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Comparison of particulate embolization in
different DCB formulations.
Aloke V. Finn, MDCVPath Institute Inc. Gaithersburg, MD.
USA
Conflict of Interest Declaration
• Institution grant/research support– 480 Biomedical, Abbott Vascular, Atrium,
BioSensors International, Biotronik, Boston Scientific, Cook Medical, Cordis J&J, GSK, Kona, Medtronic, MicroPort Medical, CeloNova, OrbusNeich Medical, ReCore, SINO Medical Technology, Terumo Corporation, and W.L. Gore, Spectronics, CSI, Lutonix Bard, Surmodics, Microport, Meril Life Sciences
• Speaking Honoraria
– Abbott, Cook Medical, Lutonix, Boston Scientific
Elements of an Effective DCB Formulation
• Must deliver large quantities of the drug within seconds
• Distribute within the media in the first few days
• Therapeutic drug levels must be maintained for morethan 4 weeks
• Must allow rapid healing as compared to DES
• No need for long-term anti-platelet therapy
• Biologic effects must be observed by histology at 28-days
• Effective drug delivery to target tissue while avoiding non-target effect (i.e. minimize emboli)
• Downstream Panniculitis Secondaryto Drug–Eluting Balloon Angioplasty.Ibrahim T et al, JACC Cardiovasc Interv. 2016;12;9(17):e177-9.
• Vasculitis resulting from a superficial femoral artery angioplasty with a paclitaxel-eluting balloon.Thomas SD et al, J Vasc Surg. 2014;59(2):520-3
• Acute hypersensitivity reaction to femoral drug-coated balloons.
Lake E et al, Vasa. 2017 May;46(3):223-225
Three Case Reports for Downstream Effect of DCB
Use: Particulate Embolization Related?
Device Company CoatingDrug dose (µg/mm2)
CE mark*
Advance 18 PTX™ Cook Medical, Bloomington, IN, USA Paclitaxel 3.0 Yes
Cotavance® Bayer Schering Pharma AG, Berlin, Germany Paclitaxel–iopromide 3.0 Yes
Freeway™ Eurocor, Bonn, Germany Paclitaxel–shellac 3.0 Yes
IN.PACT™ Admiral, Medtronic Vascular, Santa Clara, CA, USA Paclitaxel–urea 3.5 Yes
Lutonix® 035 DCB BARD, Murray Hill, NJ, USA Paclitaxel–polysorbate/sorbitol 2.0 Yes
Ranger Boston Scientific Paclitaxel–Acetyl Tributyl Citrate 2 2.0 Yes
Passeo-18 Lux® Biotronik, Bülach, Switzerland Paclitaxel–butyryl-tri-hexyl citrate 3.0 Yes
Stellarex® Covidien, Mansfield, MA, USA Paclitaxel-polyethylene glycol 2.0 Yes
SurVeilTMDCB SurModics, MN, USA Paclitaxel-proprietary photolink® 2.0 Yes
IN.PACT
ELUTAX Sequent PleasePantera Lux
SurModicsLutonix
Drug Coated Balloon Devices (Peripheral artery)
IN.PACT™ ADMIRAL™ MAINTAINS GREATER DRUG IN TISSUE
• While there is expected variability across studies, IN.PACT ™ Admiral ™ consistently provides higher PTX tissue concentration than Lutonix ™* DCB through 90 days
• Paclitaxel available for both IN.PACT ™ Admiral ™ and Lutonix ™* DCB post-24 hours, but IN.PAC T ™
Admiral ™ achieves sustained effect through slow release of solid-phase paclitaxel reservoirs
Arterial Tissue Concentration
Note: Data on file with MedtronicGranada, J; JACC INT, 2015
0
10
20
30
40
50
60
70
80
4hours
1 Day 7 Day 21 Day 30 Day 45 Day 60 Day
Dru
g i
n T
issu
e
(ng
/mg
)
Ranger DCB
In.Pact Admiral DCB
Lutonix DCB
BSX Boston Ranger DCB*
MDT IN.PACT Admiral DCB
Bard Lutonix DCB
0 2 0 4 0 6 0 8 0 1 0 0
0
1 0 0
2 0 0
3 0 0
4 0 0
5 0 0
D a y s
Dru
g i
n T
iss
ue
(n
g/m
g) IN .P A C T
L u to n ix
0 2 0 4 0 6 0 8 0 1 0 0
0
1 0
2 0
3 0
D a y s
Dru
g i
n T
iss
ue
(n
g/m
g)
Downstream Sampling for Paclitaxel Analysis and Histopathology Assessment
Coronary band
EFA
IFA
Angiogram of the SFA
• Evaluated skeletal muscle and coronary band for potential embolic changes• Distal paclitaxel concentration • Histology
• Distal embolization• Vascular changes
Gracillis
Rectus
Femoris
SemitendonosisArteries
not shown
GastrocnemiusSemimembranosis
Gluteus Maximus
Left or Right SFA Randomly Treated by
LUTONIX, In.Pact or POBA
LEF 1x or
3x OL
LIF
REF 1x or
3x OL
RIF
Histo only Treatment Scheme: A total of 2
DCB treated sites (1/vessel) in the external
femoral arteries of one leg (left or right).
