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What Are the Proper End Points for

DES Trials?

Alan C. Yeung, MD

Interventional Cardiology Professor of Medicine

Stanford University School of Medicine


The Perception

“drug”eluting

“just” bare metal

Stanford


Feeding Frenzy

Who’s ahead?

Abbott

Conor

Medtronic

Cordis/

Guidant

BSC

Stanford


Drug Eluting Stents

Clinical Results

Stanford


Drug Eluting Stents

Clinical Results

Stanford


In Search of Drugs to treat Restenosis

Drug Development

HO

HOH 2 C

CH 3

O

OH

HO

O

O

O

Mechanism of action

Cytostatic or cytotoxic

Physiochemical properties




O

CH 3 H

F H

Dexamethasone

CH 3

N

O

HO

O O HO

O

O

O

O

Drug dosage

Lipophilic and lipophobic

Drug elution profile



N

N

N

N

O

O

O

O

O

HO

Sirolimus® (Rapamycin)

O

O

O

O O OH

O

Tissue uptake

Vascular toxicity



N

O

HO

O

O

O

O

N

O

HO

O

O

O

O

Longitudinal and circumferential

distribution

Drug retention

Polymer interaction

Therapeutic window





O

ABT-578

NH O

O

OH

O

O

HO

O OH

H

O O

O

O

HO

Everolimus®

OH

CH 3

H

H H

Estradiol

Paclitaxel


Drugs that Inhibit Restenosis

• Drugs used in DES

– Induce cell-cycle arrest

in late G 1 phase

– Decrease TGF β

– Elevate p53 levels

– Inhibit microtubular

assembly

– Inhibit CDK/cyclin

complexes

Sirolimus S

Everolimus

ABT 578

G 0 G 1

cell G 2

cycle

X

M

X

Paclitaxel

Cell division

Radiation

Slide courtesy of Ron Waksman, MD. Washington Hospital Center Washington, DC

Stanford


Effect of ‘rolimus Drugs on Proliferation of

Human Coronary Artery Smooth Muscle Cells

100

Data are the average of 6 determinations ± SEM

% Inhibition of

Proliferation

75

50

25

0

ABT578

Sirolimus

Everolimus

Tacrolimus

10 -11 10 -10 10 -9 10 -8 10 -7 10 -6 10 -5

[Drug], M

Chen Y-C, Burke SE, Toner J. Comparative potency of ABT-578, Sirolimus, Everolimus,Tacrolimus,

Paclitaxel, and dexamethasone in inhibiting human coronary artery smooth muscle cell proliferation in

vitro. Abbott Laboratories 5 lR-002-AP-03-RO, 2003.

Stanford


1

Lipophilicities of Some Clinical DES Agents

45000

40000

35000

P


Drug Eluting Stents

Clinical Results

Stanford


Quanam Drug Eluting Stent

Quanam QuaDS Stent. Quanam polymer sleeves loaded with a

microtubular inhibitor. Polymere sleeves are tightly stretched over

dedicated metal stents .

Stanford


In vivo Pharmacokinetic Study

What happens to a stent bound drug?

• Stent Platform:V-Flex

PlusTM

(Cook Inc.)

Days

Paclitaxel Remaining on Stent

4 53%

14 31% 69%

Stanford


DELIVER- Non-Polymeric

Paclitaxel Stent

8 Month In-stent Angiographic Results

(mm)

1.2

1

0.8

0.6

0.81

Late Loss

p = 0.003

0.98

(%)

30

20

Binary Restenosis

16.7

p = 0.149

22.4

0.4

10

0.2

0

Paclitaxel

Coated

Bare

Stent

0

Paclitaxel

Coated

Bare

Stent

ACC 2003 Late Breaking Trials


DELIVER: 9 Month Clinical Event Results

20%

TVF*

p=0.079

2%

Death

p=NS

2%

MI

p=NS

15%

14.8%

11.7%

1.2%

10%

1%

1.0% 1.0%

1%

1.0%

5%

0%

Paclitaxel

Coated

Bare

Stent

0%

Paclitaxel

Coated

Bare

Stent

0%

Paclitaxel

Coated

Bare

Stent

* TVF = Death/MI/TLR


Late loss (mm)

PISCES (n=221): QCA at 4 Months

1

0.8

0.6

0.4

0.2

0.88

0.72

0.67

0.70

0.38

0.30

0.48

0

D0

D1

D2

D3

D4

D5

D6

N

43

29

28

28

38

26

29

Dose (ug)

-

10

10

10

10

30

30

Release (d)

-

5

10

10

30

30

10

Stanford


The Effect of Adding a Polymer Topcoat

on the Elution Rate from Drug-Eluting Stents

For in vitro testing, stents (n=12 per

group) were placed in a 1% solution of

solutol in acetate buffer, and aliquots

removed at designated time points

and assayed for ABT-578 via HPLC.

For in vivo testing, 128 stents (32

per group) were implanted in the

common iliac arteries of New

Zealand White rabbits and expanded

to a 1:1.1 balloon-to-artery ratio. At

set time (4 stents per group per time

point), animals were euthanized,

stents explanted, and the amount of

ABT-578 remaining on the explanted

stent was measured using HPLC.

% Drug Eluted

% Drug Eluted

120

100

80

60

40

20

0

100

80

60

40

20

0 5 10 15 20 25

0

Time (hr))

FIREBIRD

0 ug/mm

2 ug/mm

5 ug/mm

10 ug/mm

0 ug/mm

2 ug/mm

5 ug/mm

10 ug/mm

0 10 20 30

Time (days)

Stanford


120

100

Comparison of in vivo Elution Rates

Rabbit iliac models

120

100

ZoMaxx

Cypher

% Drug eluted

80

60

40

20

Endeavor

~75% elution in 2 days

100% elution in 10 days

% Drug eluted

80

60

40

20

~75% elution in 10 days

100% elution in 30 days

0

0 10 20 30

Time (days)

0

0 10 20 30

Time (days)

ZoMaxx and Cypher data from B. Chevalier, EuroPCR 2004

Endeavor data from G. Laarman, , EuroPCR 2004

Stanford


Drug Eluting Stents

Clinical Results

Stanford


DELIVERABILITY !

