ZIlver PTX: a Global Data Overview of a Drug Eluting Stent...

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ZIlver PTX: a Global Data Overview of a Drug Eluting Stent for

Femoropopliteal Disease

Michael D. Dake, M.D. Department of Cardiothoracic Surgery Falk Cardiovascular Research Center Stanford University School of Medicine Stanford, California

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Michael Dake, MD

• Research/Research Grants, Clinical Trial Support – W. L. Gore – Cook Medical

• Consulting Fees/Honoraria – W. L. Gore – Abbott Vascular – Medtronic

• Equity Interests/Stock Options – CVRx – Enopace – TriVascular – Cytograft Tissue Engineering – Microfabrica – 480 Medical – Arsenal – Intact Vascular

• Officer, Director, Board Member or other Fiduciary Role – VIVA Physicians Group

• Speaker’s Bureau – None

Within the past 12 months, the presenter or their spouse/partner have had a

financial interest/arrangement or affiliation with the organization listed below.

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Zilver PTX Drug-Eluting Peripheral Stent

• Mechanical scaffold: Zilver Flex® Stent Platform

• Drug therapy: Paclitaxel only – 3 µg/mm2 dose density – No polymer or binder

Uncoated

PTX Coated

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Design Rationale for Paclitaxel-Only Coating

• Some DES use permanent polymer carriers for drug delivery – Remain behind indefinitely (after drug delivery) – Suggested association with persistent inflammation

and thrombogenicity1,2,3

1. Virmani R et al. Circulation. 2004;109:701-705 2. Joner M et al. J Am Coll Cardiol. 2006;48:193-202 3. Nebeker JR et al. J Am Coll Cardiol. 2006;47:175-181

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Design Rationale for Paclitaxel-Only Coating

• Paclitaxel’s properties are favorable for polymer-free delivery – Highly hydrophobic, which helps resist wash-off into blood – Highly lipophilic and protein-bound, which help facilitate partitioning

into and retention by the vessel wall1,2

– Paclitaxel remains in the vessel wall for approximately 2 months3

• Biocompatible BMS remains after local paclitaxel delivery

1. Creel CJ et al. Circulation Research. 2000;86:879-884 2. Axel DI et al. Circulation. 1997;96:636-645 3. Dake M et al. J Vasc Interv Radiol. 2011;22:603-610

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Global Clinical Program

More than 2400 patients included in the current Zilver PTX clinical program

RCT Moderate

lesions

Zilver PTX n=242

PTA

Optimal n=118

Sub-optimal

Zilver Flex n=56

Zilver PTX n=63

SAS More

complex lesions

Pre-Market Studies

Zilver PTX n=787

China Similar

lesions to RCT

Zilver PTX n=175

Enro

lling

Japan PMS

All-comers

US PAS Similar

lesions to RCT

EU Longer Lesions

Post-Market Studies

Zilver PTX n=907

Zilver PTX n=200

Zilver PTX n=45

Enro

lling

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Zilver PTX Clinical Program

Pre-market studies • Randomized Controlled Trial (RCT)

– 479 patients enrolled in United States, Japan, Germany

• Pre-market Single-Arm Study (SAS) – 787 patients enrolled in Europe, Korea, Canada

Multiple post-market studies, including • Japan Post-market Surveillance (PMS)

– 907 patients

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Global Clinical Program

Zilver PTX RCT Zilver PTX SAS Zilver PTX Japan PMS

Key Study Criteria

No significant untreated inflow tract stenosis

ALL patients treated with Zilver PTX enrolled (up to

enrollment limit), NO exclusion criteria

At least one patent runoff vessel

Maximum 2 Zilver PTX stents per lesion

Maximum 4 Zilver PTX stents per patient

Lesion length ≤ 14 cm No exclusions

One lesion per limb

No prior stent in SFA ISR included

Excluded if serum creatinine > 2.0, renal failure, or dialysis

No exclusions

Antiplatelets Clopidogrel or ticlopidine recommended for 60 days, aspirin indefinitely

