(Circulation. 2001;103:26.)
© 2001 American Heart Association, Inc.
Clinical Investigation and Reports |
Local Delivery of Enoxaparin to Decrease Restenosis After Stenting: Results of Initial Multicenter Trial
Polish-American Local Lovenox NIR Assessment Study (The POLONIA Study)
From the Department of Medicine, Divisions of Cardiology (R.S.K.) and Cardiology and Clinical Epidemiology (M.M.R.), University of Texas Health Science Center at San Antonio; Department of Cardiology (P.B., E.G., M.T.), Silesian Medical School, Katowice, Poland; Department of Cardiology (J.L.M.), Jefferson Health System–Main Line, Radnor, Pa; Cardiology Division (E.D.), Department of Medicine, Weill Medical College of Cornell University, New York, NY; National Institute of Cardiology (M.R.), Warsaw, Poland; Department of Cardiology (P.S.), Internal Ministry Hospital, Warsaw, Poland; and Department of Cardiology (M.K.), Lodz Medical School, Lodz, Poland.
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Abstract |
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Background—Enoxaparin inhibits smooth muscle cell proliferation in experimental models. Intimal hyperplasia has been found to be the principal cause of restenosis after coronary stent implantation. We sought to determine whether the intramural delivery of enoxaparin before stenting of de novo lesions decreases restenosis.
Methods and Results—One hundred patients who were undergoing stenting were randomly assigned to either local administration of enoxaparin during predilation with reduced systemic heparinization or stenting with standard, systemic heparinization. All patients were treated with the same type of stent (NIR). The primary study end point was late luminal loss. The secondary end points were major adverse cardiac events, target lesion revascularization, and angiographic restenosis at 6 months. Angiographic follow-up at 6 months was completed in all except 1 patient. Late luminal loss was reduced to 0.76±0.42 mm in the local enoxaparin delivery group versus 1.07±0.49 mm in the systemic heparinization group (P<0.001). Restenosis, using a binary definition, occurred in 10% of patients in the enoxaparin group and in 24% of patients in the systemic heparinization group (P<0.05). Target lesion revascularization rates occurred in 8% of the enoxaparin group and 22% of the systemic heparinization group (P<0.05). There were no deaths and no emergent CABGs were performed. The only subacute stent closure and non–Q-wave infarction occurred in a patient assigned to the systemic heparinization group.
Conclusions—This is the first prospective randomized trial in which the local delivery of a drug, enoxaparin, resulted in significant reduction in late luminal loss and restenosis after stent implantation in de novo coronary lesions.
Key Words: coronary disease • drug delivery systems • stents • enoxaparin
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Introduction |
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Stenting of discrete lesions in large coronary arteries results in lower restenosis rates than conventional coronary angioplasty.1 2 3 Restenosis, however, remains an important and costly therapeutic problem. Because intimal smooth muscle cell proliferation4 5 6 7 is in large part the culprit, various attempts to inhibit this process have been studied.8 9 10 11 12 13 Reduction in in-stent restenosis was described with the application of
- and
ß-irradiation.14 15 16
Several investigators proposed the use of local drug delivery as a
strategy for the treatment of restenosis after
intervention.17 18 19 20 21 22 23
Modulation of the stimuli for neointimal hyperplasia with the
appropriate pharmacological agents would, in theory, permit vessel wall
healing after coronary stent implantation without an exaggerated,
obstructive proliferative response. Thus far, local drug delivery of
various agents and different methods of administration has failed to
affect restenosis rate after
stenting.24 25
This may be related to the agent studied, the design of the delivery
device, and both the methods and timing of drug delivery with respect
to stenting. Arterial injury triggers thrombus formation with the
release of growth factors known to stimulate neointimal proliferation:
platelet-derived growth factor, transforming growth factor-ß,
fibroblast growth factor, and
others.26 27 28
Such an interaction may contribute to restenosis. Therefore, to
