drug delivery systems for stents

Am J Drug Deliv 2003; 1 (3): 157-170EMERGING TECHNOLOGY 1175-9038/03/0003-0157/$30.00/0

© Adis Data Information BV 2003. All rights reserved.

Drug Delivery Systems for StentsAre There Clinical Implications of the ‘Polymer’ Debate?

Andrew J. Carter and Meenakshi Aggarwal

Providence Heart Institute, Providence/St Vincent’s Medical Center, Portland, Oregon, USA

Contents

Abstract . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 157

1. Components of the Drug-Eluting Stent . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 158

2. Current Status of Drug-Eluting Stents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 161

2.1 Sirolimus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 161

2.2 Paclitaxel . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 164

2.2.1 Polymeric Paclitaxel-Eluting Stents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 165

2.2.2 Nonpolymeric Paclitaxel-Eluting Stents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 167

2.3 Dactinomycin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 168

3. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 169

Drug-eluting stents have emerged as the single most promising therapeutic approach to prevent restenosis, aAbstractformidable limitation of percutaneous coronary revascularization. Stent-based drug delivery engenders a number

of critical chemical, drug, polymer, and mechanical engineering challenges that must be addressed to develop an

effective restenosis therapy. The challenges of stent-based delivery using potent antiproliferative compounds

and polymeric surface coatings are easily apparent in the design and development of first-generation drug-elut-

ing stents. Adverse clinical outcomes with potent cytotoxic stent-based therapies, such as dactinomycin and a

high dose, slow release paclitaxel derivative, represents the dark-side of the drug-eluting stent, with early

aggressive patterns of restenosis, increased stent thrombosis, and aneurysm formation. These adverse clinical

outcomes with drug-eluting stents highlight the importance of understanding the interactions of the drug and

polymer, as well as the role of the residual polymer coating in determining long-term clinical results.

The ultimate fate, or the ‘healed arterial response’ to residual polymeric material, remains a controversial

issue due to the limited availability of long-term clinical follow-up data for most drug-eluting stents.

On April 15, 2002 the British Standards Institution issued with the first approved stent-based pharmacological therapy for

Communaute Europeene (CE) Mark approval of the CYPHER™1 the prevention of restenosis. In recent months, two different

Sirolimus-Eluting Stent for the treatment of de novo coronary paclitaxel-eluting stents and a dexamethasone-eluting stent also

artery lesions (≤30mm in length) in native coronary arteries with gained CE Mark approval for similar clinical indications. Today

reference diameters ranging from 2.25–5.0 mm.[1] This landmark marks the arrival to the promised land of a ‘cure’ for restenosis that

event heralded the onset of a new era in interventional cardiology, spanned four decades of exhaustive efforts in vascular biology,

1 The use of tradenames is for product identification purposes only and does not imply endorsement.

158 Carter & Aggarwal

pharmacology, experimental and clinical research by partnering dictive of the coronary vascular response to biomaterials. In addi-

academia and industry to produce a drug-coated stent. The prom- tion, the majority of preclinical studies investigating polymerise of the drug-coated stent is obvious, but is there sufficient biocompatibility are limited to studies of 30 days’ duration, whichevidence for this technology to completely transform the practice may be insufficient to adequately document vascular biocompa-of interventional cardiology? tibility, particularly for some absorbable polymers. The spectrum

Several important questions remain unanswered regarding the of stent biocompatibility is illustrated in figure 3. In these experi-drug-eluting stent. Issues of late strut malapposition, aneurysm mental studies, despite identical implant conditions (1.1 : 1 stentformation, and delayed healing, raise concern about the possibility to artery ratio) a more severe generalized inflammatory reactionof late stent thrombosis, as observed with endovascular (figure 3c) to the devices resulted in more neointimal formationbrachytherapy. Recent studies with paclitaxel-eluting stents have than the bare metal stent (figure 3a). These examples highlight thedocumented the occurrence of delayed or late restenosis, as evi- effects of stent and polymer biocompatibility on inflammation,denced by an absence of significant treatment effect at 9–12

arterial injury, and the eventual formation of neointima. Themonths with polymeric and nonpolymeric paclitaxel-eluting

‘healed response’ to permanently implanted vascular prosthesisstents.[2,3] Adverse clinical outcomes with potent cytotoxic

may be the benign formation of a limited layer of neointima withstent-based therapies, such as dactinomycin (actinomycin D) and a

favorable biocompatibility (figure 3a), or manifest as an aggres-high dose slow release paclitaxel derivative, represents the dark

sive pattern of neointimal formation, encroaching the lumen, andside of the drug-eluting stent with early aggressive patterns of

resulting in restenosis as a consequence of adverse biocompatibili-restenosis (figure 1 and figure 2), increased stent thrombosis, andty (figure 3c). In general, vascular biocompatible stents andaneurysm formation.[3-5] These adverse clinical outcomes withpolymers typically invoke minimal chronic inflammation, limiteddrug-eluting stents highlight the importance of understanding thegiant cell reaction, and a neointimal surface of 100–250μm thick-interactions of the drug and polymer, as well as the role of theness in the porcine coronary model.[6,7] Unfortunately, humanresidual polymer coating in determining long-term clinical results.clinical data are lacking for most of the polymers used as stentThe ultimate fate or the ‘healed arterial response’ to residualsurface coatings (listed in table I). Today, 6-month clinical data arepolymeric material remains a controversial issue due to the limited

availability of clinical follow-up data beyond 6–12-months for

most drug-eluting stents. The purpose of this manuscript is to

review the current status of drug-eluting stents for the prevention

of restenosis, and to define the role of the polymer in determining

the long-term response to these bioactive vascular prosthesis.

1. Components of the Drug-Eluting Stent

The fundamental components of most drug-eluting stents are a

metallic or polymeric stent and a drug applied to the stent surface

alone, or incorporated within, or covered by a polymer (table I and

table II). The first generation drug-eluting stents (table III) have

generally employed approved stainless steel balloon expandable

stents with proven biocompatibility, although some groups have

documented the feasibility of drug delivery via nitinol self-ex-

panding stents and stents with porous cavities or depots.[1,6] A

considerable body of literature summarizes the vascular biocom-

patibility of various absorbable and non-absorbable polymers

(table I and table II). It is noteworthy to recognize that traditional

biocompatibility models of subcutaneous implant are poorly pre-

a b

c d

Fig. 1. Angiographic results of high dose, slow release paclitaxel-elutingstents. (a) Baseline occlusive in-stent restenosis of the mid-left anteriordescending coronary artery; (b) the lesion was treated with implantation oftwo 17mm long QuaDS-QP2™ stents, leaving an unintentional space be-tween the two stents (arrow); (c) angiography at 6 months showing paten-cy of the two stents with restenosis in the unprotected space – this seg-ment was treated with repeat percutaneous coronary intervention; (d) at 12months the vessel appears occluded (reproduced from Virmani et al.,[3]

with permission).

© Adis Data Information BV 2003. All rights reserved. Am J Drug Deliv 2003; 1 (3)

Drug Delivery Systems for Stents 159

Fig. 2. Photomicrographs of a coronary atherectomy specimen from a QuaDS-QP2™–eluting stent from a 50-year-old woman with in-stent restenosis at 12months. (a) Fragment of restenosis tissue near a stent wire (asterisk) surrounded by an organizing thrombus (red layering) and smooth muscle cells withina proteoglycan-rich matrix (× 100, Movat Pentachrome stain); (b) numerous stellate-shaped smooth muscle cells (× 200); (c) persistent fibrin at the site ofan organizing thrombus (× 200); (d) area of extensive chronic inflammation (× 200, hematoxylin and eosin). A small arteriole is noted within a cluster ofinflammatory cells (arrow); (e) and (f) similar area as in (d), demonstrating CD68-positive macrophages and T-lymphocytes (× 400). For immunohis-tochemistry, the counterstain is Gill’s hematoxylin (reproduced from Virmani et al.,[3] with permission).

available for only a limited number of polymer-coated stents, The physical characteristics of the compound (molecular weight,

solubility, diffusion coefficient, cellular uptake by active or pas-while considerable long-term data continues to accumulate for the

sive transport), arterial substrate (normal vessel, atheroscleroticdrug delivery stents listed in table III.

plaque, calcification, lipid content), and hydrostatic forces alsoThe use of a polymer enables application of a thin (5–10μm),

influence drug delivery via a stent.[19-21]adherent, durable, drug reservoir for stent-based delivery.

