Transcript Folie 1 - CRTOnline

What is the Data for DCB in BTK &
What Next?
Prof. Thomas Zeller
Department Angiology
University Heart-Center Freiburg - Bad Krozingen
Bad Krozingen , Germany
Faculty Disclosure
Thomas Zeller, MD
For the 12 months preceding this presentation, I disclose the
following types of financial relationships:
• Honoraria received from: Abbott Vascular, Bard Peripheral Vascular,
Veryan, Biotronik, Boston Scientific Corp., Cook Medical, Cordis Corp.,
Gore & Associates, Medtronic, Spectranetics, Straub Medical, TriReme
• Consulted for: Abbott Vascular, Bard Peripheral Vascular, Boston Scientific
Corp., Cook Medical, Gore & Associates, Medtronic, Spectranetics
• Research, clinical trial, or drug study funds received from:
480 biomedical, Bard Peripheral Vascular, Veryan, Biotronik, Cook Medical,
Cordis Corp., Gore & Associates, Abbott Vascular, Medtronic,
Spectranetics, Terumo, TriReme, Volcano
Most DCBs have shown a biologic effect in
femoro-popliteal lesions
6-month Late Lumen Loss from 8 DCB Technologies
1.
2.
3.
4.
5.
6.
7.
8.
9.
Tepe G, Zeller T, Albrecht T, Heller S, Schwarzwälder U, Beregi JP, Claussen CD, Oldenburg A, Scheller B, Speck U. Local delivery of paclitaxel to inhibit restenosis during angioplasty of the leg. N Engl J
Med. 2008 Feb 14;358(7):689-99
Werk M, Langner S, Reinkensmeier B, Boettcher HF, Tepe G, Dietz U, Hosten N, Hamm B, Speck U, Ricke J. Inhibition of restenosis in femoropopliteal arteries: paclitaxel-coated versus uncoated balloon:
femoral paclitaxel randomized pilot trial. Circulation. 2008 Sep 23;118(13):1358-65
Scheinert D, Duda S, Zeller T, Krankenberg H, Ricke J, Bosiers M, Tepe G, Naisbitt S, Rosenfield K. The LEVANT I (Lutonix paclitaxel-coated balloon for the prevention of femoropopliteal restenosis) trial
for femoropopliteal revascularization: first-in-human randomized trial of low-dose drug-coated balloon versus uncoated balloon angioplasty. JACC Cardiovasc Interv. 2014 Jan;7(1):10-9
Scheinert D, Schulte KL, Zeller T, Lammer J, Tepe G. Paclitaxel-releasing balloon in femoropopliteal lesions using a BTHC excipient: twelve-month results from the BIOLUX P-I randomized trial. J
Endovasc Ther. 2015 Feb;22(1):14-21
Werk M, Albrecht T, Meyer DR, Ahmed MN, Behne A, Dietz U, Eschenbach G, Hartmann H, Lange C, Schnorr B, Stiepani H, Zoccai GB, Hänninen EL. Paclitaxel-coated balloons reduce restenosis after
femoro-popliteal angioplasty: evidence from the randomized PACIFIER trial. Circ Cardiovasc Interv. 2012 Dec;5(6):831-40
D.Scheinert - Advance 18 PTX Study - LINC 2013 oral presentation
Schroeder H, Meyer DR, Lux B, Ruecker F, Martorana M, Duda S. Two-year results of a low-dose drug-coated balloon for revascularization of the femoropopliteal artery: outcomes from the ILLUMENATE
first-in-human study. Catheter Cardiovasc Interv. 2015 Aug;86(2):278-86
T.Albrecht – Preliminary angiographic and clinical 6-month results of the CONSEQUENT trial - LINC 2016 oral presentation
W.Guo - AcoArt I First Prospective, Randomized, Multicenter Clinical Trial for the Use of the Orchid DCB in Femoropopliteal Artery Disease - LINC 2016 oral presentation
Evidence from DEB Trials
Long-term Freedom from TLR
Significant and sustained TLR reduction up to 5 years
FEMPAC 2Y
THUNDER 5Y
Context view: 4 RCTs, 3 DCBs
1-year Primary Patency
Complex
Patient Population
p=0.002
similar patient characteristics
p<0.001
PTA
PTA
p<0.001
PTA
p<0.001
PTA
Stellarex
In.Pact
Lutonix
(ptx 2 µg/mm2)
(ptx 3.5 µg/mm2)
(ptx 2 µg/mm2)
* Corelab adjudicated (VascCore Core laboratory - Boston, MA, USA) Duplex derived Primary Patency based
on 2.5 PSVR threshold. ‡ evaluated @ day 365; † evaluated @ day 360
3.
