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Towards Standard of Care DCB-SFA Evidence Status and Outlook
Thomas Zeller, MD Universitäts‐Herzzentrum Freiburg‐Bad Krozingen
GmbH Bad Krozingen, Germany
Disclosure
Speaker name: Thomas Zeller
I have the following potential conflicts of interest to report:
Consulting
Employment in industry
Stockholder of a healthcare company
Owner of a healthcare company
Other(s)
I do not have any potential conflict of interest
3
Premise: Standard of Care?
• Legal term to position medical best- and mal-practice
• A diagnostic and treatment process that a clinician should follow for a certain type of patient, illness, or clinical circumstance
1. Blum RH. Adjuvant chemotherapy for lung cancer--a new standard of care. N Engl J Med. 2004 Jan 22;350(4):404-5
2. Peter Moffett MD and Gregory Moore MD, JD The Standard of Care: Legal History and Definitions: the Bad and Good News. West J Emerg Med. 2011
Feb; 12(1): 109–112.
• An evidence-driven standard built on a proven safety, clinical and cost effective benefit
4
Premise: Drug Coated Balloons
Restore and maintain patency
balloon-type deliverability
Avoid ISR frequency and burden
Preserve future options
Rationale and Value
PTA dilatation, short time drug-elution, long term effect
5
The DCB Technology Proliferation
Manufacturer DCB Drug Dose
(μg/mm2) Excipient
IN.PACT PTX 3.5 Urea
LUTONIX PTX 2.0 Polysorbate and Sorbitol
STELLAREX PTX 2.0 Polyethylene Glycol
PASSEO 18 LUX PTX 3.0 Butyryl-tri-hexyl Citrate
ADVANCE 18 PTX PTX 3.0 none
ELUTAX PTX 2.2 dextrane
FREEWAY PTX 3.0 shelloic acid
LEGFLOW PTX 3.0 shelloic acid
RANGER PTX 2.0 citrate ester
LUMINOR PTX 3.0 unkown
SeQuent Please PTX 3.0 Iopromide
Biopath PTX 3.0 Shellac
12 DCBs (= Drug, Doses, Excipients, Technologies)
6
1. 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
2. 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
3. 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
4. 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
5. 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
6. D.Scheinert – LINC 2013 oral presentation
7. 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 Feb 23
8. Micari A, Cioppa A, Vadalà G, Castriota F, Liso A, Marchese A, Grattoni C, Pantaleo P, Cremonesi A, Rubino P, Biamino G. 2-year results of paclitaxel-eluting balloons for femoropopliteal artery disease:
evidence from a multicenter registry. JACC Cardiovasc Interv. 2013 Mar;6(3):282-9
9. Tepe G, Laird J, Schneider P, Brodmann M, Krishnan P, Micari A, Metzger C, Scheinert D, Zeller T, Cohen DJ, Snead DB, Alexander B, Landini M, Jaff MR; 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 Feb 3;131(5):495-502
10. Rosenfield K, Jaff MR, White CJ, Rocha-Singh K, Mena-Hurtado C, Metzger DC, Brodmann M, Pilger E, Zeller T, Krishnan P, Gammon R, Müller-Hülsbeck S, Nehler MR, Benenati JF, Scheinert D; LEVANT 2
Investigators. Trial of a Paclitaxel-Coated Balloon for Femoropopliteal Artery Disease. N Engl J Med. 2015 Jul 9;373(2):145-53
11. Zeller T, Rastan A, Macharzina R, Tepe G, Kaspar M, Chavarria J, Beschorner U, Schwarzwälder U, Schwarz T, Noory E. Drug-coated balloons vs. drug-eluting stents for treatment of long femoropopliteal
lesions. J Endovasc Ther. 2014 Jun;21(3):359-68
12. Liistro F, Grotti S, Porto I, Angioli P, Ricci L, Ducci K, Falsini G, Ventoruzzo G, Turini F, Bellandi G, Bolognese L. Drug-eluting balloon in peripheral intervention for the superficial femoral artery: the DEBATE-
SFA randomized trial (drug eluting balloon in peripheral intervention for the superficial femoral artery). JACC Cardiovasc Interv. 2013 Dec;6(12):1295-302
13. Virga V, Stabile E, Biamino G, Salemme L, Cioppa A, Giugliano G, Tesorio T, Cota L, Popusoi G, Pucciarelli A, Esposito G, Trimarco B, Rubino P. Drug-eluting balloons for the treatment of the superficial
femoral artery in-stent restenosis: 2-year follow-up. JACC Cardiovasc Interv. 2014 Apr;7(4):411-5
14. Liistro F, Angioli P, Porto I, Ricci L, Ducci K, Grotti S, Falsini G, Ventoruzzo G, Turini F, Bellandi G, Bolognese L. Paclitaxel-eluting balloon vs. standard angioplasty to reduce recurrent restenosis in diabetic
patients with in-stent restenosis of the superficial femoral and proximal popliteal arteries: the DEBATE-ISR study. J Endovasc Ther. 2014 Feb;21(1):1-8