modulate the magnitude of thrombin- and thrombus-mediated stimuli for
neointimal proliferation, we chose low-molecular-weight heparin
(enoxaparin; Aventis), a potent factor Xa and thrombin
inhibitor,29 30
to be specifically administered during predilation. Enoxaparin has been shown to inhibit smooth muscle cell proliferation at high tissue concentrations.31 32 33 However, it has not reduced the incidence of angiographic restenosis or clinical events after successful coronary angioplasty when administered systemically.34 Because the antiproliferative effect of enoxaparin on smooth muscle proliferation appears to be dose dependent, we used a microporous, local drug delivery/angioplasty catheter (Transport catheter; Boston Scientific) simultaneously for predilation and the administration of enoxaparin, followed by stent deployment. To minimize trauma to the wall, we delivered small volumes of highly concentrated drug at low pressures.35 36 We postulated that this approach combined with subsequent compression of the treated wall segment by the expanded stent would result in a sufficient local concentration and retention of enoxaparin to prevent subacute stent closure and to decrease intimal hyperplastic response. This strategy, if effective, would reduce late luminal loss and, ultimately, the restenosis rate. Thus, we conducted an initial, multicenter, prospective, randomized study in which we compared stenting after local delivery of enoxaparin with reduced systemic heparinization and traditional stenting using full systemic heparinization. To eliminate any differences between the groups regarding the type of the stent used, all patients received the balloon-expandable, stainless steel NIR stent (Medinol; Boston Scientific).
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Methods |
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Study Design
The study was a multicenter, prospective, randomized trial that was performed at 4 cardiovascular centers in Poland. At each site,
400 interventions were performed annually. To participate, each
operator was required to perform 200 procedures annually with a
95% success rate, <1% mortality rate, and <5% major in-hospital
cardiac event rate in elective procedures.
Study Patients
Symptomatic patients with documented myocardial
ischemia and 1-vessel disease were included in the study. The treated
vessels had to be 2.5 mm in diameter on visual assessment, with
>60% stenosis. Only de novo, noncalcified, and <15 mm long lesions
were included. All patients were required to be acceptable candidates
for bypass surgery and to agree to 6-month clinical and angiographic
follow-up.
Patients with ostial and bifurcation lesions, recent myocardial infarction (within 7 days of the acute event), allergy to aspirin or ticlopidine, history of bleeding diathesis or coagulopathy, history of stroke or transient ischemic attack within the past 3 months, a positive pregnancy test, or any end-stage disease that influences 6-month survival were excluded from this study. Patients with diabetes mellitus were excluded from the study because of a high incidence of restenosis, of which the mechanism may differ from that in the nondiabetic population.
The ethics committee at each center approved the protocol, and all patients gave written informed consent.
Randomization and Revascularization
Strategies.
Eligible patients were randomly assigned to 1 of the
treatment modalities. The local drug delivery group received 2500 U
heparin through the arterial sheath and 10 mg enoxaparin to the treated
site during predilation with the Transport catheter. The catheter has a
monorail design with a dual-layer balloon near the distal tip. There is
a separate lumen that is used for inflation of the balloon, and a
second lumen is used for drug infusion. This allowed uncoupling of the
balloon support and drug delivery pressures. The outer balloon has
microporous holes located circumferentially along the 10-mm-long
mid-section of the balloon for controlled local drug delivery.
Radiopaque markers allow for precise placement of the catheter balloon
segment.
Lesions were predilated with a balloon-to-artery ratio of 0.9 to 1.0:1.0, and the balloon was inflated at 6 to 8 atm for 30 seconds. The pressure was then lowered to a support pressure of 3 atm, and 10 mg enoxaparin was administered in 1 mL of saline solution at a delivery pressure of 30 to 45 psi (2 to 3 atm) during a 60- to 120-second period.
