With more than 1 million percutaneous interventions performed each year in the United States alone, the scope of the vexing problem of restenosis is staggering. To date, the development and clinical application of intracoronary stents has had the single greatest impact on the prevention of restenosis. Bare metal stents effectively prevent remodeling but are unable to counteract neointimal proliferation. Elucidation of downstream molecular events responsible for restenosis has made it easier to rationally select from potential therapeutic options. Recent attention has turned toward the development of novel systems for local drug delivery; drug-coated stents represent the foremost innovation in this area. The marriage of stenting and antiproliferative agents has the potential to eradicate restenosis. Although it does not seem that drug-eluting stents are the cure for restenosis, they do represent the next major advancement.
Sanjeev Ravipudi, MD
is currently an associate of Missouri Cardiovascular Specialists as
a staff Interventional Cardiologist at Boone Hospital Center in
Columbia, MO. After receiving his MD in 1995 at the University of
Missouri in Kansas City, he completed his Internal Medicine
Residency at Baylor University Medical Center in Dallas, TX, and
his General and Interventional Cardiovascular Fellowship at the
University of Southern California in Los Angeles, CA.
With more than 1 million percutaneous interventions
performed each year in the United States alone, the scope of the
vexing problem of restenosis is staggering. To date, the
development and clinical application of intracoronary stents has
had the single greatest impact on the prevention of restenosis.
Bare metal stents effectively prevent remodeling but are unable
to counteract neointimal proliferation. Elucidation of downstream
molecular events responsible for restenosis has made it easier to
rationally select from potential therapeutic options. Recent
attention has turned toward the development of novel systems for
local drug delivery; drug-coated stents represent the foremost
innovation in this area. The marriage of stenting and
antiproliferative agents has the potential to eradicate
restenosis. Although it does not seem that drug-eluting stents
are the cure for restenosis, they do represent the next major
Restenosis has long been recognized as the "Achilles heel" of
It is a limiting factor that occurs in 12% to 48% of patients who
undergo successful percutaneous coronary interventions.
Development of restenosis subjects patients to additional risks
as well as the complications associated with repeat interventions
or bypass surgery. Retrospective analysis of Emory University data
showed that restenotic patients, when compared with patients
without restenosis, had a higher incidence of angina (71% versus
39%) and target vessel reintervention (56% versus 4% at 6 months).
Patients with restenosis were also found to have a lower freedom
from myocardial infarction (88% versus 97% at 6 months, and 85%
versus 93% at 6 years) and coronary artery bypass surgery (94%
versus 99% at 6 months, and 78% versus 91% at 6 years), as well as
a poorer survival rate (93% versus 95% at 6 years).
With over 1 million percutaneous interventions performed each year
in the United States alone, the scope of this vexing problem is
staggering. Increased awareness of unfavorable outcomes associated
with restenosis has led to improvements in disease recognition and
Numerous definitions of restenosis have been reported. Gruntzig
originally proposed the most commonly accepted definition of
angiographic restenosis, a >50% luminal diameter stenosis at
Additional classification of in-stent restenosis into focal and
diffuse is based on angiographic appearance. Focal restenosis is
considered <10 mm in length and can occur at the articulation,
margin, in the body, or be multifocal. Diffuse restenosis is
considered >10 mm in length and can be intrastent,
intrasegment/proliferative, or totally occlusive. Diffuse
restenosis has been associated with a greater incidence of target
vessel revascularization following repeat intervention.
Indices have been developed to measure and describe the
mechanics of angiographic restenosis. Acute gain is the change in
minimal luminal diameter (MLD) from baseline to immediately after
percutaneous coronary angioplasty (PTCA). Late loss is the
difference between the immediate postprocedure MLD and that
measured at follow-up angiography. Net gain is the difference
between follow-up MLD and baseline (acute gain late loss). Late
loss index refers to the percentage of early gain that is
ultimately lost to restenosis (late loss/acute gain).
