European Heart Journal Advance Access originally published online on January 31, 2006
European Heart Journal 2006 27(8):988-993; doi:10.1093/eurheartj/ehi752
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Zotarolimus-eluting stents reduce experimental coronary artery neointimal hyperplasia after 4 weeks
1Minneapolis Heart Institute and Foundation, Minneapolis Heart Institute, 920 E. 28th St., Suite 620, Minneapolis, MN 55407, USA
2Abbott Laboratories, Abbott Park, IL 60064, USA
Received 14 January 2005; revised 15 December 2005; accepted 12 January 2006; online publish-ahead-of-print 31 January 2006.
* Corresponding author. Tel: +1 612 863 3913; fax: +1 612 863 3784. E-mail address: rss{at}rsschwartz.com
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Abstract |
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Aims The addition of drug elution to coronary stents plays an integral role in coronary restenosis prevention. The present study was undertaken to determine the mechanism of action and the in vitro and in vivo efficacy of zotarolimus, a new chemical entity designed specifically for elution from phosphorylcholine (PC)-coated stents, for the reduction of neointimal hyperplasia in porcine coronary arteries.
Methods and results In vitro studies of Zotarolimus bound to FKBP-12 potently inhibited smooth muscle cells (SMCs) and endothelial cell (EC) proliferation. Twenty PC-only and 20 stents eluting zotarolimus 10 µg/mm were implanted in the coronary arteries of 20 domestic juvenile swine. After 28 days, zotarolimus stents exhibited less area stenosis (22.4±8.6 vs. 35.7±13%, P=0.01), less neointimal area (1.69±0.55 vs. 2.78±1.07 mm2, P=0.01), less neointimal thickness (0.25±0.07 vs. 0.38±0.13 mm, P=0.01), and greater lumen area (6.07±1.39 vs. 5.02±1.3 mm2, P=0.01). All arteries in both the polymer-only and polymer/drug stent showed near-complete healing and minimal toxicity. Zotarolimus did not affect the extrastent segments nor alter the overall artery size (external elastic lamina cross-sectional area 9.18±1.19 vs. 9.06±1.28 mm2, P=0.7).
Conclusion Zotarolimus binds to FKBP-12 and in vitro inhibits SMC and EC proliferation. Zotarolimus applied to PC-coated stents reduces neointima in the swine coronary model after 28 days. These results suggest potentially promising human clinical application for coronary stenting with this polymer/drug combination.
Key Words: Stents • Restenosis • Zotarolimus • Phosphorylcholine
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Introduction |
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Drug-eluting stents with anti-proliferative agents block the progression from G1 to S in the cell cycle and inhibit the overgrowth of smooth muscle cells (SMCs). These devices play an increasingly integral role in coronary restenosis prevention. Early human clinical studies of rapamycin delivered via drug-eluting stents reduced binary restenosis rates from 15–30 to 0% in clinical trials.1 Recent studies that include more complex lesions and patients, such as those in the SIRIUS trial, show restenosis rates of
9% in patients treated with rapamycin-eluting stents.2 Zotarolimus (formerly known as ABT-578) is a newly synthesized rapamycin analogue developed specifically for elution from intravascular stents. The purpose of the present study was to determine the in vitro and in vivo efficacy of zotarolimus eluted from phosphorylcholine (PC)-coated stents in reducing in-stent neointimal hyperplasia in a porcine coronary model. |
Methods |
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Drug
Zotarolimus (Abbott Laboratories, Abbott Park, IL, USA) is [3S,[3R*[S*(1R*,3S*,4R*)],6S*,7E,9S*,10S*,12S*,14R*,15E,17E,19E,21R*, 23R*, 26S*,27S*,34aR*]]-9,10,12,13,14,21,22,23,24,25,26,27,32,33,34,34a-hexadecahydro-9,27-dihydroxy-3-[2-[3-methoxy-4-(1H-tetrazol-1-yl)cyclohexyl]-1-methylethyl]-10,21-dimethoxy-6,8,12,14,20,26-hexamethyl-23,27-epoxy-3H-pyrido[2,1-c] [1,4]oxaazacyclo-hentriacontine-1,5,11,28,29(4H,6H,31H)-pentone (Figure 1). Its empirical formula is C52H79N5O12, molecular weight 966 Da. It is an analogue of the immunosuppressant drug rapamycin, made by substituting a tetrazole ring for the hydroxyl group at position 42 in rapamycin that is isolated and purified as a natural product from fermentation.
