(Circulation. 2000;101:1453.)
© 2000 American Heart Association, Inc.
Basic Science Reports |
Inhibition of Neointima Formation After Experimental Coronary Artery Stenting
A New Biodegradable Stent Coating Releasing Hirudin and the Prostacyclin Analogue Iloprost
From the I. Medizinische Klinik and Deutsches Herzzentrum (E.A., I.H., C.B., K.P., D.P., T.F., A.S.) and the Department of Experimental Surgery (A.S., W.E.), Klinikum rechts der Isar, Technische Universität München, Munich, Germany.
Correspondence to Dr Eckhard Alt, MD, I. Medizinische Klinik, Klinikum rechts der Isar, Ismaninger Straße 22, D-81675 München, Germany. E-mail alt{at}med1.med.tu-muenchen.de
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Abstract |
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Background—To minimize acute stent thrombosis and development of restenosis, stents coated with biodegradable and nonbiodegradable polymers have been proposed to serve as sustained-release drug carriers.
Methods and Results—In both a sheep and a pig model, we examined the vascular response to standard and high-pressure implantation of coronary Palmaz-Schatz stents coated with a 10-µm layer of polylactic acid (MW 30 kDa) releasing recombinant polyethylene glycol (r-PEG)–hirudin and the prostacyclin analogue iloprost, both drugs with antithrombotic and potentially antiproliferative effects. Study observation time was 28 days. Between the corresponding stent groups, no differences were observed with regard to preplacement and postplacement implantation parameters. The morphometric analysis demonstrated that the coating was associated with a greater lumen diameter through a reduction in the mean restenosis area by 22.9% (P<0.02) in the standard-pressure model (sheep) and by 24.8% (P<0.02) in the overstretch pig model compared with uncoated control stents without inducing a local inflammatory response.
Conclusions—The results from this study demonstrate beneficial effects of a polymeric stent coating with polylactic acid releasing r-PEG–hirudin and iloprost on the development of restenosis after coronary stent placement at 4 weeks, independent of the extent of vascular injury. Future studies are proposed to investigate the integration of other substances to further enhance the potential of the stent coating on reducing neointimal formation.
Key Words: angioplasty • stents • restenosis
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Introduction |
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The introduction of stent implantation in coronary lesions had a substantial impact on improving early and late outcome compared with coronary angioplasty alone, providing mechanical scaffolding that reduces the impact of early elastic recoil or dissection and eliminates late lumen loss by circumferential remodeling.1 2 Still, implantation of coronary stents is not free of complications. In addition to wall injury at the site of stent deployment, which provides a powerful stimulus to platelet activation and thrombus formation, the surface of the stent itself constitutes a thrombogenic foreign body. Thus, without treatment, a high rate of early stent thrombosis may be expected. Furthermore, together with the impact of the arterial wall injury, a multifactorial process is initiated, leading to neointimal hyperplasia and restenosis.
A number of studies have addressed these problems with aggressive anticoagulant and antiplatelet therapies and application of systemic antiproliferative strategies to inhibit neointimal growth. Although acute thrombosis has been reduced with new antithrombotic therapeutic approaches in humans, inhibition of neointimal hyperplasia is still of concern. Studies that demonstrated a significant reduction of restenosis were performed only in animals, applying much higher systemic doses than used in clinical practice.3 4 Application of comparable doses in humans is associated with toxicity and unwanted side effects, thus leading to the concept of local treatment strategies to achieve considerably higher drug concentrations at the site of the vessel wall injury than attainable by systemic administration.5
Aside from different devices to introduce drugs, stent coating with synthetic polymers has been proposed to reduce the thrombogenicity of the metal backbone and to serve as a sustained-release drug reservoir, allowing a pharmacological interaction with the vascular wall at the site of intervention. Several potential materials have been investigated so far, although without consistent results. Recently, a multicenter investigation of 8 different polymers coated on Wiktor stents and implanted into porcine coronary arteries found a marked inflammatory reaction with subsequent exaggerated neointimal thickening.6
The aim of this investigation was to establish the applicability and biocompatibility of a homogeneous yet thin layered stent coating with a polylactic acid (PLA) polymer, releasing 2 antithrombotic analogues with potentially antiproliferative effects, hirudin and the prostacyclin (PGI2) analogue iloprost. The vascular responses to implantation of the coated stents in 2 different animal models and whether the effect of the coating would be achieved independently of the pressure of deployment and the species were studied.
