Biosensors Lunch Symposium - summitmd.comsummitmd.com/pdf/pdf/4_Stephen Lee.pdf · Biosensors Lunch Symposium 25th April 2013 Prof. Stephen WL Lee, JP ... Similar rates of MACE and

Are Current DES the Final Answer?BioFreedomTM: the Polymer-Free Biolimus A9TM Coated Stent

Biosensors Lunch Symposium

25th April 2013

Prof. Stephen WL Lee, JP 李偉聯MD FRCP(Lon. Edin. Glas.) FHKCP FHKAM FACC FSCAI

Chief of Cardiology, Professor & Senior Consultant

Department of Medicine, Queen mary Hospital, University of Hong Kong

Speaker’s name: Stephen Wai-luen LEE

(Queen Mary Hospital, University of Hong Kong)

I have the following potential conflicts of interest to report:

Research contracts

Consulting

Employment in industry

Stockholder of a healthcare company

Owner of a healthcare company

Other(s)

I do not have any potential conflict of interest to declare

Potential conflicts of interest

x

The stents were provided by Biosensors as investigational devices.

The Core Laboratory Charges are supported by Biosensors.

PCI objective = purely for achieving revascularization

= without complicated issues of

• Acute failure

• Restenosis

• Stent thrombosis

• Prolonged DAPT

• BleedingBut many DES still show Poor Stent Healing :-drug cytotoxicity, polymer hypersensitivity, local inflammatory reactions, loss endothelial and vasomotor functions


• MACE

All current DES = can achieved neointimal suppression

Is stent thrombosis genuine ?

• Most powerful histological predictor of stent thrombosis = endothelial coverage• Most powerful surrogate indicator of endothelialization = neointimal coverage• Best morphometric predictor of LST = ratio of uncovered to total stent struts

Finn et al. Circulation 2007;115;2435-2441

Pooled Analysis of Data Comparing SES With BMSEstimated 4-year cumulative incidence of

stent thrombosis, death, MI, and TLR

2.0

1.5

1.0

0.5

0.00 1 2 3 4

Years Since Procedure

Ste

nt

Th

rom

bo

sis

(%

)

Sirolimus stent (1.2%)

Bare-metal stent (0.6%)

P=.20

10

6

4

2

00 1 2 3 4




P=.86

8

Myo

card

ial In

farc

tio

n (

%)

30

20

10

00 1 2 3 4



P<.001

25

5

15T

arg

et-

Lesio

n

Reva

sc

ula

rizati

on

(%

)



10

6

4

2

00 1 2 3 4



P=.23

8

Death

(%

)

Stone et al. N Engl J Med. 2007;356:998-1008

2.0

1.5

1.0

0.5

0.00 1 2 3 4


Ste

nt

Th

rom

bo

sis

(%

)

Paclitaxel stent (1.3%)


P=.30

Pooled Analysis of Data Comparing PES With BMSEstimated 4-year cumulative incidence of

stent thrombosis, death, MI, and target lesion revasc.

10

8

6

2

00 1 2 3 4


De

ath

(%

)



P=.68

4

10

8

6

2

00 1 2 3 4


Myo

card

ial In

farc

tio

n (

%)



P=.66

4

30

25

20

5

00 1 2 3 4


Targ

et-

Lesio

n

Reva

sc

ula

rizati

on

(%

)



P<.00115

10

Stone et al. N Engl J Med. 2007;356:998-1008

Cardiac

DeathTV-MI CI-TLRDeath

Cardiac death

or TV-MI

ARC ST

Def/Prob

RESOLUTE All Comers – Simple Patients

Clinical Outcomes to 12 MonthsR-ZES EES

(n=376) (n=396)

P=0.79 P=0.50 P=0.70 P=0.48 P=0.12 P=0.49

%

Stefanini et al., JACC 2011

Cardiac

DeathTV-MI CI-TLRDeath

ARC ST

Def/Prob

%

RESOLUTE All Comers – Complex Patients

Clinical Outcomes to 12 Months

P=0.02 P=0.24 P=0.90 P=0.58 P=0.26 P=0.80

R-ZES EES

(n=764) (n=756)

Cardiac death

or TV-MI

Stefanini et al., JACC 2011Resolute-US Trial: similar results between the 2 stents

Biolimus-A9™ Eluting Stent

• 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.

