Drug-eluting stents: Miscellaneous

THURSDAY 9/30/04 10:30

AM-12:30 PM

(Hall D and E on Level 2)

Drug-Eluting Stents: Miscellaneous Thursday, September 30, 2004 10:30 AM–12:30 PM Hall D and E on Level 2 (Abstract nos. 484 – 498)

TCT-484 ABT-578 Elution Profile and Arterial Penetration Using the ZoMaxx Drug-Eluting Stent. M. DuVall, Abbott Vascular Devices; J.I. Qin, Abbott Vascular Devices; A. Clifford, Abbott Vascular Devices; C.M. Barry, Abbott Vascular Devices; S.A. Nowak, Abbott Vascular Devices; K.M. Sabaj, Abbott Vascular Devices; D.A. Zielinski, Abbott Vascular Devices; G. Smits, Charles River Laboratories; J. Zhang, Abbott Vascular Devices; K. Cromack, Abbott Vascular Devices; H. Dube, Abbott Vascular Devices; L.B. Schwartz, Abbott Vascular Devices; R.W. Krasula, Abbott Vascular Devices. Background: The release pharmacokinetics and arterial penetration of antiproliferative agents from drug-eluting intravascular stents are key components of their safety and efficacy. This experiment was performed to test the hypothesis that the ZoMaxx ABT-578-eluting stent would safely deliver high concentrations of drug to the target tissue while generating relatively low systemic concentrations. Methods: The ZoMaxx coronary drug-eluting stent contains 10 ␮g/mm ABT-578 incorporated into a biocompatible phosphorylcholine coating. In this study, the release pharmacokinetics and arterial penetration of ABT-578 after 15 ⫻ 3.0 mm ZoMaxx stent implantation was compared with similar parameters of rapamycin elution from 13 ⫻ 3.0-mm Cypher stents (1.40 ␮g rapamycin/mm2; approximately 8.5 ␮g/mm). Using carotid artery access, 64 stents (32 per group) were implanted in the common iliac arteries of 32 New Zealand White rabbits expanded to a 1:1.1 balloon-to-artery ratio. After 6 hours and 1, 2, 3, 5, 7, 14, and 28 days (4 stents per group per time point), animals were euthanized and the stented arteries excised and assayed for ABT-578 or rapamycin by high-performance liquid chromatography. Using similar methods, the amount of drug remaining on the explanted stent and in the systemic circulation was measured. Results: All animals survived to the designated times of harvest, and all stented arteries were patent. The elution profiles of the ZoMaxx and Cypher stents were similar in that the drug was slowly released from the stent during the first 28 days (top Figure). However, the ZoMaxx stent exhibited consistently higher concentrations in the target arteries (middle Figure) as well as consistently lower whole blood concentrations throughout the time of elution (bottom Figure). Conclusion: In conclusion, when compared with the Cypher stent, the ZoMaxx stent delivers significantly higher concentrations of antiproliferative agent to normal target arteries and generates lower systemic drug concentrations.

The American Journal of Cardiology姞

P O S T E R TCT-485 Safety of MRI Early after Implantation of a Drug-Eluting Stent. I. Porto, Department of Cardiology, John Radcliffe Hospital, Oxford, UK; J.B. Selvanayagam, University of Oxford Centre for Clinical Magnetic Resonance Research, Oxford, UK; K.M. Channon, Departments of Cardiovascular Medicine, University of Oxford, Oxford, UK; S.E. Petersen, University of Oxford Centre for Clinical Magnetic Resonance Research, Oxford, UK; J.M. Francis, University of Oxford Centre for Clinical Magnetic Resonance Research; Oxford, UK; S. Neubauer, University of Oxford Centre for Clinical Magnetic Resonance Research; A.P. Banning, Department of Cardiology, John Radcliffe Hospital, Oxford, UK. Background: Despite emerging evidence that magnetic resonance imaging (MRI) scanning is safe early after bare-metal coronary stenting, no data are currently available on the safety of MRI early after implantation of drug-eluting stents (DES). There are theoretical concerns that the heating effects from MRI scanning might interfere with the stent– drug polymer interface, impeding drug elution.

