michael dake, md future technologies for pad: drug … · 4/7/2011 1 1 future technologies for pad:...

4/7/2011

1

1

Future Technologies for PAD: Drug-Eluting

Stents and Balloons, Bioabsorbable Stents

Michael D. Dake, M.D.

Thelma and Henry Doelger Professor

Department of Cardiothoracic Surgery

Stanford University School of Medicine

Falk Cardiovascular Research Center

PAD: From the Office to the Angiosuite and Back Again SIR Annual Scientific Meeting

Saturday, March 26, 2011

2Michael Dake, MD

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

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

• Equity Interests/Stock Options– NovoStent– Vatrix– Amaranth– CVRx– Endoluminl Sciences– REVA Medical– TriVascular– Cytograft Tissue Engineering

• 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.

3

New Endovascular Options for PAD?

1. SFA and Popliteal

– Drug-Eluting Stents

– Drug-Delivery Balloons

– Bioresorbable Stents

4

New Endovascular Options for PAD?

1. SFA and Popliteal

– Drug-Eluting Stents

– Drug-Delivery Balloons

– Bioresorbable Stents

4/7/2011

2

5

#2 DES over BMSThe lesion characteristics that maybe associated

with incremental benefits: DES relative to BMS

• Re-stenotic lesions post-PTA

• In-stent re-stenosis

• Lesions in diabetic patients

• Long lesions >14 cm (c/w short or moderate lesions)

• Higher TASC rated lesions (DES “punching above rank”)

• …but in reality, possibly all lesions

6

Sirocco Trial Design

• Double-blind, randomized, balanced, prospective, feasibility trial in the SFA

• Primary endpoints: Safety & in-stent percent mean diameter stenosis via quantitative angiography determined within six months after stent placement.

7

Drug-Eluting Stents: SIROCCO II

Presented 2004 Annual Meeting of the Cardiovascular and Interventional Radiology Society of Europe

P = NS

18 month Duplex US follow-up.

Not approved for use in the US.

8

Everolimus

Triaxial Stent Delivery System

DYNALINK Self-expanding Nitinol Stent

EVAL polymer

Everolimus-eluting Peripheral Stent System

4/7/2011

3

9Comparative DES Release Kinetics

Dynalink-E 8x28 mm stents in porcine iliac arteries (n=8 stents in 2 animals per time point); XIENCE V 3x12 mm stents in porcine coronary arteries (n=6 stents in 2 animals per time point); data represent mean ± SD; SIROCCO data from Donohoe D. Cordis Drug-Eluting Stent Evolution. Cordis, a Johnson & Johnson Company, 2004. Data on file at Abbott Laboratories.

∼80% elution after 3 months

0%

20%

40%

60%

80%

100%

0 30 60 90 120 150 180 210

Time (days)

Per

cent

dru

g el

uted

(%

)

DYNALINK-E

SIROCCO

10

N = 106

Lesion origin

De novo 91%

Restenotic 9.4%

Calcification

Moderate 51%

Severe 27%

Total occlusion 45%

Patent run off vessels

One 26%

Two 27%

Three 47%

Lesion Length, mean ±±±± SD 9.0 ± 4.3 cm

Lesion Characteristics

*106 lesions in 104 patients

11

Primary Patency

Days post index procedure 0 (0, 30] (30, 180] (180,365] (365,393]

# at Risk 104 103 103 96 69# Censored 1 0 1 1 55

# Events 0 0 6 26 14% Event Free 100% 100% 94.1% 68.5% 54.6%

Primary Patency

0%

25%

50%

75%

100%

Days Post Index Procedure

0 40 80 120 160 200 240 280 320 360 400

Primary Patency

0%

25%

50%

75%

100%


0 40 80 120 160 200 240 280 320 360 400

12

Freedom from Target Lesion Revascularization

Days post index procedure 0 (0, 30] (30, 180] (180,365] (365,393]

# at Risk 104 104 103 99 82# Censored 0 0 0 1 72

# Events 0 1 4 16 10% Event Free 100% 99.0% 95.2% 79.7% 70.0%

0%

25%

50%

75%

100%


0 40 80 120 160 200 240 280 320 360 400

Fre

edom fro

m TLR

0%

25%

50%

75%

100%


0 40 80 120 160 200 240 280 320 360 400

4/7/2011

4

13

Zilver® PTX® Drug-Eluting Stent

• Designed for the SFA

• CE Marked

– Investigational in the U.S.