These indices vary depending on which devices are used for
intervention. The acute gain and the net gain are greatest with
stenting. In aggressive directional atherectomy, the net gain may
approach that of stenting. Balloon angioplasty, laser atherectomy,
and rotational atherectomy usually have only moderate net gain. The
major angiographic predictors of restenosis are long lesions,
multivessel lesions, chronic total occlusions, ostial lesions,
angulated lesions (>45š), saphenous vein graft proximal and body
lesions, and residual stenosis >30%.
Angiographic predictors of in-stent restenosis are prior stenosis,
long lesions, multiple stents, small vessels, and high-pressure
Clinical restenosis refers to the incidence of clinical events
that ultimately lead to repeat revascularization of the index
lesion. In general, patients who develop typical symptom recurrence
gradually 1 to 6 months after angioplasty are more likely to have
restenosis of the index lesion. These patients warrant further
studies to define the presence of significant restenosis.
Development of anginal symptoms within 1 month is more commonly
associated with incomplete revascularization or abrupt vessel
closure. Symptom occurrence beyond 6 months is likely a result of
disease progression involving a different stenosis.
Although patients who present with symptoms atypical of those prior
to angioplasty infrequently have restenosis,
the presence of angiographic restenosis is commonly associated with
a return of preangioplasty symptoms. Approximately 2% to 50% of
these patients remain asymptomatic.
The long-term significance of silent restenosis is yet to be
determined. However, data suggest that the clinical outcome of
these patients is favorable.
The major clinical risk factors associated with an increased
incidence of restenosis are diabetes and unstable angina.
The restenotic process has been described as a "healing"
response to vascular injury with lesion development occurring
gradually over a period of weeks to months (Figure 1).
Elastic recoil, the difference in vessel cross-sectional area
during and shortly after balloon inflation, occurs within minutes
to hours of an intervention.
Approximately 15% of successful PTCA cases develop a >0.5 mm
luminal loss at 24 hours due to recoil and thrombus,
with one-half of these progressing to significant restenosis.
The vast majority of restenosis cases occur between 1 and 3
months due to neointimal hyperplasia and unfavorable remodeling
(Figure 2). Occurrence of clinical or angiographic restenosis after
6 months is rare.
Intracoronary stenting effectively limits elastic recoil and
unfavorable remodeling. When compared with balloon angioplasty,
stenting reduces the incidence of restenosis.
However, added stent-induced mechanical arterial injury along with
a foreign-body response further promotes an acute and chronic
inflammatory process within the vessel wall.
Subsequent elaboration of cytokines and growth factors (ie,
platelet derived growth factor [PDGF], endothelial cell growth
factor, transforming growth factor-beta [TGF-ß], and fibroblast
growth factor [FGF]) induce multiple signaling pathways. This, in
turn, activates vascular smooth muscle cell (VSMC) migration and
proliferation and excess deposition of extracellular matrix
proteins and fibrosis.
In the context of restenosis, these factors induce an excessive
neointimal fibroproliferative response composed mostly of smooth
muscle cells (Figure 3). Progressing over a period of weeks to
months, the fibromuscular overgrowth histologically comprises the
majority of the restenotic lesion.
In-stent restenosis is primarily due to neointimal hyperplasia.
The process of thrombus generation begins immediately at the
site of vessel injury and persists for up to 4 weeks following
intracoronary stent placement.
Subsequent platelet activation and aggregation lead to the release
of potent vasoactive agents and mitogens including PDGF, thrombin,
and thromboxane A2 (TXA2). In addition to promoting intimal
hyperplasia by propagating the secretion of PDGF and FGF, thrombin
also induces VSMC migration and production of VSMC growth factors,
such as serotonin.
Thus, it is suggested that platelet activation and aggregation as a
result of balloon or stent injury is one of the earliest causative
events in restenosis.
As a result, considerable effort has been directed toward the
study of antithrombotic agents in the prevention of restenosis.