Much of the stent coating technology identified in tables I–III isPolymers can serve as solid matrix for drug loading, or as a barrierproprietary. While several coating techniques have been de-to contain the drug, or drug and polymer reservoirs. Polymers arescribed, most commonly a pure drug or polymer-drug matrixgenerally classified as absorbable or nonabsorbable materials,coating is applied to the surface of the stent struts. The mostalthough a precise definition for each type remains somewhatcommon method of stent coating is a wet application of a thin layerarbitrary. The mechanism of drug delivery differs for absorbable(5–10μm) of a drug-polymer solution, such as the non-erodibleand nonabsorbable polymers. Drug delivery occurs by polymermethacrylate and ethylene-based copolymer used for sirolimusdissolution, concentration-dependent gradients, and hydrostatic(rapamycin) coating; drying techniques are then used to bind theforces with absorbable polymeric systems. For nonabsorbablematerial to the stent surface (figure 4a and 4b). This stent coatingpolymers, drug delivery occurs by concentration-dependent gradi-technique typically results in a total drug and polymer weight ofents and hydrostatic forces. The adjustment of the drug to polymerapproximately 500μg and 30% drug polymer ratio by weight.ratio, polymer thickness, and the application of a drug-free poly-

mer barrier topcoat are some of the methods utilized to modify the Some novel methods are being developed to create a polymerkinetics of drug release. Thus, absorbable and nonabsorbable sheath in which the drug is embedded or multiple drug reservoirspolymeric stent coatings can serve as matrices for drug delivery, within the stent structure.[1,22] The primary advantage of theseeach producing unique systems that can be modified to achieve the systems is to allow the stent to serve as a large volume drug

desired controlled release profile of a potentially therapeutic com- reservoir and perhaps enable combined drug therapies. The recent

pound for prevention of restenosis. Other factors, however, are publication of Finkelstein et al.[22] demonstrated how drug elution

pharmacokinetics can be ‘programmed’ by manipulating the lay-equally important in determining arterial drug delivery via a stent.




Tab

le I

. P

recl

inic

al s

tudi

es w

ith p

olym

er s

tent

coa

tings

Ste

ntP

olym

erA

bsor

babl

eM

odel

Dur

atio

nR

esul

t(d

ays)

Tub

ular

slo

tted

Pol

y-n-

buty

l met

hacr

ylat

e an

dN

oP

ig a

nd d

og28

, 56

In t

he p

orci

ne m

odel

, co

mpa

red

with

the

bar

e st

ents

, th

e 75

0μg

stai

nles

s st

eel[8

]po

lyet

hyle

ne-v

inyl

ace

tate

coro

nary

poly

mer

-coa

ted

sten

ts h

ad a

sim

ilar

hist

olog

ical

app

eara

nce,

but

copo

lym

erth

e 13

00μg

pol

ymer

-coa

ted

sten

ts h

ad g

reat

er n

eoin

timal

are

aan

d pe

rcen

t in

-ste

nt s

teno

sis.

In

the

cani

ne m

odel

, th

e ba

rem

etal

, an

d th

e 60

0μg

and

1850

μg p

olym

er-c

oate

d st

ents

eac

hha

d a

sim

ilar

appe

aran

ce o

n hi

stol

ogic

al s

ectio

ns

Wik

tor™

tan

talu

m[9

]P

olyu

reth

ane

No

Pig

cor

onar

y28

The

inju

ry s

core

, lu

min

al a

rea,

med

ial a

rea,

intim

al a

rea,

and

intim

al t

hick

ness

in t

he p

olym

er-c

oate

d st

ents

wer

e si

mila

r to

bare

met

al s

tent

s

Bio

divY

sio™

[10]

Pho

spho

rylc

holin

eN

oP

ig c

oron

ary

84T

he m

ean

min

imum

lum

en d

iam

eter

and

mea

n ne

oint

imal

thic

knes

s in

the

pol

ymer

-coa

ted

sten

ts w

ere

sim

ilar

to b

are

met

alst

ents

Pal

maz

-Sch

atz™

[11]

Met

hylm

etha

cryl

ate

and

No

Pig

cor

onar

y21

Neo

intim

al f

orm

atio

n w

as s

igni

fican

tly r

educ

ed in

pol

ymer

-coa

ted

2-hy

drox

yeth

l met

hacr

ylat

est

ents

com

pare

d w

ith t

he b

are

met

al s

tent

s

Wik

tor™

tan

talu

m[1

2]P

olyu

reth

ane

No

Pig

cor

onar

y28

Pol

ymer

evo

ked

exte

nsiv

e in

flam

mat

ory

resp

onse

s an

dfib

roce

llula

r pr

olife

ratio

n

Wik

tor™

tan

talu

m[1

2]S

ilico

neN

oP

ig c

oron

ary

28P

olym

er e

voke

d ex

tens

ive

infla

mm

ator

y re

spon

ses

and

fibro

cellu

lar

prol

ifera

tion

Wik

tor™

tan

talu

m[1

2]P

olye

thyl

ene

tere

phth

alat

eN

oP

ig c

oron

ary

28P

olym

er-c

oate

d st

ent

had

less

, bu

t st

ill s

ever

e, in

flam

mat

ory

resp

onse

s an

d fib

roce

llula

r pr

olife

ratio

n

Mul

tiLin

k™[1

3]C

hond

roiti

n su

lfate

and

gel

atin

Yes

Rab

bit

iliac

28N

eoin

timal

thi

ckne

ss a

nd in

flam

mat

ion

in p

olym

er-c

oate

d st

ents

wer

e si

mila

r to

bar

e m

etal

ste

nts

Pal

maz

-Sch

atz™

[14]

Pol

yeth

ylen

e gl

ycol

and

Yes

Rab

bit

7In

-ste

nt s

teno

sis

and

loca

l inf

lam

mat

ion

in p

olym

er-c

oate

d st

ents

poly

(lact

ide-

co-g

lyco

lide)

infr

aren

alsi

mila

r to

bar

e m

etal

ste

nts

abdo

min

alao

rta

Wik

tor™

tan

talu

m[1

2]P

olyg

lyco

lic/la

ctic

aci

dY

esP

ig c

oron

ary

28P

olym

er-c

oate

d st

ent

had

less

, bu

t st

ill s

ever

e, in

flam

mat

ory

resp

onse

s an

d fib

roce

llula

r pr

olife

ratio

n

Wik

tor™

tan

talu

m[1

2]P

olyc

apro

lact

one

Yes

Pig

cor

onar

y28

Pol

ymer

evo

ked

exte

nsiv

e in

flam

mat

ory

resp

onse

s an

dfib

roce

llula

r pr

olife

ratio

n

Wik

tor™

tan

talu

m[1

2]P

olyo

rtho

este

rY

esP

ig c

oron

ary

28P

olym

er e

voke

d ex

tens

ive

infla

mm

ator

y re

spon

ses

and

fibro

cellu

lar

prol

ifera

tion

Wik

tor™

tan

talu

m[1

2]P

olyh

ydro

xybu

tyra

te/v

aler

ate

Yes

Pig

cor

onar

y28

Pol

ymer

evo

ked

exte

nsiv

e in

flam

mat

ory

resp

onse

s an

dfib

roce

llula

r pr

olife

ratio

n

Wik

tor™

tan

talu

m[1

2]P

olye

thle

neox

ide/

poly

buty

lene

Yes

Pig

cor

onar

y28

Pol

ymer

-coa

ted

sten

t ha

d m

ild t

o m

oder

ate

infla

mm

ator

yte

reph

tala

tere

spon

se a

nd f

ibro

cellu

lar

prol

ifera

tion

Igak

i-Tam

ai[1

5]P

oly-

L-la

ctic

aci

dY

esP

ig c

oron

ary

21P

olym

er-c

oate

d st

ents

had

an

angi

ogra

phic

ally

cor

onar

y st

enos

isof

abo

ve 4

0%

Wik

tor™

tan

talu

m[1

6]H

igh

mol

ecul

ar w

eigh

t po

ly-L

-Y

esP

ig c

oron

ary

28S

imila

r in

flam

mat

ion

and

neoi

ntim

al f

orm

atio

n, a

s w

ith b

are

met

alla

ctic

aci

dst

ent


Table II. Clinical studies with polymer-only stent coatings

Stent Polymer Absorbable Model Follow-up Result(mo)

