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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.