1. S.Lyden - ILLUMENATE Pivotal Stellarex DCB IDE Study 12-month Results - oral presentation, TCT 2016
2. M.Brodmann - ILLUMENATE European Randomized Clinical Trial: 12-month Final Results from the Stellarex DCB – oral presentation, AMP 2016
Tepe G et al. IN.PACT SFA Trial Investigators.. Drug-coated balloon versus standard percutaneous transluminal angioplasty for the treatment of superficial femoral and popliteal peripheral artery
disease: 12-month results from the IN.PACT SFA randomized trial. Circulation 2015 + G.Tepe, Charing Cross 2014 oral presentation + P. Krishnan, DCB show superior 3-year outcomes vs.
PTA: results from In.Pact SFA randomized trial - oral presentation, VIVA 2016
4. K.Rosenfield et al. Trial of a Paclitaxel-Coated Balloon for Femoropopliteal Artery Disease. N Engl J Med 2015
DCB are not yet indicated in
clinical routine in BTK lesions
Further Research needed!
Why?
Conflicting Evidence
DEBATE BTK vs. IN.PACT Deep
Journal of the American College of Cardiology 2014. 64;15:1568-76
Circulation
Drug-Eluting Balloon in peripherAl inTErvention for Below The
Knee Angioplasty Evaluation (DEBATE-BTK): A Randomized Trial in
Diabetic Patients with Critical Limb Ischemia
Single-Center Randomized Trial
• 132 Patients
• CLI: 100%, Diabetes: 100%
• Average lesion length: 13 cm
• CTO: 80%
• IN.PACT™ Amphirion™ vs. PTA
Drug-Eluting Balloon Versus
Standard Balloon Angioplasty for
Infrapopliteal Arterial Revascularization in Critical Limb Ischemia
12 Month Results From the IN.PACT DEEP Randomized Trial
Thomas Zeller, Iris Baumgartner, Dierk Scheinert, Marianne Brodmann, Marc Bosiers, Antonio Micari, Patrick
Peeters, Frank Vermassen, Mario Landini, David B. Snead, K. Craig Kent, Krishna J. Rocha-Singh, IN.PACT
DEEP Trial Investigators
™
Liistro F et al. Drug-eluting balloon in peripheral intervention for below the knee angioplasty evaluation (DEBATE-BTK): a randomized trial in diabetic patients with critical limb ischemia. Circulation.
2013 Aug 6;128(6):615-21
T. Zeller LINC 2014 & Zeller et al. JACC 2014
IN.PACT Deep
12-month Freedom from Major Amputation, Binary Restenosis Rate, TLR Rate & LLL
12-month
Binary Restenosis (BR) and
Clinically Driven TLR (CD-TLR)
12-month
Late Lumen Loss
0.605
± 0.775
0.616
± 0.781
Zeller T. et al. JACC 2014
DCB-BTK - Negative Evidence: BIOLUX P II
72-patients (CLI + IC) RCT of Passeo-18 Lux vs. PTA
12-month CD-TLR Rates:
30.1% (DCB) vs. 30.6% (PTA)
12-month Loss of Primary Patency
49.2% (DCB) vs. 45.6% (PTA)
(p=0.805)
(p=0.908)
80%
80%
Event Rate: Patency loss
100%
Event Rate: TLR Lesions
100%
60%
40%
20%
0.0%
60%
40%
20%
0.0%
0
365
0
365
Time to Event (days)
uncoated
Time to Event (days)
DRB
Amputation target extremity
Major
uncoated
8/ 23.7 [12.6,42.0]
9/ 25.8 [ 14.3, 43.9]
0.975
1/ 3.3[0.5,21.4]
2/ 5.6 [1.4,20.7]
0.631
DCB
Zeller T et al., JACC CCI 2015
DCB-BTK Evidence: DCB vs. DES
50-patients (CLI + IC) RCT of IN.PACT Amphirion vs. DES
Lesion length: 14.8 (DCB) vs. 12.7 (DES) (p=0.330)
Key findings (DCB vs. DES) at 6-month:
•
Binary restenosis: 58% vs. 28% (p=0.0457)
•
LLL: 1.35±0.2 vs. 1.15±0.3 (p=0.62)
•
>50% restenosis length (cm): 4.3±1.6 vs. 3.6±1.5 (p=0.16)
•
TLR: 14.3% vs. 7.4 (p=0.21)
(P.M. Kitrou, MD, PhD – CIRSE 2013, LINC 2014)
WHY DO WE NEED DCB IN BTK
INTERVENTIONS?
