DISCLOSURE Peter A. Schneider Enter patients in studies sponsored - - PDF document

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Peter A. Schneider, MD Division of Vascular and Endovascular Surgery University of California, San Francisco

DCB-what is the appropriate role in the management of fem-pop disease in 2019?

DISCLOSURE

Peter A. Schneider Enter patients in studies sponsored by: Gore, Cordis, Medtronic, Silk Road, Bard, NIH, Limflow Consultant: Silk Road, Surmodics, Profusa Scientific Advisory Board: Abbott, Medtronic, Boston Scientific, CSI Chief Medical Officer: Intact Vascular, Cagent National co-PI: Roadster 2, Scaffold, Confidence, IN.PACT

I believe that drug delivery has been a major step forward for patients with SFA disease

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SFA Disease 2013

SFA Lesion

CFA disease Pop-trifur dis Endo failure Really bad runoff Open Surgery Or hybrid

TASC C TASC D

Primary stent

• r stent-graft

(Esp. if occlusion)

Standard PTA Atherectomy

(Focal, no-stent zone)

Selective stent

TASC A/B

Bypass, Stent

• r stent-graft

Limb salvage Claudication Bypass in good Surgical candidates

Femoral-popliteal Disease: PTA and Stents

PTA Stent

Lesion length (cm) 12-month Primary Patency

RCT Data: PTA vs Stent

RCTs Resilient FACT 4EVER Durability Astron Vienna Vienna-3 PTA Stents TASC A/B

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• Timing of SFA restenosis is longer compared to coronary stenting, which

predominantly occurs within 6 months.

• Factors for restenosis in the SFA include the number of runoff vessels,

severity of lower limb ischemia, and length of diseased segments.

Iida, O. et al. Cath and Cardiov Intv. 2011; 78:611–617. Kimura T, et al. N Engl J Med 1996;334:561–567.

Probability of Restenosis with Bare Metal Stents

Restenosis after SFA stenting peaks at 12 months

We would like to make the “peak” flatter and push it out to a longer time frame.

Jonas et al, Cathet Cardiovasc Interv, 2007

Drug Eluting Coronary Stents in the US

Adoption of DES Reduction in TLR

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7

5

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

SFA: Late Lumen Loss

6 Different Paclitaxel DCB Preparations Angiogram at 6 months: substantially less loss of lumen size

IMPORTANCE OF DRUG “RESERVOIRS”

Solid-phase paclitaxel embeds in vessel wall, creating “reservoirs” of drug that are sustained over time.

IN.PACT SFA

Kaplan/Meier'

Free from Primary Patency Event (%)

100 90 80 70 60 50 40 30 20 10 1 2 3 4 5 6 7 8 9 10 11 12 13 Months from Randomization Date PTA DCB Survival % Time Lutonix DCB Standard PTA P-value 365 days 73.5% 56.8% 0.001 Proportions-based difference was 65.2% for DCB vs. 52.6% for standard PTA 12.6% difference

Tepe et al. Circ 2015;131:495 Rosenfield et al. NEJM 2015;373:145

Levant

50.4%

@ day 410

73.7%

@ day 410

DCB 82.3% @ day 365 PTA 70.9% @ day 365 Lyden, TCT 2016

Illumenate

12 Month Patency RCTs of DCB vs PTA

5 | [footer text here] PTA Stent Stent-graft DES DCB

Lesion length (cm) 12-month Primary Patency

RCT Data: DCB/DES

RCTs DCB RCTs Levant 2 IN.PACT Illumenate DES RCT Zilver PTX Imperial Stent-graft RCTs Viper Vibrant Viastar

Drug Coated Balloons and Drug-Eluting Stents

Femoral-popliteal Disease

IN.PACT SFA Trial Primary Patency at 3 Years

2

24.4%

Schneider et al. Circ: Cardiovasc Interv 2018;11:e005891

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Vessel Preparation

§ Lumen gain § Plaque modification, change vessel compliance § Minimize arterial wall defects § Prepare for drug delivery § Prepare for definitive therapy