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Polymer
The key feature of the polymer drug carrier in this study is inclusion of a synthetic copy of PC (a constituent of the lipid bilayer of the cell membrane), which mimics the structure of natural cell membranes and is known to be minimally thrombogenic. The polymer contains a phospholipid portion [2-methacryloyloxyethyl PC (MPC) and lauryl methacrylate (LMA)] bound to a cross-linking portion [hydroxypropyl methacrylate (HPMA) and trimethoxysilylpropyl methacrylate (TSMA)] (Figure 2).3,4
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Zotarolimus in vitro studies
Rapamycin forms a molecular complex with a cytoplasmic immunophilin, FK-506 binding protein (FKBP-12). This complex binds mTOR (mammalian target of rapamycin) and inhibits phosphorylation of key substrates, blocking their processing of downstream proteins regulating cell cycle progression.5 A similar cellular mechanism was hypothesized for zotarolimus, given its chemical and structural similarity to rapamycin. The affinity of the compound for binding human recombinant FKBP-12 was tested using a competitive binding assay.
Ninety-six-well microtiter plates (Maxisorp; Nunc-Immunoplate, Denmark) were first coated with FKBP-12 CMP-KDO synthetase fusion protein at 10 µg/mL, 100 µL/well for 2–3 h, followed by addition of 50 µL/well of buffer A (2% BSA and 0.2% Tween-20 in D-PBS) for 30–60 min. Microtiter plates were then washed three times with buffer B (0.2% Tween in D-PBS, pH adjusted to 7.4). Fifty microlitres of buffer A (for maximum), 20 µM FK506 in buffer A (for background), or various concentrations of zotarolimus (10 pM–1 µM) in buffer A were added to each well followed by addition of 50 µL of A-79397 (an FK506 analogue)-alkaline phosphatase conjugate in buffer A. Microtiter plates were incubated at room temperature for 2–2.5 h followed by three washes with buffer B. About 100 µL of pNPP (p-nitrophenyl-phosphate) in 0.1 M aminomethylpropanol were added to each well and plates were incubated at room temperature for 90–120 min. Absorbance at 405 nM was read using an ELISA plate reader (Molecular Devices, Sunnyvale, CA, USA).
Cell proliferation was assayed by measuring tritiated thymidine incorporation in vitro. Human coronary artery cells (hCa) were seeded into tissue culture flasks for expansion and applied to 96-well plates at desired density in complete media [5000 hCaSMC; 10 000 hCaEC). After 2 days, complete media was replaced with incomplete media to synchronize cells and induce G0 state. Two days later, incomplete media were removed and replaced with complete media (serum/growth factors) to induce G0 to G1 transition. Complete media also contained drug at desired concentrations to determine its effects on cell proliferation. On day 7, 3H-thymidine was added to cells to monitor DNA synthesis, and cells were harvested after overnight incorporation of radioactivity. After an incubation period of 72 h, 25 µL (1 µCi/well) of 3H-thymidine (Amersham Biosciences, UK) were added to each well. The cells were incubated at 37°C for 16–18 h to allow for incorporation of 3H-thymidine into newly synthesized DNA and the cells harvested onto 96-well plates containing bonded glass fibre filters (Harvester 9600; Tomtec, Hamden, CT, USA). The filter plates were air-dried overnight, MicroScint-20 (25 µL) added to each filter well and counted (TopCount; PerkinElmer, Inc., Wellesley, MA, USA). Drug activity was determined by the inhibition of 3H-thymidine incorporation into newly synthesized DNA relative to cells grown in complete medium.
Zotarolimus in vivo studies
Animal studies were conducted in accordance with the standard guidelines for the care of laboratory animals. Stainless steel BiodivYsio coronary stents (3.0x15 mm; Abbott Laboratories) were coated with a 10 µm thick polymer base layer and crimped onto delivery balloons (polymer-only stents). Zotarolimus-eluting stents 10 µg/mm (total drug load 150 µg) were made by dipping the polymer-only stents into an ethanolic solution of zotarolimus for 30 s. To determine the total stent drug loading, five zotarolimus stents were each placed in 1.7 mL of acetonitrile/water (50:50 v/v) and sonicated for 1 h. The resulting solution was then analysed by chromatography with UV detection. The average load on the five stents was then determined to be 150 or 10 µg/mm of stent length (range 150±0.15 µg/stent). Stents were sterilized with ethylene oxide and individually packaged and coded with a serial number.