LEADERS ‘All-comers’ Trial

Clinically-Indicated TVR

* p-value for superiority

Serruys et al., oral abstract presentation, TCT 2012

LEADERS ‘All-comers’ Trial

Biomatrix (n=850) versus Cypher (n=850).DAPT = 12 months. 81% off-label use.

1o endpoint: MACE: Cardiac death, MI, clinically-indicated TVR (9 months)

5 years data available. Better outcomes than Cypher at 5 years.

Patie

nt O

rie

nte

d E

ndp

oin

ts (

Dea

th, M

I, T

LR

, T

VR

)

P for interaction=0.022

* p-value for superiority

Serruys et al., oral abstract presentation, TCT 2012

Definite ST (ARC)

Landmark Analysis @ 1 Year

LEADERS ‘all-comers’ Trial

ESC guidelines 2010

Wijns et al., Eur Heart J. 2010; 31(20): 2501-55.

But these are guidelines based on clinical outcomes.

Is there any more scientific approach:-

(In-vivo assessment of stent healing guiding of DAPT duration)

Biomatrix (Biolimus-A9™ PLA) DES

Polymer-free drug elution via porous surface

Biofreedom (Biolimus-A9™) DCS

Potential Advantages

• Reduced late adverse effects due to polymer

hypersensitivity

• Improved surface integrity with no polymer to be

sheared or peeled away from the stent struts

• Possible shorter DAPT with better healing without

polymer and inner BMS surface

11

Highest lipophilicity of the common limus drugs

Components of BioFreedom DCS

Metal / Design

Polymer Drugs

Drug and Release kinetics

determine

Anti-proliferative effects

Sirolimus-135g

Everolimus – 100 g

Paclitaxel- 80 g

Biolimus A9 – 225 g

Strut Thickness ~ 81-140

microns

Durable

Biodegradable

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

Pre-clinical efficacy evaluation

Standard Dose BioFreedom

Low Dose BioFreedom

Sirolimus-eluting stents

Bare metal stents

BFD LDBFD SD

BioFreedom FIM design

BioFreedom FIM182 patients

12 Month Angio FU107 patients

BioFreedom

standard

dose

(BFD SD)

N=35

BioFreedom

low

dose

(BFD LD)

N=36

TAXUS®

Liberté ®

N=36

Second Cohort

Enrollment Period

Jan 2009 – Jun 2009

BioFreedom

standard

dose

(BFD SD)

N=25

BioFreedom

low

dose

(BFD LD)

N=26

TAXUS®

Liberté ®

N=24

4 Month Angio FU75 patients

First Cohort

Enrollment Period

Sept 2008 – Jan 2009

Angio FU 92%

12 Month Clinical FU 99%

Angio FU 92%

1o End-point: In-stent Late Lumen Loss at 4 months (LD) and 12 months (Standard Dose)