§ Results of may help determine which definitive therapy is appropriate

Technologies that Benefit

§ Drug-coated balloon § Woven nitinol stent § Bioabsorbable vasc scaffold § Stent graft/covered stent § Self expanding nitinol stent

• Including DES

Tools for Vessel Prep

§ PTA § Modifications of

angioplasty

§ Atherectomy § Lithoplasty

Primary Patency-DCB for Long Lesions

Micari et al. JACC Cardiovasc Interv 2016;9;950

Lesions >15cm

Mean lesion length 25cm 49.5% occlusions Primary patency at 1 year=83.2%

Schmidt et al. JACC Cardiovasc Interv 2016;9;715

Lesions >15cm

Mean lesion length 24cm 65.3% occlusions Primary patency: 1 year= 79.2% 2 years=53.7% Mean length 26cm

Provisional Stent LL 15-25 cm: LL > 25 cm: 40.4% (63/156) 33.3% (33/99) 52.6% (30/57) Schneider CX 4/16 Zeller et al. J Endovasc Ther 2014;21;359

Mean lesion length 19cm 53% occlusions Primary patency at 1 year: DCB= 76.1% DES= 69.6%

Zilver PTX

• IN. PACT

Schmidt et al. JACC Cardiovasc Interv 2016;9;715

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Lesion length (cm) 12-month Primary Patency Registries IN.PACT Global Leipzig Bad Krozingen Italy Definitive LE Superb

Woven nitinol

DCB/DES for Longer Lesions

Drug Coated Balloons and Drug Eluting Stents

Femoral-popliteal Disease

Total IN.PACT All-Subjects: Long Lesion Subgroup Freedom From CD-TLR through 12 months

DCB for Long Lesions

TASC D

20-30 cm >30 cm Lesion Length 25.24±2.96 34.75±4.17 Occluded Lesion 70.0% (142/203) 76.9% (70/91) Provisional Stent 37.1% (75/202) 50.5% (46/91) Schneider LINC 2019

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DCB paradigm vs DES paradigm DCB

§ Dependent upon vessel prep § No geographic miss § How much scaffolding? § Long lesions and occlusions § Total paclitaxel dose

DES

§ Stent entire lesion § More severe morphologies § Stent across healthier

segments

§ In-stent restenosis

SFA Disease 2019

SFA Lesion

CFA disease Pop-trifur dis Endo failure Really bad runoff Open Surgery

• r hybrid

TASC C/D/D+++

Aggressive vessel prep

DCB with focal dissection repair

TASC A/B

Good result DCB with focal dissection repair as needed Bad result DES

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Mortality Rates From Trials of SFA Therapy

All-Cause Death at 2 Years

Laird J, et al. J Am Coll Cardiol 2015: 66; 2329-38 IN.PACT Japan Presented by Iida, O. LINC 2018, Leipzig Germany IN.PACT Global Micari A, et al. J Am Coll Cardiol –Cardiovasc Interv 2018: 11; 945-53 LEVANT 1 Scheinert D, et al. J Am Coll Cardiol - Cardiovasc Interv 2014: 7; 10-19 LEVANT 2 Lutonix IFU ILLUMENATE US Presented by Mathews S, NCVH 2018, New Orleans, USA ILLUMENATE EU Presented by Schroder H, CIRSE 2017, Copenhagen, Denmark ACOART-I Presented by Guo W, LINC 2017, Leipzig, Germany CONSEQUENT Albrecht T, et al. Cardiovasc Intervent Radiol 2018: 41; 1008-14 ZILVER PTX Dake M, et al. J Am Coll Cardiol 2013: 61; 2417-27 Majestic Muller-Hulsbeck S, et al. Cardiovasc Interv Radiol 2017:40;1832-1838 SMART SES and BMS Duda et al. J Endovasc Ther 2006: 14; 701-710 Complete SE SFA Data on file. Medtronic, Inc. Durability II Rocha-Singh K, et al. Cather Cardiovasc Interv 2015 : 86; 164-170 ETAP BMS Rastan A, et al. J Endovasc Ther 2015: 22; 22-27 RESILIENT BMS LifeStent IFU. Revised 2/04-16. Dashed Line: Caro J, Migliaccio-Walle K, Ishak KJ and Proskorovsky I. BMC Cardiovasc Disord. 2005;5:14.