IN.PACT 1x
or 3x Tx site
LEF 1x or
REF
RIF
PK and histo Treatment Scheme: A
total of 2 treated sites in the external
femoral arteries of one leg (left or right).
1x or 3x LUTONIX
or IN.PACT Tx site POBA 1x or
3x Tx site
LUTONIX1x or 3x Tx site
LEF:1x
or 3x
POBA
Downstream Incidence of Distal Embolization (%)
SurvivalTreatment & Arteries
Lutonix 035 IN.PACT P-value
Paclitaxel concentration in downstream tissues (ng/g)
Skeletalmuscle
Coronaryband
Skeletalmuscle
Coronaryband
Skeletalmuscle
Coronaryband
28-day (1x, n=5) 1.3
(0.6-2.3)1.5
(1.1-65.8)60.8
(32.6-118.1)189.0
(134.0-700.0)0.009 0.02
28-day (3x, n=5)3.7
(1.3-10.9)31.5
(5.9-54.1)170.9
(19.7-221.5)871.0
(567.5-1315.0)0.08 0.009
90-day (3x, n=4)0.6
(0.5-6.4)2.7
(0.0-25.5)16.1
(12.8-319.2)158.0
(6.3-1178.0)0.009 0.05
SurvivalTreatment & Arteries
Lutonix 035 IN.PACT P-value
Number of micro-vessels with paclitaxel-associated findings
28-day (1x, n=5) 1 (0-2) 4 (2-12) 0.03
28-day (3x, n=5) 1 (0-12) 26 (11-34) 0.07
90-day (3x, n=4) 0 (0-3) 11 (5-15) 0.02
0
25
50
75
100
Lutonix 035 IN.PACT
0
25
50
75
100
Lutonix 035 IN.PACT
0
25
50
75
100
Lutonix 035 IN.PACT
A
B
C
15.4% (11.5-30.8)
n=5
7.7% (0-11.5)n=5
38.5% (15.4-42.3)n=5
7.7% (0-15.4)n=5
46.2% (19.2-57.7)N=5
0% (0-11.5)N=5
P=0.04
P=0.07
P=0.01
Single Balloon (1x) Overlapping Balloons (3x) Overlapping Balloons (3x)
90-Day Survival28-Day Survival
Dis
tal
Em
bo
lizati
on
(%
)
Downstream Findings in Porcine Skeletal Muscle (28-Day)
High (20x and 40x) power images
of vascular changes in skeletal
muscle at 28 days.
Vascular changes include pyknotic
nuclei embedded in homogenous
pink material (yellow arrow),
representing fibrinoid necrosis
(black arrows), with surrounding
inflammatory cells (blue arrows).
Lutonix (1x) Vascular Change IN.PACT (1x) Vascular Change
High (40x) power images of
crystalline material (red
arrows) at 28d
IN.PACT (1x) Crystalline Material IN.PACT (3x) Crystalline Material
In. Pact DCB vs. Stellarex vs. Ranger The Second Comparative Study
LEF 1x orREF
RIF
Treatment Scheme: A total of 2 treated
sites in the external femoral arteries (left
or right) in each pig
3x IN.PACT Tx site 3x Ranger or
Stellarex Tx
site
LEF
LIF
• Same swine model - 28 day study
• 3x dose, same size DCB
• DCB inflated for 60 secs
• Blinded-device ID
• Same sampling method and evaluation endpoints as the first Lutonix vs. IN.PACT comparative study
Downstream Incidence of Distal Embolization (%)
SurvivalTreatment
Second Comparative Study
IN.PACT Ranger Stellarex
Paclitaxel concentration in downstream tissues (ng/g)
28-day (3x)
Skeletalmuscle
Coronaryband
Skeletalmuscle
Coronaryband
Skeletalmuscle
Coronaryband
216.5(326.1-146.2)
911.3(691.3-1773.8)
91.5(44.8-116.9)
822.5 (347.9-1450.6)
101.9(44.6-163.8)
962.3 (149.9-1160)
SurvivalTreatment
Second Comparative Study
IN.PACT (n=12) Ranger (n=6) Stellarex (n=6)
Percentage of sections with vascular changes in downstream nontargettissues (%)
28-day (3x) 42.9 25 30
Overlapping Balloons (3x), 28-Day Survival
First Comparative Study
Lutonix (n= 5) IN.PACT (n=5)
7.7 38.5
First Comparative Study
Lutonix IN.PACT
Skeletalmuscle
Coronaryband
Skeletalmuscle
Coronaryband
3.7(1.3-10.9)
31.5(5.9-54.1)
170.9(19.7-221.5)
871.0(567.5-1315.0)
IN .P AC T R a n g e r S te lla r e x
0
2 0
4 0
6 0
8 0
1 0 0 p=0.2
IN .P AC T R a n g e r S te lla r e x
0
2 0 0
4 0 0
6 0 0
8 0 0
IN .P A C T R a n g e r S te lla re x
0
1 0 0 0
2 0 0 0
3 0 0 0
4 0 0 0
5 0 0 0p=0.01 p=0.5
Paclitaxel concentration in downstream Skeletal muscle
Paclitaxel concentrationin downstream Coronary band
(ng/g) (ng/g)(%)
Histologic sections showingDistal Embolization
Dis
tal E
mb
oliz
atio
n
Pacl
itax
el c
on
cen
trat
ion
Pacl
itax
el c
on
cen
trat
ion
Ranger StellarexIN.PACT
Downstream changes followingIN.PACT vs. Ranger vs. Stellarex, dose 3X, at 28 days
CV38011 L SEMM1_20x
CV38007 Left GracilisCV38007 Right Gracilis
CV38010 R GASTRO1_20x CV38012 L SEMM2_20x
CV38010 Left Gastrocnemius
DCB Design: All About Balancing Safety,
Efficacy, and Biologic Response
Not all balloons are created equal.