Antiplatelet Agent UtilizationAll patients- 1st and 2nd Cohorts

* P-values compare BFSD vs TAXUS

Grube E., oral presentation, TCT 2012

BFD SD BFD LD Taxus P value*

Aspirin

At 30 days 56/58 (97%) 61/62 (98%) 58/59 (98%) 0.55

At 4 months 56/58 (97%) 61/62 (98%) 56/57 (98%) 0.57

At 1 year 56/58 (97%) 60/61 (98%) 58/60 (97%) 0.97

At 2 years 52/58 (90%) 57/59 (97%) 53/59 (90%) 0.98

At 3 years 52/56 (93%) 54/57 (95%) 53/57 (93%) 0.98

Clopidrogel or ticlopidine

At 30 days 57/58 (98%) 61/62 (98%) 59/59 (100%) 0.31

At 4 months 57/58 (98%) 61/62 (98%) 57/57 (100%) 0.32

At 1 year 48/58 (83%) 41/61 (67%) 47/60 (78%) 0.54

At 2 years 4/58 (6.9%) 7/59 (12%) 13/59 (22%) 0.020

At 3 years 7/56 (13%) 7/57 (12%) 7/57 (12%) 0.97

Dual antiplatelet therapy

At 30 days 56/58 (97%) 61/62 (98%) 58/59 (98%) 0.55

At 4 months 56/58 (97%) 61/62 (98%) 56/57 (98%) 0.57

At 1 year 47/58 (81%) 40/61 (66%) 45/60 (75%) 0.43

At 2 years 3/58 (5.2%) 7/59 (12%) 11/59 (19%) 0.025

At 3 years 7/56 (13%) 6/57 (11%) 5/57 (8.8%) 0.52

0.17[0.09, 0.39]

0.22[0.17, 0.66]

0.35[0.22, 0.57]

0.0

0.1

0.2

0.3

0.4

0.5

BFD SD BFD LD TAXUS

2nd Cohort – PRIMARY ENDPOINT

P = 0.001* (p=0.11**)

P = 0.21* (p=0.55**)

(mm

)

N = 31 N = 31N = 35

*Non-inferiority tests based on the mean. **Superiority tests.

All values are presented as median [IQR].


In-stent Late Lumen Loss (12 months)

EVENT BFD SD

N = 60

BFD LD

N = 62

TAXUS

N = 60

MACE

(All Death, MI, Emergent Bypass

or TLR)

3 (5.1%) 7 (11.5%) 3 (5.0%)

All Death 1 (1.7%) 0 (0.0%) 0 (0.0%)

MI 1 (1.7%) 1 (1.6%) 0 (0.0%)

Q Wave MI 0 (0.0%) 0 (0.0%) 0 (0.0%)

Non-Q Wave MI 1 (1.7%) 1 (1.6%) 0 (0.0%)

Emergent Bypass 0 (0.0%) 0 (0.0%) 0 (0.0%)

TLR 1 (1.7%) 6 (9.8%) 3 (5.0%)

Definite/probable stent

thrombosis (ARC)0 (0.0%) 0 (0.0%) 0 (0.0%)

All patients – 1st and 2nd Cohorts (98.9%)

All P values are non-significant.

Tests were performed for BFD SD vs. TAXUS and BFD LD vs. TAXUS.


BioFreedom 12-Month Outcomes

EVENT BFD SD

N = 60

BFD LD

N = 62

TAXUS

N = 60

MACE (All Death, MI, Emergent

Bypass or TLR)7(11.9%) 11(18.1%) 6(10.0%)

All Death 3(5.1%) 2(3.3%) 1(1.7%)

MI 1(1.7%) 2(3.4%) 1(1.7%)

Q Wave MI 0(0.0%) 0(0.0%) 0(0.0%)

Non-Q Wave MI 1(1.7%) 2(3.4%) 1(1.7%)

Emergent Bypass 0(0.0%) 0(0.0%) 0(0.0%)

TLR 3(5.2%) 8(13.2%) 4(6.7%)

Definite/probable stent

thrombosis (ARC)0(0.0%) 0(0.0%) 0(0.0%)

All patients – 1st and 2nd Cohorts (96.1%)

All P values are non-significant. Tests were performed for BFD SD vs. TAXUS and BFD LD vs. TAXUS

Grube E , TCT 2012

BioFreedom 36-Month Outcomes

A polymer free BA9 stent.

