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Drug Eluting Balloons will Drug-Eluting Balloons will Have an Important Role in Have an Important Role in Coronary and Peripheral Interventional Therapy! Juan F Granada MD Juan F . Granada, MD Executive Director and Chief Scientific Officer Skirball Center for Cardiovascular Research Skirball Center for Cardiovascular Research Cardiovascular Research Foundation Columbia University Medical Center, New York

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Drug Eluting Balloons willDrug-Eluting Balloons will Have an Important Role inHave an Important Role in Coronary and Peripheral Interventional Therapy!

Juan F Granada MDJuan F. Granada, MDExecutive Director and Chief Scientific OfficerSkirball Center for Cardiovascular ResearchSkirball Center for Cardiovascular Research

Cardiovascular Research FoundationColumbia University Medical Center, New York

Disclosure Statement of Financial InterestWithin the past 12 months, I or my spouse/partner have had a financial interest/arrangement or affiliation with the organization's listed belowinterest/arrangement or affiliation with the organization s listed below.

Affiliation/Financial Relationship Company• Grant/Research Support• Consulting Fees/Honoraria

• Abbott, BSCI, Medrad, Medtronic.• Medrad.

Affiliation/Financial Relationship Company

• Major Stock Shareholder/Equity• Royalty Income• Ownership/FounderOwnership/Founder• Intellectual Property Rights• Other Financial Benefit

Drug Coated Balloon Technologies A Viable Technological Concept?A Viable Technological Concept?

Control (hSMC) Paclitaxel (hSMC)(+) anti–ß-tubulin (+) anti–ß-tubulin

Axel DI. Circulation. 1997;96:636-645 Scheller J Am Coll Cardiol 2003

DEB 10s DEB 60s

Scheller et al., N Engl J Med 2006;355: 2113Cremers B. Thromb Haemost. 2009 Jan;101(1):201-6

New DCB Programs Under DevelopmentLutonix

2 µg/mm2

Biotronik3 µg/mm2

BTHC

Invatec3 µg/mm2

Eurocor3 µg/mm2

Urea ShellacUrea Shellac

PCB for the Treatment of ISRA i hi O t (Ab f St t)Angiographic Outcomes (Absence of Stent)

86% RRR

0 7

0.8

0.9

(%)

PCB Control

0.80 ±0.79 Total of 216 Patients!86% RRR

0 5

0.6

0.7

sten

osis

(Taxus)

55% RRR

0 3

0.4

0.5

Bin

ary

Res 0.45 ±0.68

0.31 ±0.22

(BMS + DES)

0 1

0.2

0.3

egm

ent B

0.11 ±0.44

0.20 ±0.450.16 ±0.40

N= 23

-0 1

0

0.1

PACOCCATH I/II INPACT ISR PEPCAD II PERVIDEO I Spanish Registry

In-S

e

-0.02±0.50N=54 N=54N= 23

N=66 N=65 N=39 N=34

-0.1

PCB for the Treatment of ISRAngiographic Outcomes (Absence of Stent)

P<0 01

Angiographic Outcomes (Absence of Stent)

5150

60

osis

(%)

PCB Control

P<0.01 Total of 216 Patients!

40

50

Res

teno PCB Control

P=0.06

17 620.330

Bin

ary

R

(Taxus)

6 4 7

17.6

10

20

gmen

t B

4

0PACOCCATH I/II INPACT ISR PEPCAD II Spanish Registry

In-S

eg

N=54 N=54 N=23 N=66 N=65 N=34

PACOCCATH I/II INPACT ISR PEPCAD II Spanish Registry

Clinical Outcomes Among 250 Patients P ti ith ISR (DES d BMS)Presenting with ISR (DES and BMS)

Frequency of Stent Implantation 4.9%

• DIOR II PCB Technology (3 µg/mm2)• 40.6% Diffuse ISR• Length Covered by PCB 24±9.1 mm 12

14

9,8

13,4

9,8

12,2

g y

46810

,

2 2,6

5,97,2

,

BMS

02

21,3

,

01,2 1,2 1,2 1,2 DES

Silber S, Presented at CRT 2011.

