Are Drug Eluting Stents the Future of SFA Treatment? Sahil A. - - PowerPoint PPT Presentation

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Are Drug Eluting Stents the Future of SFA Treatment? Sahil A. - - PowerPoint PPT Presentation

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SCAI 2019 May 22, 2019 Are Drug Eluting Stents the Future of SFA Treatment? Sahil A. Parikh, MD, FACC, FSCAI Associate Professor of Medicine Director, Endovascular Services Center for Interventional Vascular Therapy New York-Presbyterian

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SLIDE 1

SCAI 2019

May 22, 2019

Are Drug Eluting Stents the Future of SFA Treatment?

Sahil A. Parikh, MD, FACC, FSCAI

Associate Professor of Medicine Director, Endovascular Services Center for Interventional Vascular Therapy New York-Presbyterian Hospital Columbia University Irving Medical Center Columbia University Vagelos College of Physicians and Surgeons

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SLIDE 2
  • Grant/Research Support
  • Consulting Fees/Honoraria
  • Advisory Board
  • TriReme Medical, Shockwave Medical,

NIH, Surmodics, Silk Road Medical (CEC); Boston Scientific (DSMB)

  • Terumo, Abiomed
  • Abbott, Boston Scientific, Medtronic, CSI,

Philips Within the past 12 months, I or my spouse/partner have had a financial interest/arrangement or affiliation with the organization(s) listed below. Affiliation/Financial Relationship Company

Disclosures

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SLIDE 3

Modes of Local Endovascular Drug Delivery

Tar arge get t si site

tissue sue Clea earance rance Distribu tribution tion Drug ug Eluting ting Balloon alloon Drug g Coat ated ed Sten tent Drug ug “Co Coated ed” Balloon alloon

End ndovascular scular mo modalit alities ies

Admini minist stra ration tion

׬

𝟏 𝒖[𝑬𝒔𝒗𝒉]≈EFFECT

Drug ug Eluting Eluting Stent ent

Drug rel elease ease

FAST FAST FAST CONTROLLED/ SUSTAINED

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SLIDE 4

IMPROVE EFFICACY (overlap restenotic cascade)

Dosing Considerations Balancing Safety and Efficacy

Arterial Paclitaxel Concentration (ng/mg) Time (Days) TOXIC EFFECT THERAPEUTIC WINDOW NO EFFECT

25 100 50 75 5 100 1

Typical DCB Curve

REDUCE COMPLICATIONS

Typical DES Curve

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SLIDE 5

SCAI AUC and FP PVI: 2017 Update

Klein AJ et al. Catheter Cardiovasc Interv. 2017;90(4):E90-E110.

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SLIDE 6

SCAI Consensus Guidelines for Device Selection in FP PVI Device Selection as DEFINITIVE Therapy

Feldman DN et al. Catheter Cardiovasc Interv 2018.

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SLIDE 7

ACC/AHA AUC

DES and DCB are both APPROPRIATE for SFA lesions of any length

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SLIDE 8

5-year Primary Patency (PSVR < 2.0)

Zilver PTX vs. Standard Care

Zilver PTX Optimal PTA + BMS

66 66.4% .4% 43 43.4% .4%

p < 0.01

log-rank

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

Source: Dake M. The Zilver PTX randomized trial of paclitaxel-eluting stents for femoropopliteal artery disease: 5-year results. Presented at: VIVA 2014: Vascular Interventional Advances Conference; November 4-7, 2014; Las Vegas, Nevada.

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SLIDE 9

Zephyr Registry: Real World Support for Zilver PTX and Predictors of Restenosis

1. LENGTH >160MM 2. MLA <12mm2 3. EEM area <27mm2

Lida, et al. JACC: CI Volume 8, Issue 8, July 2015, Pages 1105–1112

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SLIDE 10

PI-549902-AE Apr2019

Patient Flow

Randomized Trial 465 randomly assigned (2:1) 852 screened 328 ineligible

61 general inclusion/exclusion criteria 267 angiographic criteria

309 assigned to Eluvia 59 in sub-studies (Eluvia only) 156 assigned to Zilver PTX 9 withdrew consent 6 died 146 in full cohort analysis at 12 months 142 clinical visit follow up at 12 months 4 withdrew consent 6 died 294 in full cohort analysis at 12 months 282 clinical visit follow up at 12 months

Gray WA, Lancet 2018.