15. van den Berg JC, Pedrotti M, Canevascini R, Chimchila Chevili S, Giovannacci L, Rosso R. In-stent restenosis: mid-term results of debulking using excimer laser and drug-eluting balloons: sustained benefit? J
Invasive Cardiol. 2014 Jul;26(7):333-7
16. Gandini R et al. Treatment of chronic SFA in-stent occlusion with combined laser atherectomy and drug-eluting balloon angioplasty in patients with critical limb ischemia: a single-center, prospective, randomized
study. J Endovasc Ther. 2013 Dec;20(6):805-14
17. Krankenberg H, Tübler T, Ingwersen M, Schlüter M, Scheinert D, Blessing E, Sixt S, Kieback A, Beschorner U, Zeller T. Drug-Coated Balloon Versus Standard Balloon for Superficial Femoral Artery In-Stent Restenosis: The Randomized Femoral Artery In-Stent Restenosis (FAIR) Trial. Circulation. 2015 Dec 8;132(23):2230-6
18. Fusaro M, Cassese S, Ndrepepa G, King LA, Tada T, Ott I, Kastrati A. Paclitaxel-coated balloon or primary bare nitinol stent for revascularization of femoropopliteal artery: a meta-analysis of randomized trials
versus uncoated balloon and an adjusted indirect comparison. Int J Cardiol. 2013 Oct 9;168(4):4002-9
19. Cassese S, Byrne RA, Ott I, Ndrepepa G, Nerad M, Kastrati A, Fusaro M. Paclitaxel-coated versus uncoated balloon angioplasty reduces target lesion revascularization in patients with femoropopliteal arterial
disease: a meta-analysis of randomized trials. Circ Cardiovasc Interv. 2012 Aug 1;5(4):582-9
20. Katsanos K, Spiliopoulos S, Karunanithy N, Krokidis M, Sabharwal T, Taylor P. Bayesian network meta-analysis of nitinol stents, covered stents, drug-eluting stents, and drug-coated balloons in the
femoropopliteal artery. J Vasc Surg. 2014 Apr;59(4):1123-1133.e8
21. Pietzsch JB, Geisler BP, Garner AM, Zeller T, Jaff MR. Economic analysis of endovascular interventions for femoropopliteal arterial disease: a systematic review and budget impact model for the United States
and Germany. Catheter Cardiovasc Interv. 2014 Oct 1;84(4):546-54
22. Diehm N, Schneider H. Cost-effectiveness analysis of paclitaxel-coated balloons for endovascular therapy of femoropopliteal arterial obstructions. J Endovasc Ther. 2013 Dec;20(6):819-25
23. Kearns BC, Michaels JA, Stevenson MD, Thomas SM. Cost-effectiveness analysis of enhancements to angioplasty for infrainguinal arterial disease. Br J Surg. 2013 Aug;100(9):1180-8
The DCB Evidence Proliferation
7
DCB concept works!
5 DCBs showing a biologic effect Paccocath PTX 3 µg/mm2
+ Ultravist
Lutonix PTX 2 µg/mm2
+ Polysorbate
& Sorbitol
In.Pact PTX 3.5 µg/mm2
+ Urea
Passeo
18 Lux PTX 3.0 µg/mm2
+ BTHC
Advance
PTX PTX 3.0 µg/mm2
NO Excipient
Stellarex PTX 2.0 µg/mm2
PEG
1. 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
2. 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
3. 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
4. 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
5. 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
6. D.Scheinert – LINC 2013 oral presentation
7. 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 Feb 23
8
TASC A-B 90% and 80% Core-lab adjudicated Primary Patency at 1 and 2-year seen in 2 DCB Trials
IN.PACT SFA ILLUMENATE FIH LEVANT 2
730-day 78.9% 80.3% 56.8%
760-day na 80.3% na
Primary Patency rates by KM estimation at
upper level of FU intervals = 87.7% (390-
day) and 80.3% (760-day)
• KM estimates of Duplex derived Primary Patency based on PSVR <2.5
• Duplex Corelab adjudicated (VascCore, Boston, MA, USA)
RCT, 220 DCB Patients single-arm, 50 DCB Patients RCT, 316 DCB Patients
2Y Primary Patency pre
-dil
cohort
9
TASC C-D Remarkable results seen in long lesions at 1 year
In.Pact GLOBAL (Long Lesion subset)
– N = 164
– Lesion length: 26.40 ± 8.61 cm
– CTO: 60.4%; Ca++: 19.6%
D.Scheinert, oral presentation – EuroPCR 2015
• 1-year Cl-driven TLR: 6.0%
• Provisional Stenting: 40.4%
1Y Primary Patency:
91.1% (360d)
80.7% (390d)
(corelab adjudicated)
In.Pact LONG
– N = 105
– Lesion length: 25.17 ±7.90 cm – CTO: 49.5%
A.Micari, oral presentation – EuroPCR 2015
1Y Primary Patency:
89.3% (360d)
77.2% (390d)
(corelab adjudicated)
• 1-year Cl-driven TLR: 4.0%
• Provisional Stenting: 10.5%
10
In Stent Restenosis
DEBATE ISR [1] N= 44
100% DM, 75% CLI
ISR length = 13.2 cm
(IN.PACT vs. PTA historical cohort)
FAIR [2] RCT DCB vs. PTA
N= 119
ISR length = 8.2
IN.PACT
DCB better than PTA @ 1 year, (but risk of complete catch-up @ 3 years?)