Hirudin, an anti-thrombin factor, inhibits the mitogenic effect of
thrombin and its synergistic interaction with serotonin.
Along with low molecular weight heparins and glycoprotein IIb/IIIa
inhibitors, hirudin theoretically offers a viable avenue for
therapeutic intervention. However, clinical studies utilizing these
agents have thus far failed to show a definite reduction in
After balloon or stent injury, acute and chronic inflammatory
cells participate in the ensuing process of arterial repair.
Neutrophils infiltrate the vessel wall within 24 hours, followed by
monocyte adhesion and infiltration.
Observations have shown that the extent of acute inflammatory cell
infiltration depends on the arterial substrate and the degree of
vascular injury. For example, presence of a lipid core and
deep-vessel wall injury is associated with greater inflammatory
It is surmised that inflammatory cells play an integral role in the
exaggerated healing response seen in restenosis.
Chronic inflammatory cells also contribute to the process with
the release of cytokines (ie, interleukin-1 [IL-1] and tumor
necrosis factor [TNF]) that stimulate VSMC migration and
Additional observations of in-stent restenosis have shown
lymphocyte, histiocyte, and giant cell infiltrate gathered around
stent struts, which also further the activation of VSMC growth. The
presence of these cells exhibits the importance of the body's
immune response to the foreign stent struts in promoting
Systemic anti-inflammatory and immunosuppressive therapy, in
theory, appear promising for treating restenosis. Small trials
utilizing nonsteroidal anti-inflammatory drugs and tranilast have
reported positive results
; however, no trial has proven any definitive benefit. Currently,
exciting possibilities for preventing restenosis involve the use of
anti-inflammatory agents with local drug delivery systems.
Vascular smooth muscle cell proliferation
Vascular smooth muscle cell growth is a key component of the
pathophysiology of restenosis. Mechanical injury of the vascular
wall induces migration of VSMCs from the media to the intima.
After migration, they proliferate and synthesize an extracellular
matrix, the major component of the restenotic lesion. Vascular
smooth muscle cells also release growth factors (ie, PDGF and FGF)
and chemotactic agents that potentiate the proliferative process.
As a major participant in the development of restenosis, the VSMC
is a prime target in the treatment of restenosis. Brachytherapy and
drug-eluting stents are successful examples of antiproliferative
therapies that target the VSMC.
Growth factors and cytokines
Vascular injury incites the release of mitogenic and chemotactic
signals. These signals are mediated by growth factors and cytokines
(ie, IL-1, tumor necrosis factor alpha [TNF-*], and interferon
alpha [INF-*]) that modulate VSMC response.
Signaling in response to these factors (Figure 4) is mediated
through their specific cell-surface receptor and transduced by
intracellular signaling pathways such as molecular target of
rapamycin (sirolimus) (mTOR).
A key regulatory kinase, mTOR is part of a signal transduction
pathway in smooth muscle cells and lymphocytes. This enzyme is
necessary for growth-factor and cytokine-signaling responses that
initiate cell proliferation, which is essential in the development
of neointimal hyperplasia. Inhibition of mTOR causes disruption of
the cell cycle at the GAP 1-synthesis phase (Figure 5) via p27,
promoting a cytostatic state. The protein p27 is an endogenous
inhibitor of cyclinE/cdk2, which controls cell cycle progression to
S phase. Additionally, mTOR inhibits protein synthesis and cell
Many intracellular signaling pathways have been elucidated and
are targets of various treatment strategies. Rapamycin is produced
and was found originally on Easter Island (Rapa Nui).
When bound to FKBP
, it inhibits the activity of mTOR. Sirolimus also produces
antimigratory and anti-inflammatory effects (Figure 6).
Paclitaxel is extracted from the bark of the Pacific yew. It
binds to microtubules and inhibits their depolymerization
(molecular disassembly) into tubulin. Thus, paclitaxel blocks a
cell's ability to break down the mitotic spindle during mitosis
(cell division). With the spindle still in place, the cell cannot
divide into daughter cells (Figure 7).