BiodivYsio™ [17] Phosphorylcholine No Coronary 7 Restenosis rate with polymer-coated stent is 12%, majoradverse cardiac event is 13%, target revascularization 6%,and coronary artery bypass graft 6%

Heparin-coated Covalently bonded heparin No Coronary 6 Binary restenosis rate is 17.2% and cardiac event-freePalmaz-Schatz™[18] survival rate is 86.3%

ers of polymer and the quantity of drug. The potential benefits of ly 160–480 μg/stent) in several species.[8,19,24,25] The most exten-

this second-generation drug-eluting stent suggest that future re- sive observational data are available from preclinical studies of

search will concentrate heavily not only on the polymer, but also sirolimus-eluting stents in the porcine coronary model. At 28 days

the integration with the stent carrier. in the porcine coronary model, the reduced neointima of the

sirolimus-coated stents consists of smooth muscle cells, matrix2. Current Status of Drug-Eluting Stents proteoglycans, and scant focal regions of residual fibrin adjacent

to the stent struts.[8] Arterial wall toxicity, such as focal medial

necrosis or aneurysm formation, has not been observed at any of2.1 Sirolimus

the doses tested with the sirolimus-coated stents.

The first drug-eluting stent to be marketed in the US was the The mechanism by which sirolimus-eluting stents inhibitsirolimus-eluting stent (CYPHER™), which was FDA approved neointimal formation in the porcine model was explored by West-and first distributed to clinicians in May 2003. The rationale for ern blot analysis of biological markers of cellular proliferation andstent-based sirolimus therapy is based on the physical properties, inflammation.[8] The analysis of arterial wall protein expression atproposed mechanism of action, and experimental data docu- 7 days suggests that the mechanism of action by which stent-basedmenting efficacy in preventing post-angioplasty intimal hyperpla- delivery of sirolimus reduces in-stent neointimal hyperplasia issia. Sirolimus is a hydrophobic drug that has low solubility in similar to systemic treatment with the agent. A Western blotaqueous solutions. The agent is lipophilic, which allows the drug analysis demonstrated a profound reduction in proliferating cellto easily pass through cell membranes, enabling intramural distri- nuclear antigen (PCNA) expression in the vessel wall at 7 days forbution and arterial tissue retention. In addition, cellular uptake the sirolimus-eluting, compared with bare metal, stents. Theseoccurs by binding to the cytosolic receptor, FKBP 12, which also studies also documented reduced phosphorylation of pRb proteinmay enhance chronic tissue retention of sirolimus.[23] by a sirolimus-eluting stent,[8] which is consistent with the proven

The sirolimus-eluting stent utilizes a non-erodible methacrylate effects of the agent on cell cycle signaling and proliferation.copolymer matrix for controlled endovascular delivery of the drug Furthermore, a significant reduction in strut-associated inflamma-to the arterial tissue.[8,19,24-26] The drug, sirolimus, is blended with tion was observed at 28 days for the sirolimus stents comparedthe polymer to create a 30% drug to polymer ratio by weight. A with bare metal stents, suggesting the potential for additionalthin (5–10μm) coating is applied to the surface of the stent (Bx mechanisms of action to inhibit neointimal hyperplasia. AnalysisVelocity™). The quantity of sirolimus loaded onto each stent is of the vessel wall protein expression documented a 70% reductionapproximately 140 μg/cm2. The release of the agent is prolonged in the inflammatory cytokine monocyte chemoattractant protein-1by the application of a thin layer of nondrug polymer over the (MCP-1) for the sirolimus-eluting stent compared with a baredrug/polymer basecoat. This stent-based drug delivery system metal stent. Unlike cyclosporine and tacrolimus, sirolimus is aprovides controlled release of sirolimus over a period of 12 weak inhibitor of cytokine production. The potent immunosup-weeks.[24] pressive effect of sirolimus is directed toward inhibiting the proli-

Preclinical efficacy studies demonstrated a profound reduction feration of T-cells by blocking interleukin (IL)-2 activation of

in strut-associated inflammation with a 35–50% reduction in in- p70s6 kinase. The observed reduction of MCP-1 may be secondary

stent neointimal hyperplasia for the sirolimus-eluting stents com- to the effects of sirolimus on cellular proliferation, and the produc-

pared with bare metal stents (drug load ranging from approximate- tion of cytokines by activated smooth muscle cells.[8]



Sirolimus-eluting stents have been shown to produce a similar stent load, degree of inhibition of neointima, and arterial and

degree of inhibition of neointimal formation, with drug loads systemic drug levels. Thirty-two pigs underwent placement of

ranging from 10–30 μg/mm of stent in the porcine coronary sirolimus (doses ranging from 6.0–1200 μg/stent or 0.3–60 μg/mm

model.[24] While these preliminary studies failed to define a dose of stent), polymer-coated and metal stents. Residual stent and

response effect within a relatively narrow range (3-fold drug arterial sirolimus levels were measured with high performance

concentration), vascular toxicity, as manifested by medial necro- liquid chromatography (HPLC) on separate vessels at 1, 3, 8, 14sis, positive remodeling, or chronic stent malapposition, were not and 30 days. At 30 days, the percent reduction of neointima withobserved. These data suggested a broad therapeutic window and sirolimus stents (6–600μg) ranged from 27–49% compared withinhibition of neointimal formation with absence of vascular toxici- polymer stents (p < 0.001). The 1200μg sirolimus load resulted inty for sirolimus-eluting stents. a 46% reduction in neointima when compared with a matched

Recently, Kopia et al. completed more extensive dose-response polymer control (p < 0.001). As observed in previous studies, a

studies in the porcine coronary model.[25] The purpose of this study significant dose-response versus inhibition of neointima was not

was to define the dose-response relationship between sirolimus observed within the 6–1200μg dose-range. Whole blood sirolimus

Table III. First generation drug-coated stents: clinical data for de novo lesion studies

Drug Stent Polymer Drug load Clinical trial(s) Status

Dactinomycin MULTI-LINK Ethylene vinyl 2.5–10 μg/mm[2] ACTION 360 patient, multicenter RCT: terminated due to(actinomycin D) Tetra™ acetate excess of MACE

Paclitaxel V-Flex™ None 0.17–3.0 μg/mm[2] ELUTES 177 patient, multicenter RCT: dose-dependentreduction in late lumen loss, diameter stenosis

Supra-G™ ASPECT 190 patient, multicenter RCT: dose-dependentreduction in late lumen loss, diameter stenosis

Penta™ None 3.0 μg/mm[2] DELIVER 1042 patient, multicenter RCT: paclitaxel equivalentto bare metal stent

NIR™ pLA/pLC 1.0 μg/mm[2] TAXUS I 61 patients, phase I safety trial: 32% reductionneointimal hyperplasia volume at 6 months for drug-coated stent arm

NIR Conformer™ pLA/pLC 1.0 μg/mm[2] TAXUS II 532 patient multicenter RCT: parallel arm slow andmoderate release formulations, 60% reduction inneointimal hyperplasia volume at 6 months, similarfor both drug release formulations

Express™ pLA/pLC 1.0 μg/mm[2] TAXUS IV 1100 patient, multicenter RCT: primary endpoint 9month TVF, enrollment completed

Quanam QP2™ Polymer sleeves 2400–4000μga SCORE 236 patient, multicenter RCT: enrollment halted dueto excess 30-day MACE in drug-coated stent arm

Sirolimus Bx Velocity™ Methacrylate 140 μg/cm[2] First-in-man 45 patient phase I safety trial: completed; no TLR at(rapamycin) copolymer 12 months

RAVEL 237 patient, multicenter RCT: ‘zero’ restenosis insirolimus arm

SIRIUS 1101 patient, multicenter RCT: 59% reduction in TVFin sirolimus arm

a 7-Hexanolytaxol.

ACTION = actinomycin eluting stent improves outcomes by reducing neointimal hyperplasia trial; ASPECT = Asian paclitaxel-coated stent clinical trial;DELIVER = a randomized comparison of paclitaxel-coated versus metallic stents for the treatment of coronary lesions; ELUTES = evaluation of paclitaxeleluting stent study; MACE = major adverse cardiac event; pLA/pLC = poly(lactic acid)/ploy(lactide-cocaprotactone); RAVEL = randomized study with thesirolimus coated Bx Velocity™ balloon expandable stent in the treatment of patients with de novo native coronary lesions; RCT = randomized clinical trial;SCORE = study to compare restenosis rate; SIRIUS = sirolimus-coated Bx Velocity™ balloon-expandable stent in the treatment of patients with de novocoronary artery lesions; TLR = target lesion revascularization; TVF = target vessel failure.



