Drug Eluting Stents Using Bioresorbable Polymers are

the Best Clinical Choice

Juan F. Granada, MD Executive Director and Chief Scientific Officer

Skirball Research Center

Cardiovascular Research Foundation

Columbia University Medical Center, New York

TCT at SOLACI-CACI 2014,Thursday April 24rd

Disclosure Statement of Financial Interest

• Grant/Research Support: Abbott Vascular, Alumend, Amaranth

Medical, Bioventrix Inc., Boston Scientific, Caliber Therapeutics Inc.,

Cardia Inc., Cardiosystems Inc., Cardiosolutions Inc., Circulite Inc.,

Corindus Vascular Robotics, Direct Flow Medical, Intact Vascular,

Juventas, Lutonix, Meril Life Sciences, Mitralign, Orbus Neich

Medical Inc., Stentys S.A., Surmodics, Thoratec, Tubrikar, Valve

Medical, Volcano, WL Gore

Within the past 12 months, I or my spouse/partner have had a financial

interest/arrangement or affiliation with the organization(s) listed below:

The Technological Evolution of PCI “A Band Aid Developmental Approach”

Acute dissections, abrupt vessel

closure & chronic negative

remodeling

Neointimal proliferation

Delayed healing & stent thrombosis

PTCA

BMS

DES

SPIRIT II, III, IV and COMPARE trials

Pooled Database Analysis (n=6,789)

Kereiakes DJ et al. EuroIntervention 2011:7:74-83

Target-Lesion Revasc

@ 4 Years

Favors BP DES Favors SES

Biodegradable Polymer DES

Versus Durable Polymer SES

Definite ST

@ 4 Years

N = 4,062 – IPD Pooled Analysis of LEADERS, ISAR-TEST 3 and 4

Favors BP DES Favors SES

Stefanini G et al. Eur Heart J 2012; 33, 1214–1222

0 to 1 year:

HR 0.80

(95% CI 0.47-1.38)

p=0.43

1 to 4 years:

HR 0.22

(95%CI 0.08 – 0.61)

p=0.004

1 to 4 years:

HR 0.73

(95% CI 0.53 – 1.00)

p=0.05

0 to 1 year:

HR 1.02

(95% CI 0.78-1.31)

p=0.91

Definite ST Cardiac Death or MI

Biodegradable Polymer DES versus Durable Polymer SES Through 4 Years

% %

A Pooled Analysis of ISAR-TEST 3, ISAR-TEST 4, and LEADERS trial

Stefanini G et al. Eur Heart J 2012; 33:1214-22

PROMUS Element™ Plus

Drug: Everolimus

Platform: Platinum-Chromium

Polymer: PVDF

Xience Prime™

Drug: Everolimus

Platform: Cobalt-Chromium

Polymer: PVDF

Non-Absorbable Polymers in 3rd Generation DES: Is There Room to

Improve Clinical Outcomes? Resolute Integrity™

Drug: Zotarolimus

Platform: Cobalt-Chromium

Polymer: Biolinx

• We currently have DES platforms delivering drugs from non-absorbable

polymers showing excellent restenosis rates and clinical outcomes

• Still, in high risk patients and complex lesions: – Acute device performance can be challenging

– Prolonged DATP therapy needs to be maintained

– Stent thrombosis rates are still high (compared to low risk cases)