Coupled with the coated-stent drug-delivery system, these
therapeutic agents have generated tremendous enthusiasm for the
prevention of restenosis. Elucidation of downstream molecular
events responsible for growth-factor or cytokine-mediated smooth
muscle cell proliferation has made it easier to rationally select
potential therapeutic options for the treatment of restenosis. The
first generation of antiproliferative stents will likely be
followed by further generations of coated stents with improved
delivery systems, tailored dosing, and utilization of multiple
agents providing a more effective blockade of the final common
pathway that leads to neointimal proliferation.
Extracellular matrix and integrins
In addition to exaggerated VSMC proliferation, major components
of a restenotic lesion also include excess deposition of
extracellular matrix (ECM) proteins and fibrosis. Initially it was
thought that the main function of the ECM was to provide a
stabilizing structural lattice for the vascular wall. However,
accumulating evidence indicates that matrix proteins also
contribute to various biochemical and mechanical stimuli.
Many extracellular components transmit their signals through
specialized cell surface receptors known as integrins, and support
a variety of cellular functions, such as migration and
proliferation in response to mitogens. Other matrix components and
growth factors have been found to work in concert with the ECM to
regulate VSMC activity responsible for vascular development and
Matrix metalloproteinases (MMPs) are a group of proteins essential
for ECM dissolution. This family of enzymes has been implicated in
VSMC and leukocyte migration during the restenotic process.
Thus, the ECM represents another possible target for therapeutic
Primary prevention of restenosis
Bare metal stenting
To date, the development and clinical application of
intracoronary stents has had the single greatest impact on
interventional cardiology. In comparison with balloon angioplasty,
stenting maximizes acute gain allowing for larger MLD and
subsequently improving procedural success rates. Despite suffering
a greater late loss, stenting has maintained its superiority over
balloon angioplasty with reduced incidence of restenosis and target
vessel revascularization (TVR) in most lesion subtypes
* In cases of acute myocardial infarction, data currently
available supports stenting.
* In the setting of chronic total occlusion, trials demonstrate
superior angiographic and clinical outcomes in patients randomized
to stenting after successful recanalization.
* It is known that diabetic patients suffer higher rates of
restenosis when compared with nondiabetic patients. Observational
data suggest that stenting in diabetics is associated with lower
restenosis rates when compared with angioplasty alone
; however, no randomized study to date has formally evaluated its
* One subset that has failed to show benefit with stenting has
been saphenous vein grafts.
Overall, based on the results of major clinical trials comparing
angioplasty with stenting in native coronary vessels
(Table 1), a strategy of stenting to prevent restenosis, reduce
overall costs, and improve procedural success is considered
appropriate in many patients. Coronary stenting is currently
performed in 80% to 90% of patients undergoing percutaneous
coronary intervention (PCI).
Used in other clinical situations to successfully stunt excess
growth, vascular brachytherapy, the intraluminal delivery of
radiation following angioplasty, was viewed as a viable solution to
inhibit restenosis. The principal of radiation biology for
prevention of restenosis is to induce apoptosis (programmed cell
death), especially in those cells undergoing mitosis after vascular
injury (Figure 8). This is accomplished by direct ionization or
indirect interaction with other molecules to produce free radicals,
which will subsequently damage critical targets (ie, DNA). The
overall effect of radiation therapy is strongly dependent on the
cumulative dose, dose rate, and cell cycle.
The main platforms developed for delivery of intravascular
ionizing radiation use catheter-based systems with line-source
wires, radioactive beads, gas/liquid-filled balloons, or stents
that utilize beta or gamma ray emitters. Gamma rays are photons
originating from the center of the nucleus; they differ from
X-rays, which originate from the orbital outside of the nucleus.
Gamma rays offer deep penetration but require excess shielding and
prolonged dwell times when compared with beta emitters. Iridium-192
(192Ir) is currently the only gamma ray isotope in use.