One control stent (coated only with PC polymer) and one zotarolimus-eluting stent were implanted into the coronary arteries of 20 domestic crossbred juvenile swine, 2–4 months old weighing 30–40 kg. Beginning the day of the procedure, animals were given oral aspirin 325 mg daily and cefazolin 200 mg twice daily. General anaesthesia was achieved with intramuscular injection followed by intravenous ketamine 30 mg/kg and xylazine 3 mg/kg. Additional medication at the time of induction included atropine 1 mg and flocillin 1 g intramuscularly. Arterial access was obtained via surgical cut down of the right external carotid artery and placement of an 8F sheath, and an intra-arterial bolus of 10 000 units of heparin was administered. Following guiding catheter access and angiography, two arteries were selected based on size and visual suitability for stenting (length, straight segments, lack of large side branches). Most often this was the left anterior descending artery and right coronary artery (RCA). Once the target arteries were selected, the randomization to zotarolimus-eluting stents or control stent was performed in a blinded fashion. Fifteen stents were deployed in the left anterior descending coronary artery (eight control/seven zotarolimus), eight in the left circumflex artery (three control/five zotarolimus), and 17 in the RCA (nine control/eight zotarolimus). The stent balloons were inflated for <30 s to achieve a 1.1:1 to 1.2:1 stent-to-artery. Following the procedure, animals were treated for the study duration with oral aspirin 325 mg and oral ticlopidine 250 mg twice daily.
After 28 days, the animals were euthanized for histopathological examination and quantification. The hearts were perfused overnight with 10% neutral buffered formalin at physiological pressure and embedded in paraffin. Sections 5 µm thick from the proximal and distal extrastent segment and from the proximal, mid, and distal stented artery were cut using a tungsten-carbide knife. The tissues were subsequently processed and stained with haematoxylin–eosin and elastic-van Gieson techniques.
Semi-quantitative histopathological evaluation included vessel injury score6 [values of 0 for endothelium denuded, 1 for internal elastic lamina (IEL) lacerated, 2 for media lacerated, and 3 for external elastic lamina (EEL) lacerated], inflammation score7 (values of 0 for no inflammatory cells, 1 for mild inflammatory response but not circumferential, 2 for moderate to dense cellular aggregate but non-circumferential, and 3 for circumferential dense cell infiltration of the struts), endothelialization score (0 for absent endothelium, 1 for present but <25% of the lumen circumference, 2 for between 25 and 75% of the circumference, and 3 for complete endothelialization), and haemorrhage, fibrin, and luminal thrombus scores (values of 0 corresponding to absence), 1 for focal findings involving any portion of the artery but <25% of the circumference of the artery, 2 for moderate accumulations involving <25% of the circumference of the artery, and 3 for severe, involving >25% of the circumference of the artery).
Quantitative morphometric measurements using digital planimetry (IP Lab Spectrum, Vienna, VA, USA) included cross-sectional areas of the EEL, IEL, and lumen. Neointimal thickness was measured by taking the average distance from the abluminal side of each strut to the lumen. Derived measurements included neointimal area (IEL area–lumen area) and percent area stenosis {[1–[lumen area/IEL area)]x100}.
Statistical analysis
A sample size of 20 was chosen to detect a projected difference in neointimal thickness of 0.2 mm with a standard deviation of 0.15 mm, at an alpha of 0.95 and 80% power. For semi-quantitative measurements, a median value of the three stent sections was used for statistical comparisons. Quantitative measurements for each stented vessel (proximal, mid, and distal stent) were averaged to produce a mean value per stent. Normal distribution was assured for continuous variables and Student's pair t-test was used to compare the polymer alone and drug-eluting devices. Ordinal measurements were analysed using the Mann–Whitney U test. Tests of significance were two-tailed, and significance was established by a value of P<0.05.
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Results |
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In vitro studies
The FKBP-12 competitive bind assay revealed potent inhibition of binding to FKBP-12 by zotarolimus with an IC50 of 2.8±0.16 nM (Figure 3). Consistent with these data, zotarolimus was highly effective in inhibiting both SMC and EC proliferation, with IC50 values of 2.9±0.7 and 2.6±1.0 nM, respectively (Figure 4).
