Drug Eluting Balloons will Drug-Eluting Balloons ... - summitMD.com

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Drug Eluting Balloons will Drug-Eluting Balloons ... - summitMD.com

Drug-Eluting Balloons will

Have an Important Role in

Coronary and Peripheral

Interventional Therapy!

Juan F. Granada, MD

Executive Director and Chief Scientific Officer

Skirball Center for Cardiovascular Research

Cardiovascular Research Foundation

Columbia University Medical Center, New York


Disclosure Statement of Financial Interest

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

interest/arrangement or affiliation with the organization's listed below.

Affiliation/Financial Relationship

• Grant/Research Support

• Consulting Fees/Honoraria

• Major Stock Shareholder/Equity

• Royalty Income

• Ownership/Founder

• Intellectual Property Rights

• Other Financial Benefit

Company

• Abbott, BSCI, Medrad, Medtronic.

• Medrad.


Drug Coated Balloon Technologies

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

Cremers B. Thromb Haemost. 2009 Jan;101(1):201-6

Scheller et al., N Engl J Med 2006;355: 2113


New DCB Programs Under Development

Lutonix

Biotronik

2 µg/mm 2 3 µg/mm 2

BTHC

Invatec

3 µg/mm 2 Eurocor

3 µg/mm 2

Urea

Shellac


PCB for the Treatment of ISR

Angiographic Outcomes (Absence of Stent) t)

In-Se egment Binary Res stenosis (%)

0.9

0.8

07 0.7

0.6

05 0.5

0.4

03 0.3

0.2

01 0.1

0

-0.1

86% RRR

0.80 ±0.79

Total of 216 Patients!

PCB Control

55% RRR

(Taxus)

0.45 ±0.68

(BMS + DES)

0.31 ±0.22

0.20 ±0.45

0.16 ±0.40

0.11 ±0.44

N= 23

N=54 N=54 -0.02±0.50

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

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


PCB for the Treatment of ISR

Angiographic Outcomes (Absence of Stent)

In-Seg gment Binary Resteno

osis (%)

60

50

40

30

20

10

0

P


Clinical Outcomes Among 250 Patients

Presenting with ISR (DES and BMS)

Frequency of Stent Implantation 4.9%

• DIOR II PCB Technology (3 µg/mm 2 )

• 40.6% Diffuse ISR

14

• Length Covered by PCB 24±9.1 mm 12

10

8

6

4

2

0

9,8

13,4

12,2

9,8

7,2

5,9

BMS

2,6

2

1,2 1,31,2 1,2 1,2 DES

0

Silber S, Presented at CRT 2011.


PCB for the Treatment of SVD

Angiographic Outcomes (Absence of Stent)

• PEPCAD I: De-novo lesions, RVD: 2.25 - 2.8 mm; SeQuent Please

• Spanish Registry: De-novo lesions, RVD:


PCB for the Treatment of De Novo

SFA Disease (ITT= PTA Only)

LEVANT I

Fem PAC

N=35

N=39 0.46

N=34

0.3

0.8

109 1.09

POBA

PCB

Fem-PAC

N=31

N=34

19

47

POBA

PCB

Fem-PAC N=31

N=48

Thunder

N=41

04 0.4

1.7

Thunder

N=41

N=48

17

43

0 0.5 1 1.5 2

Angiographic Late Loss (mm)

0 20 40 60

Binary Restenosis (%)

• FAST Trial (Luminexx, LL ~4.5 cms)

• Binary Restenosis by DU: PTA 36.6% 6% versus Stent t 23.8% (p=0.073)

073)

• Absolute Trial (LL ~13 cms)

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


DEB SFA Italian Registry

De-Novo SFA Disease

• Multicenter SFA Observational Registry

• 94 patients / 103 lesions

• Lesion length 77.0 ± 38.6 mm

• Ruth Class 2: 23.4 %; 3: 68.1 %; 4: 7.4 %

• PTA alone: 86.4% / + Stent: t 13.6%

G.Biamino EuroPCR 2010


Vascular Healing Following PCB Use

De Novo vs. ISR Applications

Can we extrapolate the data gathered from ISR trials towards the

development of DCB technologies aimed to treat de novo lesions?