Technology Drug Drug

Dose

Absorption

Time

Polymer Polymer

Thickness

Absorption

Time

Stent

Material

Stent

Thickness

SYNERGY1 Everolimus 38 - 179 µg 3 m PLGA 3-4 µm 4 m PtCr 74 µm

Abluminus2 Sirolimus 6 m PLA N/A 6-8 m CoCr 73 µm

Desyne BD3 Novolimus 85 µg 3 m PLA <3 µm 6-9 m CoCr 81 µm

Biomatrix4,5 Biolimus A9 15.6 µg/mm 9 m PLA 10 µm 6-9 m SS 112 µm

Nobori6,7 Biolimus A9 15.6 µg/mm 9-12 m PLA 20 μm 9-12 m SS 120 µm

SVELTE8 Sirolimus 220 μg/cm2 2 m AA 6 µm 12 m CoCr 81 µm

Orsiro9,10 Sirolimus 1.4 μg/mm2 3 m PLLA Abl: 7.5 µm

Lum: 3.5 µm

15 m CoCr 60 µm

FIREHAWK11 Sirolimus 3 µg/mm 3 m PLA 8 µm 9 m CoCr 86 µm

MiStent12 Sirolimus 3 µg/mm 6 m PLLA Abl: 10-15 µm

Lum: 3-5 µm

3 m CoCr 64 µm

BioMime13 Sirolimus 1.25

μg/mm2

30 d PLGA +

PLLA

2 µm N/A CoCr 65 µm

Remedee

Combo14,15

Sirolimus &

CD34 ABD

5 µg/mm N/A N/A 3-5 µm N/A SS 100 µm

Inspiron16 Sirolimus 56 μg N/A PLA +

PLGA

5 µm N/A CoCr 75 µm

Ultimaster17 Sirolimus 3.9 µg/mm N/A PDLLA+

PCL

N/A 3-4 m CoCr 80 µm

1. Meredith IT, J Am Coll Cardiol. 2012;59:1362-1370, 2. Dani S. TCT2012, 3. Abizaid AA. TCT2011, 4. Windecker S. TCT2007, 5. Windecker S. TCT2008,

6. Ostojic M. EuroIntervention. 2008;3:574-579, 7. Smits PC. The Lancet. 2013, 8. Pomeranz M. EuroPCR. 2012, 9. Windecker S. TCT2012, 10. Hamon M.

EuroIntervention. 2013;8:1006-1011, 11. Gao R-L. EuroIntervention. 2013;9:75-83, 12. Ormiston J, JACC Cardiovasc Interv. 2013, 13. Seth A. TCT2012, 14.

Haude M. TCT2012, 15. Haude M. JACC Cardiovasc Interv. 2013;6:334-343, 16. Lemos P. TCT2012, 17. Stefanini GG,Heart. 2013

Polymer Type, Distribution and

Loading in Different DES Designs

Commercially Available DES Systems Strut and Coating Thickness In Perspective

Xience CoCr-

EES

Promus PtCr-

EES

Biomatrix

316L-BES Nobori

316L-BES BVS

PLLA-EES SYNERGY PtCr-EES

Resolute

CoNi-ZES

Durable

Polymer Coated Stents

Bioabsorbable

Polymer Coated Stents

Bioabsorbable

Stent

Strut Thickness

81µm 89µm 120µm 125µm 74µm 150µm

Polymer Coating Conformable

7-8µm / side

Conformable

6µm / side

Abluminal

11µm

Abluminal

20µm

Abluminal

4µm

Conformable

3µm / side

Presented by Yen Lane Chen, PhD at EuroPCR 2012; World J Cardiol 2011 March 26; 3(3): 84-92; Garg, S, J Am Coll Cardiol. 2010;56(10s1):S43-S78. doi:10.1016. Presented by Stephen Windecker, MD, TCT2012.

Polymer: PLGA Absorption Time: 3-4 mo

% R

eco

very

Time (months)

Drug Release-Polymer Absorption Profiles

SYNERGY

Everolimus

PLGA

Nobori and Biomatrix Flex

% R

eco

very

Polymer: PLA Absorption Time: >9 mo

BA9

PLA

Orsiro

% R

eco

very

Time (months)

Polymer: PLLA Absorption Time: >12 mo

Time (months)

Sirolimus

PLLA

(molecular

weight

change)

% R

eco

very

Time (months)