Follow-up 5 years 2 years 5 years

Patency DUS core laboratory analysis DUS site analysis

Stent Integrity X-ray core laboratory analysis

Increasingly complex patients and lesions

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Patient Demographics and Comorbidities

RCT SAS Japan PMS

Patients 236 787 907

Age (years) 68 ± 10 67 ± 10 74 ± 9

Diabetes 50% 36% 59%

High cholesterol 76% 58% 61%

Hypertension 89% 80% 85%

Renal disease1 10% 11% 44%

Lesion length (cm) 6.6 ± 3.9 10.0 ± 8.2 14.7 ± 9.7

Total occlusions 33% 38% 42%

In-stent restenosis (ISR) 0% 15% 19%

Rutherford 4-6 (CLI) 9% 11% 20% 1 Of patients with renal disease in the Japan PMS, 82% were in renal failure (eGFR < 60 and/or dialysis)

Increasingly complex patients and lesions

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Zilver PTX Study Design

Provisional BMS

PTA

Optimal PTA

Enrollment

Suboptimal PTA

Zilver PTX

Provisional Zilver PTX

Primary Randomization

Secondary Randomization

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5-year Freedom from TLR Zilver PTX vs. Standard Care

83.1%

67.6%

p < 0.01 log-rank

Zilver PTX

Optimal PTA + BMS

At 5 years, Zilver PTX demonstrates a 48% reduction in reintervention compared to standard care

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5-year Freedom from TLR Provisional Zilver PTX vs. BMS

Provisional BMS

Provisional Zilver PTX 84.9%

71.6%

p = 0.06 log-rank

At 5 years, Zilver PTX demonstrates a 47% reduction in reintervention compared to BMS

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Freedom from TLR Across Studies

Months

Freedom from TLR (n=patients)

RCT (n = 305)

SAS (n = 787)

Japan PMS (n = 907)

12 91.6% 89.5% 91.0% 24 85.7% 83.3% 85.0%

Freedom from TLR consistent across studies

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Literature Comparisons: TLR at 12 Months

Literature Matching Registry

Subset

Study Inclusion Criteria TLR TLR

Resilient:

(Katzen ISET

2008 and

VEITH 2008)

• No in-stent restenosis

• Lesion length < 15 cm

• Rutherford 1-3

LifeStent

13% at 12 months

(n = 153)

Zilver® PTX™

5% at 12 months

(n = 442)

20% at 24 months

(n = 153)

Zilver® PTX™

8% at 24 months

(n = 143)

FAST:

(Krankenberg

2007)

• De novo lesions

• Length 1 - 10 cm

- Multiple lesions

< 10 cm total

• ≥ 70% DS

Luminexx Stent

15% at 12 months

(n = 127)

Zilver® PTX™

5% at 12 months

(n = 263)

Durability:

(Scheinert

TCT 2008)

• No in-stent restenosis

• Lesion length ≤ 14 cm

• Rutherford 2-4

Protégé

EverFlex Stent

21% at 12 months

(n = 134)

Zilver® PTX™

5% at 12 months

(n = 446)

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5-year Primary Patency (PSVR < 2.0) Zilver PTX vs. Standard Care

Zilver PTX

Optimal PTA + BMS

66.4%

43.4%

p < 0.01 log-rank

At 5 years, Zilver PTX demonstrates a 41% reduction in restenosis compared to standard care

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5-year Primary Patency (PSVR < 2.0) Zilver PTX vs. Standard Care

Zilver PTX

Optimal PTA + BMS

66.4%

43.4%

From 1-5 years, the relative separation increases by 35%

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5-year Primary Patency (PSVR < 2.0) Provisional Zilver PTX vs. BMS

Provisional BMS

Provisional Zilver PTX 72.4%

53.0%

p = 0.03 log-rank

At 5 years, Zilver PTX demonstrates a 41% reduction in restenosis compared to BMS