SEPTEMBER 30, 2004

TCT ABSTRACTS/Poster

223E

A B S T R A C T S

THURSDAY 9/30/04 10:30 Methods: As a part of a clinical study aiming at quantifying myocardial necrosis after percutaneous coronary intervention (PCI), 50 patients at our institution underwent cardiac MRI (1.5 T) at a median of 1 day after complex PCI. In 15 of these patients, at least 1 DES was used: paclitaxel DES in 14, and sirolimus DES in 1. In all the DES patients, MRI examination was done 1 day after PCI. Abciximab and double antiplatelet therapy with aspirin and clopidogrel were used in all patients, as per study protocol. Possible stent thrombosis was defined as sudden death without clear noncardiac cause or myocardial infarction at the site of stent implantation. All in-hospital events were recorded. DES patients were contacted by phone for a 30-day follow-up of major adverse cardiac events. Results: In our entire population, the average number of stents per patient was 2.2 ⫾ 1.1, and the average stent length per patient was 37.8 ⫾ 19.7 mm. No acute stent thrombosis (less than 48 hours after PCI, 24 hours after MRI) occurred. No serious adverse events were reported during MRI examination. In the DES group, average number of DES was 1.75 ⫾ 1.0 per patient (3 patients received 3 DES), and average length of DES was 36.5 ⫾ 14.8 mm per patient. In these 15 patients, no acute or subacute stent thromboses were reported. Conclusions: In 15 patients with complex PCI and a freshly implanted DES, MRI appears to be safe, because no stent thrombosis occurred within 30 days. This observation should be replicated in larger series.

TCT-486

AM-12:30 PM

(Hall D and E on Level 2)

served from the more hydrophobic combinations C and D (see Table). Eluted drug retained the ability to inhibit proliferation of early passage human coronary artery smooth muscle cells. When fluvastatin release was investigated for up to 38 days, eluted concentrations did not fall below 0.1 ␮M. Conclusions: Fluvastatin release from plum pudding gels can be tightly controlled in a manner that depends on the relative hydrophobicities of both microgel and matrix components of these novel systems.

TCT-487 Local Delivery of Novel Antisense AVI-4126 with Infiltrator Catheter in De Novo Native and Restenotic Coronary Arteries: Six-Month Clinical and Angiographic Follow-up from AVAIL Study. N. Kipshidze, Lenox Hill Heart and Vascular Institute, Cardiovascular Research Foundation, New York, NY; P. Overlie, Covenant Hospital, Lubbock, TX; T. Dunlap, Santa Rosa Memorial Hospital, Santa Rosa, CA; B. Titus, Legacy Good Samaritan Hospital, Portland, OR; D. Lee, Glendale Memorial Hospital Glendale, CA; M. Lauer, Borgess Medical Center, Kalamazoo, MI; M.B. Leon, Lenox Hill Heart and Vascular Institute, Cardiovascular Research Foundation, New York, NY.

Methods: Fluvastatin was incorporated into microgels at 4°C, which were dispersed in either a 65/35 or 85/15 copolymer matrix. Copolymer films were cast and dried at room temperature, and drug release (monitored as [14C]-fluvastatin) at 37°C was measured every 24 hours. Results: Fluvastatin release was most rapid from the most hydrophilic microgel/matrix combination A, and slowest release was ob-

