(Circulation. 2001;103:192.)
© 2001 American Heart Association, Inc.
Clinical Investigation and Reports |
Lack of Neointimal Proliferation After Implantation of Sirolimus-Coated Stents in Human Coronary Arteries
A Quantitative Coronary Angiography and Three-Dimensional Intravascular Ultrasound Study
From the Institute Dante Pazzanese of Cardiology, São Paulo, Brazil (J.E.S., M.A.C., A.A., A.S.A., F.F., I.M.F.P., A.C.S., R.S., L.A.M., A.G.M.R.S.); Cordis, a Johnson & Johnson Company, Warren, NJ (R.F., J.J.); Brigham and Women’s Hospital, Boston, Mass (J.J.P.); and Thoraxcenter, Dijkzigt University Hospital, Rotterdam, the Netherlands (P.W.S.).
Correspondence to Prof J. Eduardo Sousa, MD, PhD, Director of the Institute Dante Pazzanese of Cardiology, Av Dr Dante Pazzanese, 500 - Ibirapuera, 04012180, São Paulo, Brazil. E-mail diretoriaidpc{at}uol.com.br
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Abstract |
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 Top Abstract IntroductionMethodsResultsDiscussionConclusionReferences |
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Background—Restenosis remains an important limitation of interventional cardiology. Therefore, we aimed to determine the safety and efficacy of sirolimus (a cell-cycle inhibitor)-coated BX Velocity stents.
Methods and
Results—Thirty patients with angina pectoris
were electively treated with 2 different formulations of
sirolimus-coated stents (slow release [SR], n=15, and fast release
[FR], n=15). All stents were successfully delivered, and patients
were discharged without clinical complications. Independent core
laboratories analyzed angiographic and 3D volumetric intravascular
ultrasound data (immediately after procedure and at 4-month follow-up).
Eight-month clinical follow-up was obtained for all patients. There was
minimal neointimal hyperplasia in both groups (11.0±3.0% in the SR
group and 10.4±3.0% in the FR group,
P=NS) by ultrasound and
quantitative coronary angiography (in-stent late loss, 0.09±0.3 mm
[SR] and -0.02±0.3 mm [FR]; in-lesion late loss, 0.16±0.3 mm
[SR] and -0.1±0.3 mm [FR]). No in-stent or edge restenosis
(diameter stenosis 
50%) was observed. No major clinical events
(stent thrombosis, repeat revascularization, myocardial infarction, or
death) had occurred by 8 months.
Conclusions—The implantation of sirolimus-coated BX Velocity stents is feasible and safe and elicits minimal neointimal proliferation. Additional placebo-controlled trials are required to confirm these promising results.
Key Words: stents • restenosis • angioplasty
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Introduction |
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TopAbstractIntroductionMethodsResultsDiscussionConclusionReferences |
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Restenosis remains a vexing problem of percutaneous intervention. The most promising approach to prevent restenosis has been the application of intracoronary radiation1 ; however, some relevant side effects (edge restenosis and late thrombosis) have been reported.2 3 Numerous pharmacological approaches to reduce restenosis have failed, possibly due to insufficient local drug concentrations.4 Delivering medication directly to the site of vascular injury via polymeric-coated stents is a rational approach to achieve adequate local drug delivery.5 6
Sirolimus (Rapamune), a natural macrocyclic lactone, is a potent immunosuppressive agent that was developed by Wyeth-Ayerst Laboratories and approved by the Food and Drug Administration for the prophylaxis of renal transplant rejection in 1999.7 Sirolimus binds to an intracellular receptor protein and elevates p27 levels, which leads to the inhibition of cyclin/cyclin-dependent kinase complexes and, ultimately, induces cell-cycle arrest in the late G1 phase. It inhibits the proliferation of both rat and human smooth muscle cells in vitro8 9 and reduces intimal thickening in models of vascular injury.10 11 12 However, the effects of the local administration of sirolimus in a coated stent in humans have not been reported.
The aims of this pilot study were to assess (1) the feasibility and safety of implanting 2 different formulations of the sirolimus-coated BX Velocity stent in atherosclerotic human coronary arteries and (2) the impact of the stents on neointimal proliferation.
