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The

new england journal

medicine

n engl j med

354;5

www.nejm.org february

2, 2006

483

review article

Drug Therapy

Coronary-Artery Stents

Patrick W. Serruys, M.D., Ph.D., Michael J.B. Kutryk, M.D., Ph.D.,and Andrew T.L. Ong, M.B., B.S.

From the Department of InterventionalCardiology, Thoraxcenter, Erasmus Med-ical Center, Rotterdam, the Netherlands(P.W.S., A.T.L.O.); and the University of Toronto, St. Michael’s Hospital, Toronto(M.J.B.K.). Address reprint requests toDr. Serruys at the Department of Inter-ventional Cardiology, Thoraxcenter, Eras-mus Medical Center, Dr. Molewaterplein40, 3015 GD Rotterdam, the Nether-lands.N Engl J Med 2006;354:483-95.

he use of percutaneously introduced prosthetic devices

maintain the luminal integrity of diseased blood vessels was proposed by Dotter and Judkins in 1964,

well before the introduction of coronary angio-plasty by Grüntzig et al. in 1977.

Palmaz et al. introduced the use of balloon-mounted stents (as used in coronary arteries today) in peripheral arteries in 1985.

Schatz et al. subsequently modified the Palmaz stent, which led to the development of the first commercially successful stent, the Palmaz–Schatz stent.

Puel and Sig- wart were the first to implant a stent in humans in March 1986; they used a self-expanding mesh device. Sigwart and colleagues were also the first to describe theuse of this stent in 1987 for emergency vessel closure during balloon angioplasty,

on the basis of the ability of the device to act as a scaffold to move intimal andmedial flaps away from the lumen and maintain radial support to offset elasticrecoil.

Early observational trials highlighted problems associated with the use of stents, in particular, a high incidence of subacute occlusion, despite aggressiveanticoagulation regimens that prolonged hospital stays and were also associated with bleeding complications that were difficult to control and occasionally led toserious events.

Subsequent reports involving larger numbers of patients confirmedthe utility and efficacy of stenting as a means to avoid emergency bypass surgery.

In 1993, two important randomized clinical trials compared the Palmaz–Schatzstent with balloon angioplasty, establishing the elective placement of coronary stentsas a standard treatment. The 520-patient Belgium Netherlands Stent (BENESTENT)study

and the 410-patient North American Stent Restenosis Study (STRESS)

sepa-rately demonstrated that intracoronary stents significantly reduced the incidenceof angiographic restenosis (defined as more than 50 percent narrowing of a previ-ously stented site, as measured by quantitative coronary angiography) and repeatedangioplasty in patients with discrete, new lesions in large target vessels, leadingto the era of elective stent implantation. By 1999, stenting comprised 84.2 percent of percutaneous coronary interventions.

Although the implantation of an intra-coronary stent prevents the acute recoil and postinjury arterial shrinkage (constric-tive remodeling) associated with balloon angioplasty, it increases the risk of sub-acute thrombosis and, more important, replaces atherosclerotic coronary disease withthe more severe iatrogenic condition of in-stent neointimal hyperplasia — that is, thegrowth of scar tissue inside the stent through the cell-cycle pathway and as a result of the proliferation and migration of vascular smooth-muscle cells (Fig. 1).At the time of the STRESS and BENESTENT trials, despite the use of an inten-sive anticoagulation regimen, subacute occlusion occurred in 3.7 percent of patients,a value higher than that seen with balloon angioplasty alone. The use of high bal-loon pressures to optimize apposition of the stent strut to the vessel wall, together with dual antiplatelet therapy with aspirin and ticlopidine (a thienopyridine) ratherthan anticoagulation resulted in a dramatic reduction in the rates of stent throm-bosis.

Currently, clopidogrel is the more popular thienopyridine, owing to its bet-

The

new england journal

medicine

n engl j med

354;5

www.nejm.org february

2, 2006

484

m T O R A c t i v a t i o n o f v a s c u l a r s m o o t h - m u s c l e c e l l s P r o d u c t i o n o f t u m o r n e c r o s i s f a c t o r , i n t e r l e u k i n s , c h e m o - k i n e s , m a t r i x m e t a l l o p r o t e i n - a s e a n g i o t e n s i n P r o d u c t i o n o f c y t o k i n e s , m i t o g e n s , c h e m o t a c t i c f a c t o r s ( p l a t e l e t - d e r i v e d g r o w t h f a c t o r , t h r o m b i n , g r o w t h f a c t o r

, e p i - d e r m a l g r o w t h f a c t o r ) P r o l i f e r a t i o n a n d m i g r a t i o n o f v a s c u l a r s m o o t h - m u s c l e c e l l s P r o l i f e r a t i o n a n d m i g r a t i o n o f v a s c u l a r s m o o t h - m u s c l e c e l l s A c t i v a t i o n o f p l a t e l e t s E n d o t h e l i a l d e n u d a t i o n M e d i a l d i s s e c t i o n E x p o s u r e o f s u b i n t i m a l c o m p o n e n t s P e n e t r a t i o n o f l i p i d c o r e R e a c t i o n t o s t e n t s t r u t s ( m a c r o p h a g e s , g i a n t c e l l s ) S t e n t i m p l a n t a t i o n T h r o m b o s i s G

S G

M G

C e l l c y c l e

S 6 - r i b o s o m e S i r o l i m u s - a n d t a c r o l i m u s - b i n d i n g p r o t e i n M i t o g e n - a c t i v a t e d p r o t e i n k i n a s e P o l y m e r i z a t i o n o f t u b u l i n A s s e m b l y a n d s t a b i l i z a t i o n o f m i c r o t u b u l e s S i r o l i m u s P a c l i t a x e l P 7 0 S 6 k i n a s e s D o w n - r e g u l a t i o n o f P 2 7 I n h i b i t i o n I n h i b i t i o n I n h i b i t i o n I n h i b i t i o n P r o m o t i o n I n h i b i t i o n P r o m o t i o n

F i g u r e 1 .