DELIVERABILITY !

DELIVERABILITY !

Stanford


Stent Flexibility

10g

10g

Bx

OC

10g

10g

Express 2

Vision

10g

10g

Driver

TriMaxx

Stanford


Drug – Stent Interactions

“Closed Cell”

“Open Cell”

100%

80%

60%

Rapamycin

(lipophilic)

40%

20%

Uniform

Stent Expansion

Hwang, Wu & Edelman, Circ 2001

Non-uniform

Stent Expansion

0%

Stanford


Drug Eluting Stents

Clinical Results

Stanford


ARE ALL DES THE SAME ?


ARE ALL DES THE SAME ?

Stanford


ARE ALL DES THE SAME ?


Baseline

Angiographic Late Lumen Loss

L B

Follow-up

L F

Late Lumen Loss = L B - L F


Mean late loss vs. predicted restenosis rate Predicted restenosis rates for

a reference population of mean RVD 2.79 mm and mean post-stent MLD 2.67 mm.

Mauri et al Circulation 2005


Mean late loss vs. predicted restenosis rate Predicted restenosis rates for

a reference population of mean RVD 2.79 mm and mean post-stent MLD 2.67 mm.

Smaller

reference

vessels

Mauri et al Circulation 2005


Mean late loss vs. predicted restenosis rate Predicted restenosis rates for

a reference population of mean RVD 2.79 mm and mean post-stent MLD 2.67 mm.

Diabetes

Mauri et al Circulation 2005


Relation between Binary Restenosis Rate (in-segment) vs %TLR

1

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0

0 2 4 6 8 10 12

DES Trials- DES Arm

%TLR/%BAR

Stanford


When does BAR becomes TLR?

• Baseline vessel size

• Restenosis length

• Presence of disease elsewhere in the vessel

• Presence of symptoms

• Viability of the myocardium

• Method of QCA in the core lab

• Physician judgement

• Angiographic follow-up at or before clinical follow-up

Stanford


Trial Design Drives Outcomes

TLR Is also Influenced by Trial Design

10.0%

9.0%

8.0%

7.0%

6.0%

5.0%

4.0%

3.0%

2.0%

1.0%

0.0%

®

4.6% 4.9% 6.8% 8.0%

Six-Mos. Target Lesion

Revascularization (TLR)

VENUS VELVET RAVEL-Ctrl. SIRIUS-Ctrl.

Diabetics 23.4% 10.7% 21.2% 28.2%

MLD-post 2.90 mm 2.55 mm 2.41 mm 2.68 mm

Stented Length 16.3 mm 18.0 mm 18.0 mm 21.2 mm


3D-IVUS: Diffuse vs Focal

Neointima

Diffuse NIH

Focal NIH

%NI Volume = 10%

%NI Volume = 10%

Stanford


Relationship between Volume and Area Obstruction

Max.

%NIA (%)

80

70

60

50

40

30

B

Focal

20

A

10

(n=87)

0

0 10 20 30 40 50 60 70 80

C

%NIV (%)

Diffuse

A

B

C

Stanford


Impact of angiographic follow-up:

Benestent II

Benestent II Clinical Results:

Event-Free Survival at One Year with and without angio

follow-up

Event-Free Survival (%)

100%

95%

90%

85%

80%

75%

without Angio f/u (N=205)

with Angio f/u (N=208)

88.8%

79.3%

70%

0 50 100 150 200 250 300 350 400

Time (Days)

P.W. Serruys, , MD, ThoraxCenter, , Rotterdam, Netherlands

European Society of Cardiology, August, 1997

Ranking Scale


Influence of Angiography RAVEL

John Hyde, Ph.D., M.D. Interventional Cardiology Devices Branch

Center for Devices & Radiological Health

DHHS/FDA/CDRH


Influence of Angiography SIRIUS

John Hyde, Ph.D., M.D. Interventional Cardiology Devices Branch

Center for Devices & Radiological Health

DHHS/FDA/CDRH


1.6

SAT Rates Across Trials

Out of Hospital to 30 Days

5.0

Cypher Stent Endeavor Stent TAXUS Stent

4.0

2.0

1.1

0.2

1.8

1.5

1.2

0.8

0.4 0.4 0.5

0.5

0.3 0.2

0

1.0

3.0

2.0

1.0

0.0

% Thrombosis

SIRIUS

E-SIRIUS

C-SIRIUS

Cypher-REALIT

RESEARCH/TSEARCH-Cy

MILAN DES-Cyph

SIRTAX-CYPHE

ENDEAVOR I

TAXUS II

TAXUS IV

TAXUS V

TAXUS VI

TAXUS-REALIT

MILAN DES-TAXU

RESEARCH/TSEARCH-TA

SIRTAX-TAXUS

Data sources available on file.

TAXUS Stent = TAXUS ® Express 2 Stent; Cypher is a trademark of Cordis Corp. ENDEAVOR is a trademark of Medtronic.


Conclusions:

1. All three components of a DES is important and

affects the angiographic and clinical outcomes

2. The angiographic (also IVUS) outcomes (late

loss, %neointimal within the stent) can provide

efficacy and failure evaluation

3. The clinical outcomes depends on trial design

(patient populations, % angiographic follow-up)

4. DES systems are different, performance will likely

be the same in same subsets while different in

others

Stanford

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