• Paclitaxel only

– No polymer or binder

– 3 µg/mm2 dose density

• Zilver® Flex™ Stent Platform

Uncoated

PTX Coated

14

55 sites in US, Japan, and Germany

Bare Zilver®

n = 59

PTA

n = 238

Optimal PTA

n = 118

Zilver PTX® Randomized

Trial

Suboptimal PTA(>30% residual stenosis)

n = 120

Zilver PTX®

n = 236

Zilver PTX®

n = 61

Primary Randomization

Secondary Randomization

Zilver PTX® Single-Arm

Study

Zilver PTX®

n = 787

30 sites in Europe, Canada, and Korea

>1000 patients>2000 stents

Complementary Zilver PTX® Clinical Studies

15

Zilver® PTX® Effectiveness

Free from TLR

Patent(PSVR < 2.5)

91.1%

86.3%Time (months) 12 13.5

Free from TLR 91.1% 89.4%

Patent

(PSVR < 2.5)86.3% 82.1%

Lesions at risk 658 529

Zilver® PTX® stenting results in

similar 12 month primary patency

and freedom from TLR rates

16

Freedom from TLR with Zilver® PTX®

Time (months) 6 12 24

Free from TLR 98.3% 91.1% 83.3%

Lesions at risk 832 658 300

98.3%

91.1% 83.3%

Free from TLR

Zilver® PTX® stenting results in

superior long-term freedom from TLR

4/7/2011

5

17 18

19 20

Zilver PTX Single-Arm Update

Performance in Long Lesions: > 15cm

4/7/2011

6

21

Baseline Lesion Characteristics

All LesionsDe novo,

long lesions

Lesions 900 133

Lesion length (mm) 100 ± 82 226 ± 44

Diameter stenosis 85 ± 16% 97 ± 9%

TASC 2000

class

A 26% 3%

B 29% 9%

C 25% 46%

D 14% 42%

Lesions > 15 cm 22% 100%

Total occlusions 38% 83%

Restenosis (all) 24% 0%

In-stent restenosis (ISR) 14% 0%

22

Zilver® PTX® Effectiveness

in de novo lesions > 15 cm

Patent(PSVR < 2.5)

77.0%

Time 6 months 12 months

Primary patency 94.3% 77.0%

Lesions (at risk) 116 90

94.3%

Zilver® PTX® stenting

effectively treats long

SFA lesions

23

Zilver PTX Stenting

in the Diabetic Patient

Population

24

• Diabetics are a high risk patient cohort

• Higher PAD prevalence in diabetic patients than in

non-diabetics

• Associated with poor outcomes after long-segment

femoropopliteal stenting1

– 78% 12-month restenosis in lesions ≥ 10 cm

• Significantly lower long-term primary patency rate

in diabetics than non-diabetics2

– 5-year primary patency rate: 37% in diabetics and 46% in

non-diabetics

Why study diabetics?

1 Sabeti et al, J Endovasc Ther, 20062 Abularrage et al, J Vasc Surg, 2010

4/7/2011

7

25


Single-Arm Study:

All Patients

Single-Arm Study:

Diabetic Patients

Lesions 900 298

Lesion length (mm) 100 ± 82 98 ± 79


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%




26

Zilver PTX stenting is effective in diabetics

Primary Patency (PSVR < 2.5)

Zilver PTXDiabetics

Zilver PTXNon-diabetics

86%

86%

Sabeti et al(Lesions ≥ 10 cm)

