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)

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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

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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

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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%

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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]

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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

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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