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Methods |
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TopAbstractIntroductionMethodsResultsDiscussionConclusionReferences |
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From December 1999 to February 2000, a single sirolimus-coated BX Velocity stent was successfully implanted in each of 30 consecutive patients with coronary artery disease. The stent is a laser-cut, 316L stainless steel, balloon-expandable stent that contains a fixed amount of sirolimus per unit of metal surface area (140 µg of sirolimus per cm2).
Sirolimus was blended in a mixture of nonerodable polymers
that have been used clinically in bone cements, ocular devices, and a
drug-releasing intrauterine
device.13 14
Fifteen patients received a fast release (FR) formulation (<15-day
drug release), and 15 received a slow release (SR) formulation
(28-day drug release).
Procedure
All stents were 18 mm long and 3.0 to 3.5 mm in
diameter. After predilatation of the target lesion, stents were
deployed with high-pressure (>14 atm) postdilatation guided by
intravascular ultrasound (IVUS). All patients received aspirin (325
mg/d, indefinitely), which was started at least 12 hours before the
procedure, and clopidogrel (300 mg immediately after stent implantation
and 75 mg/d for 60 days). The protocol was approved by the Medical
Ethics Committee of the Institute Dante Pazzanese of Cardiology, and
informed consent was obtained from every
patient.
Quantitative Measurements
Quantitative coronary angiography (QCA) and IVUS
imaging were performed immediately after the procedure and at 4-month
follow-up in all patients after a bolus infusion of intracoronary
nitrates. IVUS images were acquired using motorized pull-back at a
constant speed of 0.5 mm/s. Quantitative angiographic and volumetric
IVUS analyses were performed by independent core laboratories (Brigham
and Women’s Hospital, Boston, Mass, and Cardialysis BV, Rotterdam, The
Netherlands,
respectively).15 16 17
Three segments were selected for volumetric IVUS analysis: the stented
segment (18 mm long) and 2 edge segments that were axially 5 mm
proximal and distal to the stent margins.
Statistical Analysis
Continuous variables are expressed as mean±SD.
Comparisons between postintervention and follow-up measurements were
performed with a 2-tailed paired
t test. Comparisons between
groups were performed using an unpaired Student’s
t test.
P<0.05 was considered
statistically significant.
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Results |
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TopAbstractIntroductionMethodsResultsDiscussionConclusionReferences |
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Twenty-six patients had stable angina and 4 patients had unstable angina. Their mean age was 57.9±10 years (SR) and 55.1±7 years (FR); 63% of the patients in each group were male. The incidence of prior myocardial infarction was 33.3% (SR) and 53.3% (FR), and 14% (FR) and 26% (SR) of the patients were diabetics. All stents were implanted successfully, and all patients were discharged without complications 24 hours after treatment. Creatine kinase and creatine kinase-MB levels, sampled at 6 and 18 hours after the procedure, were within the normal range in all patients.
Angiographic and volumetric IVUS data are presented in
Tables 1
and 2. No patient approached 50%
vessel narrowing by QCA or IVUS, and only 3 patients had >15% intimal
hyperplasia (IH) by IVUS
(Figure 1). In both the edge segments and in the stented
segment, lumen loss detected by IVUS was minimal
(Figure 2). All patients completed 4 months of angiographic
and 8 months of clinical follow-up. There were no repeat
revascularizations, stent thromboses, or major clinical events
(cerebrovascular accident, myocardial infarction, or
death).
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionConclusionReferences |
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This is the first human experience with the implantation of sirolimus-coated BX Velocity stents. The absence of adverse events for up to 8 months of follow-up suggests that the implantation of this stent, which is coated with a potent cell-cycle inhibitor, is feasible and safe.
The amount of IH after the implantation of noncoated stents
ranges from 19% to 48% of stent
volume3 18 19
by IVUS, and late loss averages 0.8 to 0.9 mm by
QCA.19 Even in nonrestenotic
stents that are 
15 mm long, an average IH of 19.7% has been observed
by IVUS.18 Although
differences in population and stent design limit scientific comparison
with other reports, it is worth noting that the amount of IH detected
in the present study (10.7%; essentially zero late loss by QCA) is
much lower than previously reported. This is likely due to the
cytostatic effect of
sirolimus.10 11 12 20
Using the same IVUS methodology, the amount of in-stent IH
with radioactive stent implantation varied from 7.4% (6 to 12 µCi
radioactive stent) to 16.7% (0.75 to 1.5
µCi).17 However, neither
edge restenosis nor stent thrombosis, both of which have been reported
after radiation,2 3
were observed after the implantation of sirolimus-coated stents
(Figure 2
).