1. Liistro F, Angioli P, Porto I, Ricci L, Ducci K, Grotti S, Falsini G, Ventoruzzo G, Turini F, Bellandi G, Bolognese L. Paclitaxel-eluting balloon vs. standard angioplasty to reduce recurrent restenosis in diabetic
patients with in-stent restenosis of the superficial femoral and proximal popliteal arteries: the DEBATE-ISR study. J Endovasc Ther. 2014 Feb;21(1):1-8
2. Krankenberg H, Tübler T, Ingwersen M, Schlüter M, Scheinert D, Blessing E, Sixt S, Kieback A, Zeller T. Drug-Coated Balloon Versus Standard Balloon for Superficial Femoral Artery In-Stent Restenosis:
The Randomized Femoral Artery In-Stent Restenosis (FAIR) Trial. Circulation. 2015 Oct 7. pii: CIRCULATIONAHA.115.017364
3. Grotti S, Liistro F, Angioli P, Ducci K, Falsini G, Porto I, Ricci L, Ventoruzzo G, Turini F, Bellandi G, Bolognese L. Paclitaxel-Eluting Balloon vs Standard Angioplasty to Reduce Restenosis in Diabetic Patients
With In-Stent Restenosis of the Superficial Femoral and Proximal Popliteal Arteries: Three-Year Results of the DEBATE-ISR Study. J Endovasc Ther. 2015 Oct 28
DEBATE ISR 3Y [3]
11
DCB Clinical Evidence Programs
More Evidence to come from structured, comprehensive high quality clinical programs
12
Cost Effectiveness
(decision-analytic Markov model) • DCB and DES cost effective vs. PTA and BMS
over a 2-year horizon
• Less “headroom” left for hospitals and facility
providers
(discrete-event simulation model) • DCB carry lowest lifetime costs, highest N of
QALYs, highest (60%) probability to be cost-
effective at any “Willingness To Pay” threshold
• DCB is a cost-effective alternative to PTA with
bail-out BMS
• DCB may be a cost-saving strategy for payers
but carry negative financial impact on providers
• A specific DCB code is needed to satisfy both
stakeholders
(Simplified, TLR driven analytical model)
TLR makes DCB cost effective for payers in different countries / HC Systems
13
Lessons learned (1)
• Geographic miss: watch out and avoid!
• Pre-dilatation: good to assess lesion type, «protect» DCB performace, limit stent use
• Dissections: leave it unless flow-limiting
• Plaque Regression: higher residual %DS vs. standard PTA is OK
14
Lessons learned (2)
• Stenting: just less needed and still necessary
• Calcium: watch out and pre-treat, especially if 360°/Ca++
• ISR: DCB good but more needed in occlusive / long diffuse ISRs
• Combination Therapies: likely to improve DCB outcomes in complex settings
DCB prov. Stent rates based on lesion length
15
Conclusions
• Standard of Care: an evidence driven path
• Implies a diligent evidence appraisal by physicians and Regulatory Authorities of the Quality of Evidence and Quality of Outcomes
• Few DCBs have shown sound performance and great potential, hence are driving «DCB Therapy» towards standard of care
• However not all DCBs are even until they all prove to be even
Towards Standard of Care DCB-SFA Evidence Status and Outlook
Thomas Zeller, MD Universitäts‐Herzzentrum Freiburg‐Bad Krozingen
GmbH Bad Krozingen, Germany
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