Fig. 3. Low-power photomicrographs of a porcine coronary artery at 30 days after stent placement. (a) The localized giant cell accumulation at the stentstruts (*) is more typical for metallic balloon expandable stents in the porcine coronary model. Granuloma formation is commonly observed at 10% or lessof the stent struts; (b) a moderate foreign-body reaction is evident in this stent cross-section, as manifested by diffuse inflammation and granulomaformation involving 25–33% of the circumference of the artery; (c) a severe inflammatory and foreign-body response to the stent with diffuse inflammatorycell infiltration, multiple giant cells, and medial destruction.

levels peaked within 1–24 hours post-implantation, were dose- scopy revealed complete coverage of sirolimus-eluting, polymer,

and metal stent struts with an endothelial cell layer. Light micro-related, and declined at 1 week. Tissue sirolimus levels within the

scopy demonstrated a similar endothelialization score forstent border peaked at 1 day and were similar for the 18, 60, and

sirolimus-eluting, polymer, and metal stents. Transmission elec-180μg sirolimus stents (2–5 ng/mg arterial tissue), and for the 600tron microscopy confirmed the presence of tight junctions betweenand 1200μg sirolimus stents (35–37 ng/mg arterial tissue), thenendothelial cells for sirolimus-treated vessels at 14, 30, and 90declined to 0.5–4.0 ng/mg of arterial tissue after 30 days. In thedays. These data suggest a similar temporal course of morphologicadjacent arterial and myocardial tissue, sirolimus levels were <1endothelialization for sirolimus-eluting and bare metal stents.ng/mg at all time points. Together, these data suggest that stent-Therefore, despite potent inhibition of neointimal formation,based delivery of sirolimus via a non-erodible polymeric control-sirolimus-eluting stents do not substantially delay endothelial cellled release system produces a flat dose-response over a 200-foldregrowth in the porcine coronary model.range of drug loads, despite dose-dependent differences in arterial

tissue concentrations with minimal axial drug diffusion and virtual A substantial number of studies have documented the efficacyabsence of arterial or systemic toxicity. The data by Kopia et al. of sirolimus-eluting stents in various experimental models at 30further support a broad therapeutic window for sirolimus-eluting days.[8,19,24,25] In addition, these studies also supported evidence ofstents in the porcine coronary model. Furthermore, these data polymer biocompatibility in two species at 60 days after experi-provide preliminary evidence of safety and potential efficacy for mental intracoronary stent placement.[8] The long-term effects ofclinical applications of sirolimus-eluting stents where multiple or fast- and slow-release formulations of sirolimus-eluting stentsoverlapping stents are required. document a profound reduction in neointimal hyperplasia, and

clinical and angiographic restenosis up to 2 years in humans.[27,28]The endothelium is an important modulating factor in the

growth of neointima following vascular injury, and in preventing We recently evaluated the chronic vascular response to thethrombotic complications following stent placement. Therefore, sirolimus-eluting stent on regulatory proteins of the cell cycle anddetailed histomorphologic studies are necessary to characterize the expression of inflammatory cytokines in a porcine coronary mode-temporal course of endothelial cell growth following stent-based l.[29]At 3 days, the mean neointimal area was similar for the baredelivery of sirolimus. Kopia et al.[26] recently characterized the metal (0.38 ± 0.19mm2) and sirolimus slow release (0.29 ±temporal course of endothelialization following placement of 0.09mm2) groups. After 30 days, the mean neointimal area wassirolimus-eluting (193μg or approximately 10 μg/mm of stent), significantly less for the sirolimus (1.40 ± 0.35mm2) versus the

polymer coated and bare metal Bx Velocity™ stents in the porcine bare metal stents (2.94 ± 1.28mm2, p < 0.001). In contrast, by 90

coronary model. At 3 days following implantation, remnant endo- days the mean neointimal area was similar for the sirolimus (3.03

thelial cells populated the stented segment, while the struts were ± 0.92) compared with the bare metal stents (3.45 ± 1.09mm2),

covered with a thin protein matrix material. By 14 days and resulting in similar lumen area and percent in-stent stenosis.

beyond, following stent implantation, scanning electron micro- Vascular segments treated with sirolimus-eluting stents demon-



The randomized study with the sirolimus coated Bx Velocity™balloon expandable stent in the treatment of patients with de novo

native coronary lesions (RAVEL) was a prospective, multicenter,

randomized, double-blind clinical trial comparing bare metal and

sirolimus-coated stents.[31] Two-hundred-and-thirty-eight patients

were randomized to either the single sirolimus-coated stent (140

μg/cm2) or the bare metal Bx Velocity™ stent. This landmark

clinical trial produced the unexpected outcome of ‘zero’ restenosis

in the sirolimus-coated stent group compared with 26% in the bare

metal group. Furthermore, the sirolimus-coated stent group main-

tained an ‘internal mammary arterial graft-like’ 94% clinical

event-free survival (death, myocardial infarction, coronary artery

Fig. 4. An example of a drug coated stent. (a) The sirolimus-eluting stentutilizes a non-erodible methacrylate copolymer matrix for controlled en-dovascular delivery of the drug to the arterial tissue. The drug, sirolimus(rapamycin), is blended with the polymer to create a 30% drug: to polymerratio by weight; (b) scanning electron microscope demonstrates a thin,5–10μm, coating is applied to the surface of the stent (CYPHER™). bypass graft, target lesion revascularization [TLR]) at 1 year, in

contrast to 72% for the bare metal stent group. These promisingstrated increased PCNA levels at 90 days despite upregulation of data, however, mandate longer-term follow-up to firmly establishp27kip1, compared with bare metal stents. Local production of ‘durability’ and evaluation in ‘day-to-day’ or ‘real world’ lesionsIL-2, IL-6, MCP-1, CD45, and tumor necrosis factor-β were not to determine appropriate incorporation of the Cypher™ sirolimus-detected by Western blot analysis at 90 days for sirolimus or bare eluting stent into the practice of coronary stenting.metal stents.[29] These data confirm that sirolimus-eluting stents The multicenter, randomized, double-blind study of thefavorably modulate neointimal formation for 30 days in the por- sirolimus-coated Bx Velocity™ balloon-expandable stent in thecine coronary model. Long-term inhibition of neointimal hyper- treatment of patients with de novo coronary artery lesions (SIRI-plasia is not sustained due to late cellular proliferation despite US), was a 1101 patient, prospective, multicenter, randomized,evidence of persistent cyclin-dependent kinase (CDK) upregula- double-blind clinical trial that was conducted in 53 centers in thetion. These data suggest that other biologic factors contribute to US.[32] Eleven-hundred-and-one patients with focal de novo nativelate neointimal formation, resulting in ‘normalization’ of the ves- coronary arterial lesions (2.5–3.5mm diameter, 15–30mm long)sel lumen or bioequivalence of bare metal and sirolimus-eluting were randomized to treatment with sirolimus-coated (140 μg/cm2)stents in the porcine model. or bare metal Bx Velocity™ stents. The primary endpoint of the

SIRIUS study, target vessel failure (TVF) [death, myocardialThe safety and feasibility of a sirolimus-coated stent was evalu-infarction, TLR], was reduced 50% at 9 months with sirolimus-ated in a phase I clinical trial.[27,28] Forty-five patients with stableeluting stent placement compared with the Bx Velocity™ stent.angina were electively treated with a 3.0 or 3.5mm diameter,