27

Zilver PTX effectiveness

in treating diabetics

with long SFA lesions

28


Single-Arm Study:

Diabetic Patients

Single-Arm Study:

Diabetics with long lesions

Lesions 298 67

Lesion length (mm) 98 ± 79 224 ± 54


TASC 2000 class A 29% 3%

B 31% 6%

C 31% 59%

D 9% 32%

Lesions > 7 cm 51% 100%

Lesions > 15 cm 22% 100%




4/7/2011

8

29

Zilver PTX in long lesions (> 15 cm)

Primary Patency (PSVR < 2.5)

77%

73%

Zilver PTXNon-diabetics

Zilver PTXDiabetics

30

• Prospective, multinational trial– Protocol approved by FDA, PMDA and German regulatory authorities

• CEC and DSMB oversight, and imaging Core Lab analyses

• Key inclusion/exclusion criteria– Rutherford classification ≥ 2

– Reference vessel diameter 4-9 mm

– Lesion length ≤ 14 cm

– De novo or restenotic lesions (no in-stent restenosis)

– > 50% diameter stenosis

– One lesion per limb (bilateral treatment allowed)

Zilver PTX Randomized Trial

31

V. Ramaiah, Arizona Heart Institute: Phoenix, AZ

B. Katzen / J. Benenati, Baptist Cardiac and Vascular Institute: Miami, FL

M. Schermerhorn, Beth Israel Deaconess Medical Center: Boston, MA

G. Daniel / G. Elsner, The Care Group: Indianapolis, IN

M. Rinaldi, Carolinas Medical Center: Charlotte, NC

J.K. White, Christus St. Patrick Hospital: Lake Charles, LA

G. Pierce, Cleveland Clinic: Cleveland, OH

J. Joye, El Camino Hospital: Mountain View, CA

N. Farhat, EMH Regional Medical Center: Elyria, OH

Y. Khatib, First Coast Cardiovascular Institute: Jacksonville, FL

C. Ruhlmann, Gemeinschaftspraxis: Leipzig, Germany

P. Muck, Good Samaritan Hospital: Cincinnati, OH

B. Gray, Greenville Memorial Hospital: Greenville, SC

D. Scheinert, Heart Center Leipzig: Leipzig, Germany

T. Zeller, Herz Zentrum: Bad Krozingen, Germany

G. Daniel / G. Cardenas, JFK Medical Center: Atlantis, FL

T. Ohki, Jikei University Hospital: Tokyo, Japan

M. Malas, Johns Hopkins Bayview Medical Center: Baltimore, MD

H. Yokoi, Kokura Memorial Hospital: Fukuoka, Japan

T. Kimura, Kyoto University Hospital: Kyoto, Japan

C. Harker, LDS Hospital: Salt Lake City, UT

G. Roubin, Lenox Hill Hospital: New York, NY

C. Kwolek, Massachusetts General Hospital: Boston, MA

S. Misra, Mayo Clinic: Rochester, MN

B. Walton, Methodist Hospital: Houston, TX

R. Molnar, Michigan Vascular Center: Flint, MI

G. Ansel, MidWest Cardiology Research Foundation: Columbus, OH

E. Lipsitz, Montefiore Medical Center: New York, NY

K. Kichikawa, Nara Medical University: Nara, Japan

N. Morrissey, New York Presbyterian Hospital – Columbia: New York, NY

N. Morrissey, New York Presbyterian Hospital - Cornell: New York, NY

T. Maldonado, New York University Medical Center: New York, NY

J. Reilly, Ochsner Clinic Foundation: New Orleans, LA

C. Thompson, Orlando Regional Medical Center: Orlando, FL

H.B. Smouse, OSF Saint Francis Medical Center: Peoria, IL

S. Fritcher, Peripheral Vascular Associates: San Antonio, TX

B. Reddy, Piedmont Hospital: Atlanta, GA

R. Dave, Pinnacle Health: Harrisburg, PA

J. Gill, Prairie Heart Institute of St. John’s Hospital: Springfield, IL