Background: A novel antisense phosphorodiamidate Morpholino oligomer, AVI-4126, has been shown to be effective in reducing neointimal formation in various animal models following delivery by pluronic gels, porous balloon catheters, and coated stents. The purpose of the AVAIL study was to investigate both safety and efficacy of AVI4126 delivered locally via an Infiltrator catheter after percutaneous coronary intervention (PCI) in humans. Methods: The AVAIL trial is prospective, evaluator-blinded, randomized study including clinical follow-up at 30 days and 6 months after intervention and 6-month angiographic and intravascular ultrasound (IVUS) follow-up. Infiltrator catheter was advanced to target lesion, and either drug was delivered (group A and B) or catheter was inflated (group C) after stent implantation in de novo lesions or percutaneous transluminal coronary angioplasty in restenotic lesions. Primary endpoints include major cardiac adverse events (MACE), target vessel revascularization (TVR), angiographic restenosis, and IVUS at 6 months. Results: Forty-six patients with either de novo lesions or restenosis were randomized into 3 groups: A (low dose), 3 mg (n ⫽ 15); B (high dose), 10 mg (n ⫽ 15), and C, control (n ⫽ 16). Baseline angiographic characteristics did not differ between the groups (reference vessel diameter: 2.5– 4 mm, lesion length ⬍16 mm). Procedural success was 84.2% (unable to advance Infiltrator catheter to target lesion in 7 patients: 1 patient in group B and 6 patients from group C). There was no in-hospital or 30-day MACE recorded in any group. Clinical follow-up was available in 36 patients. At 6 months, 3 patients (33.3%) from the control group (n ⫽ 9) and 6 (46.1%) patients from the low-dose group A (n ⫽ 13) required TVR. In contrast, in the high-dose group B (n ⫽ 14), only 1 patient (7.1%) needed TVR. Angiographic follow-up in 33 patients (12 patients in group A, 12 patients in group B, and 9 patients in group C) demonstrated late loss of 1.45 ⫾ 0.19, 0.74 ⫾ 0.16, and 1.26 ⫾ 0.19, respectively (p ⫽ 0.025). Binary restenosis was 33.3% in group C (control), 33.3% in group A (low dose), and 8.3% in group B (high dose). Conclusions: Local delivery of antisense is safe and feasible. These preliminary findings from the small cohort of patients require confirmation in a larger trial using more sophisticated drug-eluting technologies.

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SEPTEMBER 30, 2004

Evaluation of Novel “Plum-Pudding” Gels as Vehicles for Local Delivery of Fluvastatin. F. McGillicuddy, Conway Institute, University College Dublin, Ireland; I. Lynch, University College Dublin, Ireland, and University of Lund, Sweden; K.A. Dawson, University College Dublin, Ireland; A.K Keenan, Conway Institute, University College Dublin, Ireland.

P O S T E R

Background: Controlled delivery of the HMG-CoA reductase inhibitor fluvastatin from the intravascular stent surface represents a potential therapeutic modality for prevention of in-stent restenosis. The aim of this study was to evaluate novel structural motifs known as “plum pudding” gels as potential drug-eluting stent coatings. These gels comprise thermoresponsive microgel particles containing (w/w) 50/50 or 65/35 p(N-isopropylacrylamide)/N-tert-butylacrylamide p(NiPAAm/NtBAAm) randomly dispersed in a 65/35 or 85/15 copolymer matrix (see Table). Gels containing the hydrophilic monomer NiPAAm can be made more hydrophobic by mixture with increasing amounts of NtBAAm.

A B S T R A C T S

Total Drug Microgel/Matrix Loaded/Film % Eluted by % Eluted by % Remaining Combination (nmol/mL) 24 Hours Day 24 at Day 24 A 65:35 microgel 85:15 matrix B 50:50 microgel 85:15 matrix C 65:35 microgel 65:35 matrix D 50:50 microgel 65:35 matrix

17.25 ⫾ 0.67 21.0 ⫾ 0.58 65.63 ⫾ 1.72

36.74 ⫾ 2.55

17.42 ⫾ 0.29 15.67 ⫾ 1.03 53.41 ⫾ 1.75

46.11 ⫾ 0.99

19.27 ⫾ 0.56 2.67 ⫾ 0.21 14.53 ⫾ 0.89

85.31 ⫾ 2.24

14.11 ⫾ 0.33 2.76 ⫾ 0.25 12.55 ⫾ 0.62

87.27 ⫾ 2.22

The American Journal of Cardiology姞

TCT ABSTRACTS/Poster

THURSDAY 9/30/04 10:30

AM-12:30 PM

(Hall D and E on Level 2)