Patients randomized to stenting with full systemic heparinization (systemic heparinization group) received 10 000 U heparin through the arterial sheath to obtain a target activated clotting time (ACT) of 300 seconds. The baseline ACT was obtained in all patients and was monitored throughout the procedure with the Hemochron 400. The NIR stents (16 mm long, 9-cell design) were deployed with a 1.1:1 balloon-to-artery ratio with noncompliant balloons. Biplane angiograms were performed in all patients using orthogonal projections after the intracoronary administration of 100 to 200 µg nitroglycerin. The procedure was deemed successful if there was no residual stenosis by visual estimation, TIMI 3 flow was present, and there were no major cardiac complications (death, myocardial infarction, emergency CABG). Sheaths were removed at an ACT of <160 seconds. All patients had blood drawn for creatine kinase level determination 6 and 12 hours after the procedure. Values of >2 times baseline were considered abnormal.
Every patient received 150 mg aspirin QD and 250 mg ticlopidine BID for at least 48 hours before the procedure. The ticlopidine was continued for 4 weeks, and aspirin was continued indefinitely. Complete blood cell counts were determined at baseline and at 2, 4, and 6 weeks. Additional treatment consisted of a calcium channel antagonist or ß-blockers and nitrates administered at the discretion of the patient’s physician.
Clinical and Procedural Data Collection
An independent clinical data collection center was
established at the Upper Silesian Cardiology Center in Katowice,
Poland. Basic demographic data, risk factors, past medical history, and
clinical presentation information were obtained for all patients
included in the trial. Any cardiac or noncardiac events were recorded
during the 6-month follow-up. Investigators who collected clinical data
were blinded to the patient’s procedural characteristics. Final data
analysis, including procedural data, was performed by the investigator
(M.M.R.) not directly involved in the study at the University of Texas
Health Science Center at San Antonio.
Angiographic Analysis
The independent core laboratory at University of
Texas Health Science Center at San Antonio processed angiographic data.
Quantitative coronary angiography was performed off-line, without
knowledge of the patient’s clinical or procedural characteristics. The
Transport drug delivery catheter is indistinguishable from a PTCA
catheter in angiographic images. We used a previously
validated,37 interactive
automatic edge detection algorithm computer program (Artrek Quantin
2000I; QCS Inc, ImageComm Systems, Inc). Frames that display the
most severe lumen narrowing without foreshortening of the selected
coronary segment in at least 2 orthogonal projections were selected.
The distal end of the guiding catheter was used for calibration in each
analyzed projection. Follow-up angiograms were performed with matching
views and after the administration of intracoronary nitroglycerin. The
same reference segment was selected after intervention and at
follow-up. Minimal lumen diameter, lesion length, proximal and distal
reference diameters, and luminal diameter stenosis of dilated segments
were measured from the coronary angiograms obtained before and just
after the procedure, as well as at repeat coronary angiograms 6 months
later. Acute and net gain, late loss, and loss index were calculated
according to previously described
definitions.38 A
>50%-diameter stenosis was used as a binary definition of
restenosis.
Study End Points and Statistical
Analysis
The primary end point of the study was late luminal
loss at 6 months, not the binary restenosis rate. The sample size (45
patients in each arm) was calculated on the basis of angiographic data
from other
studies.39 40 The
study was powered to detect statistically significant differences in
the late luminal loss (
=0.05; difference of mean values to be
detected, 0.3 mm; expected SD within groups, ±0.5 mm; power of the
test, 80%). The unpaired t
test was used for comparison between the 2
groups.41
Major adverse cardiac events (death, myocardial infarction, emergency CABG, or repeat balloon angioplasty) that targeted lesion revascularization and angiographic restenosis during 6 months were selected as the secondary end points.
All data were expressed as mean±SD values. Continuous
variables were compared using the 2-tailed, Student’s
t test. Nonparametric values
were compared using a 
2 test. The
right-tailed Fisher’s exact test was used to analyze the angiographic
restenosis. A value of P<0.05
was considered statistically
significant.