18mm long stent. Antiplatelet therapy with clopidogrel 75 mg/day

was prescribed for 60 days. At 6 months, using the binary 50% 2.2 Paclitaxel

stenosis definition, no patient had restenosis. Angiographic and

three-dimensional (3D) volumetric intravascular ultrasound ana- Paclitaxel is an antineoplastic agent approved by the FDA for

lysis immediately post-procedure, at 4, 12, and 24 months, showed the management of ovarian cancer. It is extracted from the pacific

minimal intimal hyperplasia without edge effects. One patient yew tree. Paclitaxel prevents cell migration and proliferation. Like

developed late stent thrombosis at 14 months, which was attribut- sirolimus, paclitaxel is lipophilic, which facilitates cellular uptake

ed to plaque rupture proximal to the stent. Sousa et al.[30] reported by allowing the drug to pass through the hydrophobic barrier of

stable angiographic lumen dimensions at 24 months, with a late cell membranes. The mechanism of action of paclitaxel constitutes

lumen loss of 0.1mm in 15 patients treated with the slow release polymerization of tubulin, which results in the formation of abnor-

formulation Cypher™ sirolimus-eluting stent. These data, together mal, stable and nonfunctional microtubules, thereby blocking cel-

with pivotal randomized clinical trials, add to the body of evidence lular replication in the G0/G1 and G1/M phases. Sollot et al.[33]

documenting the sustained potent antiproliferative effects of the have reported that paclitaxel inhibits rat vascular smooth muscle

Cypher™ sirolimus-eluting stent. cell migration and proliferation in vitro. Furthermore, both local



and systemic paclitaxel delivery has been demonstrated to reduce multi-sleeve drug-eluting stent (QuaDS-QP-2™) was the first of

neointimal hyperplasia in vivo.[13,33-35] its kind used in human clinical trials. Between February 1999 and

January 2001, 32 patients in Argentina were enrolled in a non-Paclitaxel-coated stents have been shown to reduce neointimalrandomized pilot trial to study the safety of this drug-eluting stent.hyperplasia at 4 weeks in a porcine coronary injury model.Thirteen of these 32 patients have been restudied, either viaHeldman et al.[34] evaluated various doses of nonpolymeric pacli-coronary angiography and/or intravascular ultrasound after antaxel coated stents (0.2–187 μg/stent) in the porcine coronaryaverage of 11.2 months (range 6–15 months). Baseline meanmodel. These authors reported a dose-dependent increase in thediameter stenosis was 84% ± 9%, reduced to 3.5% ± 2.1% post-luminal area with paclitaxel-eluting stents, which was not only duestenting, and only 13% ± 10% at follow-up. Quantitative angiogra-to a reduction in neointimal hyperplasia, but also due to arterialphy revealed a post-stent deployment minimum luminal diameterexpansion caused by necrosis of the medial wall. This study(MLD) of 3.3 ± 0.3mm, and a follow-up MLD of 2.9 ± 0.3mm.clearly indicated that stent-based nonpolymeric paclitaxel deliveryTwo of the 32 patients (6%) required target vessel revasculariza-suppresses neointimal hyperplasia with a dose-dependent toxiction (TVR); one with a bare metal stent previously placed in theeffect on the vessel wall, as exhibited by a decrease in medial walltarget vessel and the other with disease proximal and distal to thethickness, neointimal and medial wall hemorrhage, and cell necro-drug-eluting stent. Angiographic restenosis was not detected insis. Farb et al.[13] reported similar results with a polymeric pacli-any QuaDS-QP-2™ drug-eluting stent. Twenty-five of the 32taxel-coated stent in a rabbit model, although the neointimalpatients underwent stress echocardiography or single photon emis-suppression seen at 28 days was not sustained at 90 days. Togethersion computed tomography (SPECT) Thallium; no evidence ofthese studies raised concern regarding possible vascular complica-myocardial ischemia was revealed.[36]tions, such as thrombosis and aneurysm formation, as well as

questioning the long-term efficacy of paclitaxel-coated stents. On the basis of these preliminary data, a multicenter, random-The local delivery of paclitaxel via a controlled polymer slow ized, controlled trial, the study to compare restenosis rate

release mechanism via a stent has also been studied. Drachman et (SCORE), was designed to assess the efficacy of this uniqueal.[35] evaluated stents containing the polymer poly lactide-co-∑- polymeric sleeve paclitaxel derivative coated stent for the preven-caprolactone and 200μg of paclitaxel in rabbit iliac arteries. They tion of in-stent restenosis. Unfortunately, enrollment in this trialwere able to demonstrate a reduction in neointimal hyperplasia at was terminated after review of the 30-day major adverse cardiac180 days. They also described delayed intimal healing character- event (MACE) revealed increased periprocedural myocardial in-ized by increased local arterial inflammation and fibrin deposition. farction and subacute thrombosis in the drug-eluting group. Re-

cent data from a single center in-stent restenosis (ISR) registryTogether these experimental studies demonstrate the challengesreported an increased frequency of MACE and TLR at 12 monthsand future clinical potential of paclitaxel-eluting stents in reducingwith this unique 7-hexanolytaxol-eluting stent.[4] The failure of thein-stent restenosis. At the same time, they raise concern aboutQuanam 7-hexanolytaxol-eluting stent remains an elusive ques-incomplete healing of the intimal surface, arterial toxicity, andtion. Was it the stent design, polymeric sleeves, or drug dose alonelong-term biocompatibility. The dose-dependent arterial toxicityor in combination that resulted in adverse device performance andwith these various paclitaxel-eluting stents suggests a narrowintolerable biocompatibility? The consequences of system com-therapeutic window for this stent-based pharmacologic therapy.patibility with anatomic considerations (branch vessels) and poorThe first clinical trial with a drug-eluting stent used a paclitaxelbiocompatibility have obvious clinical implications. Currently,derivative (7-hexanolytaxol) as the antiproliferative agent deliv-other modes for stent-based delivery of paclitaxel are under clin-ered via a polymer sheath. In this mode of delivery, the drug isical investigation for the prevention of restenosis.loaded onto a 4mm long polymer sheath and the sheath wrapped

around an unexpanded stent.[3,4] Each sheath contained 800μg of2.2.1 Polymeric Paclitaxel-Eluting Stents7-hexanolytaxol, and the number of sleeves varied with the length

of the stent, typically three or five sleeves per stent. Thus, each TAXUS I was a phase I safety trial conducted as a prospective,

stent contained approximately 2400–4000μg of 7-hexanolytaxol. randomized, double-blind study comparing paclitaxel-eluting

With delivery and expansion of the stent, the sheath containing the stents with bare metal stents.[37] The stent platform was an NIR®

drug is positioned between the stent and the arterial wall. This conformer stent coated with an inert polymer containing paclitaxel



at a dose of 1.0 μg/mm2, released in a slow manner over several In the moderate release cohort, the paclitaxel-eluting stent

weeks. A total of 61 patients with focal de novo native coronary resulted in a 60% reduction of in-stent neointimal hyperplasia

lesions, <12mm in length and 3.0–3.5mm reference vessel diame- volume obstruction compared with the bare metal group. In-ter, were enrolled at three centers in Europe. The TAXUS I segment angiographic restenosis was observed in 8.6% of thepatients were treated with clopidogrel 75mg once daily for 6 moderate release paclitaxel stent group versus 23.8% of the baremonths, and aspirin for 12 months post-stenting. The primary metal stent group (p < 0.001). A 60% reduction in 6-month MACEendpoint was 30 day MACE (death, Q-wave myocardial infarc- was observed in the moderate release paclitaxel stent group, again,tion, TVR, angiographic stent thrombosis). Secondary endpoints primarily driven by less TLR. TLR was required in 3.1% ofincluded 6-month MACE and coronary angiography. Six-month patients in the moderate release paclitaxel group, while 14.6% ofangiography demonstrated a restenosis rate of 10.3% in the control the bare metal stent group had undergone TLR at 6 months, (p =group compared with 0% in the paclitaxel-eluting group (p = 0.002). The frequency of TVR for the moderate release paclitaxel0.11). Intravascular ultrasound imaging demonstrated a 32% re- stent group was 6.2% compared with 17.7% at 6 months (p =duction of neointimal hyperplasia volume index in the paclitaxel- 0.007).eluting stent group compared with bare metal stents.

