Review Article 195
Drug-eluting stents: A pharmacoclinical perspective
MATHEW K. THOMAS, Y. K. GUPTA
ABSTRACT
In the 26 years since Gruntzig introduced a simple balloon
angioplasty technique, percutaneous coronary intervention
has made extraordinary progress and has now surpassed bypass
surgery in frequency. The area of coronary stenting has
been the focus of intense research. One of the major problems
encountered after stenting is an exaggerated vascular neointimal
proliferation called in-stent stenosis. The evolution of
drug-eluting stents has helped in reducing the incidence
of in-stent stenosis by almost half. A number of pharmacological
agents have been tried in coronary stents with varying
degrees of success; many more are being developed and tested.
Serious doubts have been expressed about the pharma-coeconomics
of drug-eluting stents compared with bare metal stents,
because of the huge disparity in costs. Drug-eluting stents,
which can be grouped under both device and instrument,
have thrown up interesting challenges for clinical trials.
The future could see the development of more compact devices
with the help of diverse fields such as nanotechnology,
microelectronics and advanced materials technology.
Natl Med J India 2006;19:195–9
INTRODUCTION
Coronary artery disease (CAD) accounts for approximately
25% of total deaths in the developed world and 15% in the
developing world.1 In India, the prevalence of CAD is said
to be around 3.9%.2 The multiple approaches to treatment
involve lifestyle changes such as diet, exercise, meditation,
etc., and medications such as antiplatelet and hypolipidaemic
drugs as well as intervention procedures. The major interventional
treatment options for CAD are percutaneous coronary inter-vention
(PCI), which includes mainly percutaneous transluminal
coronary angioplasty (PTCA), and coronary artery bypass
graft (CABG) surgery. In 1964, Dotter and Judkins proposed
the concept of implanting intravascular stents to support
the arterial wall following coronary angioplasty.3 The
first implantation of a stent in a human was performed
in 1986 by Sigwart et al. (Schneider Wallstent).4 The Palmaz–Schatz
stent was approved by the FDA in 1994 after two randomized
control trials (STRESS and BENESTENT) showed better clinical
and angiographic outcomes
with its use.5,6 In the early days, stents were not widely
used because of an unacceptably high incidence
of thrombotic complications. Consequently, drug-eluting
and drug-coated stents were developed. Their introduction
has broadened the spectrum of indications for angioplasty,
with a shift towards PCI from medical and surgical treatments
for patients with CAD. Current data show that more than
90% of PTCA
procedures use stents.7
RESTENOSIS OR IN-STENT STENOSIS
One of the major problems encountered after stenting is
an exaggerated vascular neointimal proliferation—namely
restenosis or, more specifically, in-stent restenosis.
It occurs in 15%–40% of cases,8 and has a high recurrence
rate in those with more severe and associated disease conditions.
The aetio-pathogenesis of restenosis and its severity differs
from primary stenosis (Fig. 1). Whereas stenosis is mostly
an atherosclerotic lesion in the native vessel wall, restenosis
is a reduction in lumen size after PTCA. In-stent stenosis
could be categorized as a special form of restenosis that
occurs exclusively after stent insertion, though both terms
are used interchangeably. Metallic stent struts activate
platelets and macrophages
through cytokines and growth factors as well as by upregulation
of genes and metalloproteinases, leading to in-stent stenois.9 It 
depends
almost entirely on intimal thickening as opposed to constriction
of the vessel from the outside, known as negative remodelling,
which is the main reason for restenosis after PTCA without
stenting. The pathophysiological features of in-stent
stenosis are the targets of therapeutic strategies.10
DRUG-ELUTING STENTS (DES)
Stents have undergone several changes since their introduction
19 years ago, and improvements in design and better adjuvant
medical therapy have made stent placement near mandatory
in a majority of angioplasty procedures. Stents have
evolved through three generations:
First: Uncoated stents or bare stents made of
surgical- grade stainless steel
Second: Coated stents with carbon or gold attached to
the stent surface
Third: Drug-eluting stents (DES) with polymer coatings
that act as drug reservoirs.11
DES are coated stents that release single or multiple
bioactive agents which are deposited in or affect blood
vessels, cells, plaque or the surrounding tissues.
They provide high concentrations of a drug at the
site of
action, thereby decreasing the chances of systemic
toxicity. The first-in-man (FIM, 2001) trial showed
zero restenosis
after sirolimus-eluting stent implantation.12 Paclitaxel-eluting
stents have also been shown to decrease restenosis.
Today, both sirolimus- and paclitaxel-eluting stents
are known
to have similar efficacy in reducing restenosis. In
contrast to the lack of success with systemic drug
therapy in
preventing restenosis, DES have been successful in
suppressing local neointimal proliferation that is
responsible for
angiographic and clinical restenosis.13 In India, both
paclitaxel- and sirolimus-eluting stents are available
since 2002 and are widely used.