TCT-488 Abluminal Bioerodable Polymer Stent Coating, Applicable at Point-of-Care, Provides Safe Delivery of Paclitaxel in Porcine Coronary Arteries. A.R. Groothuis, P. Seifert, A. Spognardi, T. Aldrich, D.S. Baim, C. Rogers, Brigham and Women’s Hospital, Boston, MA. Background: Current drug-eluting stents (DES) are limited to single drugs uniformly applied to specific stent designs. Future generations should offer greater flexibility to tailor stent design and drug choice to patient- or lesion-specific needs. Methods: We evaluated in porcine coronary arteries stents coated with a novel technology allowing precise and rapid coating of some or all of the abluminal surface of any stent design with a mixture of a bioerodible polymer and paclitaxel (PACL). Stents ([bare, B, n ⫽ 3], polymer only [P, n ⫽ 8], low polymer formulation [LL, 2% PACL, 0.5% polymer, n ⫽ 8], or high polymer formulation [HL, n ⫽ 7, 2% PACL, 2% polymer]) were examined 28 days after implant. Results: There was no occurrence of stent thrombosis, and intimal thickening was equivalent in all groups (range 0.22 ⫾ 0.04 to 0.29 ⫾ 0.04 mm). Immunohistochemistry (CD 45) showed absence of polymer-induced inflammation compared with B. HL showed clear evidence for PACL effect (greater fibrin [Carstair’s] and inflammatory cells and fewer endothelial cells [CD 31]). Some stents were coated partially (distal segment only) and showed clear regionality to PACL effect limited to the coated portion (Table)

Carstair’s, Carstair’s, CD 45, CD 45, CD31, CD31, prox (0–4) dist (0–4) prox (0–4) dist (0–4) dist (0–5) dist (0–5) Bare 0 Polymer 0.2 ⫾ 0.2 only High 0.2 ⫾ 0.2 loading

0 0.2 ⫾ 0.2

1⫾0 1.8 ⫾ 0.3

2 ⫾ 0 3.0 ⫾ 0.3 5.0 ⫾ 0.3 1.5 ⫾ 0.6 4.4 ⫾ 0.2 3.8 ⫾ 0.5

2.0 ⫾ 0.3†

2.0 ⫾ 0

3.0 ⫾ 0

3.2 ⫾ 0.7 2.3 ⫾ 0.5*

*p ⬍0.06 vs polymer. †p ⬍0.001 vs polymer. Conclusions: (1) Juxtaposed abluminal (JA) stent coating using low basis weight of an abluminally applied bioerodable polymer is safe and capable of delivering drugs. (2) The JA Coating process appears to reduce the inflammatory response traditionally documented with highbasis weight enveloped-coated stents with similar polymer-only coatings. (3) Segmental coating of stents of varied design may provide a unique method for evaluating complex drug effects and multiple drug strategies.

angiomax in 18%. There were 2,265 elective procedures and 162 ST-segment elevation MI interventions. For elective procedures, 29% had percutaneous coronary intervention (PCI) only, 51% had ad hoc PCI, and 20% had cath and PCI on separate days during the same admission; 1,696 received Cypher stents, 114 received Taxus stents, and 10 received both. Median cost of BMS PCI only (n ⫽ 45) was $7,501 vs $9,432 for DES (n ⫽ 500). Coronary artery bypass graft (CABG) volume decreased by 33.3% compared with a predicted decrease of 10%. There has been no significant change in interventional volume, yet readmission rates for PCI cases have fallen 50% compared with a predicted decrease of 25%. The vendor modeled 1.5 stents per case vs 1.7 DES/procedure actually implanted. Vendor models suggested a 1-year adoption rate of 75% vs actual 1 year adoption of 79%. Once supply abated, DES were used in ⬎90% of cases. As stent use has increased, cost per stent has fallen and procedure costs have remained stable (see Table).