Absorb BVS

Scaffold: PLLA Polymer: PDLLA

Absorption Time: >2 yrs

Everolimus

PLLA

DES Using Bioresorbable Polymers

0,7

0,28

0,6

0,15

1,3

0,3

0,62

0,31

1,4

0,7

1,24

0,53

2,14

0,54

1,1

0,3

0

0,5

1

1,5

2

2,5

Stent Thrombosis: Latest Generation DES 1 vs. 3 Year Thrombotic Events

PLATINUM Presented by Ian Meredith AM, MBBS, PhD at ACC 2013; SPIRIT III presented by Gregg Stone at TCT 2001; SPIRIT IV

presented by Gregg Stone, MD at TCT 2011; COMPARE Presented by Peter Smits, MD at TCT 2011; Resolute All-Comers presented by

Stephan Windecker at PCR 2012; Resolute International presented by F-J. Neumann at TCT2012; LEADERS Presented by Patrick Serruys,

MD at TCT 2010

PROMUS Element

Xience V

Resolute

A A B C D E E F

ARC ST (Def/Prob)

3-Year Cumulative

VLST (Def/Prob)

From 1 to 3 Years

A A B C D E E F

A: PLATINUM Trial

B: SPIRIT III Trial

C: SPIRIT IV Trial

D: COMPARE Trial

E: RESOLUTE All-Comers Trial

F: RESOLUTE International

<1-YEAR STENT THROMBOSIS

• Non-device related variables

• Patient, lesion and technique

• Device thrombogenicity

• Polymer-drug

• Stent design

>1-YEAR STENT THROMBOSIS

• Vascular response to implant

• Acquired malapposition

• Neoatherosclerosis

• Delayed strut healing

• DATP compliance

Early Stent Thrombogenicity Non-Absorbable vs. Absorbable Polymer

Conformal distribution of non-

absorbable polymer and drug

Luminal Side Luminal Side

Abluminal distribution of

absorbable polymer and drug

“+” denotes biological activity of drug eluting polymer

*Technology dependent

+ + +

+

+

+

+ + +

+

+ +

+ + +

+

+

Abluminal Side Abluminal Side

4 to 12 month polymer

absorption time*

According to the polymer-drug absorption time*, the net effect

on healing may be comparable between bioresorbable and

durable polymers within the first 6 to 9 months

Early Stent Thrombogenicity of EES Durable PVDF Polymer + Drug vs. CoCr Control

Kolandaivelu K, Circulation 2011, 123:1400-1409

Comparable degree of

thrombogenicity of PVDF-coated

EES vs. CoCr metal only controls

Late Stent Thrombogenicity Non-Absorbable vs. Absorbable Polymer

Conformal distribution

of non-absorbable

polymer ONLY

Metallic surface

ONLY

Healing and thrombogenicity differences?

NO DRUG PRESENT

Platelet Adhesion and Activation PVDF Durable Polymer vs. Metallic Surfaces

% S

urf

ac

e A

rea

(+

) P

-Se

lec

tin

%

Su

rfa

ce

Are

a (

+)

CD

41

NS p < 0.05

compared to

PVDF

P= NS

p < 0.05

compared to

PVDF

Eppihimer M, Granada JF, TCT2012

Platelet Accumulation on Stent Surface PVDF Durable Polymer vs. Metallic Surfaces

*

*

*

Eppihimer M, Granada JF, TCT2012

Metallic

Surface

Cell

Migration

(mm)

Cell

Morphology

Cell

Size

Cell

Confluence

Cell

Concentration

Surface 1 1.99 ± 0.25 ++ Normal ++ ++

Surface 2 1.62 ± 0.37 ++ Normal ++ ++

Surface 3 1.57 ± 0.33 ++ Normal ++ ++

Surface 4 1.3 ± 0.4 + Elongated - +

Surface 5 1.18 ± 0.43 - Elongated - +

Surface 6 1.08 ± 0.29 + Elongated - -

Endothelial Cell Migration Correlates with Surface Coverage and Morphology

Left figure (modified) courtesy of A. Tellez, SCCR

0

0,5

1

1,5

2

2,5

Surface 6 Surface 5 Surface 4 Surface 3 Surface 2 Surface 1

<1.4 mm >1.4 mm

Cell M

igra

tio

n (

mm

)