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Results |
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Between February 1996 and April 1998, 100 patients were prospectively randomized to either receive local drug delivery of low-molecular-weight heparin or full systemic heparinization before stent implantation. All patients received NIR stents. Clinical follow-up was completed for all patients, and 6-month angiographic follow-up was obtained for all except 1 patient. There were no significant differences between the treatment groups in their baseline clinical and angiographic characteristics (Tables 1
and 2). The local drug delivery did not
prolong the stenting procedure compared with systemic heparinization
(Table 3). Technical data concerning the local drug delivery
by means of the Transport catheter are shown in
Table 4. Significant but nonocclusive dissection after
predilatation occurred in 4 patients in the local drug delivery group
and in 3 patients in the systemic heparinization group
(P=NS); each case was treated
with additional stent placement.
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ACTs were comparable in the 2 groups at baseline but
significantly lower in the local drug delivery group at the end of the
procedure (146.9±39.8 versus 381.9±182.2 seconds;
P<0.001), which facilitated
earlier removal of the vascular sheaths
(Table 3
). There were no vascular complications in the local
drug delivery group: 1 patient in the systemic heparinization group
developed hematoma that did not require transfusion. No deaths occurred
and no emergent CABGs were performed in either group. One patient in
the systemic heparinization group, in whom ticlopidine was discontinued
because of an allergic reaction, experienced subacute stent closure and
myocardial infarction. This patient was successfully treated with
emergency PTCA. Sixty-seven percent of all target lesion
revascularizations occurred before the scheduled angiographic
follow-up; the remainder of target lesion revascularizations occurred
at the time of control angiography, and none occurred afterward. When
the local drug delivery group was compared with the systemic
heparinization group, there was a statistically significant reduction
(8% versus 22%, P<0.05) in
target lesion revascularization rates at 6 months
(Table 5). Quantitative coronary angiography revealed no
differences at baseline between the 2 groups, and acute results of
stenting were comparable. However, at 6-month follow-up, the late
luminal loss and loss index were significantly reduced in the local
drug delivery group (P<0.001)
(Table 6), which resulted in a larger late minimal luminal
diameter in this group
(Figure 1). Angiographic restenosis after stenting was also
significantly reduced to 10% in the local drug delivery group versus
24% in the systemic heparinization group
(P=0.049)
(Table 6). The total number of major cardiac events
(in-hospital and during 6-month follow-up) was significantly
diminished in the local drug delivery group
(Table 5).
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Discussion |
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This current prospective, randomized study demonstrates for the first time that the local delivery of enoxaparin during predilation and before coronary stent implantation reduces late lumen loss and restenosis compared with a conventional stent implantation strategy and systemic heparinization. The study involved <3.0-mm vessels treated with the first generation of the NIR stent. The late luminal loss and restenosis rates in the control arm correspond well with the findings from other studies, in which <3.00-mm vessel stenting was performed with the early-generation stents.42 43 On the other hand, observed luminal loss and the restenosis rate in the local drug delivery group compare favorably to the results of small vessel stenting.42 43 The incidence of subacute closure in this vessel category ranges from 2.5% to 3.6% with full systemic heparinization.42 43 In the local drug delivery group, there were no subacute closure events, despite the lack of systemic heparinization. This may suggest a local, persistent antithrombotic effect of enoxaparin.
Our data are in contrast to those of 2 recent studies that examined the impact of the local delivery of a pharmacological agent during coronary stent procedures on long-term outcomes. Neither the Heparin Infusion Prior to Stenting (HIPS) trial,24 in which unfractionated heparin was delivered after predilation but before stent implantation, nor the ITALICS trial,25 in which antisense to the proto-oncogene c-myc was delivered after stent implantation, demonstrated an impact on late lumen loss and restenosis.
