william a. gray md system chief of cardiovascular services ... · main line health lankenau heart...

William A. Gray MD

DISRUPT PAD III Principal Investigator

System Chief of Cardiovascular Services, Main Line Health

President, Lankenau Heart InstituteWynnewood, Pennsylvania

USA

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Lankenau Heart Institute

Disclosures

•Shockwave Medical

– Consultant

– Institutional Research Support

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Calcification is a frequent problem

Allison et. al Arterioscler Thromb Vasc Biol. 2004;24:331-336

Above 70 years, all have calcium in at least one vascular

bed and 2/3 in all arterial beds

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Calcification risk factors and prevalence

Hirsch AT, et al. Circulation 2006: 113:e463-e654

Occurs in 30-50% of asymptomatic US patients1

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Problem: Rigid fibrotic, calcified tissue

Today’s endovascular therapies fail

Current Cycle of Therapy

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Calcified lesions are challenging to treat

• Calcium is not well studied – excluded or limited follow-up

• Calcified lesions respond poorly to balloon angioplasty and

require high rate of stent usage 1

• Calcified lesions are associated with high incidence of

angiographic complications 2, 3

• Calcified lesions limit effectiveness of drug-coated balloons 4

1. Laird J et al. Twelve-Month Results From the RESILIENT Randomized Trial. Circ Cardiovasc Interv. 2010;3:267-276.

2. Adams GL et al. Subanalysis of the CONFIRM Registries. J INVASIVE CARDIOL 2015;27(11):516-520.

3. Roberts D. : Final Results of the DEFINITIVE Ca11 Trial. Catheteriz and Cardiovas Intervent 2014 84:236–244.

4. Fanelli F et al. Calcium Burden Assessment and Impact on Drug-Eluting Balloons in Peripheral Arterial Disease.

Cardiovasc Intervent Radiol (2014) 37:898–907.

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Severe calcium likely acts as a barrier to DCB

drug distribution and modifies its effectiveness

Calcium distribution evaluation by CTA (circumferential) and DSA (longitudinal)

Fanelli F et al. Calcium Burden Assessment and Impact on Drug-Eluting Balloons

in Peripheral Arterial Disease. Cardiovasc Intervent Radiol (2014) 37:898–907.

1a 1b 2a 2b 3a 3b 4a 4b0%

25%

50%

75%

100% 1.0

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0.0

0.45 0.460.52

0.590.68 0.66

0.72 0.75

100% 100% 100%90% 90% 87.5%

50% 50%

Primary Patency LLL

12 month Results

Zeller T . ViVa 2014

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Insights from Prior Studies

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• Designed to normalize vessel wall compliance prior to controlled, low

pressure dilatation

• Effective lesion expansion with minimized impact to healthy tissue

• Familiar balloon-based endovascular technique

• “Front-line” balloon strategy (.014”compatible)

Tissue-selective:

Hard on hard tissue, Soft

on soft tissue

Lithotripsy waves travel

outside balloon

Designed to disrupt both

superficial, deep calcium

in situ

Lesion modification using localized lithotripsy in a balloon

Lithoplasty®

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Mechanism of Action

Lithoplasty DCB

Drug coating transfer

Diffusion

Tissue Binding

Retention

Calcium

Belay T. Journal of Controlled Release 238 (2016) 149–156

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Next Phase in Clinical Development

DISRUPT PAD I DISRUPT PAD II DISRUPT PAD III

Lithoplasty as primary therapy in

severely calcified lesion

Results:

• Low rate of vascular complications

• provisional stenting (1.1%)

• Consistent effectiveness

• high acute gain (3.0 mm)

• low residuals stenosis (23.8%)

• Sustained 6 month results

Combination therapy

Goal is to assess the

optimal therapy to

dilate heavily calcified

lesions. All patients

who do not receive a

stent will be treated

with a drug-coated

balloon.

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• Study Design: Randomized trial of the Shockwave Lithoplasty used in

combination with DCB versus standard balloon angioplasty used in combination

with DCB to treat moderate and severely calcified femoropopliteal arteries

(DISRUPT PAD III).