• In CLI most BTK lesions are longer than 10cm
• Bare metal stents did fail to show a benefit over PTA
Ferraresi R, LINC 2016
• In CLI most BTK lesions are longer than 10cm
• Bare metal stents did fail to show a benefit over PTA
• No dedicated DES for BTK use are yet commercially available and
clinically tested
– Appropriate length, at least 8cm for balloon expandable stents
– Drug eluting nitinol stents not yet tested below the knee
• Are stents the right choice for long distant BTK lesions extending
to the foot?
• DCB are the optimal treatment tool for long BTK lesions an din
particular foot arteries
NO DCB Class Effect?!
IN.PACT DEEP failure applies to IN.PACT Amphirion only.
Each DCB stands on the merits of its own data
480-patient RCT of Lutonix DCB vs. PTA in BTK-CLI
Marianne Brodmann LINC 2014
DCB in BTK Interventions
What next?
• Is paclitaxel the right drug for BTK interventions?
Below the knee
Paclitaxel Eluting DES vs PTA/BMS
PADI CLI: PTA±BMS vs DES for
infrapopliteal lesions
• Multi-center randomized two-arm study
• 136 patients with 144 limbs
–
–
–
CLI, Rutherford 4-6
De novo stenoses or occlusions below knee
joint
Vessel diameter 2-6 mm, length ≤ 90 mm
• PTA±BMS or paclitaxel-DES (Taxus Liberté)
• Heparin, Aspirin, Clopidogrel
Overhagen et al. Circ Cardiovasc Interv 2016
DCB in BTK Interventions
What next?
• Is paclitaxel the right drug for BTK interventions?
• “Limus” eluting DCB might become the appropriate solution
for long BTK lesions.
Below the knee
DES vs PTA/BMS
Systematic Review of infrapopliteal DES: A meta-analysis of randomized
controlled trials
• 3 RCTs with 501 patients
–
–
–
Achilles: DES vs PTA in CLI & IC, n=200
Destiny: DES vs BMS in CLI, n=140
Yukon-BTX: DES vs BMS in CLI & IC, n=161
• Relatively short and focal infrapopliteal lesions
InfraPop: Meta-Analysis of RCT
Results at 1 year
DES
PTA/BMS
P=
Primary Patency
80.0%
58.8%
<0.0001
Rutherford class improvement
79.0%
69.6%
0.045
Wound healing
76.8%
59.7%
0.04
TLR
9.9%
22.0%
0.001
Event-free survival
72.2%
57.3%
<0.0001
Survival
85.5%
86.6%
0.75
Amputation
6.4%
10.8%
0.11
Katsanos K et al, Cardiovasc Intervent Radiol 2013
Sirolimus Coated Balloon – Selution
• Use of micro-reservoirs made out of biodegradable
polymer intermixed with Sirolimus
– Controlled and sustained drug release
– Long-term distribution of Sirolimus into tissue
to maintain therapeutic levels
• Novel Cell Adherent Technology – CAT™
– Minimizes wash-off during insertion, tracking and lesion
crossing
– Optimizes drug transfer to tissue during short-term
balloon dilatation
© M.A. Med Alliance – 2016
Med Alliance SELUTION™ – PK Study
Mean Arterial Tissue – Drug Concentration (Sirolimus vs Paclitaxel)
300
Drug Concentration [µg/g]
262
Med Alliance SELUTION - RAP 1.0 ug/mm2
250
Medtronic IN.PACT - PAX 3.5 ug/mm2
200
Bard LUTONIX - PAX 2.0 ug/mm2
150
100
44
50
19
21
0
0
5
10
15
20
25
30
35
40
45
50
55
60
65
70
75
80
85
90
Time Point [Days]
Source: Med Alliance – PK Study (2014-004) / Bard – Catheterization and Cardiovascular
Interventions 83:132–140 (2014) / Medtronic – Presentation Melder (LINC 2012).