A coronary DES essentially has 3 components—stent,
coating and bioactive agent. The main challenge in
designing
a DES is to achieve a compatible relationship among these
3 components.
Coating: The differentiator between bare stents and DES
The coating is essentially a drug carrier vehicle that
permits elution of the drug into the vessel wall at the
required concentrations and kinetic profile with the purpose
of uniform delivery of the drug to the underlying tissue.
The selection of a non-inflammatory, inert coating matrix
has been a major obstacle to the development of DES. Stents
may be either actively or passively coated. The first substance
that was loaded directly onto the bare metal of the stent
was heparin, and is an example of passive coating.14 Paclitaxel,
prostacyclin and tacrolimus can also be directly coated
onto the metal. In active coating, a polymer coating matrix
is present which acts as a reservoir and facilitates prolonged
drug delivery. Sustained release of up to 3 weeks is necessary
to prevent smooth muscle migration and proliferation.
Bioactive agents
The ideal antirestenotic agent for local delivery should
have the following properties:
- Potent antiproliferative effects
- Non-interference with vascular healing
- Wide therapeutic index
Bioactive agents can be classified according to their
properties.
- Immunosuppressive: Sirolimus, everolimus,
mycophenolic acid, tacrolimus
- Antiproliferative: Actinomycin D, paclitaxel,
taxanes
- Anti-inflammatory: Dexamethasone,
prednisolone, tranilast
- Antithrombotic: Glycoprotein IIb/IIIa
antagonists, heparin, iloprost, hirudin
- Extracellular matrix inhibitors:
Batimastat
- Prohealing agents: Oestrogen
-
Others: Statins
Fig 2. Mechanisms of vessel wall injury VEGF vascular
endothelial growth factor MMP matrix metalloproteinase
Some
agents such as sirolimus may affect multiple
targets in the restenotic process.9
STENTS ELUTING IMMUNOSUPPRESSIVE AGENTS
The limited success with ionizing radiation therapy
led to
the use of immunosuppressive agents in stents.
Different classes of immunosuppressive agents
such as xenobiotics
(sirolimus, cyclosporin and its analogues) and
antimetabolites (mycopheno-late mofetil) have
been tried with varying
degrees of success.
Sirolimus-eluting stents
Sirolimus has antifungal, immunosuppressive and
antimitotic properties.15 The
sirolimus–FK binding protein
complex binds to a specific cell cycle regulatory
protein, the mammalian target of enzyme rapamycin
(mTOR), and
inhibits its activation resulting in decreased
growth factor- and cytokine-induced cell division.16 There
are two forms of drug formulations: fast-release
(<15-day
drug release) and slow-release (28-day drug
release). Only slow-release formulations are
commercially available.
Rapamycin analogue-eluting stents
Everolimus is also an inhibitor of mTOR. Although
the immuno-suppressive activity of everolimus
is 2- to
3-fold lower than sirolimus in vitro, animal
studies have shown a potent anti-restenotic effect
when it
is given orally or via a DES.17
Methyl rapamycin is another synthetic analogue
of sirolimus which has shown some potential
in preliminary animal
studies.
Tacrolimus-eluting stents
Tacrolimus is a hydrophobic immunosuppressive
agent that acts by preventing activation of the
T cells.
Initial in vitro and in vivo studies have failed
to demonstrate inhibition of smooth muscle cell
proliferation.
Mycophenolic acid-eluting stents
Mycophenolic acid is the active metabolite of
mycophenolate mofetil, and has both antineoplastic
and immunosuppressive
properties. Preliminary results suggest no beneficial
effects when used in coronary stents, but results
of ongoing studies are awaited.
Paclitaxel-eluting stents
Paclitaxel is a microtubule stabilizing agent
with potent antitumour activity. Many different
platforms
that use polymer coatings or surface modifications
to cause paclitaxel to adhere onto the stents
have been utilized over the past 2 years. Paclitaxel
exerts
its antiproliferative effects at concentrations
much lower than those used for the treatment
of cancer.18
Angiopeptin-eluting stents
Somatostatin, an angiopeptin analogue, has been
shown to reduce tissue response to several growth
factors.
In humans, systemic administration of angiopeptin
has improved the clinical outcome after angioplasty
but
showed no effect in restenosis.19
Tyrosine kinase inhibitor-eluting stents
The results of clinical studies on the use of
these agents are awaited.
Actinomycin D-eluting stents
Actinomycin D is an anticancer drug that selectively
inhibits RNA synthesis. Clinical trials using
this drug were stopped prematurely because its use
led to a high incidence of repeat revascularization.