In the TAXUS II study, slow- and moderate-release paclitaxel-TAXUS II was a pivotal global randomized efficacy trial eluting stents demonstrated a 60% reduction in in-stent net volume

designed to study the efficacy of slow and moderate releaseobstruction, the primary endpoint of the trial. The suppression of

polymeric 1.0 μg/mm2 paclitaxel-eluting stents in 536 patientsneointimal hyperplasia at 6 months by the slow- and moderate-

with focal de novo lesions.[38] The stent platform was an NIR®release paclitaxel-eluting stents was associated with a significant

conformer paclitaxel-eluting stent with slow and moderate pacli-reduction in MACE, principally due to less TLR compared with

taxel release kinetics and bare metal. The moderate release pacli-bare metal stents. Quantitative coronary angiography documented

taxel system produced an early burst of drug release to the arterya 60% reduction in binary restenosis (>50% diameter stenosis) due

during the first 72 hours, then provided long-term release kineticsto less late loss, increased 6-month MLD, and diameter stenosis

similar to the slow release platform. The angiographic inclusionfor the slow- and moderate-release paclitaxel-eluting stents com-

criteria were a single, focal, 12mm long lesion, in vessels with apared with bare metal stents. There was no significant difference

reference diameter of 3.0–3.5mm. Overlapping paclitaxel-elutingin clinical dose response for the slow- and moderate-release pacli-

stents was prohibited, therefore, bailout stenting for edge dissec-taxel-eluting stents. Together, these encouraging data at 6 months

tion required the use of a bare metal stent. Patients were treatedprovides initial proof of concept for polymeric paclitaxel-elutingwith aspirin) ≥75 mg/day, and clopidogrel 75 mg/day for 6stent to prevent restenosis. These data require confirmation inmonths. The primary endpoint was volumetric analysis of thelarger prospective randomized clinical trials and documentation ofstented segment by intravascular ultrasound at 6 months. Secon-a long-term treatment effect beyond 6 months. A preliminarydary clinical endpoints included 6-month MACE, TLR, TVR andreport of 12 months clinical follow-up indicates a component ofangiographic restenosis.late restenosis for the slow release cohort, with insignificant

In the slow release cohort, the paclitaxel-eluting stent resultedreduction in TVR compared with the control cohort.[39]

in a 62% reduction of in-stent neointimal hyperplasia volumeTAXUS IV is a pivotal prospective, double-blind, randomizedobstruction compared with the bare metal group. In-segment angi-

clinical trial for the evaluation of slow release polymeric pacli-ographic restenosis was observed in 5.5% of the slow releasetaxel-eluting stents in the treatment of de novo lesions, 10–28mmpaclitaxel stent group versus 20.1% of the bare metal stent groupin length, treated with a single stent, conducted at 72 clinical sites(p < 0.001). A 60% reduction in 6-month MACE was observed inin the US. In the TAXUS IV study, 1326 patients were randomizedthe slow release paclitaxel stent group, primarily driven by lessto a single 2.5–3.5mm diameter, 16, 24, or 32mm in length, to bareTLR. TLR was required in 4.6% of patients in the slow releasemetal Express™ stent or a slow release polymeric paclitaxel-paclitaxel group, while 14.3% of the bare metal stent group hadeluting Express™ stent.[40] Patients were treated with aspirin ≥ 75undergone TLR at 6 months (p = 0.043). The frequency of TVR

mg/day and clopidogrel 75 mg/day for 6 months. The primaryfor the slow release paclitaxel stent group was 7.7% compared

clinical endpoint is 9-month ischemic TVR. Enrollment in thewith 14.3% at 6 months (p = 0.114).



TAXUS IV trial was completed in the third quarter of 2002 and combination of aspirin and cilostazol. In general, rates of MACE

results are expected by September 2003. were higher in the aspirin and cilostazol group. In particular, the

high dose paclitaxel group was more sensitive to the aspirin andThe slow release paclitaxel-eluting NIR® stent received CEcilostazol combination, with significantly more patients exper-mark approval on 16 January 2003. The device is currently avail-iencing MACE with the aspirin/cilostazol combination than withable for clinical use in South America, and is expected to beaspirin/ticlopidine/clopidogrel combination (33% versus 4%).marketed in Europe by mid 2003. Post-marketing studies (WIS-Cilostazol, rather than conventional therapy with ticlopidine orDOM and TAXUS V) will evaluate more complex lesion subsetsclopidogrel, was associated with a higher rate of subacute throm-(bifurcation, ISR), as well as exploring the safety of an abbreviatedbosis. In conclusion, stents coated with pure paclitaxel demonstra-post-procedural course of dual antiplatelet therapy with aspirinted a dose-dependent reduction in angiographic binary restenosis,and clopidogrel.percent diameter stenosis, by reducing intimal hyperplasia and

maintaining a larger minimum lumen diameter, as documented by2.2.2 Nonpolymeric Paclitaxel-Eluting Stentsintravascular ultrasound at 6 months. In combination with conven-The Asian paclitaxel-coated stent clinical trial (ASPECT) was ational antiplatelet therapy, aspirin, and ticlopidine or clopidogrel,randomized, multicenter clinical study designed to compare thehigh dose paclitaxel-eluting stents had a similar safety profile tosafety and efficacy of high- (3.1 μg/mm2) and low-dose (1.3 μg/control.mm2) pure paclitaxel-eluting stent to bare metal stents in de novo

coronary lesions.[41] One-hundred-and-seventy-five patients were A similar, but broader, dose-finding and safety trial was con-enrolled between February 2000 and March 2001 into one of the ducted in Europe with nonpolymeric paclitaxel-eluting stents. Thethree arms. Lesion requirements included a diameter of evaluation of paclitaxel eluting stent study (ELUTES) was a2.25–3.5mm, with a lesion length of <15mm. Supra G™ stents multicenter, randomized, controlled, blinded study which evalu-(diameter of 2.5–3.5mm, length 15mm) were used and coated with ated four doses of paclitaxel-eluting stents compared with controlpaclitaxel through a proprietary process without a polymer. The bare metal stents.[42] The doses of paclitaxel evaluated were 0.2,primary endpoint was angiographic percent diameter restenosis at 0.7, 1.4, and 2.7 μg/mm2 stent surface area on a 3.0–3.5 mm4–6 months post-stent implantation, as measured by quantitative diameter, 16mm long V-flex™ coronary stent. One-hundred-and-coronary angiographic analysis. Six-month efficacy data demon- ninety-two patients with de novo lesions, <15 mm in length, werestrated a significant reduction in angiographic binary restenosis enrolled by April 2001. The primary endpoint of the study wasbetween the high dose group and control group, 4% versus 27% angiographic percent diameter stenosis at 6 months, as measuredrespectively (p<0.001). The percent diameter stenosis was signifi- by quantitative coronary angiography. MACE at 1 and 6 monthscantly lower in the high dose group compared with controls (14 ± were also recorded. Antiplatelet therapy with aspirin and21% for high dose paclitaxel versus 23 ± 25% for low dose clopidogrel was required for 3 months post-stent implantation.paclitaxel, and 39 ± 27% for the control group). The minimum Six-month coronary angiography demonstrated decreased percentlumen diameter was significantly higher in the high dose group diameter stenosis in the 2.7 μg/mm2 paclitaxel group comparedcompared with the control group (2.53 ± 0.72mm for high dose, with controls, 14.2 ± 4.1% versus 33.9 ± 4.1% respectively (p =2.28 ± 0.83mm for low dose, and 1.79 ± 0.86mm for control). 0.0007). Angiographic binary in-stent restenosis at 6 months wasIntimal volume assessed by intravascular ultrasound demonstrated 3.1% for the 2.7 μg/mm2 paclitaxel group compared with 20.6%decreased neointimal hyperplasia in the high dose paclitaxel group for the control group (p = 0.055). A dose-dependent reduction incompared with the control group (12 mm3 for high dose, 18 mm3 angiographic late lumen loss was observed, with the 2.7 μg/mm2

for low dose, and 31 mm3 for control). dose showing a late lumen loss of only 0.10 ± 0.12mm versus 0.73

Six-month evaluation of MACE varied by type of antiplatelet ± 0.12mm for the controls (p = 0.002). In the high dose group,

drug administration. All patients were scheduled to receive aspirin there was one TLR, which was proximal to the stent. No signif-

and ticlopidine/clopidogrel. A subgroup received cilostazol in lieu icant differences in death and non–Q-wave myocardial infarction

of ticlopidine/clopidogrel; 12 patients in the high dose paclitaxel were noted between the four paclitaxel-eluting and control stent

group, 15 patients in the low dose paclitaxel group, and 10 patients groups. There were no cases of late stent thrombosis. The AS-

in the control group, a total of 37 out of 177 patients, received the PECT and ELUTES trials documented the feasibility and safety of



this nonpolymeric paclitaxel-eluting stent. These data required treatment of malignancies. The antineoplastic properties of dacti-

confirmation in larger prospective, randomized clinical trials and nomycin arise from its ability to inhibit cell proliferation. It works

documentation of a long-term treatment effect beyond 6 months. by forming a stable complex with double-stranded DNA, thereby