As a result of their permanent scaffolding action, stents have become an attractive platform for delivering medications locally.5 21 Although some polymers have been associated with a marked inflammatory reaction,22 these findings were not observed with the polymers used in the present investigation or in other clinical situations.13 14 In the present study, similar favorable results were observed with both the FR and SR formulations of the sirolimus-coated stent. Whether one sirolimus coating matrix is superior to the other (SR versus FR) requires further investigation.
Limitations
The study comprises a registry of only 30 patients with
4 months of QCA and 3D IVUS data and 8 months of clinical data.
However, considering the absence of late loss by QCA and the virtual
absence of IH observed in the present study by 3D IVUS and the
well-documented degree of late loss with uncoated stents, these early
results are promising. Twelve-month angiographic and IVUS follow-up
will be performed in all patients to assess whether this effect is
sustained.
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Conclusion |
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TopAbstractIntroductionMethodsResultsDiscussionConclusionReferences |
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Sirolimus-coated BX Velocity stents seem to be safe and effective in preventing neointimal formation at 4 months after stent implantation in de novo lesions. These seminal findings warrant further confirmation by large, placebo-controlled, multicenter trials.
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Acknowledgments |
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This study was sponsored by Cordis, a Johnson & Johnson Company. We thank Dr Brian Firth for his careful review of the manuscript.
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Footnotes |
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This article originally appeared Online on December 18, 2000.<(/PARAGRAPH> (Circulation. 2000;102:r54–r57.)
Received November 3, 2000; accepted December 4, 2000.
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References |
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TopAbstractIntroductionMethodsResultsDiscussionConclusionReferences |
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J. Aoki, A. C. Abizaid, P. W. Serruys, A. T.L. Ong, E. Boersma, J. E. Sousa, and N. Bruining Evaluation of Four-Year Coronary Artery Response After Sirolimus-Eluting Stent Implantation Using Serial Quantitative Intravascular Ultrasound and Computer-Assisted Grayscale Value Analysis for Plaque Composition in Event-Free Patients J. Am. Coll. Cardiol., November 1, 2005; 46(9): 1670 - 1676. [Abstract] [Full Text] [PDF]
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A E Rodriguez, M Rodriguez Alemparte, C F Vigo, C Fernandez Pereira, C Llaurado, D Vetcher, A Pocovi, and J Ambrose Role of oral rapamycin to prevent restenosis in patients with de novo lesions undergoing coronary stenting: results of the Argentina single centre study (ORAR trial) Heart, November 1, 2005; 91(11): 1433 - 1437. [Abstract] [Full Text] [PDF]
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A. E. Rodriguez, J. Baldi, C. F. Pereira, J. Navia, M. R. Alemparte, A. Delacasa, F. Vigo, D. Vogel, W. O'Neill, I. F. Palacios, et al. Five-Year Follow-Up of the Argentine Randomized Trial of Coronary Angioplasty With Stenting Versus Coronary Bypass Surgery in Patients With Multiple Vessel Disease (ERACI II) J. Am. Coll. Cardiol., August 16, 2005; 46(4): 582 - 588. [Abstract] [Full Text] [PDF]
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M. Togni, S. Windecker, R. Cocchia, P. Wenaweser, S. Cook, M. Billinger, B. Meier, and O. M. Hess Sirolimus-Eluting Stents Associated With Paradoxic Coronary Vasoconstriction J. Am. Coll. Cardiol., July 19, 2005; 46(2): 231 - 236. [Abstract] [Full Text] [PDF]