Stents eluting anti-inflammatory agents
Anti-inflammatory agents were considered an obvious
target to prevent restenosis because of the role
of inflammatory cells in the pathological process.
However, clinical trials failed to demonstrate major
benefits.
Corticosteroid-eluting stents
Multiple trials involving corticosteroid-eluting
stents have assessed the efficacy of steroid-eluting
stents, but none have proved clinically beneficial.
Dexamethasone stents have been approved for clinical
use in Europe.
Tranilast-eluting stents
Tranilast, N-(3, 4-dimethoxycinnamoyl) anthranilic
acid, has been shown to inhibit proliferation and
migration of vascular smooth muscle cells in experimental
models. Systemic use of this agent for prevention
of restenosis has been disappointing.
STENTS ELUTING ANTITHROMBOTIC AGENTS
Though vessel injury with resulting platelet aggregation
and thrombus formation plays a prominent role in
the development of restenosis, antithrombotic pharmacological
approaches have been proven to be ineffective in
preventing restenosis. Nitrous oxide and glycoprotein
IIb/IIIa inhibitors have been used as stent coatings,
but their efficacy is yet to be proved.20
STENTS ELUTING EXTRACELLULAR MATRIX MODULATORS
Matrix metalloproteinases (MMP) have the ability
to digest collagen and facilitate smooth muscle cell
migration. Batimastat, a non-specific MMP inhibitor,
as well as other MMP inhibitors have been shown to
inhibit neointimal hyperplasia in animal models.21 However, in human trials they have not shown significant
benefits.
STENTS ELUTING PROHEALING AGENTS
There are reports suggesting that endothelialization
of stents with a functional endothelium reduces the
restenotic process.22 In a recent study, implantation
of endothelial progenitor cell (EPC) capture stents
showed promising results; there was no increase in
major adverse cardiac and cerebrovascular events
(MACCE).23 Nitric oxide, vascular endothelial growth
factor, and 17-b-oestradiol have all been tested
as prohealing and antirestenotic agents, but the
results are conflicting.
ADVANTAGES OF DES
The main benefit of DES is the prevention of restenosis.
In the case of PTCA, initial restenosis rates were
as high as 30%–40%; they decreased to 20%–25%
with bare stents and are now <10% with DES.24 Stents
are currently used for complicated lesions, and in
high risk patients. In spite of this, complication
rates have decreased significantly (restenosis, mortality,
myocardial infarction and emergency CABG). DES can
be safely and effectively placed in most lesions
without predilatation, reducing the cost and procedural
time. Since the drug and stent are delivered as a
complex, its action begins at the time of vessel
injury, and additional interventions or manipulations
are not needed.
DES AND STENT THROMBOSIS
Even though DES have decreased restenosis rates by
almost one-fourth, restenosis remains high in a subset
of patients who have lesions in difficult anatomical
sites such as vessel bifurcations and side branches
(25% after 6 months).25 Also, late thrombosis (1
year later) occurs after the use paclitaxel- and
sirolimus-eluting stents following discontinuation
of antiplatelet therapy.26 Restenosis rates ranging
from 15% to 30% have been reported in diabetic patients
who have undergone DES placement.27 Histological
analysis of vessels with paclitaxel-coated stents
showed reduced healing of the vessel wall and chronic
low-grade inflammation and intraintimal haemorrhage.28 These
aspects have raised the concern that a delayed
loss of the initial benefit with DES can occur
after
3–4 years in terms of restenosis and major
adverse cardiac events. Though these are isolated
reports in a few patients, they merit attention
since DES have been in use for about 2 years and
there
are no data on the long term restenosis rates.29
SAFETY AND EFFICACY OF DES: THE DEBATE
Since DES is a combination product, it presents the
combined challenges of a drug and a device. The pharmacokinetics
of DES consist of local, regional and systemic effects.
Though the purpose of DES is local delivery, drugs
can reach detectable systemic levels. Studies indicate
that after insertion of a single sirolimus stent,
10% of the level used for immunosuppression is reached.
Animal studies have shown that there is a dose-dependent
cytotoxic effect with DES, which results in impaired
wound healing.28 However, such studies in patients
with CAD are lacking. Patient studies are difficult
in real world situations; therefore, adequate pharmacokinetic
testing data are not available. Another major drawback
is the lack of a reliable animal model as different
models have not provided consistent results in humans.