PCB for the Treatment of SVDAngiographic Outcomes (Absence of Stent)Angiographic Outcomes (Absence of Stent)

19 6

• PEPCAD I: De-novo lesions, RVD: 2.25 - 2.8 mm; SeQuent Please• Spanish Registry: De-novo lesions, RVD: <2.5 mm; Dior I (87%)

17.319.6

15

20

s (%

) PEPCAD I

S i h0 3

0.4

(mm

)

PEPCAD I0.32±0.56

0.34±0.23

10

Res

teno

si SpanishRegistry

0.2

0.3

men

Los

s (

SpanishRegistry

5

Bin

ary

R

0.1

Late

Lum

N=120 N=120N=51 N=510%

0mm

N=120 N=51

PCB for the Treatment of De Novo SFA Disease (ITT= PTA Only)

1 09N=35

SFA Disease (ITT= PTA Only)

0.46

0.8

1.09

Fem PAC

LEVANT IPOBAPCB

N=35N=39

N=3419

47Fem-PAC

POBAPCB

N=34

N=31

0 4

0.3

1.7Thunder

Fem-PAC N=31

N=48N=41 17

43Thunder

PCB

N=48N=41

0.4

0 0.5 1 1.5 2

A i hi L t L ( )

N=41

0 20 40 60

Bi R t i (%)Angiographic Late Loss (mm)

• FAST Trial (Luminexx, LL ~4.5 cms)Bi R t i b DU PTA 36 6% St t 23 8% ( 0 073)

Binary Restenosis (%)

• Binary Restenosis by DU: PTA 36.6% versus Stent 23.8% (p=0.073)• Absolute Trial (LL ~13 cms)

• Binary Restenosis by DU: PTA 45% versus Stent 25% (p=0.06)

DEB SFA Italian RegistryDe-Novo SFA DiseaseDe-Novo SFA Disease

• Multicenter SFA Observational RegistryMulticenter SFA Observational Registry• 94 patients / 103 lesions• Lesion length 77 0 ± 38 6 mm• Lesion length 77.0 ± 38.6 mm• Ruth Class 2: 23.4 %; 3: 68.1 %; 4: 7.4 %

PTA l 86 4% / St t 13 6%• PTA alone: 86.4% / + Stent: 13.6%

G.Biamino EuroPCR 2010

Vascular Healing Following PCB UseD N ISR A li tiDe Novo vs. ISR Applications

Can we extrapolate the data gathered from ISR trials towards the

In-Stent Restenosis De-Novo (+Stent)

Can we extrapolate the data gathered from ISR trials towards the development of DCB technologies aimed to treat de novo lesions?

DES• Ballooning inside of a stent.• Quiescent disease state.

( )• Disrupting a plaque.• Active disease state.

DES MarketEmerging DCB

Trial Designs

• Mature neointima. • Smaller degree of injury induced.• No additional material left behind.

• Presence of necrotic tissue. • Higher degree of injury.• Stent left behind.No additional material left behind. Stent left behind.• Plaque drug uptake?• Best mechanism of delivery?

• Pre, post, crimped stent?• Stent healing in vivo?

ISR De Novo

Angiographic Outcomes: PCB Trials f “D N ” A li tifor “De Novo” Applications

• PEPCAD III: BMS Crimped on PCB (3 µg/mm2) versus Cypher Stent• Lutonix De Novo Registry: Pre or Post Dilatation Using PCB (2 µg/mm2)

Binary Restenosis (%)Angiographic Late Loss (mm)

13.84.9

Lutonix Pre

PEPCAD IIIN= 312

N= 325 P<0.0010.2

0.11

Lutonix Pre

PEPCAD III ControlPCB

N= 312N= 325 P<0.001

9.1

Lutonix Post

Lutonix Pre-DCB

ControlPCBN= 110.53

Lutonix Post

Lutonix Pre-DCB N= 11

16.7

0 5 10 15 20

DCB N= 120.45

0 0.2 0.4 0.6

DCB N= 12

Synergistic Use of PCB and BMS Lessons Learned From the PEPCAD Trials

• PEPCAD I (SVD):• Binary Restenosis: DEB Only (5.5%) versus

DEB+BMS (41.3%)• Stent Thrombosis: DEB Only (0%) versus

DEB+BMS (1.7%)• PEPCAD III (De Novo + BMS):

• Definite Stent Thrombosis: DEB+BMS (1.3%) versus Cypher (0.3%)

PEPCAD V (28 P ti t Bif ti St d )• PEPCAD V (28 Patients Bifurcation Study)• Late Stent Thrombosis Rate (7.1%)

Now, Where Are We in 2011?DES

TechnologiesWhat do DCB need to

gprove to become mainstream therapy?

