Diagnostic standards for PE - prof. Tomasz Rakowski
Novel paclitaxel coated balloon - dr Piotr Buszman
1. Novel, microcrystaline paclitxel coated
balloon - preclinical evaluation and
insights into First in Man application
Piotr P. Buszman M.D., PhD
Center for Cardiovascular Research and Development
American Heart of Poland, Katowice, Poland
Silesian Center for Heart Diseases, Zabrze, Poland
2. Peripheral Atherosclerosis: A Different Pathological State
PTA Restenosis Rates Complex Biomechanical Behavior
Iliacs (in-flow) 10-20%
SFA/ Popliteal
Artery 20-60%
Tibio-peroneal 50-75%
Different biological
architecture
consistent of
significant amount of
medial calcification
compared to other
vascular territories
3. Two ideas of leaving nothing behind
Bioresorbable scaffolds Paclitaxel Coated Balloons
BVS PCB
Vessel scaffolding ++ - / BMS bail out 20-30%
Implant free - (pending 2-3 years) +++
Tissue drug retention ++ +
Anti restenotic efficacy +++ ++
Positive vessel remodeling ++ ++
Restoration of vasomotive function ++ ++
Healing / DAPT requirement 1 year 1 month
4. PCB clinical prospective registries and randomized trials
Trial Design Territory
PCB
Control
Pt.#
Bail out
stenting
Patency at
6 m – 1y
Restenosis
6m-1y
TLR/
Amputation/
Death
6m-1y
TLR
6m-1y
LL
1. Micari et al Registry
Femoro-popliteal
In Pact 105 12.3% 83.7% 7.6%
2.DEBATE
BTK
Registry-
CLI
Infra-popliteal
In Pact 104 4.8% 72.6% (3m) 27.4% (3m) 38.3 17.3%
3. DEBATE-BTK
CRT –
CLI + DM
Infra-popliteal
In Pact 57 27%
POBA 61 65%
4. PACIFIER CRT
Femoro-
Popliteal
In Pact 44 20.5% 90% 8.6% 7.3% 7.1% -0.01
POBA 47 30.4% 69% 32.4% 26.8% 21.4% 0.65
5. LEVANT 1 CRT
Femoro-
Popliteal
Moxy 49 24.5% 72% 13.4% 13% 0.46
POBA 52 27% 49% 42.8% 22% 1.09
6. FEMPac CRT
Femoro-
Popliteal
Paccocath 45 9% 94% 19% 8.9% 7% 0.3
POBA 42 14% 94% 47% 42.8% 33% 0.8
7. THUNDER CRT
Femoro-
Popliteal
Paccocath 48 12% 98% 17% 8.3% 4% 0.4
POBA 54 22.0% 92% 44% 42.6% 37% 1.7
1. Micari A. et al. J Am Coll Cardiol Intv. 2012;5:331-338.
2. Schmidt et al. J. Am. Coll. Cardiol. 2011;58;1105-1109
3. Lisstro et al. TCT 2011 LBCT
4. Werk et al. LINC 2012
5. Scheinert et al. TCT 2010 LBCT
6. Circulation. 2008; 118: 1358-1365
7. Tepe et al. N Engl J Med 2008;358:689-99
5. Thunder
FEMPac
LEVANT 1
PACIFIER
Composite of Death/Amputation/TLR:
Pooled estimate
Meetanalysis Of 4 CRT’s
Odds 95% CI p
0.0348 0.00943 to 0.128 <0.05
0.108 0.0304 to 0.385 <0.05
0.0614 0.019 to 0.199 <0.05
0.128 0.0326 to 0.499 <0.05
0.0737 0.0391 to 0.139 <0.05
0.001 0.01 0.1 1 10
Favors PCB Favors POBA
Piotr Buszman et al. Drug Coated Balloon Technologies 2012
6. Paclitaxel-Coated vs. Uncoated Balloon Angioplasty
Reduces TLR in Femoropopliteal Disease
Meta-analysis of 4 randomized trials involving 381 pts.
Conclusion: In femoropopliteal lesions, a paclitaxel-coated balloon reduces
the need for reintervention vs. conventional angioplasty with no safety signal.
Cassese S, et al. Circ Cardiovasc Interv.
2012;Epub ahead of print.