A consensus group has recommended certain parameters
for in vivo estimation of the pharmacokinetics of
DES. These include (i) full temporal characterization
of drug release and better definition of the therapeutic
window, (ii) levels of drug in arterial and myocardial
tissue proximal and distal to the stent, (iii) justification
of proposed clinical drug dose and release characteristics
by preclinical data, and (iv) use of a minimum of
5 time points examining release from 3 separate stents
to determine the t1/2.30
There is skepticism about the universal benefits
of the use of stents. Recent reviews indicate that
there is no evidence of a difference in mortality
between patients receiving DES and those treated
with bare metal stents at 1 year; however, there
was a reduction in event rates with DES. Though
CABG is more expensive than bare metal stenting in multivessel
disease and may have higher immediate risks, over
time the cost differential gets reduced and long
term outcomes favour CABG over stenting.31
DES: PRESENT REGULATORY STATUS IN INDIA
Issues regarding the safety, efficacy, quality and
cost aspects of coronary stents have been discussed
widely among the medical fraternity and were raised
in the Indian Parliament. The Ministry of Health
and Family Welfare, Government of India, notified
the guidelines for import and manufacture of medical
devices including stents (S.O. 1468 (E) dated 6/10/2005).
Control over manufacture of these devices would be
exercised by the Drug Controller General of India
under the said Rules. According to the notification,
if a device incorporates a medicinal product which
is intended to act upon the body along with the device,
data on the safety, quality and usefulness of the
medicinal substance used should be furnished. Additional
data on compatibility of the device with medicinal
products are required if the device is intended to
deliver medicinal products. Further, if the device
is to be manufactured in India, the manufacturers
have to adhere to strict norms which are more or
less similar to the manufacture of pharmaceutical
products.32
THE PHARMACOECONOMIC ASPECTS OF DES
Another factor that needs to be considered is the
pharmaco-economics of DES. The list price of the
sirolimus-eluting stent in Europe is € 2300
(US$ 2500). In India, a DES costs nearly Rs 130 000
(US$ 5000) whereas a bare stent costs only one-fourth
of this. This high price relative
to bare stents, as well as the absence of incremental
reimbursement in most countries, has been an obstacle
to more widespread utilization of DES. However, it
is estimated that the treatment of restenosis costs
US$ 8000–28 000 per episode, and it could be
economically viable to use DES for patients who need
stenting, especially if only one stent is used and
the patients’ risk of restenosis is high.33
CHALLENGES IN CLINICAL TRIALS
The rapid evolution of stent design, deployment approaches
and adjunctive therapy have led to challenges in
clinical practice patterns and data interpretation,
necessitating consideration of major issues while
comparing data from different clinical trials. While
trials on sirolimus-eluting stents cover an identical
group utilizing one single device (CypherTM,
Cordis J&J, NJ), those on paclitaxel-eluting
stents represent a non-homogeneous group that includes
both
non-polymer based and polymer-based devices. This
makes the results of the second group of studies
more difficult to interpret and analyse. Also,
care is needed while extrapolating the data from
these
studies to a large and diverse population base
from a low risk population. It is not ethically
permissible
to conduct studies of a new device on a high risk
population, thereby limiting the assessment of
a new device on more extreme parameters such as
death
or myocardial infarction.34
Another difficulty is defining the most appropriate
end-point and the duration of the study. In various
clinical trials, angiographic and clinical data
have been compiled at different time points (4, 6, 8,
9, or 12 months). The most commonly used end-point
is the restenosis rate, but this gives limited
information on whether the effect of a device on neointimal proliferation
is essentially restraining or inhibitory. The use
of stents for a wide variety of clinical indications,
many of which have not been evaluated in randomized
studies, is another problem.35 Absolute restenosis
rates with DES have been higher in those with diabetes
and when used in small vessels, in-stent restenosis
lesions and bifurcation lesions.36
It is therefore not clear how the available clinical
trials reflect the real life situation when the
stents are used in patients with a wide variety and severity
of disease. Until now no trial has been adequately
powered to evaluate the benefits within subgroups
with different risk factors.37 Therefore, there is
an urgent and clear need for randomized clinical
trials with simple end-points that truly reflect
the real clinical situation. This could help in achieving
more uniformity of trials and better analysis of
benefits with various models of stents.
FUTURE TRENDS
Several critical breakthrough technologies account
for the remarkable progress in the field of interventional
cardiology in the past 3 decades: intracoronary stents
have increased success rates and reduced restenosis,
adjunctive antiplatelet therapy has reduced periprocedural
complications, and restenosis after stent placement
has been effectively treated with local radiation.6 The role of other agents with potential benefits
(e.g. statins, adenovirus-mediated arterial gene
transfer, tyrosine kinase inhibitors, L-arginine,
abciximab, angiopeptin, r-PEG-hirudin and iloprost)
as well as biodegradable stents may be tested in
the future. The rapidly developing fields of nanotechnology,
microelectronics, and advanced materials technology
will enable the surface engineer to design molecular-specific
surfaces for a new generation of vascular devices.37
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