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L. Mauri, E. J. Orav, and R. E. Kuntz Late Loss in Lumen Diameter and Binary Restenosis for Drug-Eluting Stent Comparison Circulation, June 28, 2005; 111(25): 3435 - 3442. [Abstract] [Full Text] [PDF]
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K. Sakakibara, B. Liu, S. Hollenbeck, and K. C. Kent Rapamycin inhibits fibronectin-induced migration of the human arterial smooth muscle line (E47) through the mammalian target of rapamycin Am J Physiol Heart Circ Physiol, June 1, 2005; 288(6): H2861 - H2868. [Abstract] [Full Text] [PDF]
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F. B. Mehrhof, R. Schmidt-Ullrich, R. Dietz, and C. Scheidereit Regulation of Vascular Smooth Muscle Cell Proliferation: Role of NF-{kappa}B Revisited Circ. Res., May 13, 2005; 96(9): 958 - 964. [Abstract] [Full Text] [PDF]
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J. B. Hermiller, A. Raizner, L. Cannon, P. A. Gurbel, M. A. Kutcher, S. C. Wong, M. E. Russell, S. G. Ellis, R. Mehran, G. W. Stone, et al. Outcomes with the polymer-based paclitaxel-eluting TAXUS stent in patients with diabetes mellitus: The TAXUS-IV trial J. Am. Coll. Cardiol., April 19, 2005; 45(8): 1172 - 1179. [Abstract] [Full Text] [PDF]
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K. Fujii, S. G. Carlier, G. S. Mintz, Y.-m. Yang, I. Moussa, G. Weisz, G. Dangas, R. Mehran, A. J. Lansky, E. M. Kreps, et al. Stent underexpansion and residual reference segment stenosis are related to stent thrombosis after sirolimus-eluting stent implantation: An intravascular ultrasound study J. Am. Coll. Cardiol., April 5, 2005; 45(7): 995 - 998. [Abstract] [Full Text] [PDF]
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R. Wessely, J. Hausleiter, C. Michaelis, B. Jaschke, M. Vogeser, S. Milz, B. Behnisch, T. Schratzenstaller, M. Renke-Gluszko, M. Stover, et al. Inhibition of Neointima Formation by a Novel Drug-Eluting Stent System That Allows for Dose-Adjustable, Multiple, and On-Site Stent Coating Arterioscler Thromb Vasc Biol, April 1, 2005; 25(4): 748 - 753. [Abstract] [Full Text] [PDF]
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A. A. Bavry, D. J. Kumbhani, T. J. Helton, and D. L. Bhatt What is the risk of stent thrombosis associated with the use of paclitaxel-eluting stents for percutaneous coronary intervention?: A meta-analysis J. Am. Coll. Cardiol., March 15, 2005; 45(6): 941 - 946. [Abstract] [Full Text] [PDF]
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W. K. Laskey Late Follow-Up From RAVEL: Transition From Intention to Observation Circulation, March 1, 2005; 111(8): 958 - 960. [Full Text] [PDF]
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I. Herz, Y. Moshkovitz, A. Hendler, S. Z. Adam, G. Uretzky, Y. Ben-Gal, and R. Mohr Revascularization of Left Anterior Descending Artery With Drug-Eluting Stents: Comparison With Off-Pump Surgery Ann. Thorac. Surg., January 1, 2005; 79(1): 88 - 92. [Abstract] [Full Text] [PDF]
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P. A. Lemos, N. Mercado, R. T. van Domburg, R. E. Kuntz, W. W. O'Neill, and P. W. Serruys Comparison of Late Luminal Loss Response Pattern After Sirolimus-Eluting Stent Implantation or Conventional Stenting Circulation, November 16, 2004; 110(20): 3199 - 3205. [Abstract] [Full Text] [PDF]
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A. Keogh, M. Richardson, P. Ruygrok, P. Spratt, A. Galbraith, G. O'Driscoll, P. Macdonald, D. Esmore, D. Muller, and S. Faddy Sirolimus in De Novo Heart Transplant Recipients Reduces Acute Rejection and Prevents Coronary Artery Disease at 2 Years: A Randomized Clinical Trial Circulation, October 26, 2004; 110(17): 2694 - 2700. [Abstract] [Full Text] [PDF]
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T. Miyahara, H. Koyama, T. Miyata, H. Shigematsu, J.-I. Inoue, T. Takato, and H. Nagawa Inflammatory signaling pathway containing TRAF6 contributes to neointimal formation via diverse mechanisms Cardiovasc Res, October 1, 2004; 64(1): 154 - 164. [Abstract] [Full Text] [PDF]