Beta rays are high-energy electrons emitted by nuclei and contain
too many or too few neutrons. These negatively charged particles
have a wide variety of energies and a diverse range of half-lives.
Beta emitters are associated with high gradients to the near wall,
as they rapidly lose their energy to surrounding tissue. This
quality limits the depth that brachytherapy can be delivered
Early trials evaluating safety, efficacy, and dosing of
brachytherapy delivered after angioplasty or stenting in de novo
coronary lesions showed promising results.
The landmark SCRIPPS trial of 55 patients demonstrated an
improvement in target vessel revascularization at 6 months with 45%
TVR in the placebo group versus 12% TVR in the group treated by
catheter-based gamma radiation.
The difference between the two groups persisted at follow-up even
years after treatment.
The beta energy restenosis trial (BERT) was a feasibility study of
23 patients that evaluated catheter-based beta radiation delivered
after conventional PTCA. At 6-month follow-up, the rate of
restenosis for the entire cohort was 17%.
BETA-CATH, in contrast to the smaller preliminary trials, was a
large prospective, randomized, blinded, placebo-controlled study
that tested brachytherapy in de novo lesions after PTCA alone or
with combined stent placement.
In spite of a 38% reduction in in-lesion restenosis, there was no
significant reduction in target vessel failure. This was explained
by an increase in in-segment (injury and radiation segment + 5 mm
at each end) stenosis and edge stenosis. Additionally, there was a
higher rate of late thrombosis, especially in the stent plus
Similar disappointing findings were seen with radioactive
stents. At dosing levels that inhibited in-stent restenosis, a 36%
to 44% rate of edge stenosis was observed. This unique angiographic
pattern is known as the "candy wrapper" effect.
These observations identified two major problems associated with
the use of this technology for primary prevention of restenosis:
late thrombosis and edge stenosis. Late thrombosis is due to a
delay in healing associated with radiation and is avoided easily
with extended antiplatelet therapy following intervention.
The main explanation for the incidence of edge effect is a
combination of low/dropped-off dose delivery at the edges of the
radiation source and an injury created by the device for
intervention that is not covered by the radiation source (a
Before brachytherapy can be considered for general use after de
novo PCI, further evaluation is necessary to address the identified
problems. Alternatively, brachytherapy has demonstrated definitive
advantages in the treatment of in-stent restenosis and is
FDA-approved (beta and gamma) for secondary prevention.
Bare metal stents effectively prevent remodeling but are unable
to counteract neoinimal proliferation. The marriage of stenting and
antiproliferative agents has the potential to eradicate restenosis.
Several systemic approaches have been tested, but promising
experimental results have not translated into clinical
effectiveness. A proposed explanation for the repeated failure of
clinical drug studies has been the inability of agents given
systemically to reach sufficient levels in the injured arteries to
effectively inhibit restenosis. Local drug administration would
allow active drug delivery to the site of injury at the time of
injury and the ability to achieve higher tissue concentrations of
the drug. Recent attention has turned toward the development of
novel systems for local drug delivery; drug-coated stents represent
the foremost innovation. Current ubiquitous use of bare metal
stents along with permanent scaffolding properties make bare metal
stents an attractive reservoir for medication delivery.
In the development of drug-eluting stents (DES), a number of
issues had to be addressed
* Stents cover <10% of the target coronary segment and only a
limited amount of drug can be loaded onto the stent (varies with
* The delivery system has to be tissue compatible.
* Coatings and antiproliferative agents should not induce
inflammation or other detrimental responses.
* Stent expansion and sterilization should not affect coating or
* Types of coating or drug binding should not interfere with
pharmacokinetics or biological activities of the compound. The
release of the drug must be predictable and controllable in terms
of length of time and concentration.
* The coating/drug should not affect the mechanical properties
of the stent.