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SLIDE 11

PI-549902-AE Apr2019

Baseline Patient Characteristics

Eluvia (N=309) Zilver PTX (N=156) Age (years) 68.5 ± 9.5 67.8 ± 9.4 Male 66.0% 66.7% Smoking status Current 35.3% 40.4% Previous 50.8% 43.6% Diabetes Mellitus 41.7% 43.6% Hyperlipidaemia 76.3% 75.6% Hypertension 82.2% 85.3% Coronary Artery Disease 50.8% 45.2% Renal Insufficiency 8.1% 7.1%

Gray WA, Lancet 2018.

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SLIDE 12

PI-549902-AE Apr2019

Baseline Lesion Characteristics

Eluvia (N=309) Zilver PTX (N=156) Arterial Segments Ostial 1.6% 0.6% Proximal SFA 12.9% 10.3% Mid SFA 65.0% 66.7% Distal 66.3% 65.4% Proximal Popliteal Artery 18.0% 12.7% Lesion length (mm) 86.5 ± 36.9 81.8 ± 37.3 Calcification None/Mild 36.5% 32.3% Moderate 22.8% 34.8% Severe 40.1% 32.3% Reference Vessel Diameter (mm) 5.0 ± 0.8 5.1 ± 0.8 % Diameter Stenosis 80.7% ± 16.5% 80.8% ±16.4% <50% 1.6% 1.9% 50%-<100% 67.2% 67.7% 100% (Occlusion) 31.2% 30.3%

Angiographic Core Laboratory Data

Gray WA, Lancet 2018.

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SLIDE 13

PI-549902-AE Apr2019

Treatment Difference for Primary Patency

Primary patency defined as duplex ultrasound PSVR ≤2.4, in the absence of clinically-driven target lesion revascularization or bypass of the target lesion, as assessed by the DUS core lab.

Superior primary patency for Eluvia vs Zilver PTX Effectiveness I Primary Patency at 12 Months

Eluvia (N=309) Zilver PTX (N=156) 77.5% (110/142) Δ (95% CI) p value 86.8% (243/280) 9.3% (1.4%, 17.3%) 0.0144

Gray WA, Lancet 2018.

IMPERIAL Trial: A global randomized controlled multi-center trial with 2:1 randomization of the Eluvia™ Drug- Eluting Stent against Cook Medical’s Zilver™ PTX™ Stent, single-blind, non-inferiority design; independent core lab adjudication. Superiority determined in a post hoc analysis that was specified prior to unblinding. 12-Month Primary Patency rate of 86.8% in the Eluvia arm vs. 77.5% in the Zilver PTX arm (p-value = 0.0144).

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SLIDE 14

PI-549902-AE Apr2019

Effectiveness I Primary Patency at 12 Months Kaplan-Meier Analysis of Primary Patency

Primary patency defined as duplex ultrasound PSVR ≤2.4, in the absence of clinically-driven target lesion revascularization or bypass of the target lesion, as assessed by the DUS core lab.

Gray WA, Lancet 2018.

Error bars are 95%CI.

1 2 3 4 5 6 7 8 9 10 11 12 13

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SLIDE 15

PI-549902-AE Apr2019

Safety

  • Non-inferior MAE rate for Eluvia vs Zilver PTX
  • Eluvia CD-TLR and stent thrombosis rates ~50% less than Zilver PTX
  • 6 cases of positive remodeling in Eluvia arm (2.1%)

–

All 6 lesions patent at 1 year

–

None had TLR or stent thrombosis

Eluvia (N=309) Zilver PTX (N=156) Difference 95%CI p value MAE 4.9% 9.0%

  • 4.1%
  • 9.4%,1.2%

0.0975 Any death at 1 month 0.0% 0.0% NA NA Target limb major amputation 0.3% 0.0% 0.3%

  • 0.3%, 1.0%

1.0000 Clinically-driven TLR 4.5% 9.0%

  • 4.4%
  • 9.7%, 0.8%

0.0672 Stent Thrombosis 1.7% 4.0%

  • 2.3%
  • 5.8%, 1.2%

0.1956 Stent Fractures 0.3% 0.0% 0.3%

  • 0.3%, 0.9%

0.4315

Clinical Events Committee-adjudicated adverse events included MAE and stent thrombosis. Potential stent fractures were identified by radiography and verified by the angiographic core lab. Stent-based fracture rate calculation based on 319 implanted Eluvia and 197 Zilver PTX stents. MAE, major adverse events; CD-TLR, clinically-driven target lesion revascularization.

Gray WA, Lancet 2018.