Non-inferiority (with trend towards superiority) in the primary endpoint (in-stent LLL 12M) vs. Taxus (P=0.001 for non-inferiority;

P=0.11 for superiority)

Similar rates of MACE and TLR up to 3 years vs. Taxus Liberté.

Sustained safety up to 3 years, including absence of definite/probable stent thrombosis.

BioFreedom FIM Conclusions

• Could be promising “better healing” (no polymer hypersensitivity).

• May reduce DAPT duration.

• Less late stent thrombosis.

Leaders Free Trial

• Biosensors BioFreedom™ BA9 Drug-Coated Coronary Stent (DCS)

• Biosensors Gazelle™ Bare Metal Coronary Stent (BMS)

Two stents

• ASA 100-160 mg OD, indefinitely

• 1 month DAPT (Clopidogrel 75 mg OD or another P2Y12 inhibitor)

One DAPT regimen

Randomise, double-blind, 1:1 control study.

60+ centres world-wide 2400+ patients with high risk of bleeding.

FU for 2 years.

Co-Primary Endpoints(1) Safety (non-inferiority) – MACE (Death, MI, Stent Thrombosis)

(2) Efficacy (superiority) - clinically-driven TLR

Brazil

Canada

Australia

Argentina

Hong Kong

Malaysia

Singapore

Thailand

Austria

Belgium

Denmark

France

Germany

Israel

Italy

Latvia

Netherlands

Norway

Spain

Switzerland

Poland

UK

Participating Centers

Principal Investigators:

P. Urban (Switzerland)

A. Abizaid (Brazil)

I. Meredith (Australia)

Primary Endpoint: OCT % strut coverage from 1 to 6 months.

Secondary Endpoints: Clinical Endpoints (MACE)

QCA & OCT Findings at 9 months

Drug therapy: ASA and clopidogrel (per guidelines for 9 months)

Clinical Follow up: 30d, 6mo, 9mo, 12mo, 1yr, 2yr.

N = 100 patients Single Center

Initial PCI procedure angiogram (baseline OCT)Randomly assigned to 6 FU groups at 1,2,3,4,5 & 6 months (OCT)Final restudy angiogram & OCT at 9 months

1mo 9 mo

OCT

Clinical

Endpoint

BioFreedom DCS Stent

Real World, All Comers

With symptomatic coronary artery disease

3mo 4mo 5mo 6mo 12mo 24moBaseline 2mo

1st Angiographic & OCT FU 2nd OCT FU

EGO-BioFreedom Study

EGO-BioFreedom Study

The EGO-BioFreedom Study

Stringent Classification

of Early Strut Coverage

1 Month FU 2 Month FU

A B C

D E F

Very stringent strut coverage classification

Sequential longitudinal OCT FU with a very stringent strut coverage classification

May predict / prevent late stent thrombosis, ratherthan waiting for years to observe for adverse effects.

OCT should be adopted as a vigorous & novel step for guiding any new stent platform.

BioFreedom Stent : could be a Novel Device ?!!

No Stent Thrombosis

Minimal late catch-up

Baseline OCT9 months OCT(late loss NIH)

5 groups (1 to 5 months)OCT strut coverage

Degree of early coverage (healing profile)

Guiding appropriate DAPT duration Reduced stent thrombosis

Little late loss as a DES Proper stent apposition

The Leaders-Free & EGO-Biofreedom Study

Thank you

PCI objective = purely for achieving revascularization

= without complicated issues of

• Acute failure

• Restenosis


• Prolonged DAPT

But many DES still show poor Stent Healing =

drug cytotoxicity, polymer hypersensitivity, local inflammatory reactions, loss endothelial and vasomotor functions


• MACE

BMS vs. DES

All current DES = can achieved neointimal suppression

Documents

Biosensors Lunch Symposium - summitmd.comsummitmd.com/pdf/pdf/4_Stephen Lee.pdf · Biosensors Lunch Symposium 25th April 2013 Prof. Stephen WL Lee, JP ... Similar rates of MACE and