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Results |
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Stent Placement Parameters
Angiographic vessel diameters before (not shown) and after stent deployment did not show any differences between uncoated and coated stents in both animal models, nor did stent deployment characteristics (Table
).
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Arterial Injury Score
As shown in Figure 1, the
extent of damage inflicted on the vessel wall by the stent placement,
represented by the numerical injury score, was similar for
the coated and uncoated groups in both animal models. However, because
of the greater stent-to-vessel ratio with higher inflation pressures in
the pig overstretch model, higher injury score values were reached,
which were associated with a greater range.
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Histological Examination
Histological examination demonstrated that all
struts were completely covered with
endothelium/neointimal cells (Figure 2A). The stented vessel segments showed a
neointimal thickening by smooth muscle cell proliferation
in all examined cross sections, with an abundance of extracellular
matrix with collagen and elastic fibers and some fibroblasts. Most
importantly, histological examination corresponding to
biocompatibility parameters revealed no apparent acute
inflammatory reaction with infiltrates of lymphocytes,
histiocytes, or eosinophils in coated-stent samples compared
with uncoated stents and nonstented control segments (Figure 2B). Adjacent to stent struts cutting deeply into the
arterial wall, there was frequently
hemosiderin pigment deposition and sometimes signs of
hemorrhage, thrombus formation, and invasion of
macrophages and multinucleated giant cells, suggesting a
foreign-body type of reaction after severe arterial injury
(Figure 2C), but with no apparent difference between coated and
uncoated stents (not shown).
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Histomorphometry
Morphometric analysis of stent diameters, equivalent to
the postprocedural lumen diameter, revealed no apparent differences
between uncoated and coated stents in the standard-pressure group
(2.8±0.13 versus 2.90±0.18 mm, P=NS) or in the
overstretch group (2.71±0.17 versus 2.73±0.15 mm,
P=NS). Representative photomicrographs of
sections with coated and uncoated stents in both animal models are
shown in Figure 3. These figures
demonstrate that in both animal models, the PLA stent coating eluting
r-PEG–hirudin and iloprost resulted in a significant reduction of the
neointimal formation compared with the control groups,
equaling -22.9% in the standard-pressure sheep model and -24.8% in
the overstretch pig model in neointimal area (from 2.50 to 1.92
mm2 in sheep and from 4.13 to 3.11
mm2 in pigs, both P<0.02; Figure 4A). This newly formed tissue was
composed primarily of cells of smooth muscle cell origin, shown by a
positive staining for smooth muscle cell 
-actin. The quantitative
comparison of coated and uncoated stents corresponding to the
restenosis rate is depicted in Figure 4B. This
beneficial effect was independent of the applied balloon pressure, as
shown by a comparable reduction of the restenosis in the
standard-pressure model as well as the high-pressure overstretch
model.
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Discussion |
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In this study, we demonstrated that a very thin (10-µm) biodegradable stent coating with a high-molecular-weight PLA (30 kDa), serving as a sustained-release reservoir for r-PEG–hirudin and the PGI2 analogue iloprost, significantly reduced the neointimal formation after stent placement after 4 weeks. In contrast to most other polymers investigated so far, no local inflammatory reaction was induced by the PLA polymer used in this study, in agreement with its well-described biocompatibility.14 Also, van der Giessen and colleagues implanted stents with the same coating for a follow-up period of 3 months and found good biocompatibility (W.J. van der Giessen et al, unpublished data, 1999).