The effectiveness of local drug therapy may depend on many
factors, such as choice of pharmacological agent, methods of drug
delivery, and timing with regard to stent deployment. Several studies
showed efficacy of local drug
delivery.36 44 45 46
Longer infusion and higher drug concentration resulted in greater
intramural drug deposition. Moreover, autoradiography demonstrated
homogeneous distribution of heparin throughout the intima, media, and
adventitia with localization in the nuclei, cytoplasm, and
extracellular space. Wash-out studies showed biexponential
disappearance of intramurally deposited drug: the rapid release of
heparin during the first 60 minutes and the persistence of a small
amount of drug for 7
days.44 Our strategy
involved the delivery of enoxaparin during predilation to improve
intramural penetration of the drug. To prolong retention of the
compound, we deployed the stents at the treated vascular segment to
seal drug-containing microdissections caused by the balloon injury.
This is an important consideration, because studies in animals in which
a rabbit model was used for the intramural delivery of enoxaparin with
the Transport catheter without subsequent stenting revealed poor
retention of the agent.33 To
avoid significant injury of the treated vascular segment during drug
administration, we delivered small volumes of concentrated enoxaparin
at low delivery
pressures.35 36
The design of the Transport catheter allowed for uncoupling of balloon
inflation and drug delivery pressures, making drug delivery safe and
possible during the predilation.
In the baboon angioplasty model, low molecular weight heparin blocked serum-induced but not platelet-derived growth factor induced smooth muscle cell proliferation and migration, suggesting heparin-sensitive and -insensitive pathways.47 If the assumption that human smooth muscle cells are less sensitive to growth inhibition by heparin is true, one could consider the possibility that in-stent restenosis may be reduced through the local prevention of early prothrombotic events. The strategy of local delivery of enoxaparin, a potent factor Xa and thrombin inhibitor,29 30 during predilation was specifically designed to modulate the magnitude of thrombin- and thrombus-mediated stimuli for neointimal proliferation. The purpose of enoxaparin delivery during predilation was to have an antithrombotic agent in place at the time of the initial balloon deflation, when the injured vessel wall is first exposed to circulating prothrombotic elements. This strategy was applied to de novo lesions, which contain tissue factor (factor VIIa) and other procoagulant molecules.48 49
Due to its low molecular weight, enoxaparin has the additional advantage of efficient diffusion capability, thus enabling efficient local delivery. However, previous trials in humans with systemic administration of enoxaparin to inhibit restenosis were unsuccessful, possibly due to an insufficient local concentration of low molecular weight heparin at the target lesion.34 We hypothesized that the local delivery of enoxaparin during predilation and subsequent stenting at the delivery site would result in sufficient concentration and retention to reduce the late luminal loss.
Quantitative analysis of coronary angiography demonstrated that stenting was performed equally effectively in both groups, yielding comparable minimal luminal diameters, known to be strong predictors of restenosis.50 Therefore, it appears that the observed results can be attributed only to the local delivery of enoxaparin. Normal ACTs at the end of the procedures allowed for immediate sheath removal and faster patient ambulation.
Our study demonstrates, for the first time, a significant decrease in late lumen loss and angiographic restenosis as a result of local delivery of enoxaparin. However, we must stress that our findings are preliminary and require confirmation by a larger trial. The precise antirestenosis mechanism of enoxaparin, although not fully elucidated, is likely the combination of a reduction in thrombotic events, downregulation of thrombotic growth factor generation, and perhaps a direct inhibitory effect on smooth muscle cell proliferation. These data suggest that local drug delivery may constitute a viable therapeutic option to prevent restenosis after coronary stent implantation. Thus, there is a need for a large, randomized trial and the further development of active antiproliferative agents, as well as improved drug delivery devices.
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Acknowledgments |
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The authors wish to thank Dr Robert A. O’Rourke for his invaluable comments on the manuscript.
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Footnotes |
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Reprint requests to R. Stefan Kiesz, MD, UTHSC/Medicine, Division of Cardiology, 7703 Floyd Curl Dr, San Antonio, TX 78229-7872.
Received June 7, 2000; revision received August 9, 2000; accepted August 10, 2000.