A randomized comparison of paclitaxel-coated versus metallic inhibiting RNA synthesis. Dactinomycin is more potent and has

stents for the treatment of coronary lesions (the DELIVER study) greater cytotoxic potential than sirolimus or paclitaxel.[43]

was a pivotal prospective, double-blind, randomized clinical trial Preclinical studies in a porcine coronary model were used tofor the evaluation of nonpolymeric paclitaxel-eluting MULTI- determine the theoretical dose for dactinomycin-eluting stents.LINK PENTA™ stents (ACHIEVE™ Drug Eluting Coronary Adult Yucatan miniature swine received either a non-coated stentStent System) in the treatment of de novo lesions, in vessels or one of four formulations of dactinomycin-eluting stents (4, 10,2.5–4.0mm in diameter, <25mm in length, treated with a single 40, or 70 μg/cm2) in each of their coronary arteries. The drug wasstent, conducted at multiple clinical sites in the US.[2] In DELIV-

coated to the surface of the stainless steel balloon expandableER, 1042 patients were randomized to a bare metal PENTA™

MULTI-LINK™ Tetra stent with a non-erodible polymer to en-stent or a nonpolymeric paclitaxel-eluting PENTA™ stent. Pa-

able controlled release of dactinomycin over several weeks. At 28tients were treated with aspirin ≥75 mg/day and clopidogrel 75

days, the percent area stenosis was reduced and the minimummg/day for 3 months. The study was designed to demonstrate a

lumen diameter was increased in the dactinomycin-treated groups.40% reduction in the primary endpoint of 270-day TVF for the

The high dose group (40 or 70 μg/cm2) demonstrated incompleteACHIEVE Drug Eluting Coronary Stent System compared with

healing, positive vessel remodeling, and mural thrombus. The lowthe PENTA Coronary Stent System.

dose group (4 or 10 μg/cm2) had lower percent stenosis comparedWhile the final analysis of the DELIVER clinical results is still

with the control group, but without obvious evidence of toxicin progress, the preliminary analysis indicates that although there

changes in the vessel, as seen with the high dose group.[44,45] Theseis a trend toward improvement in TVF, the primary endpoint will

data led the way for a randomized clinical trial to evaluate thenot be met. Additionally, while there appeared to be a trend toward

efficacy of dactinomycin-coated stents at the lower doses.a reduced angiographic binary restenosis rate, the planned 50%

The actinomycin eluting stent improves outcomes by reducingreduction in angiographic binary restenosis was not achieved. Theneointimal hyperplasia (ACTION) trial was designed as a pivotalpercent reductions in both TVF and angiographic binary restenosistrial to gain CE Mark approval of the MULTI-LINK™ TETRA-Drate were less than expected due to the combination of results indrug-eluting stent system.[5] This multi-center study randomizedthe PENTA™ Coronary Stent System control arm (9-month TVF360 patients at 25 centers in Europe, Australia, and New Zealandof 14–15% and in-segment angiographic binary restenosis ofto an uncoated bare metal stent, a 2.5 μg/cm2 dactinomycin-21–22%), and a higher than expected 11–12% TVF and 16–17%eluting stent, or a 10 μg/cm2 dactinomycin-eluting stent. Thein-segment angiographic binary restenosis in the ACHIEVE arm

primary endpoints were MACE at 30 days and percent diameterof the study. The failure of pure paclitaxel-coated stents to signifi-

cantly reduce TVF compared with bare metal stents suggests stenosis by quantitative coronary angiography, along with in-

potential limitations of a nonpolymeric stent-based drug delivery travascular ultrasound analysis at 6 months. Thirty-day MACE

system to reliably achieve a therapeutic tissue concentration, or demonstrated an event rate of 2.5% for the group receiving 2.5 μg/perhaps of the agent itself. Despite differences in dose and rate of cm2 dactinomycin-eluting stent, 0.8% for the group receiving 10delivery for polymeric and nonpolymeric paclitaxel-eluting stents, μg/cm2 dactinomycin-eluting stent, and 0.8% for the controlthe DELIVER data now raise serious questions regarding the long- group. Overall, the 30-day MACE rate was 1.4%. Routine reviewterm efficacy of this stent-based therapy for the prevention of of clinical events by the data safety and monitoring committeerestenosis. after 30 days demonstrated a high TLR rate in the dactinomycin

groups. Therefore, it was recommended that patients who received

a dactinomycin-eluting stent continue clopidogrel therapy, under-2.3 Dactinomycin

go immediate angiographic and intravascular ultrasound assess-

ment, as well as an additional angiographic assessment 1 year afterDactinomycin is an antibiotic derived from Streptomyces

initial stent placement. As a result of these disappointing clinicalparvulus. It has been used in numerous treatment protocols for the



findings, further development and clinical evaluation with dacti-

nomycin-eluting stents was halted by the sponsor. References1. Carter AJ. Drug eluting stents for the prevention of restenosis: standing the test of

time. Catheter Cardiovasc Interv 2002; 57: 69-713. Conclusions2. O’Neill WB, Midei M, Cox DA, et al. The DELIVER Trial: a randomized

comparison of paclitaxel-coated versus metallic stents for the treatment ofThe recent CE mark and FDA approval of the Cypher™coronary lesions. 52nd Annual Meeting of the American College of Cardiology;

sirolimus-eluting stent for the treatment of focal de novo native 2003 Mar 30-April 2; Chicago

3. Virmani R, Liistro F, Stankovic G, et al. Mechanism of late in-stent restenosis aftercoronary arterial lesions documents the emergence of perhaps theimplantation of a paclitaxel derivate: eluting polymer stent system in humans.single most promising technology in the history of interventionalCirculation 2002; 106: 2649-51

cardiology. However, the safety and efficacy of the sirolimus- 4. Liistro F, Stankovic G, Di Mario C, et al. First clinical experience with a paclitaxelderivate-eluting polymer stent system implantation for in-stent restenosis:eluting stent is yet to be established for the treatment of severeimmediate and long-term clinical and angiographic outcome. Circulation 2002;

fibrocalcific, aorto-ostial, left main, bifurcation, and saphenous 105: 1883-6

vein graft lesions. Furthermore, recent conflicting data on the 5. Serruys P. The ACTION trial [online]. Available from URL: http://www.TCTMD.com [Accessed 2003 Mar 31]application of drug-eluting stents for the treatment of in-stent

6. Schwartz RS, Edelman ER, Carter A, et al. Drug eluting stents in preclinicalrestenosis highlight the necessity of intensive clinical evaluation to studies: recommended evaluation. Circulation 2002; 106: 1867-73

7. Bertrand O, Rajender S, Mongrain R, et al. Biocompatibility aspects of new stentestablish proof of efficacy rather than ‘assumption’ of benefit. Thetechnology. J Am Coll Cardiol 1998; 32: 562-71lessons from failed approaches with drug-eluting stents, in particu-

8. Suzuki T, Wilenski R, Bailey LR, et al. Stent-based sirolimus therapy reduceslar stent-based delivery of potent cytotoxic antineoplastic agents neointimal formation and in-stent restenosis in a porcine coronary model.