Local inflammation caused by foreign-body implants or degradation of
biomaterials can cause a remarkable degree of intimal hyperplasia and
therefore increase the extent of the evolving
restenosis,6 15 even causing complete
arterial occlusion after polymer-coated-stent
implantation.10 This has been attributed to the initial
polymer tissue load as well as the speed of its degradation, which
correlates inversely with the molecular weight. After implantation, the
specific degradation pattern is connected to the polymer thickness
diameter: thin coatings degrade continuously, whereas thicker coating
layers tend to bulk-degrade because of water penetration into the
matrix. This not only increases the total surface area of coating
material to be processed by the surrounding tissue but also causes
uncontrolled drug release during breakup of the matrix.14
In a recently published study, PLA (80 and 321 kDa) was used as a drug
carrier for dexamethasone at a total concentration of 800
µg per 400-µg carrier. This allowed a fast release of the drug
within several days. However, at least with 80-kDa PLA, an intense
local inflammatory neointimal response was induced as a
result of a local tissue "overload" with the polymer degradation
products by dramatically increasing the carrier surface available
for erosion.16 We have shown in extensive in vitro studies
that the 30-kDa PLA can carry an additional "drug load" of at most
20% (wt/wt) without compromising its degradation
pattern.9 In this study, the thickness of the PLA coating
was only 10 µm, resulting in an overall weight per stent of
200 µg, much less than that used in other studies with less
favorable results from implanting coated stents because of marked
inflammatory infiltration.6 17
The rationale for selecting the drugs to be released from the coating
was based on a combination of strong antiplatelet action and a
potential effect on proliferation as well. Hirudin is a specific,
highly potent, direct inhibitor of thrombin. Thrombin plays
an important role in thrombus formation after vessel injury and acts as
a potent mitogen and chemotactic agent for monocytes.18 19
In particular after a prolonged application of hirudin,
neointimal thickening was significantly reduced after
balloon angioplasty in 2 animal studies.20 21 One of these
studies provided evidence that thrombin formation at the site of
vascular injury is maintained for 
2 weeks, supporting the approach in
our study for the sustained release of hirudin.21
Iloprost is a PGI2 analogue with a prolonged action profile. PGI2 has been shown to inhibit platelet aggregation markedly and to limit both platelet and leukocyte activation after interaction with artificial surfaces.22 Prostaglandins also possess a certain antiproliferative effect.23 Even though in vivo application of prostaglandins to control smooth muscle cell proliferation in response to arterial injury has produced conflicting results, 2 clinical studies with short-term administration demonstrated a beneficial effect on neointimal proliferation.24 25
The measurements of the PLA carrier degradation clearly demonstrated a
slow and continuous erosion pattern, which accounts for the favorable
biocompatibility features of the stent coating described in this 4-week
study. In contrast to the release of iloprost, which was similar to the
degradation of the PLA carrier, r-PEG–hirudin was eluted up to 59% of
the total amount loaded during the first 24 hours. This was a result of
the incorporation of crystals into the carrier, which allowed a fast
antithrombotic effect during the most critical phase after stent
implantation. Both drugs were still released as pharmacologically
active compounds for 3 months (Figure 5).
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Strong evidence has been presented, at least in studies in animal models, that postinjury neointimal hyperplasia and therefore the development of restenosis are linked to platelet adhesion, aggregation, and thrombus formation.26 27 28 Sirois et al29 demonstrated a suppression of restenosis after balloon angioplasty of the rat carotid artery by platelet depletion. The neointimal hyperplastic potential was fully restored by infusion of fresh platelets even 14 days after the initial injury. This is even more important after stent implantation, which provides a continuous trigger of extensive arterial wall stress, also a major cofactor of restenosis.13 There is some indication that the growth-promoting stimuli are present significantly longer, with prolonged platelet activation30 and neointimal hyperplasia reaching its peak only after 2 to 3 weeks.31
In clinical studies on the effects of antithrombus-aimed strategies, however, results have been conflicting. Recently published clinical trials on the use of GP IIb/IIIa inhibitors demonstrated a protection against ischemic complications32 33 ; however, with regard to restenosis after stent implantation, a study in patients randomized to either a combined antiplatelet therapy with aspirin and ticlopidine or a conventional anticoagulant regimen with phenprocoumon revealed only a slight, nonsignificant trend toward less restenosis with ticlopidine.34 In contrast, a recently published paper suggested a role for organization of mural thrombus for in-stent restenosis.35
Currently, in clinical practice, antithrombotic therapy after stent
implantation includes the combination of aspirin and ticlopidine or
clopidogrel, although it is encumbered by a delayed onset of the
pharmacological effects. We previously showed in vitro that the
antiplatelet and anticoagulatory effects of r-PEG–hirudin and
iloprost eluted from the PLA stent coating is present immediately
and that the release of both drugs is maintained for 90
days.9 The stent coating may therefore serve as a bridge
covering delayed pharmacological onset of orally administered
antiplatelet drugs, such as ticlopidine. The conflicting data on
the long-term benefit of GP IIb/IIIa inhibitors on
neointimal hyperplasia, however, support the view that
early thrombus deposition and release of platelet-derived mediators
are not alone responsible for development of restenosis.