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Primary Patency by DUS

Months

Primary Patency (n = lesions)

RCT (n = 318)

SAS (n = 842)

Japan PMS (n = 702)

12 84.4% 82.8% 86.4% 24 76.3% N/A 72.3%

Primary patency rate is consistent across studies

Department of Cardiothoracic Surgery, Stanford University School of Medicine

86.2%

Effectiveness: Patency (PSVR < 2.5)

Time (months) 1 6 12 13.5

Patency Rate 99.3% 97.2% 86.2% 82.1%

Lesions (at risk) 839 823 791 778

RCT: Paclitaxel Coating Effect Primary Patency Provisional Zilver PTX vs. Bare Zilver

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72.9%

90.2%

p < 0.01 log rank

Months 0 6 12 24

LESIONS at Risk

Provisional Zilver PTX 63 60 54 46

Provisional Bare Zilver 62 53 41 35

64.1%

83.4%

GEE Model

Time 12 mo

p-value 0.02

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Zilver PTX Stenting in the Diabetic Patient Population

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Baseline Lesion Characteristics

Single-Arm Study: All Patients

Single-Arm Study: Diabetic Patients

Lesions 900 298

Lesion length (mm) 100 ± 82 98 ± 79

Diameter stenosis 85 ± 16% 81 ± 17%

TASC 2000 class A 26% 29%

B 29% 31%

C 25% 31%

D 14% 9%

Lesions > 7 cm 48% 51%

Lesions > 15 cm 22% 22%

Total occlusions 38% 30%

Restenosis (all) 24% 26%

In-stent restenosis (ISR) 14% 16%

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Zilver PTX stenting is effective in diabetics Primary Patency (PSVR < 2.5)

Zilver PTX Diabetics

Zilver PTX Non-diabetics

86%

86%

Sabeti et al (Lesions ≥ 10 cm)

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4-Year Primary Patency (PSVR < 2.0) Zilver PTX in Diabetic Patients

p = 0.50 log-rank

Non-Diabetics

Diabetics

Zilver PTX results are similar in diabetic and non-diabetic patients

69.3%

65.9%

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But what about the effect when

treating longer,

more complicated, real world

lesions?

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Such as extensive complex SFA disease?

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Or diffuse in-stent restenosis?

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4-Year Primary Patency in > 10 cm Lesions

p > 0.99 log-rank

> 10 cm lesions

≤ 10 cm lesions

Zilver PTX results are similar in lesions ≤ 10 cm and lesions > 10 cm

67.7%

67.6%

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4-Year Primary Patency in > 10 cm Lesions

Years Post-Procedure

Standard Care Zilver PTX

> 10 cm lesions ≤ 10 cm lesions

> 10 cm lesions

4 36.4% 67.6% 67.7%

Zilver PTX results are superior to standard care in lesions > 10 cm

p < 0.01 log-rank

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12-Month Results with Zilver PTX® in Long Femoropopliteal Lesions

Thomas Zeller, M.D. Clinical and Interventional Angiology Herz-Zentrum Bad Krozingen, Germany

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Baseline Lesion Characteristics

Lesions 45

Lesion length (mm) 1 189.3 ± 91.1

Diameter stenosis (%)1 95.4 ± 11.1

Total occlusions1 82.2%

De novo lesions 97.8%

Lesion calcification1 None 11.1%

Mild 33.3%

Moderate 15.6%

Severe 40.0% 1 Angiographic core lab assessment

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12-Month Primary Patency

Pri

mar

y P

aten

cy

86.1%

Similar to 12-month Kaplan-Meier patency estimates in RCT and SAS pre-market studies

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Study Comparison

Zilver PTX RCT1

Zilver PTX SAS2

Zilver PTX SAS LL3

Zilver PTX Longer Lesions

Durability 2004

Patients 236 787 134 45 100

Lesions 247 900 135 45 100

Lesion length (mm) 66 ± 39 100 ± 82 226 ± 44 189 ± 91 242

Diameter stenosis (%)a 80 ± 17% 85 ± 16% 97 ± 9% 95 ± 11% N/A

Total occlusions 30% 38% 84% 82.2% N/A

1-year Primary Patency 82.7%

(PSVR < 2.0)