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SLIDE 16

PI-549902-AE Apr2019

IMPERIAL Summary of Deaths: RCT (2:1

randomization)

CEC-Adjudicated Cause of Death* 1-year Rate Eluvia Zilver PTX All 2.0% (6/301) 3.9% (6/152) Cardiac 1.0% (3/301) 3.3% (5/152) Vascular 0.0% (0/301) 0.7% (1/152) Non-Cardiovascular 1.0% (3/301) 0.0% (0/152)

Device Type Site-Reported Cause of Death CEC Adjudication* Days from Index Procedure Eluvia Cardiac arrest Cardiac 89 Eluvia Unknown cause of death Cardiac 195 Eluvia Congestive heart failure diastolic dysfunction acute on chronic Cardiac 275 Eluvia Multi organ failure Non-cardiovascular 140 Eluvia Giant cell B-cell non-Hodgkin lymphoma Non-cardiovascular 192 Eluvia Respiratory insufficiency type 1 Non-cardiovascular 329 Zilver PTX Worsening heart failure Cardiac 31 Zilver PTX Cardiac arrest Cardiac 78 Zilver PTX Unknown cause of death Cardiac 171 Zilver PTX Cardiopulmonary failure Cardiac 327 Zilver PTX Coronary heart disease Cardiac 353 Zilver PTX Intra-cerebral haemorrhage Vascular 271

CEC, Clinical Events Committee. *The CEC considered all deaths cardiac unless an unequivocal non-cardiac cause could be established.

Gray, WA LINC 2019

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SLIDE 17

PI-549902-AE Apr2019

IMPERIAL Diabetic Cohort I Primary Patency at 12 Months

Primary patency defined as duplex ultrasound PSVR ≤2.4, in the absence of clinically-driven target lesion revascularization or bypass of the target lesion, as assessed by the DUS core lab.

Observed Rate: 84.6% (88/104) Eluvia vs 79.3% (46/58) Zilver PTX Kaplan-Meier Estimate

Months Since Procedure Primary Patency Rate (%)

1 2 3 4 5 6 7 8 9 10 11 12 13 0% 20% 40% 60% 80% 100%

80.2% 87.4%

Müller-Hülsbeck S, LINC 2019 Month At risk: 6 9 12 13 Eluvia 56 54 42 24.5 Zilver PTX 28 24.5 17 8.5 Log-rank p= 0.2905

180 patients had medically-treated diabetes (116 Eluvia & 64 Zilver PTX)

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SLIDE 18

PI-549902-AE Apr2019

IMPERIAL Eluvia Baseline CTO I Primary Patency at 12 Months

Kaplan-Meier estimate. Primary patency defined as duplex ultrasound PSVR ≤2.4, in the absence of clinically- driven target lesion revascularization or bypass of the target lesion, as assessed by the DUS core lab.

Months Since Procedure Primary Patency Rate (%)

1 2 3 4 5 6 7 8 9 10 11 12 13 0% 20% 40% 60% 80% 100%

90.6%

Non-CTO

83.9%

CTO

Vermassen, F. CX 2019. Log-rank p= 0.0762

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SLIDE 19

PI-549902-AE Apr2019

IMPERIAL Eluvia Calcified Lesions I Primary Patency at 12 Months

Months Since Procedure Primary Patency Rate (%)

1 2 3 4 5 6 7 8 9 10 11 12 13 0% 20% 40% 60% 80% 100%

Log-rank p= 0.569

87.0%

None/Mild

89.2%

Moderate/Severe

Vermassen, F. CX 2019. Kaplan-Meier estimate. Primary patency defined as duplex ultrasound PSVR ≤2.4, in the absence of clinically- driven target lesion revascularization or bypass of the target lesion, as assessed by the DUS core lab.

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PI-549902-AE Apr2019

  • Kaplan-Meier estimate: 87.9% at 12 months
  • Observed rate: 87.0% (40/46)

Long Lesion Effectiveness I Primary Patency at 12 Months

Primary patency defined as duplex ultrasound PSVR ≤2.4, in the absence of clinically-driven target lesion revascularization or bypass of the target lesion, as assessed by the DUS core lab.

Months Since Procedure Primary Patency Rate (%)

1 2 3 4 5 6 7 8 9 10 11 12 13 0% 20% 40% 60% 80% 100%

87.9%

Gray WA, VIVA 2018

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SLIDE 21

PI-549902-AE Apr2019

IMPERIAL

Pharmacokinetics Sub-study (N=13)

  • All patients treated with Eluvia
  • Plasma paclitaxel unquantifiable (<1 ng/mL) in all 13

patients at >10 minutes post-implantation

  • 1-year mortality 0%

Plasma paclitaxel measured at 10 min, 30 min, and 1, 2, 3, 4, 6, 12, 24, 48 hours post-implant. Gray WA, Lancet 2018

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SFA Patency Decreases with Lesion Length for PTA and “Conventional Stenting” but less so for Newer Technologies Including Vascular Mimetic Implants and Drug Delivery

Adapted from: Gray B. CCI. 2011

Conventional PTA VMI/Covered Stents/DCB/DES Nitinol Stents

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SLIDE 23

Do the patency data give us a clue for an algorithm?

