Nearly 30 years have passed since the concept of vascular stenting originated, yet it was only recently that we started to understand those factors governing stent-related patency and restenosis. This review summarizes what we know about vascular stents, as well as some of the new approaches that may improve the patency of future devices.
The concept of vascular stenting originated with Charles Dotter
in 1969 but didn't become a clinical reality until the late 1980s.
Nearly 30 years have passed since the Dotter concept, yet it has
only been during the past decade that we have started to understand
those factors governing stent-related patency and restenosis. The
following review summarizes what we know about vascular stents, as
well as some of the new approaches that may improve the patency of
What stents do and don't do
Stents are really just braces that prevent elastic recoil of
tissue after angioplasty. Stents hold an angioplasty site open,
tack back a dissection flap, and counteract the compressive effects
of extrinsic masses and fibrosis. This is illustrated in figure 1,
showing poor results following iliac angioplasty that have been
improved by placement of a Palmaz stent. Beyond iliac artery
intervention, stents have been used in a number of other vascular
situations to increase procedural success. For instance, the
technical success of ostial renal vein angioplasty is quite
variable, but most interventional radiologists would agree that it
ranges from 30 to 70%. This can be increased to greater than 95%
with the addition of a Palmaz stent.1 On the venous side,
subclavian vein angioplasty is approximately 75% successful in
achieving a less than 50% rate of residual stenosis.2 The
procedural success is increased to greater than 95% with the
addition of a stent.3-5
While stents may dramatically improve the immediate
post-angioplasty appearance in a number of locations, they are not
able to prevent restenosis. A stent is no more than mesh
scaffolding through which tissue may propagate. The process of
restenosis, in fact, starts when a stent is placed, due to vascular
"injury" that is induced by PTA and/or stent placement followed by
deposition of fibrin, platelets, and leukocytes on the metallic
stent struts.6-8 The processes which contribute to restenosis are
complex and beyond the scope of this review. Nevertheless, it is
fair to state that if vessel wall trauma does not incite an overly
exuberant neointimal response, and if the buildup of fibrin and
thrombus is not excessive, most stents will be incorporated with a
thin, non-stenotic neointimal layer. In humans, this neointimal
tissue consists of a collagen matrix, smooth muscle-like cells, and
a luminal layer of endothelial cells.6,7 On the other hand,
exuberant neointimal tissue formation may lead to stenosis.
Factors that lead to neointimal stenosis
When the neointimal response is exuberant, stenosis may occur
within a stent. This is called stent-related restenosis or in-stent
restenosis (figure 2). There are a number of factors that portend
to stent-related restenosis. "Excessive" trauma at the time of
angioplasty and/or stent placement is a proven method for inducing
neointimal stenosis in a number of animal models, including the rat
carotid artery and the pig coronary and iliac circulation. Care
should be taken not to overdilate the initial stenotic lesion or
the adjacent "normal" segments of vessel. Additionally, stents
should be placed with minimal trauma to the angioplasty site, and
overexpansion of the stent should be avoided. In our lab, the
characteristic finding following stent placement in the canine
iliac artery has been disruption of the internal elastic lamina at
the ends of stented segment-not at the middle of the stent. We
believe that this represents trauma induced by balloon dilation of
the stent at the time of deployment (for balloon expandable stents)
or after deployment of self-expanding stents when the stent is
apposed to the vessel wall. We also have noted thicker neointima at
the ends of these stents compared to the middle of the stents. We
believe this is, in part, due to vessel wall trauma at the time of
Another factor related to in-stent stenosis is adherence of
fibrin and thrombus to the stent struts. Excessive thrombus can
serve as the substrate for exuberant neointima. Smooth muscle cells
may migrate into maturing thrombus, ultimately leading to an area
of neointimal stenosis. Unfortunately, angiography is an
insensitive way to look at deposition of thrombus and cells on a
stent at the time of placement, and there is no way to assess
thrombus deposition after the procedure has been completed.
Intravascular ultrasound is far more sensitive for angiographically
occult thrombus but is rarely used in a systematic manner for this
Some patients may be more susceptible to accelerated
atherosclerosis and/or neointimal hyperplasia at the stented site.
Factors that cause any given patient to be at risk remain to be
defined, but it has often been observed that patients who continue
to smoke and/or have diffusely small arteries seem to have an
increased risk of restenosis involving stented peripheral arteries.
Some patients with in-stent restenosis will ultimately be found to
have metabolic abnormalities, such as primary and secondary
hyperlipidemic states, hypercoagulable states (such as
antiphospholipid-antibody syndrome), and disorders of the
fibrinolytic system (including elevated lipoprotein(a) and
Finally, a number of lesion types and locations are particularly
prone to stent-related restenosis. This is certainly true for renal
failure patients with AV shunts who have subclavian vein stenosis.
In one recent series, the 6-month patency for subclavian vein
stents was 42%, and at one year only 25% of the stented central
veins were not stenosed or occluded.5 These disappointing results
were found despite 100% technical stenting success with 10 and 12
mm stents. Clearly, the subclavian location is one of the sites
where stent patency is reliably poor, perhaps due to continuous
mechanical stress from extrinsic muscle and bony impingement upon
the stented vein. Patency rates for stented AV shunt stenoses
(figure 3) are only slightly better, with a reported 12-month
patency of 20 to 40%.3,4,9,10
On the arterial side, femoropopliteal stenting has had poor
patency in most series. Gray et al reported that only 22% of the
femoropopliteal Wallstents placed in 58 limbs maintained primary
patency at a year.11 Poor durability of stents in this circulation
may have been related to a number of factors, including the long
segments of diseased vessels that were stented. Nevertheless, most
interventionalists are disappointed with the long-term patency of
Transjugular intrahepatic portosystemic shunts (TIPS) are prone
to restenosis, with a one-year primary patency of 25 to 66%.12,13
There are 2 predominant sites of TIPS stenosis: one at the hepatic
vein end of the stent and the other in the mid-stent (figure 4).