Integration of treatments focusing on a combination of strong
antiplatelet and specific antiproliferative action profiles into
stent coatings may have even greater effects on the limitation of
restenosis after stent implantation than those demonstrated in
this study.
Limitations of the Study
The sheep animal model has not been widely used to evaluate
restenosis after experimental coronary interventions,
although the activity of the ovine coagulation and fibrinolytic system
has more similarities to humans than other species.36 This
is considered particularly important for a
representative animal model of the development of
restenosis, because the dog animal model with a particularly
high fibrinolytic activity showed a diminished response to vascular
injury.12 The implantation of coronary stents in
pigs has been used more extensively because of the similar
histological appearance of the proliferative
neointimal tissue to human restenosis. However, to
generate comparable amounts of restenosis, an oversizing of
30% to 50% is required.4 Although the similarities
between animal models and humans in this respect might be adequate, it
is not clear whether the beneficial results from this study might
translate acceptably to humans. In this study, normal coronary
arteries were used for stent implantation, in contrast to the general
application in humans to treat atherosclerotic lesions, which may
respond differently to the stent coating with drug release. And
finally, even though many drugs have proved to be effective in animal
models with regard to prevention or reduction of restenosis,
they later failed in human studies.
Conclusions
The results presented in this study showed a significant
reduction of neointimal hyperplasia and hence
restenosis after experimental implantation of Palmaz-Schatz
stents coated with a PLA polymer, releasing r-PEG–hirudin and
iloprost. The histopathological examination revealed no apparent
inflammatory reaction after 28 days. Considering the failure of oral
pharmacological treatments to reduce restenosis after
interventional stent implantation in humans, the method of local drug
delivery deserves further attention.
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Methods |
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Drugs
Both substances to be released from the polylactide (PLA) stent coating were selected in modified forms to fulfill pharmacokinetic demands that they allow continuous release without compromising their pharmacological efficacy7 : Hirudin is relatively hydrophobic and therefore depends on passive release by slow degradation of the polymer matrix. To ensure an immediate antithrombin effect, a derivative of r-hirudin covalently bound to polyethylene glycol was used to increase hydrophilicity (rPEG–hirudin; Knoll). Iloprost (Schering) is a PGI2 analogue with prolonged action profile that has been widely used systemically for treatment of peripheral vascular disease.
Stent Coating
Palmaz-Schatz stents 7 mm long (Johnson & Johnson) were
coated with the polymer poly(D,L-lactic acid) (PLA; MW 30
kDa; R 203, Boehringer Ingelheim) as previously
described.8 Briefly, a 7% (wt/vol) solution of PLA in
chloroform was prepared, containing 5% (wt/wt) r-PEG–hirudin and 1%
(wt/wt) iloprost. The stents were dip-coated twice to achieve a
homogeneous coating with a thickness of 10 µm (total
weight, 200 µg/stent; n=8). Carrier degradation was measured by loss
of total weight of stents coated with PLA only. Drug elution of
r-PEG–hirudin and iloprost was measured by platelet aggregation
and TAT/F1–2 generation compared with the
effects of the total amount of the integrated drugs per stent. Samples
were taken at 10 minutes; 1, 6, 12, and 24 hours; and 2, 4, 16, 30, 60,
and 90 days and analyzed by standard techniques with
commercially available test kits. The in vitro effects on platelet
aggregation and coagulation parameters are described
elsewhere.9
Carrier Degradation and Drug Elution
The PLA carrier degraded slowly and continuously over the
observation period of 3 months, losing 12% of its total weight. The
elution of the PGI2 analogue iloprost was similar
to the degradation of the carrier. r-PEG–hirudin was released much
faster, peaking at 24 hours, followed by a plateau phase running
parallel to further carrier degradation. The total amounts of each drug
released after 4 weeks was 200 ng iloprost and 6 µg
r-PEG–hirudin. At the end of the observation period, 15% of
iloprost and 60% of r-PEG–hirudin had been released (Figure 5
).