M e c h a n i s m s o f R e s t e n o s i s a f t e r S t e n t I m p l a n t a t i o n a n d T a r g e t s o f T h e r a p y w i t h S i r o l i m u s a n d P a c l i t a x e l .

S i r o l i m u s a n a l o g u e s a c t t h r o u g h t h e s a m e p a t h w a y a s s i r o l i m u s . T h e r e s t e n o s i s c a s a d e t h a t i s i n i t i a t e d a f t e r s t e n t i m p l a n t a t i o n i s s h o w n i n r e d . T h e m e c h a n i s m o f a c t i o n o f s i r o l i - m u s ( a n d a n a l o g u e s ) i s s h o w n i n b l u e , w h e r e a s t h e m e c h a n i s m o f a c t i o n o f p a c l i t a x e l i s s h o w n i n y e l l o w . m T O R d e n o t e s m a m m a l i a n t a r g e t o f r a p a m y c i n .

Drug Therapy

n engl j med

354;5

www.nejm.org february

2, 2006

485

ter safety profile, with a lower incidence of rashand neutropenia.

A recent meta-analysis of 29published, randomized studies involving 9918patients and comparing balloon angioplasty with routine coronary stenting with bare stentsconfirmed that stenting reduces restenosis andrepeated intervention, but does not reduce mor-tality or myocardial infarction.

Once a role forelective stent implantation was established, thenext goal was to overcome the complications of subacute stent thrombosis and neointimal hy-perplasia through pharmacologic and physicalmeans.

Barrier and BioactiveStent Coatings

Barrier Stent Coatings

Stent implantation, inherently a thrombogenic pro-cedure, initiates a complex interaction between theblood components and the metal surface of thestent, which includes the deposition of protein;the activation of platelets, the complement system,and coagulation factors; and the eventual propa-gation of thrombi over the surface of the stent

and the establishment of a confluent endothelialmonolayer. Various biologically inert surface coat-ings, such as carbon, platinum, phosphorylcho-line, and gold, have been applied to stainless-steelstents in an attempt to reduce thrombosis and re-stenosis, but the effectiveness of these strategieshas not been proven in clinical trials. Indeed, goldcoatings result in increased rates of restenosis.

Active Stent Coating to Prevent Thrombosis

In contrast to barrier laminates, heparin coatingsprovide a biologically active surface that interacts with circulating blood. The BENESTENT II ran-domized trial demonstrated that heparin-coatedstents resulted in a lower rate of adverse events at one year than did balloon angioplasty (11 percent vs. 21 percent, P = 0.004).

Analysis of data froma large, single-center registry demonstrated that,as compared with bare-metal stents, heparin-coat-ed stents significantly reduced the rate of stent thrombosis.

DRUG-ELUTING STENTS

Considerable efforts have gone into the develop-ment of stents with an active coating to inhibit in-stent restenosis — the drug-eluting stent. Thecomponents of a drug-eluting stent can be dividedinto a platform (the stent), a carrier (usually a poly-mer), and an agent (a drug) to prevent restenosis.Stents are ideal delivery systems because they al-low the local delivery of the active agent to thearea of vascular injury, averting the need to de-liver high doses systemically. The development of a suitable carrier to transport an appropriate agent has been challenging, since it must have mechan-ical resistance to abrasion during implantation, besuitable for sterilization, allow time- and dose-controlled drug release, and not promote throm-bogenesis and inflammation of the vessel walland tissue.

Various coatings have been devel-oped, including phosphorylcholine; biocompat-ible nonerodable, biodegradable, or bioabsorbablepolymers; and ceramic layers.

20-25

Polymers arethe most commonly used carriers. A drug that issuccessfully eluted should inhibit the complexcascade of events that leads to neointimal forma-tion after stent implantation (Fig. 1). The inflam-matory and proliferative mechanisms of the gen-eral tissue-healing response and specific bloodand vessel-wall components of the vascular re-parative processes are potential targets for thera-peutic approaches aimed at reducing neointimalproliferation.The success of eluting devices is highly depen-dent on each component of the complex, as wellas on the interactions among these elements. It istherefore unlikely that drug-eluting stents have aclass effect, since there are myriad possible thera-peutic combinations. Different drug-eluting stents vary in their ability to inhibit neointimal growth.

Finally, because the results of experiments inanimal models cannot be directly translated tohumans, specific clinical trials of safety and ef-ficacy are required for each device.

Successful Drug-Eluting Stents

Sirolimus-Eluting Stents

The first positive clinical data on drug-elutingstents came from trials examining sirolimus-coat-ed stents. Sirolimus, a natural macrocyclic lactone with potent antiproliferative, antiinflammatory,and immunosuppressive effects, acts by inhibitingthe activation of the mammalian target of rapa-mycin (mTOR), ultimately causing arrest of thecell cycle (Fig. 1).

28,29

The Cypher sirolimus-eluting stent (Cordis, Johnson & Johnson) is produced by coating a stain-less-steel stent with a thin layer of a nonerodable