86.2%

(PSVR < 2.5)

77.6%

(PSVR < 2.5)

86.1%

(PSVR < 2.0)

64.8%

(PSVR < 2.4)

1-year Freedom from TLR 90.8% 89.3% 85.4% 86.1% 68.2%

1-year Fracture Rate 0.9% 1.5% 2.1% 0.0% 6.0%

a Angiographic core lab assessment for RCT and longer lesions Zilver PTX

1. Dake MD, et al. Circ Cardiovasc Interv. 2011;4:495-504. 2. Dake MD, et al. J Endovasc Ther. 2011;18:613-23. 3. Bosiers M, et al. J Cardiovasc Surg (Torino). 2013;54:115-22. 4. Bosiers M, et al. JVS. 2011;54-1042-1050.

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Analysis

• 5-year results support sustained safety and effectiveness of Zilver PTX (no evidence of late “catch-up”)

– Significantly lower TLR rate and significantly higher patency rate than standard care

• Zilver PTX results are similar in diabetic and non-diabetic patients

• Zilver PTX results are superior to standard care in lesions > 10 cm

– Significantly higher patency rate than BMS

– Greater than 40% reduction in restenosis due to the drug effect

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Department of Cardiothoracic Surgery, Stanford University School of Medicine

New Endovascular Options for PAD

SFA and Popliteal

– Drug-Eluting Stents

– Drug-Coated Balloons

– Bioresorbable Scaffolds

Department of Cardiothoracic Surgery, Stanford University School of Medicine

Department of Cardiothoracic Surgery, Stanford University School of Medicine

Department of Cardiothoracic Surgery, Stanford University School of Medicine

Department of Cardiothoracic Surgery, Stanford University School of Medicine

Department of Cardiothoracic Surgery, Stanford University School of Medicine

Department of Cardiothoracic Surgery, Stanford University School of Medicine

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Department of Cardiothoracic Surgery, Stanford University School of Medicine

DCB – BMS - Supera

1:1 match for each comparison

BMS cohort (N=432)

Supera cohort (N=470) DCB cohort (N=390)

368 pairs, 736 patients

254 pairs, 508 patients

284 pairs, 568 patients

Comparison: DCB - BMS

BMS cohort (N=432)

Supera cohort (N=470) DCB cohort (N=390)

368 pairs, 736 patients

254 pairs, 508 patients

284 pairs, 568 patients

DCB - BMS Matched Cohort: DCB BMS P-Value

Lesion length, mm 171 ± 108 159 ± 114 0.2

Instent restenosis, % 18 19 0.8

Surv

ival

pro

bab

ility

: Pri

mar

y p

ate

ncy

BMS

DCB

DCB BMS

No. at risk

K-M curve with 95% Confidence Interval

Hazard ratio (95%CI): 0.87 (0.68-1.1)

Department of Cardiothoracic Surgery, Stanford University School of Medicine

Choice between DCB and DES

• NOT CLEAR

– Lack of data currently - no direct comparisons of effectiveness

– Different metrics utilized

– Variable populations/lesion sets

– Current studies with heterogeneous length of follow-up

– Unknown costs

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• As the first randomized controlled SFA device trial with 5-year follow-up, these results with the Zilver PTX stent provide important insights regarding long-term outcomes for endovascular treatment

• Abundant Zilver PTX data for more complex anatomy (TASC C and D lesions) in patients at high risk of re-stenosis (DM, CRF, ISR, etc.) – Promising >1 year outcomes (TLR, patency)

– These benefits increase with time – results with Zilver PTX continue to diverge from standard care over 5 years with no late catch-up

– Await similar long-term analyses for DEB, atherectomy + DEB, biomimetic stents, etc.

Conclusions: When and Why I Use DES