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References |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
1. 1. Serruys PW, de Jaegere P, Kiemeneij F, et al. A comparison of balloon-expandable-stent implantation with balloon angioplasty in patients with coronary artery disease: Benestent Study Group. N Engl J Med. 1994;331:489–495.
2.
Fischman DL, Leon
MB, Baim DS, et al. A randomized comparison of coronary-stent placement
and balloon angioplasty in the treatment of coronary artery disease:
Stent Restenosis Study Investigators.
N Engl J Med. 1994;331:496–501.
3. Serruys PW, van Hout B, Bonnier H, et al. Randomised comparison of implantation of heparin-coated stents with balloon angioplasty in selected patients with coronary artery disease (Benestent II). Lancet. 1998;352:673–681.[Medline] [Order article via Infotrieve]
4. Pickering J, Weir L, Jekanowski J, et al. Proliferative activity in peripheral and coronary atherosclerotic plaque among patients undergoing percutaneous revascularization. J Clin Invest. 1993;91:1469–1480.
5. Dussaillant GR, Mintz GS, Pichard AD, et al. Small stent size and intimal hyperplasia contribute to restenosis: a volumetric intravascular ultrasound analysis. J Am Coll Cardiol. 1995;26:720–724.[Abstract]
6. Painter JA, Mintz GS, Wong SC, et al. Serial intravascular ultrasound studies fail to show evidence of chronic Palmaz-Schatz stent recoil. Am J Cardiol. 1995;75:398–400.[Medline] [Order article via Infotrieve]
7. Carter AJ, Laird JR, Kufs WM, et al. Coronary stenting with a novel stainless steel balloon-expandable stent: determinants of neointimal formation and changes in arterial geometry after placement in an atherosclerotic model. J Am Coll Cardiol. 1996;27:1270–1277.[Abstract]
8. Forrester J, Fishbein M, Helfanat R, et al. A paradigm for restenosis based on cell biology: clues for the development of new preventive therapies. J Am Coll Cardiol. 1991;17:758–769.[Abstract]
9. Ferns G, Raines E, Sprugel K, et al. Inhibition of neointimal smooth muscle cell accumulation after angioplasty by an antibody to PDGF. Science. 1991;235:1129–1132.
10.
Wilensky RL,
March KL, Gradus-Pizlo I, et al. Vascular injury, repair, and
restenosis after percutaneous transluminal angioplasty in the
atherosclerotic rabbit.
Circulation. 1995;92:2995–3005.
11.
Waksman R,
Robinson KA, Crocker IR, et al. Intracoronary radiation before stent
implantation inhibits neointima formation in stented porcine coronary
arteries. Circulation. 1995;92:1383–1386.
12. Waksman R. Local catheter-based intracoronary radiation therapy for restenosis. Am J Cardiol. 1996;78:23–28.[Medline] [Order article via Infotrieve]
13.
Farb A, Sangiorgi
G, Carter AJ, et al. Pathology of acute and chronic coronary stenting
in humans. Circulation. 1999;99:44–52.
14.
Carter AJ, Laird
JR, Bailey LR, et al. Effects of endovascular radiation from a
ß-particle–emitting stent in a porcine coronary restenosis model: a
dose-response study.
Circulation. 1996;94:2364–2368.
15.
Teirstein PS,
Massullo V, Jani S, et al. Catheter-based radiotherapy to inhibit
restenosis after coronary stenting. N
Engl J Med. 1997;336:1697–1703.
16.
King SB 3rd,
Williams DO, Chougule P, et al. Endovascular ß-radiation to reduce
restenosis after coronary balloon angioplasty: results of the Beta
Energy Restenosis Trial (BERT).
Circulation. 1998;97:2025–2030.
17. Eccleston DS, Horrigan MC, Ellis SG. Rationale for local drug delivery. Semin Intervent Cardiol. 1996;1:8–16.[Medline] [Order article via Infotrieve]
18. Riessen R, Isner JM. Prospects for site-specific delivery of pharmacologic and molecular therapies. J Am Coll Cardiol. 1994;23:1234–1244.[Abstract]
19. Camenzind E, Kutryk MJ, Serruys PW. Use of locally delivered conventional drug therapies. Semin Intervent Cardiol. 1996;1:67–76.[Medline] [Order article via Infotrieve]
20.