Most cases of stent-related TIPS stenosis can be treated simply by
repeat angioplasty and sometimes with placement of an additional
stent. However, a small subset of patients with TIPS-related
stenosis will develop recurrent stenosis in their TIPS shunt
despite angioplasty and restenting.
No current stent design favors patency
It would be exciting to find stent-related factors that could be
modified to significantly lower the risk of restenosis within the
stented segment. Theoretically, a number of designs and materials
offer advantages that should improve stent durability and limit
in-stent restenosis. Unfortunately, the following variables make
little difference in animal models and, in some cases, human
1) flexible vs rigid stents14
2) self-expanding vs balloon-expanded stents14
3) stent metal (nitinol, Elgiloy, steel)14
4) articulated vs non-articulated stents15
5) degree of radial force16
6) amount of metal surface area17
7) heparin coating18
Of course, there are some limitations to the list. No one would
argue that a long solid lead tube stent would perform as well as a
flexible mesh nitinol stent. Within the range of currently
available stent designs and materials, however, there is no proven
difference in stent-related restenosis or occlusion. In addition,
neither aggressive systemic 4-week
anticoagulation (coumadin with initial heparin, and aspirin) nor
antiplatelet regimens (aspirin and ticlopidine) improved 6-month
angiographic patency in a prospective coronary artery stent
Currently, our choice of stents for vascular use is based upon
appropriateness of the stent for a specific lesion (for example,
diameter, length and, perhaps, flexibility), ease of stent
delivery, cost, and (often) whether the stent has been approved for
the given indication. In my view, bare metal stents are an
important but interim step in the development of devices for
achieving durable percutaneous revascularization.
Possible approaches to limit neointimal in-stent
A number of strategies to limit stent-related restenosis are
under evaluation. For medium size vessels, 5 to 8 mm in diameter,
covered stents or "stent-grafts" may provide a physical barrier to
neointimal ingrowth (figure 6). A variety of synthetic graft
materials are being explored, including polyethylene terephthalate
(PET), polyurethanes, and expanded polytetrafluoroethylene (ePTFE).
Both PET and ePTFE have been used extensively as surgical bypass
conduits, but their use as endoluminal prostheses for occlusive
disease is only recently being explored. We have investigated ePTFE
and PET stent-grafts in a canine model,20,21 and have noted a
number of features related to healing and patency associated with
these different devices. There are currently 2 stent-graft trials
for occlusive disease in humans: one using a PET stent-graft
(Wallgraft, Schneider, Minneapolis, MN) and the other testing an
ePTFE stent-graft (HemoBahn, ProGraft, W.L. Gore and Associates,
Flagstaff, AZ). A polyurethane stent-graft trial (Corvita
Endoluminal Graft, Corvita, Miami, FL/Schneider) has been suspended
by the sponsor pending modifications.
Another promising approach is vascular irradiation, exposing the
stented segment to therapeutic levels of ionizing radiation. This
can be accomplished with radioactive stents, catheter-delivered
radiation, or external beam irradiation.22 A series of coronary
trials are underway, but peripheral studies have been slow to
A number of pharmacologic and immunologic approaches are being
considered as stent adjuncts. The efficacy of local drug or
antibody delivery to the stented segment is being evaluated with
the hope of interfering with early fibrin/platelet formation on the
stent (IIb/IIIa receptor inhibition) or smooth muscle cell
proliferation and migration (for example, Taxol). If any of these
approaches prove successful in limiting in-stent restenosis, there
will no doubt be interest in preparing pharmacologically active
Oral (systemic) medication would be an attractive alternative to
local delivery if an agent can be found that limits restenosis.
Cilostazol (an antithrombotic agent), Angiopeptin (an
antiproliferative agent), and a variety of oral anti-IIIb/IIIa
agents all are being studied. Is this a search for the "Holy
Grail"? Perhaps, but maybe we truly are closer than ever to an oral
medication that limits restenosis.
Regardless of how the technology ultimately develops, the next
generation of vascular "stents" will offer improved patency by
linking the intrinsic mechanical support of a stent with some other
physiologic or mechanical inhibitor of neointimal proliferation.
Exactly which new approach is most likely to succeed is not yet
known. In fact, it is likely that several adjunctive approaches
will prove valuable. Even if covered stents have no use in small
vessels, combined brachytherapy and oral medication will limit
neointimal formation. These are dynamic times, and the only
certainty is that the contemporary interventionalist can no longer
ignore the pharmacology, cell biology, and biomaterials data that
is exploding in the vascular literature. AR
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occlusion or stenosis following transjugular intrahepatic
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optimized ultrasound-guided deployment of Palmaz-Schatz stents.
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following arterial placement of self-expanding stents of different
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after coronary stent placement
and randomization to a four-week combined antiplatelet or
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response related to two types of polytetrafluoroethylene-covered
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Dr. Dolmatch is section head of Vascular/Interventional
Radiology at the Cleveland Clinic Foundation in Cleveland, OH.