  • PTA/stents
  • Femoral-popliteal

55-75%

  • Surgical reconstruction
  • Femoral-popliteal

65-80%

  • Femoral-tibial

60-75%

The long term primary patency of different types of conduits for the SFA and possible place in the “algorithm” of therapy for SFA disease Vein Bypass ~75%

Long, Calcified, Endo failure

ePTFE Graft 40-50%

No option

Nitinol Stent 60% (3-5year)

Short Focal, flow limiting dissection

Stent Graft ~60%

Long disease, perforation, aneurysm

VMI (Supera) >80% (3yr TLR)

Calcified disease, SFA/pop, long disease, be wary of deployment and lesion preparation

DES ~66% (5yr – TASC A/B)

1-2 stent length, calcified, be wary of small vessels - ? Eluvia>Zilver PTX

DCB >65-80% (1-5yr) (>5yr?)

10-15cm, noncalcified, no scaffolding needed, “no stent” preferred zones, small vessels (?)

Atherectomy ~80% (1yr)

Adjunctive therapy to all of the above

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SLIDE 24

Since the VIVA VLF….

  • Signal of Mortality Identified in 3 Data Sets
  • Data should be interpreted with caution

especially because “the specific cause and mechanism of the increased mortality is unknown.”

  • “[B]ecause of this concerning safety signal,

we believe alternative treatment options should generally be used for most patients.”

  • Convening FDA Panel in June, 2019
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SLIDE 25

Drug-Eluting Stent Implantation and Long-Term Survival Following Peripheral Artery Revascularization

Eric A. Secemsky, Harun Kundi, Ido Weinberg, Marc Schermerhorn, Joshua A. Beckman, Sahil A. Parikh, Michael R. Jaff, Jihad Mustapha, Kenneth Rosenfield and Robert W. Yeh

March 1, 2019

http://www.onlinejacc.org/content/early/recent

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Long-Term Survival after Peripheral DES

*No No di differ erence ence in in su survi vival al in in adjusted sted analyses ses

  • CLI:

: Adjusted sted HR 0.97; ; 95%CI, , 0.92- 1.03; ; P P = = .32

  • No

Non-CLI: CLI: Adjusted sted HR 1.01; ; 95%CI, , 0.91- 1.13; ; P P = = .80

CLI CLI Non Non-CLI CLI

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SLIDE 27

PCR Statement on Interventions with DCB

What is Known: Current Evidence with DCB?

  • 1. As for any meta analysis, the Katsanos analysis has major inherent methodological

limitations that prevent reliable interpretation of primary findings, these include:

  • Study level rather than patient level data
  • Limited long-term data: >80% loss of patients at 4-5 years (3/28 trials), 45% are DES and High

drop out rates within trials (>35% loss to FU)

  • Unmeasured crossovers and re-interventions, and unknown additional PTX exposure
  • Lack of adjudication of cause of death
  • Errors in published death rates with subsequent corrections
  • Lack of a plausible or reproducible dose response

2.At least 4 new patient-level analyses and a large-scale claims data analysis have failed to replicate the results of the meta analysis with DCB

  • 3. Coronary DCB applications are not associated with a long-term safety signal

➢There is currently no strong evidence of a mortality signal

Courtesy: Alexandra Lansky, MD

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SLIDE 28

PCR Statement on Interventions with DCB

PCR Position on DCB

  • 1. Although the results of the meta analysis are not conclusive, they cannot be ignored

due to the mortality implications and the lack of high quality long-term safety data

  • 2. PCR acknowledges the need for a more reliable industry-wide patient level (DCB
  • nly) pooled analysis, expected to be presented at the upcoming FDA panel on June

19/20

  • 3. PCR strongly encourages resuming the previously suspended prospective

randomized DCB trials (SWEDPAD and BASIL 3) under careful adjudication and safety oversight as these will provide the evidence necessary to address the safety

  • f DCB
  • 4. Until more robust data to the contrary, there is currently no strong evidence to

justify changing clinical practice and clinicians should continue to use best judgment

Courtesy: Alexandra Lansky, MD

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SLIDE 29

Physiologically OLDER Physiologically YOUNGER CLI Reasonable Maybe Reasonable IC Maybe Reasonable Caution