Losordo DW, Vale
PR, Symes JF, et al. Gene therapy for myocardial angiogenesis: initial
clinical results with direct myocardial injection of phVEGF165 as sole
therapy for myocardial ischemia.
Circulation. 1998;98:2800–2804.
21.
Witzenbichler B,
Asahara T, Murohara T, et al. Vascular endothelial growth factor-C
(VEGF-C/VEGF-2) promotes angiogenesis in the setting of tissue
ischemia. Am J Pathol. 1998;153:381–394.
22.
Sellke FW, Laham
RJ, Edelman ER, et al. Therapeutic angiogenesis with basic fibroblast
growth factor: technique and early results.
Ann Thorac Surg. 1998;65:1540–1544.
23.
Rogers C, Edelman
ER, Simon DI. A mAb to the beta2-leukocyte integrin Mac-1 (CD11b/CD18)
reduces intimal thickening after angioplasty or stent implantation in
rabbits. Proc Natl Acad Sci
U S A. 1998;95:10134–10139.
24. Wilensky R, Tanguay J-F, Ito S, et al. The Heparin Infusion Prior to Stenting (HIPS) Trial: procedural, in-hospital, 30 day, and six month clinical, angiographic and IVUS results. J Am Coll Cardiol. 1998;31:457A.
25. Serruys P, Kurtyk M, Bruining N, et al. Antisense oligonucleotide against c-myc administered with the transport delivery catheter for the prevention of in-stent restenosis: results of the randomized ITALICS Trial. Circulation. 1998;98(suppl I):I-363. Abstract.
26.
Dinbergs ID,
Brown L, Edelman ER. Cellular response to transforming growth
factor-beta1 and basic fibroblast growth factor depends on release
kinetics and extracellular matrix interactions.
J Biol Chem. 1996;271:29822–29829.
27. Unterberg C, Meyer T, Wiegand V, et al. Proliferative response of human and minipig smooth muscle cells after coronary angioplasty to growth factors and platelets. Basic Res Cardiol. 1996;91:407–417.[Medline] [Order article via Infotrieve]
28.
Skaletz-Rorowski
A, Schmidt A, Breithardt G, et al. Heparin-induced overexpression of
basic fibroblast growth factor, basic fibroblast growth factor
receptor, and cell-associated proteoheparan sulfate in cultured
coronary smooth muscle cells. Arterioscler
Thromb Vasc Biol. 1996;16:1063–1069.
29. Gikakis N, Khan MM, Hiramatsu Y, et al. Effect of factor Xa inhibitors on thrombin formation and complement and neutrophil activation during in vitro extracorporeal circulation. Circulation. 1996;94(suppl II):II-341–II-346.
30.
Gikakis N, Rao
AK, Miyamoto S Jr, et al. Enoxaparin suppresses thrombin formation and
activity during cardiopulmonary bypass in baboons.
J Thorac Cardiovasc Surg. 1998;116:1043–1051.
31. Hammerle H, Betz E, Herr D. Human endothelial cells are stimulated and vascular smooth muscle cells are inhibited in their proliferation and migration by heparins. Vasa J Vasc Dis. 1991;20:207–215.
32. Taylor A, Ao P, Fletcher J. Inhibition of intimal hyperplasia and occlusion in Dacron graft with heparin and low molecular weight heparin. Int Angiol. 1995;14:375–380.[Medline] [Order article via Infotrieve]
33. Hong MK, Wong SC, Barry JJ, et al. Feasibility and efficacy of locally delivered enoxaparin via the channeled balloon catheter on smooth muscle cell proliferation following balloon injury in rabbits. Cathet Cardiovasc Diagn. 1997;41:241–245.[Medline] [Order article via Infotrieve]
34.