Angiographic, Clinical
Outcomes
Paclitaxel
Balloon
(n = 186)
Uncoated
Balloon
(n = 195)
P Value
Restenosis 18.7% 45.5% 0.001
Late Lumen Loss (Range), mm -0.05 to 0.50 0.61 to 1.7 0.0001
TLR 12.2% 27.7% < 0.00001
There was no mortality difference between groups.
7. Safety Concerns
Impaired healing Surface Thrombus/Fibrin
SCCR 2012
Emboli with Crystalline material
8. Potential for Toxic Vascular Effects
Late coronary aneurysm with
severe stent malapposition
within the segment treated
with a PCB2
Aneurysm formation
after PCB treatment of
DES-ISR: first case
report3
Occurrence of
aneurysm
formation at
preclinical studies1
1Skirball Research Center
2Eur Heart J. 2011 June; 32(11): 1432
3Vassilev D. Catheter Cardiovasc Interv. 2012 Mar 14
9. Defining the PAST: Technical Characteristics
of the Original PACOCCATH Technology
Exp. Radiologie, Charité Mitte (Berlin, Germany)
Ulrich Speck
First Generation Coating:
• Clinically effective formulation
• Manual “dip coating” technique
• Inconsistent drug coating concentration
• Significant drug loss at insertion
• High balloon-artery transfer rates
• High particulate formation
Slide courtesy Juan F. Granada
11. Second Generations Coatings
Paclitaxel Coated Balloon Technologies
1st Gen PCB 2nd Gen PCB
• Manual dipping process
•Inconsistent D:E mixture
•Limited scale production
•Automated and controlled
drug coating
•Improved and controlled
coating mixture and
uniformity
•Low particle size
•Large scale reproducibility
12. Technology Evolution versus Performance
Cotavance® PCB: Technical Improvements
Figure courtesy of MEDRAD, INC.
Particle Diameter (mm)
Number of particles, %
13. Optimizing Coating Homogenity Improves
Drug - Neointimal Distribution and Healing
54.76
50.50
78.22
100
90
80
70
60
50
40
30
20
10
0
1st Gen PCB 2nd Gen PCB POBA
%
1st Gen PCB 2nd Gen PCB
80
70
60
50
40
30
20
10
20 25 30 35 40 45 50 55 60 65 70 75 80 85 90 95
5
4
3
2
1
0
25 30 35 40 45 50 55 60 65 70 75 80
5
4
3
2
1
0
%AS %AS
0
Proximal ReferenPcroeximal Medial Distal Distal Reference
ng/mg
1st gen PCB 2nd gen PCB
p=0.07
p=0.54 p=0.01
Treatment segment
Piotr P. Buszman et al., JACC Cardiovascular Interventions 2013
14. Optimizing Coating Homogenity Improves
Drug - Neointimal Distribution and Healing
p=ns
p<0.05 p<0.05
p=ns
p<0.05 p<0.05
p=ns
p<0.05 p<0.05
p=ns
p<0.05 p<0.05
p=ns
p<0.05 p<0.05
AS 50.5%* AS 54.8%*# 78.2%
2nd Gen PCB
1 POBA st Gen PCB
Piotr Buszman et al., JACC Cardiovascular Interventions 2013
15. Vascular Healing of Coronary BMS Following
Post-Dilatation with a 2nd Gen PCB
AS 21.5%* AS 29.6%*# AS 55.1%#
Taxus Stent 2nd Gen PCB + BMS BMS
p=0.01
p=0.01 p=ns
p=0.02
p=0.01 p=0.01
p=0.01
p=0.01
p=0.01
p=ns
p=ns
p=ns
p=0.02
Piotr P. Buszman et al., Eurointervention 2013
p=0.11
p=ns
*p=ns
#p<0.05
16. Microcrystalline Paclitaxel Balloon
Coating Technology
The first, novel polish DCB
mcPCB, PAX®, Balton, Warsaw, Poland:
• Over-the-wire balloon catheter coated with a microcrystalline form of
paclitaxel at a dose of 3 μg/mm2 and a proprietary excipient.