• Objective: The objective is to assess the optimal therapy to dilate heavily

calcified lesions with Lithoplasty versus traditional angioplasty, in achieving less

than 30 % stenosis without the need for a stent. In addition, all patients who do

not receive a stent will be treated with a drug-coated balloon.

Moderate and severely calcified femoropopliteal

arteries

Rutherford 2 to 4

RVD 4-7, stenosis >70%,

Lesion length 5 – 18 cm occlusive or < 10 cm CTO

Treatment arm

(N=167)

Lithoplasty +

IN.PACT DCB

Control arm

(N=167)

PTA +

IN.PACT DCB

334 subjects

45 global sites

Randomization 1:1

24 months follow-up

Disrupt PAD III Study Design

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DISRUPT PAD III : Key Inclusions

• Rutherford Clinical Category 2, 3, or 4 of the target limb.

• Target lesion in de novo superficial femoral (SFA) or popliteal artery

• Target lesion reference diameter is 4.0mm to 7.0mm.

• Target lesion is ≥70% stenosis.

• Target lesion length is 50-180mm for occlusive disease.

• Chronic total occlusion lesion length is ≤100mm.

• One patent tibial vessel with runoff to the foot (Stenosis <50%).

• Calcification is at least moderate defined as presence of calcification:

• 1) on parallel sides of the vessel and

• 2) extending > 50% the length of the lesion.

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DISRUPT PAD III : Key Exclusion

• MI or stroke within 60 days.

• Renal disease (serum creatinine of >2.5 mg/dL or >220 umol/L), or on dialysis.

• In-stent restenosis within the target zone.

• Lesions extending into common femoral or within 10 mm of the anterior tibial.

• Evidence of aneurysm or thrombus in target vessel.

• No calcium or mild calcium in the target lesion.

• Target lesion within native or synthetic vessel grafts.

• Stenosis (>50% ) or occlusion of inflow tract not successfully treated.

• Requires simultaneous treatment of a peripheral lesion distal to target site.

• Unable to pass the guidewire across the target lesion.

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Primary Effectiveness Endpoint:

Procedural Success defined as:

• Residual stenosis <30% prior to DCB or stenting by

angiographic core lab quantitative assessment

Powered Secondary Effectiveness Endpoint:

Primary Patency defined as freedom from:

• Clinically-driven target lesion revascularization (TLR)

• Restenosis determined by duplex ultrasound or angiogram

>50% stenosis

Disrupt PAD III Study Endpoints

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Investigator Site Enrollment

M Brodmann, MD Universitätsklinikum LKH, Graz, Austria

W Bachinsky, MD Pinnacle Health Cardiovascular, PA, USA

N Shammas, MD Midwest Cardiovascular RC, Iowa, USA

R Gammon, MD St. David's Heart and Vascular, Texas, USA

C Nolte Ernsting, MD Krankenhaus Mulheim, Mulheim, Germany

Marshall, MD Northeast Georgia Medical, Georgia, USA

A Holden, MD Auckland City Hospital, Auckland, New Zealand

JO Balzer, MD Katholisches Klinikum, Mainz, Germany

G Tepe, MD RoMed Hospital, Rossenheim, Germany

D Scheinert, MD Universitätsklinikum, Leipzig, Germany

T Zeller, MD Universitatas Herzzentrum, Bad Krozingen, Germany

R Langhoff, MD Sankt Gertrauden-Krankenhaus, Berlin, Germany

P Soukas, MD The Miriam Hospital, Rhode Island, USA

13 patients enrolled at 7 sites as of Apr 2017 Current Enrollment Status by Site

4

3

2

1

1

1

1

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Study Flow Diagram

Randomization

Lithoplasty PTA

Post Dilatation Post Dilatation

Assess Procedure

Success

Assess Procedure

Success

Stent Required? Stent Required?

DCB BMS/DES DCB BMS/DES

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Summary

•Calcium has not been well studied in existing clinical

studies

•Existing 6 month DISRUPT PAD data has demonstrated

safety and performance of Lithoplasty as a primary

therapy for calcified lesions

•DISRUPT PAD III is the largest, randomized study in a

difficult to treat, calcified patient population.

•The goal is to provide level one evidence on the best

treatment strategy for calcified lesions in a leave nothing

behind strategy

william a. gray md system chief of cardiovascular services ... · main line health lankenau heart...

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