R. Raabe, Sacred Heart Medical Center: Spokane, WA

S. Laster, Saint Luke’s Hospital: Kansas City, MO

P. Hall, South Carolina Heart Center: Columbia, SC

M. Mewissen, St. Luke’s Medical Center: Milwaukee, WI

J. Lantis, St. Luke’s Roosevelt Hospital Center: New York, NY

K. Krol / K. Natarajan, St. Vincent Hospital: Indianapolis, IN

J. Frisoli / D. Sze, Stanford University Medical Center: Stanford, CA

R. Saxon, Tri-City Medical Center: Oceanside, CA

J. Ricke, Universitatsklinikum Magdeburg: Magdeburg, Germany

R. Feezor / A. Lee, University of Florida College of Medicine: Gainesville, FL

J. Carpenter / E. Woo, University of Pennsylvania: Philadelphia, PA

M. Burket, University of Toledo Medical Center: Toledo, OH

M. Dake / J. Angle, University of Virginia Medical Center: Charlottesville, VA

L. Satler / N. Bernardo, Washington Hospital Center: Washington, DC

G. McLean, Western Pennsylvania Hospital: Pittsburgh, PA

W. Romano / P. Bove, William Beaumont Hospital: Royal Oak, MI

55 sites in the US, Japan and Germany

479 patients

32

• 12-month event-free survival – Primary safety endpoint– Per patient freedom from death, amputation, target lesion

revascularization, or worsening Rutherford score (by 2 classes or to class 5 or 6)

• 12-month primary patency – Primary effectiveness endpoint– Per lesion patency by duplex ultrasonography, patent = PSVR < 2.0 (or

angiography if available, patent = diameter stenosis < 50%)– One lesion per limb, bilateral treatment allowed

• 5 year ongoing follow-up– 2, 3, 4 and 5 year patency evaluations for all stent patients and a

randomly selected subset of patients with acutely successful PTA– 3 and 5 year stent radiographs

Zilver PTX Randomized Trial

4/7/2011

9

33

Clinical Trial Design

* Failed PTA = Acute PTA Failure Due to:

• ≥ 30 %DS (including persistent, flow-limiting dissection) on arteriography

- OR -• ≥ 5 mmHg mean trans-

stenotic pressure gradient

Enrollment

479 Patients

PTA

238 Patients

Successful PTA

118 Patients

Provisional

Bare Zilver

59 Patients

*Failed PTA

120 Patients

Zilver PTX

241 Patients

Provisional

Zilver PTX

61 Patients

Primary

Randomization

Secondary

Randomization

34

Patient Demographics and Comorbidities

PTA Zilver PTX P-value

Patients 238 236

Age (years) 68 ± 11 68 ± 10 0.88

Male 64% 66% 0.70

Height (in) 66 ± 4 67 ± 4 0.55

Weight (lbs) 179 ± 44 180 ± 40 0.62

Diabetes 42% 49% 0.13

High cholesterol 70% 76% 0.12

Hypertension 82% 89% 0.02*

Past/current smoker 84% 86% 0.70

* Statistically significant

35


PTA Zilver PTX P-value

Lesions 251 247

Normal-to-normal lesion length (mm) 63 ± 41 66 ± 39 0.35

Stenosed lesion length (mm)1,2 53 ± 40 54 ± 41 0.76

Diameter stenosis (%)1 78 ± 17 80 ± 17 0.44

Total occlusions 25% 30% 0.20

De novo lesions 94% 95% 0.69

Lesion calcification1 None 5% 2%

< 0.01*Little 38% 26%

Moderate 22% 35%

Severe 35% 37%

1 Angiographic core lab assessment 2 Region with > 20% diameter stenosis

*Statistically significant

36

SafetyEvent-free Survival

4/7/2011

10

37

24-Month SafetyEvent-free Survival

77.6%(n = 216 patients)