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A. J Carter, M. Aggarwal, G. A Kopia, F. Tio, P. S Tsao, R. Kolata, A. C Yeung, G. Llanos, J. Dooley, and R. Falotico Long-term effects of polymer-based, slow-release, sirolimus-eluting stents in a porcine coronary model Cardiovasc Res, September 1, 2004; 63(4): 617 - 624. [Abstract] [Full Text] [PDF]
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D. H. Walter, M. Cejna, L. Diaz-Sandoval, S. Willis, L. Kirkwood, P. W. Stratford, A. B. Tietz, R. Kirchmair, M. Silver, C. Curry, et al. Local Gene Transfer of phVEGF-2 Plasmid by Gene-Eluting Stents: An Alternative Strategy for Inhibition of Restenosis Circulation, July 6, 2004; 110(1): 36 - 45. [Abstract] [Full Text] [PDF]
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W S Weintraub, E M Mahoney, Z Zhang, H Chu, J Hutton, M Buxton, J Booth, F Nugara, R H Stables, P Dooley, et al. One year comparison of costs of coronary surgery versus percutaneous coronary intervention in the stent or surgery trial Heart, July 1, 2004; 90(7): 782 - 788. [Abstract] [Full Text] [PDF]
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J. R Sindermann, V. Verin, J. W Hopewell, H. P. Rodemann, and J. H Hendry Biological aspects of radiation and drug-eluting stents for the prevention of restenosis Cardiovasc Res, July 1, 2004; 63(1): 22 - 30. [Abstract] [Full Text] [PDF]
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R. Mehran, M. B. Leon, D. A. Feigal, D. Jefferys, M. Simons, N. Chronos, T. J. Fogarty, R. E. Kuntz, D. S. Baim, and A. V. Kaplan Post-Market Approval Surveillance: A Call for a More Integrated and Comprehensive Approach Circulation, June 29, 2004; 109(25): 3073 - 3077. [Full Text] [PDF]
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S. Sonoda, Y. Morino, J. Ako, M. Terashima, A. H. M. Hassan, H. N. Bonneau, M. B. Leon, J. W. Moses, P. G. Yock, Y. Honda, et al. Impact of final stent dimensions on long-term results following sirolimus-eluting stent implantation: Serial intravascular ultrasound analysis from the sirius trial J. Am. Coll. Cardiol., June 2, 2004; 43(11): 1959 - 1963. [Abstract] [Full Text] [PDF]
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D. R. Holmes Jr How Many Grails Do We Need? Circulation, May 11, 2004; 109(18): 2158 - 2159. [Full Text] [PDF]
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T. Schachner, Y. Zou, A. Oberhuber, A. Tzankov, T. Mairinger, G. Laufer, and J. O. Bonatti Local application of rapamycin inhibits neointimal hyperplasia in experimental vein grafts Ann. Thorac. Surg., May 1, 2004; 77(5): 1580 - 1585. [Abstract] [Full Text] [PDF]
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J. P. Carrozza Jr Sirolimus-eluting stents: does a great stent still need a good interventionalist? J. Am. Coll. Cardiol., March 17, 2004; 43(6): 1116 - 1117. [Full Text] [PDF]
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A. Colombo, J. W. Moses, M. C. Morice, J. Ludwig, D. R. Holmes Jr, V. Spanos, Y. Louvard, B. Desmedt, C. Di Mario, and M. B. Leon Randomized Study to Evaluate Sirolimus-Eluting Stents Implanted at Coronary Bifurcation Lesions Circulation, March 16, 2004; 109(10): 1244 - 1249. [Abstract] [Full Text] [PDF]
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W. W. O'Neill and S. R. Dixon The year in interventional cardiology J. Am. Coll. Cardiol., March 3, 2004; 43(5): 875 - 890. [Full Text] [PDF]
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R. Virmani, G. Guagliumi, A. Farb, G. Musumeci, N. Grieco, T. Motta, L. Mihalcsik, M. Tespili, O. Valsecchi, and F. D. Kolodgie Localized Hypersensitivity and Late Coronary Thrombosis Secondary to a Sirolimus-Eluting Stent: Should We Be Cautious? Circulation, February 17, 2004; 109(6): 701 - 705. [Abstract] [Full Text] [PDF]