DCB in BTK Interventions
What next?
• Is paclitaxel the right drug for BTK interventions?
• “Limus” eluting DCB might become the appropriate solution
for long BTK lesions.
• The vessel preparation prior to DCB angioplasty might solve
the problem of early recoil as one potential failure mode of
paclitaxel releasing DCB
Early Recoil After Balloon Angioplasty of Tibial
Artery Obstructions in Patients With Critical
Limb Ischemia
Frederic Baumann, MD; Jacqueline Fust; Rolf Peter Engelberger, MD;
Ulrike Hügel, MD; Do-Dai Do, MD; Torsten Willenberg, MD; Iris
Baumgartner, MD; Nicolas Diehm, MD.
1Department of Clinical and Interventional Angiology, Swiss
Cardiovascular Center, Inselspital, University Hospital of Bern,
Switzerland.
2Department of Internal Medicine, Inselspital, University Hospital of
Bern, Switzerland.
3Department of General and Orthopedic Surgery, Hospital of
Münsterlingen, Switzerland.
Baumann et al. J Endovasc Ther February 2014 vol. 21 no. 1 44-51
Results:
• Elastic recoil:
29/30 patients (97%)
• Mean luminal compromise:
29%
• Acute lumen gain:
• Subacute lumen loss (15 min.):
1.77 mm (2.00 mm - 0.23 mm)
0.53 mm (2.00 mm - 1.47 mm)
Author’s Conclusions:
Early recoil is frequently observed in CLI patients undergoing tibial
angioplasty and may significantly contribute to restenosis. These findings
support the role of dedicated mechanical scaffolding approaches for the
prevention of restenosis in tibial arteries.
Baumann et al. J Endovasc Ther February 2014 vol. 21 no. 1 44-51
Atherectomy and Drug-Coated
Balloon Angioplasty in Treatment of
Long Infrapopliteal Lesions
(ADCAT-Study)
Atherectomy (Turbohawk, Medtronic) and paclitaxelcoated balloon angioplasty (Lutonix14, Bard) for
treatment of long atherosclerotic BTK lesions
Prospective, randomized, multicentric study
Combination Therapy
OPTIMIZE BTK1
Multicenter, randomized (atherectomy+DCB vs. DCB)
Target N = 50 at up to 10 EU sites
RCC 3-5, BTK lesions
Diamondback (CSI) + 0.014” DCB
Primary Endpoints:
Technical success
(< 50% residual stenosis without significant angiographic complications
Procedural success
(achievement of technical success for all target lesions treated during the index procedure)
Device success
(successful delivery and deployment of the DCB to the target lesion as described IFU)
Treatment success
(percentage of target lesions meeting technical success with <30% residual stenosis post DCB angioplasty
without the use post-adjunctive treatments)
Estimated target completion date: June 2018
1.Clinicaltrials.gov record NCT02561299.
https://www.clinicaltrials.gov/ct2/show/NCT02561299?term=cardiovascular+systems+atherectomy&rank=11
We Know…
Not all lesions are the same
Below the Knee1
Above the Knee1
• Mixed morphology
(multiple plaque types & thrombus)
• Medium to large vessels
(4 - 9 mm)
• Lesions more commonly calcified
• Tortuous, challenging anatomy
• Small vessels (1.5 - 3.5 mm)
Thrombus
Soft Plaque
ISR
Thrombus
Fibrotic
Soft
Plaque
Calcium
CTOs
ISR
Calcium
Fibrotic
CTOs
1. VIVA 2011 survey – 100 physicians surveyed.
2. Bishop et al. Ann Vasc Surg. 2008;22:799-805
DCB in BTK Interventions
Summary
• The combination of atherectomy and DCB should be considered
in calcified BTK lesions
– To reduce friction
– To reduce recoil
– To potentially improve drug uptake / wall persistence
• Alternative antiproliferative drugs such as “limus” drugs should
be explored
• Alternative ways of applying the drug to the adventia (Bullfrog,
LIMBO study, dexamethasone)