Circulation 2001; 104: 1188-93that delay vascular healing, induce medial necrosis, and promote9. Yoon JH, Wu CJ, Homme J, et al. Local delivery of nitric oxide from an eluting

positive vascular remodeling, should serve to guide future pro- stent to inhibit neointimal thickening in a porcine coronary injury model.Yonsei Med J 2002; 43 (2): 242-51spective drug-eluting stents and polymer coatings. Experimental

10. Whelan DM, van der Giessen WJ, Krabbendam SC, et al. Biocompatibility ofstudies in accepted models of vascular stenting with comprehen-phosphorylcholine coated stents in normal porcine coronary arteries. Heart

sive histopathologic analysis of the vessel wall at 1, 3, and 6 2000; 83 (3): 338-45

11. Bar FW, van der Veen FH, Benzina A, et al. New biocompatible polymer surfacemonths will provide sufficient evidence in most cases to determinecoating for stents results in a low neointimal response. J Biomed Mater Resthe safety and biocompatibility of a novel stent, material, polymer,2000; 52 (1): 193-8

or polymer and drug surface coatings. 12. van der Giessen WJ, Lincoff AM, Schwartz RS, et al. Marked inflammatorysequelae to implantation of biodegradable and nonbiodegradable polymers inAlthough recent 3-year data from the sirolimus-eluting stentporcine coronary arteries. Circulation 1996; 94 (7): 1690-7

first-in-man study[46] provides reassurance of a durable treatment 13. Farb A, Heller PF, Shroff S, et al. Pathological analysis of local delivery ofpaclitaxel via a polymer-coated stent. Circulation 2001; 104 (4): 473-9effect and chronic vascular biocompatibility, the effects of rem-

14. Elkins CJ, Waugh JM, Amabile PG, et al. Development of a platform to evaluatenant polymer and degradation products remains a potential threatand limit in-stent restenosis. Tissue Eng 2002; 8 (3): 395-407

to chronic vascular biocompatibility. Will the drug-eluting stent 15. Yamawaki T, Shimokawa H, Kozai T, et al. Intramural delivery of a specifictyrosine kinase inhibitor with biodegradable stent suppresses the restenoticsimply delay restenosis? Will residual polymer incite neointimalchanges of the coronary artery in pigs in vivo. J Am Coll Cardiol 1998; 32 (3):

formation and restenosis after the drug is exhausted from the stent 780-6

16. Lincoff AM, Furst JG, Ellis SG, et al. Sustained local delivery of dexamethasoneand artery? The debate of the drug-eluting stent continues withby a novel intravascular eluting stent to prevent restenosis in the porcineuncertainty regarding the long-term consequences of these vascu-coronary injury model. J Am Coll Cardiol 1997; 29 (4): 808-16

lar prostheses. Ultimately, meticulous clinical follow-up, likely to 17. Galli M, Sommariva L, Prati F, et al. Acute and mid-term results ofphosphorylcholine-coated stents in primary coronary stenting for acute myocar-be 3–5 years for nonabsorbable polymer stent coatings, will bedial infarction. Catheter Cardiovasc Interv 2001; 53 (2): 182-7

necessary to determine the ultimate fate of drug, device, polymer,18. Shin EK, Son JW, Sohn MS, et al. Efficacy of heparin-coated stent in early setting

and vessel wall interactions in order to document chronic vascular of acute myocardial infarction. Catheter Cardiovasc Interv 2001; 52 (3): 306-12

19. Kopia GA, Lauer M, Fischell T, et al. Pharmacokinetics and pharmacodynamics ofbiocompatibility. The saga continues for the polymer debate.sirolimus-eluting stents [abstract]. Am J Cardiol 2002; 90 Suppl. 6A: 117H

20. Hwang CW, Wu D, Edelman ER. Physiological transport forces govern drugAcknowledgements distribution for stent-based delivery. Circulation 2001; 104: 600-5

21. Lovich MA, Creel C, Hong K, et al. Carrier proteins determine local pharmaco-No sources of funding were used to assist in the preparation of this kinetics and arterial distribution of paclitaxel. J Pharm Sci 2001; 90: 600-5

manuscript. Dr Carter has research grants with Boston Scientific, Inc., Gui- 22. Finkelstein A, McClean D, Kar S, et al. Local drug delivery via a coronary stentwith programmable release pharmacokinetics. Circulation 2003; 107: 777-84dant, Inc., Cordis, Inc. (a Johnson and Johnson company), and Medtronic, Inc.



23. Schreiber SL. Chemistry and biology of the immunophilins and their immunosup- 36. de la Fuenta LM, Miano J, Mrad J, et al. Initial results of the Quanam drug-elutingpressive ligands. Science 1991; 251: 283-7 stent (QuaDS-QP-2) registry (BARDDS) in human subjects. Catheter Cardi-

ovasc Interv 2001; 53: 480-824. Carter AJ, Wilensky R, Bailey LR, et al. Stent-based sirolimus therapy reducesneointimal formation and in-stent restenosis in a porcine coronary model 37. Grube E. TAXUS I: 2 year results [online]. Available from URL: http://[abstract]. J Am Coll Cardiol 2000; 35: 13A

www.TCTMD.com [Accessed 2003 Jun 16]

25. Klugherz BD, Llanos G, Lieuallen W, et al. Stent-based delivery of sirolimus for 38. Colombo A. The TAXUS II trial [online]. Available from URL: http://the prevention of restenosis. Coron Artery Dis 2002; 13: 183-8

www.TCTMD.com [Accessed 2003 Mar 31]

26. Kopia GA, Carter AJ, Gallagher L, et al. Temporal course of endothelialization 39. Colombo A. 12-month clinical follow-up of the TAXUS II paclitaxel eluting stentfollowing implantation of sirolimus-eluting stents [abstract]. Am J Cardiol

study. 52nd Annual Meeting of the American College of Cardiology; 2003 Mar2002; 90 Suppl. 6A: 113H

30- Apr 2; Chicago27. Sousa JE, Costa MA, Abizaid AC, et al. Lack of neointimal proliferation after

40. Stone GW. The TAXUS IV clinical trial [online]. Available from URL: http://implantation of sirolimus-coated stents in human coronary arteries. Circulation

www.TCTMD.com [Accessed 2003 Mar 30]2001; 103: 192-5

41. Park SJ, Shim WH, Ho DS, et al. A paclitaxel-eluting stent for the prevention of28. Sousa JE, Costa MA, Abizaid AC, et al. Sustained suppression of neointimalcoronary restenosis. N Engl J Med 2003; 348: 1537-45proliferation by sirolimus-eluting stents: one year angiographic and intravascu-

lar ultrasound follow-up. Circulation 2001; 104 (17): 1996-8 42. de Scheerder I, Gershlick A, Chevalier B, et al. The ELUTES clinical study:

12-month clinical follow-up. Circulation 2002; 106 Suppl. II: II-39429. Aggarwal M, Tsao P, Kopia G, et al. Stent based delivery of sirolimus is associatedwith increased levels of p27[kip1] without long-term suppression of neointimal 43. Hiatt BL, Ikeno F, Yeung AC, et al. Drug-eluting stents for the prevention ofhyperplasia in the porcine model. Circulation 2002; 20: 1781 restenosis: in quest for the Holy Grail. Catheter Cardiovasc Interv 2002; 55:

30. Sousa JE, Costa MA, Abizaid A, et al. Two-year angiographic and intravascular 409-17ultrasound follow-up after implantation of sirolimus-eluting stents in human

44. Virmani R, Kolodgie FD, Farb A, et al. Drug-eluting stents: are human and animalcoronary arteries. Circulation 2003; 107: 381-3

studies comparable? Heart 2003; 89 (2): 133-831. Morice MC, Serruys PW, Sousa JE, et al. A randomized comparison of a

45. Virmani R, Farb A, Kolodgie FD. Histopathologic alterations after endovascularsirolimus-eluting stent with a standard stent for coronary revascularization. N

radiation and antiproliferative stents: similarities and differences. Herz 2002;Engl J Med 2002; 346 (23): 1773-8027: 1-6

32. Moses J. The SIRIUS trial [online]. Available from URL: http://46. Sousa E, Abizaid A, Abizaid A, et al. Late (three-year) follow-up from the first-in-www.TCTMD.com [Accessed 2003 Mar 31]

man (FIM) experience after implantation of sirolimus-eluting stents [abstract].33. Sollott SJ, Cheng L, Pauly RR, et al. Taxol inhibits neointimal smooth muscle cell

Circulation 2002; 106 (II): 394accumulation after angioplasty in the rat. J Clin Invest 1995; 95: 1869-76

34. Heldman AW, Cheng L, Jenkins GM, et al. Paclitaxel stent coating inhibitsneointimal hyperplasia at 4 weeks in a porcine model of coronary restenosis. Correspondence and offprints: Dr Andrew J. Carter, Interventional Cardiol-Circulation 2001 May 8; 103: 2289-95

ogy Research, Providence/St Vincent’s Medical Center, 9455 SW Barnes35. Drachman DE, Edelmam ER, Seifert P, et al. Neointimal thickening after stent

Road, Portland, OR 97225, USA.delivery of paclitaxel: change in composition and arrest of growth over 6months. J Am Coll Cardiol 2000; 36: 2325-32 E-mail: [email protected]


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