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D. R. Holmes Jr, M. B. Leon, J. W. Moses, J. J. Popma, D. Cutlip, P. J. Fitzgerald, C. Brown, T. Fischell, S. C. Wong, M. Midei, et al. Analysis of 1-Year Clinical Outcomes in the SIRIUS Trial: A Randomized Trial of a Sirolimus-Eluting Stent Versus a Standard Stent in Patients at High Risk for Coronary Restenosis Circulation, February 10, 2004; 109(5): 634 - 640. [Abstract] [Full Text] [PDF]
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Y Huang, K Salu, X Liu, S Li, L Wang, E Verbeken, J Bosmans, and I De Scheerder Methotrexate loaded SAE coated coronary stents reduce neointimal hyperplasia in a porcine coronary model Heart, February 1, 2004; 90(2): 195 - 199. [Abstract] [Full Text] [PDF]
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A. Abizaid, M. A. Costa, D. Blanchard, M. Albertal, H. Eltchaninoff, G. Guagliumi, L. Geert-Jan, A. S. Abizaid, A. G.M.R. Sousa, E. Wuelfert, et al. Sirolimus-eluting stents inhibit neointimal hyperplasia in diabetic patients: Insights from the RAVEL Trial Eur. Heart J., January 2, 2004; 25(2): 107 - 112. [Abstract] [Full Text] [PDF]
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D. Mancini, S. Pinney, D. Burkhoff, J. LaManca, S. Itescu, E. Burke, N. Edwards, M. Oz, and A. R. Marks Use of Rapamycin Slows Progression of Cardiac Transplantation Vasculopathy Circulation, July 8, 2003; 108(1): 48 - 53. [Abstract] [Full Text] [PDF]
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P. A. Lemos, P. W. Serruys, and J. E. Sousa Drug-Eluting Stents: Cost Versus Clinical Benefit Circulation, June 24, 2003; 107(24): 3003 - 3007. [Full Text] [PDF]
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W. W. O'Neill and M. B. Leon Drug-Eluting Stents: Costs Versus Clinical Benefit Circulation, June 24, 2003; 107(24): 3008 - 3011. [Full Text] [PDF]
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J. E. Sousa, P. W. Serruys, and M. A. Costa New Frontiers in Cardiology: Drug-Eluting Stents: Part I Circulation, May 6, 2003; 107(17): 2274 - 2279. [Full Text] [PDF]
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P. B. Berger Can euphoria be bad? J. Am. Coll. Cardiol., April 16, 2003; 41(8): 1289 - 1292. [Full Text] [PDF]
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R Seabra-Gomes In-stent restenosis: intracoronary {beta}-radiation at the crossroads Eur. Heart J., April 1, 2003; 24(7): 583 - 585. [Full Text] [PDF]
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A. Diez-Juan and V. Andres Coordinate Control of Proliferation and Migration by the p27Kip1/Cyclin-Dependent Kinase/Retinoblastoma Pathway in Vascular Smooth Muscle Cells and Fibroblasts Circ. Res., March 7, 2003; 92(4): 402 - 410. [Abstract] [Full Text] [PDF]
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G. A. Visner, F. Lu, H. Zhou, J. Liu, K. Kazemfar, and A. Agarwal Rapamycin Induces Heme Oxygenase-1 in Human Pulmonary Vascular Cells: Implications in the Antiproliferative Response to Rapamycin Circulation, February 18, 2003; 107(6): 911 - 916. [Abstract] [Full Text] [PDF]
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M.-K. Hong, G. S. Mintz, C. W. Lee, J.-M. Song, K.-H. Han, D.-H. Kang, J.-K. Song, J.-J. Kim, N. J. Weissman, N. E. Fearnot, et al. Paclitaxel Coating Reduces In-Stent Intimal Hyperplasia in Human Coronary Arteries: A Serial Volumetric Intravascular Ultrasound Analysis From the ASian Paclitaxel-Eluting Stent Clinical Trial (ASPECT) Circulation, February 4, 2003; 107(4): 517 - 520. [Abstract] [Full Text] [PDF]
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P.W Radke, A Kaiser, C Frost, and U Sigwart Outcome after treatment of coronary in-stent restenosis: Results from a systematic review using meta-analysis techniques Eur. Heart J., February 1, 2003; 24(3): 266 - 273. [Abstract] [Full Text] [PDF]
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R Virmani, F D Kolodgie, A Farb, and A Lafont Drug eluting stents: are human and animal studies comparable? Heart, February 1, 2003; 89(2): 133 - 138. [Abstract] [Full Text] [PDF]
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