90.4%

82.6%82.6%

86.6%

Eve

nt-f

ree

Surv

ival

Event-free Survival: Freedom from CEC-adjudicated death, amputation, and target lesion revascularization, or worsening Rutherford score (by 2 classes or to class 5 or 6)

77.6%

p < 0.01

(Zilver PTX,203 Patients)

(PTA,216 Patients)

Months

38

Low Stent Fracture Rate

• 546 stents implanted

– 453 Zilver PTX (average of 1.5 stents per patient)

– 93 Zilver BMS

• X-ray core laboratory analysis of 457 stents at 12 months

• Four stent fractures

– No associated adverse events

0.9% stent fracture rate through 12 months(next evaluations at 3 and 5 years)

39

12-Month EffectivenessPrimary Patency (PSVR < 2.0): Zilver PTX vs. PTA

Zilver

PTXPTA

(All)

p < 0.01

Zilver

PTX

Successful

PTA

p < 0.01

40

Pri

ma

ry P

ate

ncy

Months

Randomized Trial, 24-Month EffectivenessPrimary Patency (PSVR < 2.0): Zilver PTX® vs. PTA

83.1%

64.5%57.8%

32.4%

Successful PTA116 Lesions1

All PTA241 Lesions

Successful PTA long-term subset,

56 Lesions2

Zilver PTX®187 Lesions

p = 0.029

1 Excludes patients with a clinically unacceptable acute PTA result (~ 50% of initial PTA cohort)

2 A randomly selected subset of 56 acutely successful PTA patients assigned to long-term (> 12 mo) follow-up

74.8%

4/7/2011

11

41

12-Month Paclitaxel EffectPatency (PSVR < 2.0): Provisional Zilver PTX vs. BMS

Zilver PTXProvisional

Bare Zilver

Provisional

Zilver PTX

p < 0.01

42

Pri

ma

ry P

ate

ncy

Months

Randomized Trial, 24-Month Paclitaxel EffectPatency (PSVR < 2.0): Provisional Zilver PTX® vs. BMS

89.9%

ProvisionalBare Zilver®56 Lesions

Provisional Zilver PTX® 56 Lesions

73.0%

ProvisionalGroup

24-month Restenosis

Rate Reduction

Zilver PTX® 18.8%50%

Bare Zilver® 37.3%

p < 0.01

81.2%

62.7%

43

Complementary Studies

Zilver PTX® Single-Arm Study Randomized Study

Protocol Prospective, detailed case report forms, extensive monitoring

Antiplatelets Clopidogrel for 60 days, aspirin indefinitely

Outcomes Patency by ultrasound, stent integrity by X-ray, clinical benefit

Patients Symptomatic PAD with Rutherford score ≥ 2

Control Group(s) None PTA ± provisional BMS

Lesions

De novo or restenotic, > 50% diameter stenosis, Real-world:•Unlimited per limb•Included in-stent restenosis•Length not limited•Unlimited Zilver PTX® stents per lesion*

Controlled/Moderate:•One lesion per limb•No prior stent in study vessel•Length ≤ 14 cm•Maximum of 2 Zilver PTX® stents per lesion

Imaging Analysis Site-basedCore laboratories (duplex

ultrasound, angiography, X-ray)

Primary Analysis 12 months

Ongoing

Follow-up2 years 5 years

* Maximum four per patient

44

Complementary 24-Month Clinical ResultsFreedom from TLR: Zilver PTX®

Randomized Trial Zilver PTX®

Fre

ed

om

fro

m T

LR

Months

91.1%

Single-arm Study Zilver PTX®

84.3%86.5%

91.1%

4/7/2011

12

45

Summary

• Drug and device combination opportunities will

continue to grow with technological advances

that promise to impact clinical practice and

transform medicine. High quality data is critical

to our understanding of what role these

therapies will legitimately play. Political,

regulatory and economic forces will have key

roles in creating these changes. Without a doubt,

we all need to prepare for these inevitable

developments.

michael dake, md future technologies for pad: drug … · 4/7/2011 1 1 future technologies for pad:...

Documents