Polymers are long-chain molecules consisting of small repeating
units. Their ability to attach medications to metallic surfaces and
facilitate prolonged drug delivery make polymers an appealing
material to serve as coating matrices. Other coating considerations
include naturally occurring substances, such as phosphorylcholine
(PC), fibrin, cellulose, or albumin.
In addition to resolving all of the preceding issues, optimal
drug selection from a long list of potential agents has to be
determined (Table 2). A major requirement of the selected drug
would include the ability to inhibit key components involved in the
restenosis process. As yet, trials employing stents coated with
actinomycin-D, batimastat, heparin,
low-molecular-weight heparins, and dexamethasone have not shown a
favorable influence on neointimal proliferation. To date, stents
with or without polymer coatings utilizing antiproliferative
medications (anti-neoplastic or immunosuppressive) have
demonstrated the greatest success.
Sirolimus blended with a mixture of nonerodable polymers has
been mounted on the BX Velocity stent (Cypher, Cordis, Johnson
& Johnson; Warren, NJ). Early studies using these coated stents
in animal models exhibited a significant reduction in neointimal
Sousa et al,
in Brazil, then implanted two different formulations of
sirolimus-coated stents (slow and fast release) in 30 patients with
angina pectoris. On follow-up of 4 months, 8 months, and 1 year, no
restenosis or adverse outcomes were observed.
This led to the RAVEL trial, which prospectively compared the BX
Velocity bare metal stent (Cordis) with the BX Velocity
sirolimus-coated stent (Cypher, Cordis) for treatment of de novo
coronary lesions among 230 patients in a randomized, double-blinded
manner (Table 3).
Even though treatment was limited to favorable lesion subtypes, the
restenosis rate of zero and the event-free survival of 97% are
To date, the sirolimus group remains patent and no long-term
adverse events have occurred.
Advancing to the next step, SIRIUS is a multicenter,
prospective, randomized, double-blinded trial that has enrolled
1101 patients in the United States with focal de novo coronary
artery lesions. Patients were randomized to receive either a bare
metal stent or a sirolimus-coated stent. Preliminary results of 400
patients were recently presented in Paris at Euro PCR.
Results are still impressive; in-stent restenosis was 2% versus 31%
in the control group with no significant differences in other major
adverse events. Slightly dulling the brilliance of a significant
reduction in in-stent restenosis, investigators reported an
observed increase in in-segment restenosis of 9% versus 32%.
Thoughts accounting for this finding included possible geographic
miss, inadequate stent coverage, and possible need for higher
medication delivery at the edges. Again, this is preliminary data
and no definite conclusions can be made from these early
observations. As anticipated, the restenosis rates are not zero,
but remain extremely low and represent a hopeful advance in the
treatment of restenosis. Also important to note is the lack of
thrombosis, aneurysms, or late malaposition, which are some of the
possible delayed complications.
TAXUS is a family of trials on paclitaxel polymeric-coated NIR
Conformer and Express stents (both stents from Boston Scientific;
Natick, MA). TAXUS I randomized 61 patients to a NIR Conformer
slow-release drug-coated or non-drug-coated stent. Zero percent
restenosis rates were observed in this early safety study.
TAXUS II evaluated efficacy and enrolled 532 patients to receive
paclitaxel-coated NIR Conformer stents with slow- and
Preliminary 30-day observational data shows 0% restenosis in both
groups. The rate of target lesion revascularization (TLR) was 0.4%
and 0% in the slow- and moderate-release groups, respectively, and
was due to subacute thrombosis in both cases. Results should be
available later this year.