Stent procedures DES use (%) CABG volume (cases) % Cases instent restenosis DES stents per patient Change in DES cost Elective DES only cost (median) Elective DES ⫹ cath cost (median) Elective ad hoc DES cost (median) STEMI DES procedure cost (median)

May 2003July 2003

Aug 2003Oct 2003

Nov 2003Jan 2004

Feb 2004Apr 2004

633 57.0 153 11.7%

576 83.8 134 9.4%

591 86.1 112 8.8%

627 91.3 102 6.1%

1.6 0 $8,964

1.7 ⫺6% $9,326

1.9 ⫺11% $10,698

1.8 ⫺24% $9,638

$13,103

$14,793

$17,283

$15,356

$9,905

$10,492

$10,580

$10,962

$14,251 (n ⫽ 11)

$13,628 (n ⫽ 21)

$15,282 (n ⫽ 24)

$12,836 (n ⫽ 21)

Conclusions: Drug-eluting stent use increased significantly over the first year. CABG volume has decreased significantly. Repeat procedures for in-stent restenosis have decreased. Despite reduction in cost of DES, elective procedure costs have increased slightly, whereas the cost of acute MI procedures has dropped. Stents per patient were higher than the 1.5 predicted by vendor model.

TCT-490

Economic Impact of Drug-Eluting Stents (DES). A. Moore, C. Lucore, G. Mishkel, R. Ligon. Prairie Heart Institute, Springfield, IL.

A Novel Porcine Model Predicts Drug-Eluting Stent Efficacy and Safety. A.G. Touchard, Minneapolis Heart Institute Foundation, Minneapolis, MN; M.E. Russell, Boston Scientific Corporation; B. Poff, Boston Scientific Corporation; G.S. Price, Boston Scientific Corporation; R.S. Schwartz, Minneapolis Heart Institute Foundation, Minneapolis, MN.

Background: We evaluated the impact of drug-eluting stents (DES) on the cardiology product line at a high-volume cardiac center and compared those findings with prerelease economic models. Methods: We reviewed interventional and surgical volumes, readmission rates, and hospital costs during the first year of commercial release of DES. These data were then compared with commercial economic assumptions. Results: From May 1, 2003, to April 31, 2004, we performed 2,427 stent procedures. Overall 13% had bare-metal stents (BMS), 75% had DES, and 4% had both DES and BMS during the same admission. Glycoprotein IIb/IIIa inhibitors were used in 78% of patients and

Background: The porcine coronary artery overstretch injury model effectively predicts the safety of drug-eluting stents (DES) in humans, but it is not useful to test stent efficacy because of the variable and modest neointimal response that occurs. Therefore, we developed a model using thermal injury to induce diffuse and robust neointimal thickening and restenosis and examined its ability to predict DES efficacy. Methods: Porcine coronary arteries were focally exposed to high temperatures (74 – 82°C ⫻ 30 sec), followed by immediate placement of drug-eluting stents at the heat lesion site. The heat injury ablated normal media in a single, time-limited event.

TCT-489

The American Journal of Cardiology姞

SEPTEMBER 30, 2004

TCT ABSTRACTS/Poster

225E

P O S T E R A B S T R A C T S

THURSDAY 9/30/04 10:30 Results: Sixteen each of bare metal (BMS) and paclitaxel-eluting stents (PES) were deployed to the coronary arteries in 11 juvenile domestic crossbred swine after thermal injury. Within 28 days, quantitative coronary angiography (QVA), intravascular ultrasound (IVUS), and morphometry demonstrated that thermal injury produced diffuse stenosis within the stents. The neointimal burden induced by thermal injury was 2-fold greater than that observed with the traditional porcine overstretch injury model. Abundant concentric neointimal hyperplasia without IEL or EEL disruption or excessive inflammation was confirmed by histopathology. PES were associated with significantly less neointimal thickness (0.25 ⫾ 0.08 vs 0.45 ⫾ 0.14 mm, p ⬍0.0001), percent stenosis (29 ⫾ 8% vs 50 ⫾ 14%, p ⬍0.0001), and late loss (1.00 ⫾ 0.38 vs 1.85 ⫾ 0.38 mm p ⬍0.0001) vs BMS, suggesting neointimal inhibition by paclitaxel. Conclusion: This thermal coronary lesion model generates voluminous neointima by 28 days and discriminates between different antirestenosis treatments. Paclitaxel-eluting stents significantly reduce neointima in a manner that is qualitatively and quantitatively similar to results reported in PES human clinical studies. This unique model appears promising for accurately predicting DES efficacy in patients.