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In vivo studies
All animals survived to harvest and all stented coronary arteries were patent. Representative histopathological sections are shown in Figure 5. On pathological examination of arterial sections, there was no significant difference in mean injury score between control and zotarolimus-stented arteries (0.08±0.14 vs. 0.04±0.07, P=0.3). Unstented reference arterial wall sections appeared uninjured and normal in all cases in both control and drug stent groups. Similarly, there were no significant differences in the semi-quantitative histological analysis in any of the variables measured. All arteries in both the polymer-only and polymer/drug stent groups showed near-complete healing or only minimal toxicity. Minimal luminal focal thrombus and near-complete endothelialization were observed in both groups (thrombus score: control 0.16±0.37 vs. zotarolimus 0.05±0.23, P=0.5; endothelialization score: control 2.4±1.2 vs. zotarolimus 2.6±0.9, P=0.7). In general, the neointima consisted of mature SMCs and matrix proteoglycans with occasional focal regions of residual fibrin adjacent to the stent struts (fibrin score: control 0.21±0.42 vs. zotarolimus 0.05±0.23; P=0.4). A uniform and limited inflammatory response composed predominantly of macrophages, occasional lymphocytes, and rare eosinophils was evident around the stent struts (inflammation score: control 1.0±0.0 vs. zotarolimus 1.0±0.33; P=1). Lastly, focal haemorrhage was observed in only one drug-coated stent, and no cases of medial necrosis were seen in either group.
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Morphometric evaluation revealed that after 28 days coronary arteries treated with zotarolimus-eluting PC-coated stents developed lower per cent lumen stenosis (22.4±8.6 vs. 35.7±13%, P=0.01), less neointimal area (1.69±0.55 vs. 2.78±1.07 mm2, P=0.01), less neointimal thickness (0.25±0.07 vs. 0.38±0.13 mm, P=0.01), and greater lumen area (6.07±1.39 vs. 5.02±1.3 mm2, P=0.012). These results are shown graphically in Figure 6. There were no drug effects on arterial remodeling, as overall arterial size was similar between the two groups (external elastic lamina cross-sectional area: control 9.06±1.28 vs. zotarolimus 9.18±1.19 mm2, P=0.7).
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Discussion |
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The present study was undertaken to determine the mechanism of action of zotarolimus, a rapamycin analogue, and its in vitro and in vivo efficacy. This study showed that, like rapamycin, zotarolimus binds to the intracellular protein FKBP-12 and is a potent inhibitor of SMC and EC proliferation. In vivo, zotarolimus-eluting stents effectively reduced neointima formation in a 28-day, well-characterized swine model of coronary artery restenosis. In addition, both the polymer/drug and the polymer-only groups showed nearly complete healing with a low toxicity profile. This is characterized by virtually complete endothelialization, with at most mild inflammation and minimal focal fibrinoid deposition and haemorrhage, and no medial necrosis.
Since the introduction of percutaneous transluminal coronary angioplasty and stenting, restenosis has been a major factor limiting its long-term success. Over the past few years, drugs loaded in polymer matrices and eluted from stents have radically changed interventional outcomes. Drug-eluting stents are complex intravascular devices in which the careful selection of the combination of stent, drug, and coating can result in sustained therapeutic success. Of these components, the carrier polymer is probably the most undervalued and least understood element of a drug eluting stent system. Polymers can induce stent thrombosis, stimulate inflammation, and neointimal hyperplasia.8 Therefore, appropriate polymer selection and biocompatibility testing are crucial for both pre-clinical and clinical studies. This study included a control group with devices that were coated with polymer-only (rather than bare stents), which allowed biocompatibility testing of the polymer alone and the bioactive agent plus polymer. PC polymer-only stents had excellent biocompatibility as shown by mild inflammatory reactions, near-complete endothelialization, and near absence of thrombus. These results are consistent with previously published results showing that the PC coating is minimally thrombogenic3 and associated with rapid re-endothelialization and only mild inflammation in implanted coronary arteries.9–11
The combination of an appropriate biocompatible polymer with a suitable cell proliferation inhibitor represents an attractive approach to the in-stent restenosis problem. Zotarolimus was selected as a drug for delivery from PC-coated stents based on the combination of both physicochemical properties and in vitro testing. Results from the in vitro studies presented herein showed that zotarolimus binds to FKBP-12 and potently inhibits SMC cell proliferation by blocking the cell-cycle progression at the juncture of G1 and S phases. This mechanism of action is similar to that described for rapamycin5 and the results are not surprising given their close structural analogy. Results of (dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assays additionally indicate that zotarolimus is non-cytotoxic at the concentrations used in the present study (data not shown). Lastly, substituting a tetrazole ring for the hydroxyl group at position 42 in rapamycin confers zotarolimus a higher octanol:water partition coefficient conferring the potential advantage of marked lipophilicity and low aqueous solubility. This property may be useful for elution from an intravascular stent, because theoretically it provides both preferential uptake by the vessel wall and minimal loss of drug to the systemic circulation.12
The potential efficacy of zotarolimus demonstrated in vitro was confirmed by the in vivo results. Porcine coronary arteries treated with zotarolimus-eluting stents showed significant reductions in neointimal thickness, neointimal area, and per cent lumen stenosis compared with their PC-only counterparts. This degree of efficacy is comparable to similar studies published with paclitaxel and sirolimus eluted from stents. For example, Heldman et al.,13 testing paclitaxel-coated stents deployed in the coronary arteries of minipigs demonstrated similar reductions in neointimal area after 28 days (39% reduction). Suzuki et al.14 implanted stents containing rapamycin in a poly-n-butyl methacrylate and polyethylene–vinyl acetate copolymer matrix and showed a 50% reduction in neointimal hyperplasia compared with a bare metal stenting. Although pre-clinical results only infrequently mimic the eventual clinical experience, it is noteworthy that each of rapamycin,1 paclitaxel,14 and, recently, zotarolimus15,16 have been shown to be effective in pivotal clinical trials of percutaneous coronary intervention.