Effic
acy S
afe
ty
Drug Load
Use of Carrier / Excipient
Drug Retention
Repeat Inflations
More
Less
Less
More
Rapid vascular healing
Good re-endothelialization
No distal emboli
Less neointima
Absence of restenosis
No early or late thrombosis
Biologic changes, but no emboli
No Restenosis
Goal of Efficacy
No Aneurysms No Emboli
Goal of Safety
Acknowledgments
CVPath Institute
Sho Torii, MDKazuyuki Yahagi, MDHiroyoshi Mori, MDEmanuel Harari, MDElena Ladich, MDRobert Kutz, MSEd Acampado, DVMYouhui Liang, MDAbebe Atiso, HTJinky BeyerLila Adams, HTFrank D Kolodgie, PhDLiang Guo, PhDRenu Virmani, MD Washington DC
Funding
CVPath Institute Inc.
My email: [email protected]
Clinical Relevance
• In the absence of randomized clinical data, preclinical studies can provide excellent information about the relative performance of different technologies
Randomized studies generally exclude high risk patients who probably would be affected most by downstream adverse events
• DCBs which obtain effective drug transfer into the arterial wall while minimizing downstream embolic effects are the goal
Lutonix® 035 vs. In.Pact™ Admiral First Comparative Study in Swine
• Blinded study – Side-by-side
• 1x and 3x dose
• Evaluated skeletal muscle and coronary band at 28 and 90 days
Distal drug concentration
Histology
• Distal embolization
• Vascular changes
Different test methods may yield different results. Pre-clinical test data on file. Pre-clinical results may not be indicative of clinical performance.
Histologic Parameters for
Evaluation of DCB Efficacy
Key parameters include:
• Endothelial loss
• Fibrin / Platelets
• Inflammation
• Injury
• Medial smooth muscle cell loss
• Matrix replacement
• Proteoglycan
• Collagen
• Adventitial fibrosis
Fibrin
SMC loss
Proeoglycan
H&E
α-SMA
Movat
Left or Right SFA Randomly Treated by
LUTONIX, or In.Pact
LEF 3x OL
LIF
REF 3x OL
RIF
Histo only Treatment Scheme: A total of 2
DCB treated sites (1/vessel) in the external
femoral arteries of one leg (left or right).
IN.PACT 3x
Tx site
LUTONIX 3x Tx site
Kolodgie, FD et al. J Vasc Interv Radiol. 2016 Sep 15. pii: S1051-0443(16)30338-4.
Histologic Vascular Changes following
Lutonix vs. In.Pact DCB Treatment (3x)
Lutonix 3x-28d In.Pact 3X-28d POBA-28d
Lutonix 3x-90d In.Pact 3x-90d POBA-90d
0
10
20
30
40
50
Lutonix035
IN.PACT POBA Lutonix035
IN.PACT POBA
28 days 90 days
0
1
2
3
4
Lutonix035
IN.PACT POBA Lutonix035
IN.PACT POBA
28 days 90 days
Luminal Stenosis, %P=0.02 P=.044
Neointimal Area, mm2
P=0.02 P=.030
Kolodgie, FD et al. J Vasc Interv Radiol. 2016 Sep 15. pii: S1051-0443(16)30338-4.
0
1
2
3
4
Lutonix 035 IN.PACT POBA Lutonix 035 IN.PACT POBA
28 days 90 days
Histologic Vascular Changes following
Lutonix 035 vs. IN.PACT DCB Treatment (3x) at 28 and 90 days
SMC loss score (Depth) SMC loss score (Circumference)
Medial proteoglycan score Fibrin/thrombus score
Lutonix 035: n=5, In.Pact DCB: n=5, POBA: n=4
P=0.004 P=0.02
0
1
2
3
4
Lutonix 035 IN.PACT POBA Lutonix 035 IN.PACT POBA
28 days 90 days
P=0.01 P=0.02
0
1
2
3
4
Lutonix 035 IN.PACT POBA Lutonix 035 IN.PACT POBA
28 days 90 days
0
1
2
3
4
Lutonix 035 IN.PACT POBA Lutonix 035 IN.PACT POBA
28 days 90 days
P=0.01 P=0.007 P=0.41 P=1.00
Kolodgie, FD et al. J Vasc Interv Radiol. 2016 Sep 15. pii: S1051-0443(16)30338-4.