• The coating of this device is achieved by semi-automatic
microsyringe surface drug deposition and a proprietary drying
process which allow to achieve more consistent, uniform and micro-particle
paclitaxel coverage
Data on file at Balton
17. Tissue Transfer Study
3 DS
12 Iliofermoral segments
Study design Time point (day)
Vascular Response Study
8 DS
16 Iliofemoral segments
mcPCB
n=9
Injury:
Balloon overstretch
SE BMS implantation
mcPCB
N=10
POBA
N=5
Terminal imaging and
histology
Paclitaxel uptake at 1 hour, 3
and 7 days
Angiography
Baseline
procedur
e
(Day 0)
Follow up:
28 days
Study flowchart
Piotr P. Buszman et al., Catheterization and Cardiovascular Interventions 2013
18. mc PCB Paclitaxel Vessel Baseline
Uptake And Temporal Retention
152.9
36.5
0.9
1000.0
100.0
10.0
1.0
0.1
1 hour 3 days 7 days
[ng/mg]
Piotr P. Buszman et al., Catheterization and Cardiovascular Interventions 2013
19. Vascular response study:
Histomorphometric analysis
mcPCB
n=10
POBA
n=5
p
EEL area [mm2] 27.60±6.5 22.55±2.6 0.13
IEL area (stent area) [mm2] 24.58±6.8 19.37±2.1 0.13
Medial area [mm2] 3.03±0.4 3.19±0.8 0.6
Lumen area [mm2] 19.32±4.6* 12.65±2.8 0.01
Area of stenosis [%] 19.8±8.7* 34.2±15.7 0.03
Neointimal thickness [mm] 0.29±0.15 0.47±0.26 0.1
19.78
34.16
60
50
40
30
20
10
0
[%]
Percent area stenosis
0.29
0.47
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0
[mm]
Neointimal thickness
Pax
POBA
P=0.03 P=0.1
21. Vascular response study:
Sustained efficacy, despite low paclitaxel tissue retention
*p<0.05 vs. uncoated
Piotr P. Buszman et al., Catheterization and Cardiovascular Interventions 2013
22. First in Man, CE approval Trial
Prospective, Pivotal, First - in Man Clinical Trial of the Safety and Efficacy of a Novel
Microcrystalline Paclitaxel Coated Balloon for Treatment of Femoropopliteal Restenotic
Disease.
PAX-r
Aim: The purpose of this pivotal, first in man study will be to evaluate safety and
efficacy of the novel, microcrystalline paclitaxel coated balloon (mcPCB, PAX, Balton)
in the treatment of femoro-popliteal restenotic disease.
Design: multicenter, pivotal, prospective, controlled, randomized
Study sites: 3 Cardiovascular Centers of American Heart of Poland
Collaborator: Silesian Center for Heart Diseases
Principal Investigators: Piotr P. Buszman M.D. PhD, Przemysław Nowakowski M.D. PhD
Bioethical committee approval: April 2014, obtained
Clinical Trials: pending
Enrollment start: June 2014,
Estimated completion: June 2015
23. PAX-r, First in Man Trial
Patient eligibility
Inclusion Criteria:
•Age > 18 y.o.
•Claudication in Rutherford Class 1-5
•Prior femoro-popliteal revascularization procedure utilizing plain balloon
angioplasty or atherectomy
•Prior femoro-popliteal revascularization procedure with stent
implantation
•Restenosis within previously revascularized segment defined as >50%
and < 99% diameter stenosis with length of up to 10 cm in vessel
diameter of 3-7 mm
•Chronic total restenotic occlusions of lenght less than 60 mm
•Ability to cross the lesions with a guidewire.
24. PAX-r, First in Man Trial
Patient eligibility
Exclusion Criteria:
• Critical limb ischemia
• Acute coronary syndrome
• Chronic kidney disease stage III-V
• De novo femoro-popliteal lesion
• Femoro-popliteal graft
• Known allergy to clopidogrel or aspirin
• History of stroke within past 6 months
• age > 80 y.o.
• Life expectancy < 2 years
25. PAX First in Man, CE Approval Study
40 patients
Femoro-popliteal
restenosis
mcPCB
(Balton, PAX)
POBA
Primary efficacy outcome measure: Late Loss at 6 months – hypothesis
generating
Secondary endpoints: Primary patency, TLR, TVR,ABI, flow velocity of
treated limb, Walking Impairment Questionarre
Safety outcome measures: Device related adverse events, CLI, amputation
26. Summary
• As the 2nd generation PCB technologies evolve and the tissue
delivery and distribution of paclitaxel becomes more consistent,
the introduction of this technology into the clinical practice
becomes more appealing.
• These new generation coatings appear to induce lower degrees of
delayed healing, there is a potential to expand the use of this
technology to a broader range of applications – i.e. de novo
coronary lesions, adjunctive use of BMS
• New PCB’s trials and policies are required to increase the
availability of this technology in Poland