In-Stent Restenosis

• Ballooning inside of a stent.

• Quiescent disease state.

• Mature neointima.

De-Novo (+Stent)

Emerging • Disrupting DCB a plaque.

Trial Designs

• Active disease state.

DES

Market

• Presence of necrotic tissue.

• Smaller degree of injury induced. • Higher degree of injury.

• 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

for “De Novo” Applications

• PEPCAD III: BMS Crimped on PCB (3 µg/mm 2 ) versus Cypher Stent

• Lutonix De Novo Registry: Pre or Post Dilatation Using PCB (2 µg/mm 2 )

Angiographic Late Loss (mm)

Binary Restenosis (%)

PEPCAD III

N= 325 0.11 P


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 Patients t Bifurcation Study)

• Late Stent Thrombosis Rate (7.1%)


Now, Where Are We in 2011?

DES

Technologies

What do DCB need to

prove to become

mainstream therapy?

Regulatory

Challenges

Emerging

DCB Field

Emerging

DCB Field


(1) Systemic Release of Paclitaxel

Clinical Indication:

• SFA

• 120 mm balloon

• 7 mm diameter

• Overlapping balloons

?% of Systemic Dose

• Acute drug loss during transit

• Short term human PK studies

• Biodistribution (other tissues).


(2) Mechanism of Action of DCB

Sustained Tissue Retention of Paclitaxel

Transit Drug Loss

DCB

Acute Drug Transfer

TISSUE LEVEL ENDPOINTS

• Below toxic threshold

• Homogeneous distribution

• Sustained therapeutic levels

l

Acute Drug Transfer

Drug Transfer Technology


Deposition of a Drug Delivery Biofilm

Proposed Mechanism of Action

Cotavance DCB Technology

Localized endovascular retention of paclitaxel particles

serving as a reservoir for sustained drug delivery

Histology picture obtained from CVPath


Concentration vs. Depth at 90 Days

G)

PACLITAX XEL (NG/

Log Concentration vs. Depth at Follow Up Times

100.0 1 HOUR

10.0

1.0

1 DAY

7 DAYS

30 DAYS

90 DAYS

0.1

0 200 400 600 800 1000

Endothelium

Neointima Media (SMC Layer) Adventitia

TRANSMURAL TISSUE DEPTH (ΜM)

Slide courtesy of Lutonix Inc


(3) Local Tissue Effects (Safety)

Vascular Healing According to Dose

1= Minimal

2= Slight

3= Moderate

2.5

4= Marked

2

5= Massive

15 1.5

1 1

Mean Sc core

1

0.5

Uncoated 0

Delayed Endothelialization

2.17

1.75

Mean Score

2.5

2

1.5

1

0.5

0

Fibrin (Endothelial + Medial)

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

1

1.2

1.7

1.95

Cotavance

(1x)

Cotavance

(6x)

Mean

Score

3

2.5

2

1.5

1

0.5

0

IEL Rupture

Presence Amorphous Material

2.5 3.5

2.87

2 2

3

1.62

2.5

1.87

2

15 1.5

1

1

0.5 0

0

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

Score

Mean

Histology picture obtained from CVPath


(4) Particulate Coating Formation

Local Tissue Effects

Transit Drug Loss

Acute Drug Transfer

Micro-Particles

DCB

Acute Drug Transfer

Macro-Particles

• Vascular occlusions.

• Tissue drug effect.

• 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

studied in a prospective manner in a larger population.

• Newer generations of PCB appear to offer improved coating

platforms providing more precise drug transfer to the tissue.

• Preliminary data suggests that specific features of the

coating regulates the long-term transfer and retention ti of the

drug.

• The 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 proper technical balance is achieved (acute transfer-tissue

ti

levels-particulate formation), PCB have the potential to

become a strong competitor in the PCI arena.

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