RegulatoryChallenges

mainstream therapy?

Challenges

EmergingDCB Field

EmergingDCB Field

(1) Systemic Release of Paclitaxel Clinical Indication:• SFA• 120 mm balloon• 120 mm balloon• 7 mm diameter• Overlapping balloons

?% of Systemic Dose?% of Systemic Dose

• Acute drug loss during transit• Short term human PK studies • Biodistribution (other tissues).( )

(2) Mechanism of Action of DCBSustained Tissue Retention of Paclitaxel

Transit Drug LossAcute Drug Transfer

TISSUE LEVEL ENDPOINTSg TISSUE LEVEL ENDPOINTS • Below toxic threshold• Homogeneous distribution

S i d h i l l

DCB

• Sustained therapeutic levels

Acute Drug Transfer

Drug Transfer Technology

Deposition of a Drug Delivery BiofilmProposed Mechanism of ActionProposed Mechanism of Action

Cotavance™ DCB Technology

Localized endovascular retention of paclitaxel particles serving as a reservoir for sustained drug deliveryserving as a reservoir for sustained drug delivery

Histology picture obtained from CVPath

Concentration vs. Depth at 90 Days

100.0 1 HOUR

Log Concentration vs. Depth at Follow Up Times

1 DAY

7 DAYS

30 DAYS

90 DAYSG)

10.0

XEL

(NG

/

1.0

PAC

LITA

X

0.10 200 400 600 800 10000 200 400 600 800 1000

Endothelium

TRANSMURAL TISSUE DEPTH (ΜM)

Neointima Media (SMC Layer) Adventitia

TRANSMURAL TISSUE DEPTH (ΜM)

Slide courtesy of Lutonix Inc

(3) Local Tissue Effects (Safety)Vascular Healing According to Dose

Delayed Endothelialization Fibrin (Endothelial + Medial)1= Minimal

Vascular Healing According to Dose

Delayed Endothelialization2.17

1.75

1 52

2.5

core

Fibrin (Endothelial Medial)

11.2

1.71.95

1.5

2

2.5

Scor

e

2= Slight3= Moderate4= Marked5 M i 1 1

00.5

11.5

Mea

n Sc 1

0

0.5

1

Mea

n S5= Massive

Uncoated 0Control 2x 4x 6x Control 2x 4x 6x

IEL Rupture3

Presence Amorphous Material

2 21.62

2.5

1.52

2.53

n Sc

ore

2.87

1.87

1 52

2.53

3.5

Sco

re

Cotavance(1x)

00.5

1

C

Mea

n

0

1

00.5

11.5

Mea

nCotavance

(6x)

Control 2x 4x 6x Control 2x 4x 6x

Histology picture obtained from CVPath

(4) Particulate Coating FormationLocal Tissue Effects

Transit Drug LossAcute Drug Transfer

g

Micro-Particles

DCBMacro-Particles

Acute Drug Transfer• Vascular occlusions.• Tissue drug effect.• End organ effects• End-organ effects.

Conclusions: PCB Technologies• PCB technologies continue to show efficacy in reducing

restenosis in specific clinical scenarios (i.e., ISR). • However the synergistic use of stents must be carefully• However, the synergistic use of stents must be carefully

studied in a prospective manner in a larger population. • Newer generations of PCB appear to offer improved coating g pp p g

platforms providing more precise drug transfer to the tissue.• Preliminary data suggests that specific features of the

ti l t th l t t f d t ti f thcoating regulates the long-term transfer and retention of the drug.

• The real clinical effect of micro-particle drug release intoThe real clinical effect of micro-particle drug release into distal tissues needs to be carefully evaluated against the potential therapeutic benefit of this technology.If t h i l b l i hi d ( t t f ti• If proper technical balance is achieved (acute transfer-tissue levels-particulate formation), PCB have the potential to become a strong competitor in the PCI arena.