In addition to the efficacy of zotarolimus demonstrated in this experimental model, several histological findings also suggest the clinical safety of this approach. Endothelialization was largely complete by 28 days, and there was no acute or subacute thrombosis. Histopathological evaluation of the stent edges showed that zotarolimus did not affect the extrastent segments, as proximal and distal extrastent margins were similar in appearance to normal, unstented arteries (similar results were seen in the polymer-only group). Lastly, there were no apparent effects on arterial remodelling, as overall arterial size was similar in PC-only and zotarolimus stents.
The principal limitation of the present study is lack of long-term follow-up. Although the porcine stent experimental model is an accepted standard for evaluation of pre-clinical safety and efficacy, the potential for long-term arterial toxicity and possible induction of late thrombosis is not addressed by these results. However, data from the present study suggest promising human clinical application for coronary stenting with this polymer/drug combination. Large-scale clinical testing of intravascular-delivered zotarolimus and PC has begun. Preliminary results of the Endeavor studies (ENDEAVOR I15, the first-in-man trial, and ENDEAVOR II16, conducted to evaluate the efficacy of the zotarolimus-eluting stent compared with bare metal stents) are concordant with safety and efficacy results obtained in the present study. In both clinical studies, the zotarolimus stent was shown to be safe, providing a sustainable clinical outcome with low rates of major adverse cardiac events (2%)15 and 8.1% target vessel failure (TVF) (composite of cardiac death, myocardial infarction, and target vessel revascularization)16. In addition, acute and subacute stent thrombosis associated with this platform did not occur in the Endeavor I study15 and was rare in the Endeavor II study typically occurring during the first month post-intervention.16 There is no evidence of late-stent malapposition or late aneurysm associated with this platform. In addition to the promising safety profile, zotarolimus appears effective in preventing neointimal thickening, reducing late loss from 1.03 to 0.62 mm with a 47% reduction in TVF compared with bare metal stents (15.4% with the Driver stent to 8.1% with the Endeavor stent).16
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Conclusions |
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TopAbstractIntroductionMethodsResultsDiscussionConclusionsAcknowledgementReferences |
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Zotarolimus binds to the intracellular receptor FKBP-12 and potently inhibits SMC and EC proliferation. PC-coated stents eluting zotarolimus delivered to porcine coronary arteries significantly reduce neointimal hyperplasia in this 28-day swine model showing nearly complete healing with a low toxicity profile. These results suggest potentially promising human clinical application for coronary stenting with this polymer/drug combination.
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Acknowledgement |
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A.G.-T. is supported by a grant from the Working Group on Ischemic Heart Disease of the Spanish Society of Cardiology.
Conflict of interest: R.S.S. has previously received research support from Abbott Laboratories and serves on an Abbott Scientific Advisory Board. S.E.B., J.L.T., and K.C. are employees of Abbott Laboratories.
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- Morice MC, Serruys PW, Sousa JE, Fajadet J, Ban Hayashi E, Perin M, Colombo A, Schuler G, Barragan P, Guagliumi G, Molnar F, Falotico R. A randomized comparison of a sirolimus-eluting stent with a standard stent for coronary revascularization. N Engl J Med 2002;346:1773–1780.