Chen CS, Science 1997

Induced cell spreading

stimulates growth and

decreases apoptotic

rate in vitro

Impact of Stent Surface on EC Coverage PVDF Durable Polymer vs. Metallic Surfaces

Eppihimer M, Circ Cardiovasc Interv. 2013;6:370-377

Cadherin Expression on Stent

Surface at 90 Days

Coronary FH Swine Model

Skirball Research Center

Figure Courtesy of M. Eppihimer

Sprague E, Circ Cardiovasc Intervent, 2012;5:499

Biological Effect of Micro-Grooved Stent

Surfaces on EC Migration and Function Smooth

Grooved

3-Day Stent EC Coverage

GS= 81.3% vs. NGS= 67.5%, P<0.05

DES Surface Type and Long

Term Para-Strut Inflammation

Hypersensitivity Reactions (180 Days) • Familial hypercholesterolemic swine model

• Coronary DES Implantation (3 arteries)

• Inflammation at 30 Days:

• DES<<<BMS (Drug Effect)

• Inflammation at 90 Days:

• DES>>>BMS (Polymer Effect)

• Inflammation at 180 Days:

• DES with BRP<<<DES with DP (Residual

Surface Effect)

Eppihimer M, Granada JF 2014

Vascular Response to Polymeric Carriers PVDF (PROMUS) CONFORMAL DURABLE POLYMER ONLY COATED STENTS

PLGA (SYNERGY) ABLUMINAL BIOABSORBABLE POLYMER ONLY COATED STENTS

Eppihimer M, Circ Cardiov Int. 2013 Aug;6(4):370-7

DAPT Agent 1 Month

Cost ($)

12 Month

Cost ($)

3 Month

Cost ($)

Cost

Savings ($)

(per patient)

Share of

Market

(%)

Weighted

Average

Plavix® 277 3324 831 2493 3.7 92.24

Effient® 299 3588 897 2691 5.3 142.62

Brilinta® 340 4080 1020 3060 .8 24.48

Mean Drug Cost Savings per Patient $300

Cost of DATP: Type and Duration

(3 versus 12 Months)

• High end considers Effient®, Plavix®, and Brilinta® in model

• Low end assumes all DAPT is Clopidogrel at $5 per month cost

• In the high end scenario, model utilized 30 day AWP Prices and IMS share of market data for:

– Plavix (clopidogrel bisulfate), Effient (prasugrel), Brilinta (tricagretor)

• Assumed additional incidence of major bleeding of 1.3% between 3 and 12 month DAPT*

• Assumed Effient and Brilinta have similar incidence of major bleed as Clopidogrel /Plavix

• Assumed 3 and 12 month DAPT patients are compliant and adherent

Hypothetical Group of 1,000 PCI patients • Major Bleeds

-1.3% higher incidence with 12 month DAPT (13 patients)

- $8,000 cost per major bleeding event $104,000 additional costs

- Overall cohort consists of 1,000 patients $104 per patient

• Additional Major Bleeds (post secondary surgery)

- 25% will have second surgery 250 patients

- 25% taking DAPT during 2nd surgery 62.5 patients

- 3.3% higher incidence with 12 month DAPT 2.1 patients

- $10,000 cost/major bleeding event $21,000 additional costs

- Overall cohort consists of 1,000 patients $21 per patient

Duration of DATP and Cost of

Treating Bleeding Complications

Duration of DATP + Reduction of

Stent Thrombosis???

Absorbable vs. Non-Absorbable DES

Polymers on Metallic Stent Platforms

• In the initial healing phase (9 to 12 months) and due to the

comparable nature of the biological process induced by the

presence of polymer and drug, minimal differences in device

thrombogenicity may be seen

• In vivo human data suggests that at the end of this phase,

stent surface exposure caused by delayed healing occurs in

a small proportion of the patients

• In these cases, the exposure of a metallic stent surface (over

a durable polymer) may offer biological advantages in

healing and thrombogenicity

• However, due to the very low incidence of this biological

event, large RCT may be required to prove this hypothesis