Animals, Coronary Stent Placement Procedure
Interventional procedures and animal handling were approved by
our institution’s Animal Care and Use Committee, which conforms to the
standards of the American Heart Association’s "Guidelines for the
Use of Animals in Research" and the NIH Guide for the Care and
Use of Laboratory Animals (National Academy Press, Revised
1996).
Experiments were performed in 18 farm-bred female Merino sheep (weight,
52 to 103 kg) and in 18 Deutsche Landrasse pigs (weight, 25 to 37 kg).
Under sterile conditions, via left carotid artery access, a 7F catheter
was placed, and baseline coronary angiography was performed.
The procedure was conducted by experienced interventional cardiologists
using standard methods, as previously described.10 Stents
were mounted on deflated conventional angioplasty balloon catheters
with a manufacturer-specified balloon diameter of 3.0 to 3.5 mm.
Coated and uncoated stents were randomly assigned to either the left
anterior descending or left circumflex coronary artery,
providing each animal with 1 coated and 1 uncoated stent. Initial
selection of appropriate vessel segments was visually guided, using the
defined dimensions of the guiding catheters as reference, and suitable
coronary segments with vessel diameters of 2.5 to 3.0
mm were selected for stent placement. To achieve the characteristic
vascular injury of the vessel wall, appropriate overstretch was
achieved by use of the compliance curves of the balloon catheters. In
the standard-pressure experiments in the sheep, a stent-to-vessel ratio
of 1.2 to 1.3 was aimed for. In this model, the balloons were inflated
with a maximal pressure of 8 atm for 40 seconds. In the high-pressure
experiments in pigs, the targeted stent-to-vessel ratio was 1.4 to 1.5,
and the balloons were inflated with a maximal pressure of 18 atm for 20
seconds.
After the balloon catheter had been withdrawn, repeat angiograms were performed to confirm patency of the stented vessels. During the stent placement procedure, the animals were provided with 15 000 IU heparin and 500 mg aspirin. Neither antiplatelet or anticoagulation drugs were given during the 28-day follow-up period. The recorded angiography data were subsequently processed by standard quantitative coronary arteriography procedures using the guiding catheter for calibration.
Follow-Up, Processing, and Histomorphometric Analysis of
the Stented Vessels
After 28 days, a repeat angiography was performed, following the
same procedure as described above. Then, the animals were fully
heparinized (10 000 U/animal IV) and euthanized by injection of lethal
doses of sodium pentobarbital. The heart was quickly removed, flushed
with sterile saline, and immediately perfusion-fixed with 6% formalin
at 100 mm Hg pressure for 15 minutes. The stent-carrying vessels
were dissected and removed, including a 5- to 10-mm stretch of
nonstented vessel proximal and distal to each stent.
Specimens were dehydrated and embedded in poly(methyl
methacrylate).11 Samples were cut into 700-µm sections
and polished down to a thickness of 100 µm, leaving the stent
struts within the section. After standard staining,11
photomicrographs were scanned and transformed to a computer-based
digital planimetry system (NIH Image 1.59). From each vessel, 6
sections were analyzed by 2 independent investigators: 2
sections from each proximal and distal end of the stent and 4 stented
sections. Morphometric analysis comprised lumen diameter, stent
area corresponding to the original lumen area subtended within the
internal elastic lamina, and neointimal and medial
thickness, measured according to Anderson.12 The extent of
restenosis was defined as the neointimal area at
the stent area. Vessel injury was classified by a numeric injury score
according to the depth of penetration of each stent strut, according to
Schwartz et al.13
Statistical Analysis
Data are presented as the average of cross sections per
stent in the treatment groups in each animal species and expressed as
mean±SD. Statistical analysis for angiographic and
morphometric data was performed with the Wilcoxon test for
paired samples. A value of P
0.05 was considered
statistically significant.
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Footnotes |
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The Methods section of this article can be found at http://www.circulationaha.org
Received April 8, 1999; revision received September 30, 1999; accepted October 8, 1999.
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