Faxon DP, Spiro
TE, Minor S, et al. Low molecular weight heparin in prevention of
restenosis after angioplasty: results of Enoxaparin Restenosis (ERA)
Trial. Circulation. 1994;90:908–914.
35. Buszman P, Kiesz R, Gaszewska E, et al. Local intramural delivery of low molecular weight heparin during coronary stent implantation: preliminary report. Kardiol Polska. 1998;48:227–231.
36. Kimura T, Miyauchi K, Yamagami S, et al. Local delivery infusion pressure is a key determinant of vascular damage and intimal thickening. Jpn Circ J. 1998;62:299–304.[Medline] [Order article via Infotrieve]
37.
Mancini GB, Simon
SB, McGillem MJ, et al. Automated quantitative coronary arteriography:
morphologic and physiologic validation in vivo of a rapid digital
angiographic method.
Circulation. 1987;75:452–460.
38. Reiber J, Serruys P, eds. Developments in Cardiovascular Medicine. Dordrecht, the Netherlands: Kluwer Academic Publishers; 1993.
39. Serruys PW, deJaegere P, Kiemeneij F, et al. A comparison of balloon-expandable-stent implantation with balloon angioplasty in patients with coronary artery disease: Benestent Study Group. N Engl J Med. 1994;331:489–495.
40. George CJ, Baim DS, Brinker JA, et al. One-year follow-up of the Stent Restenosis (STRESS I) Study. Am J Cardiol. 1998;81:860–865.[Medline] [Order article via Infotrieve]
41. Stanton A. Primer of Biostatistics. New York, NY: McGraw-Hill; 1992.
42.
Elezi S, Kastrati
A, Neumann FJ, et al. Vessel size and long-term outcome after coronary
stent placement. Circulation. 1998;98:1875–1880.
43.
Savage MP,
Fischman DL, Rake R, et al. Efficacy of coronary stenting versus
balloon angioplasty in small coronary arteries: Stent Restenosis Study
(STRESS) Investigators. J Am Coll
Cardiol. 1998;31:307–311.
44. Fram DB, Mitchel JF, Azrin MA, et al. Local delivery of heparin to balloon angioplasty sites with a new angiotherapy catheter: pharmacokinetics and effect on platelet deposition in the porcine model. Cathet Cardiovasc Diagn. 1997;41:275–286.[Medline] [Order article via Infotrieve]
45. Dick A, Kromen W, Jungling E, et al. Quantification of horseradish peroxidase delivery into the arterial wall in vivo as a model of local drug treatment: comparison between a porous and a gel-coated balloon catheter. Cardiovasc Intervent Radiol. 1999;22:389–393.[Medline] [Order article via Infotrieve]
46. Mitchel JF, Azrin MA, Fram DB, et al. Localized delivery of heparin to angioplasty sites with iontophoresis. Cathet Cardiovasc Diagn. 1997;41:315–323.[Medline] [Order article via Infotrieve]
47.
Geary RL, Koyama
N, Wang TW, et al. Failure of heparin to inhibit intimal hyperplasia in
injured baboon arteries: the role of heparin-sensitive and -insensitive
pathways in the stimulation of smooth muscle cell migration and
proliferation. Circulation. 1995;91:2972–2981.
48.
Toschi V, Gallo
R, Lettino M, et al. Tissue factor modulates the thrombogenicity of
human atherosclerotic plaques.
Circulation. 1997;95:594–599.
49.
Gertz SD, Fallon
JT, Gallo R, et al. Hirudin reduces tissue factor expression in
neointima after balloon injury in rabbit femoral and porcine coronary
arteries. Circulation. 1998;98:580–587.
50. Kuntz RE, Gibson CM, Nobuyoshi M, et al. Generalized model of restenosis after conventional balloon angioplasty, stenting and directional atherectomy. J Am Coll Cardiol. 1993;21:15–25.[Abstract]
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