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.

O

O

O OH

OO

OO

OO

N

OH

O

O

O

NOBORI – DAT StudyNobori DES components

BMS Platform PLA Biodegradable Polymer Biolimus A9™ (rapamycin derivative)

Excellent Flexibility and Scaffolding

Optimal Side Branch Access

Innovative Delivery System with Hydrophilic M-coating

Abluminal Coating

Controlled Biodegradability

Precise Drug Release Kinetics

Simultaneous Polymer Degradation and Drug Release

A Potent New “Limus” Designed for Stent Applications

Powerful Anti-proliferative and Anti-inflammatory properties

Highly Lipophilic with Optimal Local Tissue Uptake

LEADERS: Definite ST in Complex PatientsSTEMI

1.0

2.0

3.0

%

2.6%

5.1%

0 6 12 18 24 3630Months

2.6%

5.1%4.6%

2.6%

3-year HR0.50 [0.18 to 1.34]

P = 0.16*

0

4.0Δ2.0% Δ3.5% Δ3.5%

5.0

6.0

High SYNTAX SCORE (>16)

1.0

2.0

3.0

%

2.0%

4.3%

0 6 12 18 24 3630Months

2.0%

3.8%

2.5%

2.0%

3-year HR0.46 [0.16 to 1.35]

P = 0.15*

0

4.0

Δ0.5%Δ1.8%

Δ2.3%

5.0

6.0

Bifurcation

1.0

2.0

3.0%

1.5%

5.2%

0 6 12 18 24 3630Months

1.5%

5.2%

3.4%

1.5%

3-year HR0.28 [0.08 to 1.03]

P = 0.04*

0

4.0

Δ1.9%Δ3.7% Δ3.7%

5.0

6.0

Multi Vessel

2.0

4.0

6.0

%

BESSES

0 6 12 18 24 3630Months

3.8%

8.1%8.1%

3.0%

3-year HR0.45 [0.16 to 1.31]P = 0.14*

0

8.0

Δ 5.1%Δ 4.3%

10.0

3.8%

8.1%

Δ 4.3%

*P values for superiorityWindecker, S., oral presentation ,TCT 2010

LEADERS :Effect of DAPT Discontinuation

%%

N=0/165 N=4/169 N=2/515N=0/540

Overall Population Patient who d/c

DAPTP = 0.12*

P = 0.24*

*P values for superiority (Fisher Exact Test)** KM estimates

N=24/850N=19/857

0,0%

0,5%

1,0%

1,5%

2,0%

2,5%

3,0%

0,37% 0,49%

0,26%0%

Late ST Rates (30 Days - 1 Year)After DAPT Interruption

Su

bse

qu

ent

Lat

e S

T (

AR

C D

ef/P

rob

) (%

)

No Interruption Interruption After 30 Days*

13/3500 0/292

Interruption After 180 Days*

2/435

Interruption After 90 Days*

1/378

Overall

11

*Out to 1 year

NOBORI 2- DAT Study

Primary Endpoint: Target Lesion Failure at 12 months

Composite of Death, MI Target vessel related and TLR

Clinical Follow-Up up to 5 years

DAT group:Patients under DAT at 1 year

n=2303

non-DAT group:Patients who stopped DAT earlier

n=668

12 months data for DAT available for 2971 patients

12 Months FU = 97%

DAT

N=2303

Non-DAT

N=668P-value

Age, years (meanSD) 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

Charlson Comorbidity, N (meanSD)

3.16±1.79 3.18±1.66 0.6

NOBORI – DAT StudyBaseline Demographics

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%

DAPT Interruption Pattern*

14

*Out to 1 year**Adverse Events include all events regardless of their severity and/or relationship with drugs or device

DATN=2303

Non-DATN=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 StudyClinical outcomes at 1 year

0,2 0,2

0,5

0,1 0,2

1,2

0,9

0,00,0

0,5

0,9

0,40,4

0,0

0,5

0,00,0

1,0

2,0

CardiacDeath

MI TVR-CABG

TLR-PCI TVR-NTL MACE TLF ST

(%)

Events during DAT

Events after stopping DAT

TLF = Target Lesion Failure (Cardiac death, MI, clinically driven TLR);

ST = Definite/Probable according to ARC; MACE = Cardiac Death, any MI, TVR

NOBORI – DAT StudyPatients that stopped DAT before 1 year

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

Proprietary Highly Lipophilic Limus drug

Hypothesis: Polymer-free drug release via porous-eluting stents

may reduce late events caused by polymer stent coatings.

Potential advantage

• 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

Tada et al., Circ Cardiovasc Interv 2010;3;174-183

Pre-Clinical Safety Evaluation

2nd Cohort PRIMARY ENDPOINTP = 0.001* (p=0.11**)

P = 0.21* (p=0.55**)

(m

m)

N = 31 N = 31N = 35

*Non-inferiority tests. **Superiority tests.Grube E., oral presentation, TCT 2010

In-Stent LLL at 12 Months FU

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: 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

(BMS) 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 attentionThank you for your attention