TCT-491 QCA and IVUS Correlate with Histomorphometry in a Novel Porcine Coronary Restenosis Model. A.G. Touchard, Minneapolis Heart Institute Foundation, Minneapolis, MN; M.E. Russell, Boston Scientific Corporation; B. Poff, Boston Scientific Corporation; G.S. Price, Boston Scientific Corporation; R.S. Schwartz, Minneapolis Heart Institute Foundation, Minneapolis, MN.

P O S T E R A B S T R A C T S

Background: We developed a novel porcine coronary restenosis efficacy model in which focal exposure to heat (74 – 82°C ⫻ 30 sec) before stent implantation induces a neointimal burden of approximately 450 ␮ within 28 days. This study was designed to compare results of clinical diagnostic quantitative coronary angiography (QCA) and intravascular ultrasound (IVUS) with the standard histopathology assessments. Methods: Bare metal (n ⫽ 16) and paclitaxel-eluting stents (n ⫽ 16) were deployed in 11 juvenile domestic crossbred pigs after coronary thermal injury. After 28 days, both neointimal and lumen area and percent stenosis were measured by QCA, IVUS, and morphometry. Results: Regression analysis shows a strong correlation between morphometry and both QCA- and IVUS-based measurements (Table). Moreover, QCA- and IVUS-based % stenosis measurements were also correlated (r2 ⫽ 0.86).

AM-12:30 PM

(Hall D and E on Level 2)

Antirestenotic Agent. J.F. Granada, Baylor College of Medicine, Pearland, TX; G.L. Kaluza, Baylor College of Medicine, Pearland, TX; S. Furnish, Endovascular Devices; A.E. Raizner, Baylor College of Medicine, Pearland, TX; A.N. Keswani, Baylor College of Medicine, Pearland, TX; W. Durante, Baylor College of Medicine, Pearland, TX. Background: Mitomycin (MMc) is an antiproliferative compound known to inhibit the proliferation of several cell lines in vitro. However, there are few data regarding the biological effect of MMc on vascular smooth muscle cells (SMCs). We aimed to determine the mechanism of action by which MMc inhibits the proliferation of SMCs and the effect of MMc on cellular structure. Methods: Serum (5%)-stimulated rat aortic SMCs were used in these experiments. Escalating doses of MMc (1 nm to 30 ␮M) were used to determine the degree of inhibition of cell growth and to identify the concentration at which MMc became cytotoxic to SMC. Cell cycle dynamics were evaluated by flow cytometry and protein expression determined by Western blot analysis. Results: MMc inhibited SMC proliferation by arresting cells in the G2/M phase of the cell cycle. At doses less than 100 nmol/mL, MMc exerted a cytostatic effect on SMC without causing apoptosis or necrosis. No SMC apoptosis or necrosis was seen at this dose. At 30 nmol/mL, MMc failed to block serum-mediated increases in cyclin D, E, A, and B expression or the phosphorylation of retinoblastoma protein, but it caused a marked increase in the expression of the cyclin-dependent kinase inhibitor p21. MMc concentrations above 0.3 ␮mol/mL induced SMC apoptosis, as reflected by cell rounding and blebbing, DNA laddering, and caspase-3 activation. Conclusion: MMc inhibits SMC proliferation by arresting cells in the G2/M phase of the cell cycle. At doses less than 100 nmol/mL, MMc exerts a potent cytostatic effect with no structural cellular damage. MMc may be a suitable candidate to prevent neointimal proliferation after vascular injury if adequate tissue concentrations can be achieved in vivo.

TCT-493 Stent Struts Number and Distribution Influence the Magnitude of Neointimal Hyperplasia after Sirolimus-Eluting Stent Implantation. H. Takebayashi, S.G. Carlier, K. Fujii, T. Yasuda, G.S. Mintz. Cardiovascular Research Foundation, Lenox Hill Heart and Vascular Institute, New York, NY.