Conclusions-—There is increased risk of death following application of paclitaxel-coated balloons and stents in the femoropopliteal artery of the lower limbs. Further investigations are urgently warranted.

JAHA 2018;7:e011245

Figure 3. Random effects forest plot of all-cause death at 4 to 5 years. Pooled point estimate was expressed as risk ratio (RR).

Coincidental, statistical aberration, real danger sign?

What is the mechanism?

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Drug-eluting Devices Some unique characteristics of these trials.

§ Powered for short-term patency, not long-term mortality. § Small control groups (some RCTs 2:1). § Expected attrition due to age and co-morbid factors. § Missing data, censored patients not accounted. § Assumptions about drug kinetics and doses. § Not clear if valid to include DCB and DES in same analysis. § Chance results (lowest mortality ever in RCT PTA group). § No way to know who got paclitaxel (15% annual TLR rate). § Ascertainment bias in assessment of mortality. Clinic Visit Compliance After Treatment

PTA patients had more frequent follow-up

Schneider et al. JACC 2019

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Dual Antiplatelet Therapy After Treatment

PTA patients more likely to continue dual antiplatelet therapy

Schneider et al. JACC 2019

Figure 1. Long-term Survival Following Femoropopliteal Artery Revascularization With Drug-Coated Devices Compared With Non–Drug-Coated Devices DES vs BMS

• No. at risk

• No. at risk

• No. at risk

16,560 patients admitted for FP revasc

Secemsky et al. JAMA Cardiol 2019; published online 2/12/19 CENTRAL ILLUSTRATION Kaplan-Meier Freedom From All-Cause Death by Paclitaxel Dose in

All DCB Patients 95% 90% 85% 100% 80% 10% 0% 48 36 Time After Index Procedure (Months) Freedom from All-Cause Death 24 12 60 Number at risk 696 90 485 526 634 49 526 62 373 407 468 29 614 8 440 501 558 3 Adjusted p-value* = 0.731 *p-value was from frailty model with study as random efect and IPTW adjusted 88.2% 85.8% 84.2% DCB Lower Tercile DCB Mid Tercile DCB Upper Tercile Paclitaxel Dose DCB Lower Tercile DCB Mid Tercile DCB Upper Tercile Distribution of Paclitaxel Dose in Each Paclitaxel Tercile in DCB N 696 526 614 Mean µg 5019.0 10007.5 19978.2 Std µg 1508.6 1757.7 6122.1 Median µg 4752.0 9504.0 18654.0 Q1, Q3 µg 3653, 6924 8448, 11618 15399, 22705 Range µg 1850, 6951 6989, 13822 13902, 61949 Schneider, P.A. et al. J Am Coll Cardiol. 2019;-(-):-–-.

1837 DCB patients

No difference in mortality

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Patient-Level Meta-Analysis

Key Differences from JAHA Meta-analysis

JAHA

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Drug Coated Balloons-2019

Conclusion

§ On the ground

• Patients must be informed, Paclitaxel as secondary treatment, Trials?

Physicians and institutions decide with FDA guidance

§ 30,000 foot view

• DCB a major advance more restenosis, Future of paclitaxel? Patient-

level meta-analysis, Time frame at least 1 year, May not be resolved, Thousands of patients will receive less efficacious treatment.

§ 50,000 foot view

• Likely to wipe out dozens of vascular start ups, R&D funding?,

vascular clinical trial research in limbo, class action in PAD space?, stimulate search for other anti-restenotic compounds?