[Abstract/Free Full Text] - Moses JW, Leon MB, Popma JJ, Fitzgerald PJ, Holmes DR, O'Shaughnessy C, Caputo RP, Kereiakes DJ, Williams DO, Teirstein PS, Jaeger JL, Kuntz RE. Sirolimus-eluting stents versus standard stents in patients with stenosis in a native coronary artery. N Engl J Med 2003;349:1315–1323.
[Abstract/Free Full Text] - Lewis AL, Stratford PW. Phosphorylcholine-coated stents. J Long Term Eff Med Implants 2002;12:231–250.[Medline]
- Lewis AL, Cumming ZL, Goreish HH, Kirkwood LC, Tolhurst LA, Stratford PW. Crosslinkable coatings from phosphorylcholine-based polymers. Biomaterials 2001;22:99–111.[Medline]
- Sehgal SN. Sirolimus: its discovery, biological properties, and mechanism of action. Transplant Proc 2003;35:7S–14S.[CrossRef][Web of Science][Medline]
- Schwartz RS, Huber KC, Murphy JG, Edwards WD, Camrud AR, Vlietstra RE, Holmes DR. Restenosis and the proportional neointimal response to coronary artery injury: results in a porcine model. J Am Coll Cardiol 1992;19:267–274.[Abstract]
- Kornowski R, Hong MK, Tio FO, Bramwell O, Wu H, Leon MB. In-stent restenosis: contributions of inflammatory responses and arterial injury to neointimal hyperplasia. J Am Coll Cardiol 1998;31:224–230.
[Abstract/Free Full Text] - Bertrand OF, Sipehia R, Mongrain R, Rodes J, Tardif JC, Bilodeau L, Cote G, Bourassa MG. Biocompatibility aspects of new stent technology. J Am Coll Cardiol 1998;32:562–571.
[Abstract/Free Full Text] - Malik N, Gunn J, Shepherd L, Crossman DC, Cumberland DC, Holt CM. Phosphorylcholine-coated stents in porcine coronary arteries: in vivo assessment of biocompatibility. J Invasive Cardiol 2001;13:193–201.[Medline]
- Lewis AL, Tolhurst LA, Stratford PW. Analysis of a phosphorylcholine-based polymer coating on a coronary stent pre- and post-implantation. Biomaterials 2002;23:1697–1706.[CrossRef][Web of Science][Medline]
- Whelan DM, van der Giessen WJ, Krabbendam SC, van Vliet EA, Verdouw PD, Serruys PW, van Beusekom HM. Biocompatibility of phosphorylcholine coated stents in normal porcine coronary arteries. Heart 2000;83:338–345.
[Abstract/Free Full Text] - DuVall M, Ji Q, Clifford A, Barry CM, Nowak SA, Sabaj KM, Zielinski DA, Smits G, Zhang J, Cromack K, Dube H, Schwartz LB, Krasula RW. ABT-578 elution profile and arterial penetration using the ZoMaxx drug-eluting stent. (Abstract). Am J Cardiol 2004;94:223E.
- Heldman AW, Cheng L, Jenkins GM, Heller PF, Kim DW, Ware M Jr, Nater C, Hruban RH, Rezai B, Abella BS, Bunge KE, Kinsella JL, Sollott SJ, Lakatta EG, Brinker JA, Hunter WL, Froehlich JP. Paclitaxel stent coating inhibits neointimal hyperplasia at 4 weeks in a porcine model of coronary restenosis. Circulation 2001;103:2289–2295.
[Abstract/Free Full Text] - Suzuki T, Kopia G, Hayashi S, Bailey LR, Llanos G, Wilensky R, Klugherz BD, Papandreou G, Narayan P, Leon MB, Yeung AC, Tio F, Tsao PS, Falotico R, Carter AJ. Stent-based delivery of sirolimus reduces neointimal formation in a porcine coronary model. Circulation 2001;104:1188–1193.
[Abstract/Free Full Text] - Meredith IT, Ormiston J, Whitbourn R. ENDEAVOR I ‘first-in-human’ safety and efficacy study—12-month clinical, angiographic, and intravascular ultrasound results. AHA 2004 Annual Scientific Session, 2004.
- Wijns W, Fajadet J, Kuntz RE. ENDEAVOR II: a randomized comparison of the endeavor ABT-578 drug-eluting stent with a bare metal stent for coronary revascularization. ACC 2005 Annual Scientific Session, 2005.
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