TAXUS III is a feasibility trial that enrolled 30 patients with
in-stent restenosis, a less favorable treatment group. Patients
were treated with paclitaxel-coated slow-release NIR Conformer
stents. Cumulative 10-month major adverse cardiac event (MACE)
rates for 28 of the 30 TAXUS III patients included 6 TLRs, 1
coronary artery bypass graft, 1 periprocedural non-Q-wave MI, 0
stent thromboses, and 0 deaths. Two of the TLRs targeted restenosis
in gaps between two stented segments, while two others were
performed to improve stent apposition to the artery wall. A fifth
TLR was warranted after a bare stent adjacent to two
paclitaxel-eluting stents became occluded, while the sixth TLR was
TAXUS IV and V are pivotal United States studies that are currently
underway. They will be enrolling 1600 patients with de novo or
in-stent restenosis lesions, respectively. Patients with de novo
lesions will be randomized to moderate-release paclitaxel-coated or
non-coated Express stents. Patients with in-stent restenosis will
be randomized to PCI with a moderate-release paclitaxel-coated
Express stent or brachytherapy.
Enrollment is complete and results will be anticipated eagerly.
Cook has combined its paclitaxel coating with their Supra G and
V-Flex plus stents (Cook Inc.; Bloomington, IN) in the ASPECT
trials. ASPECT randomized 177 patients in Asia to high-dose,
low-dose, and no paclitaxel coating. Restenosis rates were 4%, 12%,
and 27%, respectively.
ELUTES assessed the safety and efficacy of four doses of paclitaxel
in 192 patients. The rate of restenosis for the bare stent group
was 34%, 33% for the coated stents with the lowest dose, then 26%,
23%, and 14% for respective ascending doses.
Many other stents, drug coatings, and indications are being
tested actively. The DELIVER trial is investigating the ACHIEVE
drug-coating (Cook Inc.) on a multilink stent platform (Guidant
Corp.; Indianapolis, IN).
Numerous potential future indications are also being evaluated,
including use in patients with diabetes, saphenous vein grafts,
chronic total occlusions, left main artery disease,
complex/bifurcation lesions, multivessel disease, in-stent
restenosis, small vessel disease, and peripheral arterial
Although it does not seem that drug- eluting stents are the cure
for restenosis, they do represent the next major advancement.
Future advancements in understanding restenosis, drug delivery
systems, and drug therapies, including combination therapy, will
likely further the success of the technology. At present, the next
major hurdles are the repercussions following widespread use and
the possible complications that may be revealed on long-term
Secondary prevention of restenosis
Repeat intervention for the treatment of in-stent restenosis
with or without rotational atherectomy and cutting balloon is
effective in acutely restoring luminal patency and dimensions.
However, high rates of recurrent restenosis continue to plague
standard treatment options.
At present, brachytherapy is the only treatment available
demonstrating significant reduction in recurrent in-stent
restenosis rates. Multiple trials have supported the use of gamma
radiation. Key trials, including SCRIPPS,
all showed definitive evidence that adjunctive brachytherapy after
PCI for in-stent restenosis significantly reduces recurrent
stenosis and recurrent revascularization rates.
Similar support exists for beta radiation. BETA WRIST
demonstrated a reduction in restenosis rates that approached that
The current debate regarding brachytherapy involves the choice
between gamma and beta radiation. Gamma radiation has been
demonstrated conclusively to be effective in the treatment of
in-stent restenosis. Its drawbacks remain those associated with
increased radiation exposure, the need for special shielding, and
slightly longer dwell times. Beta radiation is unquestionably
easier to use, which is its greatest advantage. Currently both are
FDA approved for use in in-stent restenosis.
Future trial results of drug-eluting stents for the treatment of
in-stent restenosis are greatly anticipated. It is possible that
favorable results for drug-eluting stents will greatly limit the
need for brachytherapy. However, as we have seen in early trial
results, the restenosis rate associated with drug-eluting stents is
not yet zero. Until that occurs, brachytherapy will continue to
have this niche role.
At the start of the millennium, the problem of restenosis
As we gain a better understanding of the complex process involved,
more effective targeted therapies can be developed. Although it
appears that the current generation of drug-eluting stents have not
eliminated the problem, there is little doubt that future
generations have the potential to do so. Advancements in delivery
platforms and drug therapies will help refine this technology.
Future directions, generating just as much excitement, include
genetic therapy. Although we have not yet discovered a panacea, we
have never been so close.