zilver ptx: a global data overview of a drug eluting stent...
TRANSCRIPT
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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