Cytostatic Effect of Mitomycin C on Smooth Muscle Cell Proliferation: Mechanistic Implications for a Potential

Background: In vitro it has been shown that nonuniform circumferential stent strut distribution affects local drug concentration. We sought to investigate whether stent strut number and distribution in vivo could also affect the magnitude of intimal hyperplasia (IH) after sirolimus-eluting stent (SES) implantation. Methods: Intravascular ultrasound (IVUS) was performed in 17 lesions with intra-SES restenosis and a comparison group of 14 nonrestenotic SES. Measurements were performed in 5 cross-sections: at minimum lumen area (MLA) and at 2.5 and 5 mm proximal and distal locations (remote sites). To assess stent strut distribution, the maximum interstrut angle was measured with a protractor centered on the stent. The number of visible struts was counted and normalized for the number of stent cells (2.5- and 3.0-mm SES have 6 cells, and 3.5-mm SES have 7 cells). Results: See Table. In SES restenosis patients, MLA site had smaller IVUS minimal lumen area, larger IH area, thicker IH at maximum interstrut angle, fewer stent struts (even when normalized for the number of stent cells), and larger maximum interstrut angle when compared with restenosis remote sites and nonrestenosis sites. Multivariate analysis identified the number of visualized stent struts normalized for the number of stent cells as the only independent IVUS

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SEPTEMBER 30, 2004

HISTOLOGY Lumen area (mm2) Neointimal area (mm2) % stenosis

QCA

IVUS

0.85

0.91 0.83 0.91

Correlation is r2, p ⬍0.001 for all. Conclusion: QCA and IVUS appear to be useful efficacy surrogates for histomorphometry. These parameters may allow for more rapid and dynamic preclinical assessment of antirestenosis therapies. Correlation to drug-eluting stents with demonstrated clinical efficacy validates this model.

TCT-492

The American Journal of Cardiology姞

TCT ABSTRACTS/Poster

THURSDAY 9/30/04 10:30

AM-12:30 PM

(Hall D and E on Level 2)

predictor of IH CSA (coefficient ⫺2.756, p ⬍0.05) and IH thickness (coefficient ⫺0.570, p ⬍0.01).

mm2

Lumen area, IH area, mm2 IH thickness at maximum interstrut angle, mm Maximum angle between stent struts (°) Number of stent struts, n “Normalized” number of stent struts

Restenosis MLA

Restenosis Remote Sites

Non-Restenosis MLA

p

2.9 ⫾ 0.9* 3.0 ⫾ 1.5* 0.7 ⫾ 0.2*

6.1 ⫾ 2.0† 0.6 ⫾ 1.1 0.1 ⫾ 0.2

6.4 ⫾ 2.1‡ 1.3 ⫾ 1.2‡ 0.4 ⫾ 0.2‡

⬍0.01 ⬍0.01 ⬍0.01

127.0 ⫾ 40.0*

73.0 ⫾ 21.0†

89.0 ⫾ 29.0‡

⬍0.01

4.9 ⫾ 1.2* 0.79 ⫾ 0.18*

5.9 ⫾ 0.3† 0.95 ⫾ 0.13†

5.9 ⫾ 0.5‡ 0.96 ⫾ 0.12‡

⬍0.01 ⬍0.01

p: analysis of variance. *p ⬍0.01 restenosis MLA vs restenosis remote sites. †p ⬍0.01 restenosis remote sites vs nonrestenosis MLA. ‡p ⬍0.01 restenosis MLA vs nonrestenosis MLA. Conclusions: The number and distribution of stent struts affects the amount of neointima after SES implantation.

TCT-494 In-vitro Analysis of Anti-Thrombotic and Anti-Proliferative Potential of Eptifibatide Eluting Stent. K. Chitkara, UHL NHS TRUST, Leicester, UK; K. Hogrefe, Cardiovascular Sciences, Glenfield, UK; M. Vasa-Nicotera, Cardiovascular Sciences, Glenfield, UK; A.H. Gershlick, Cardiovascular Sciences, Glenfield, UK. Background: Stent thrombosis and restenosis remains problematic, especially in patients with diabetic or with small vessel disease. Eptifibatide is a platelet glycoprotein IIb/IIIa receptor and inhibit smooth muscle cell (SMC) ␣v␤3-receptor and thus may influence both thrombosis and proliferation. We studied the adsorption-elution characteristics of eptifibatide on polymer-coated stents and its effects on SMC proliferation, platelet deposition to the stent, and platelet aggregation in vitro. Methods: Eptifibatide was mixed with polyvinyl butyrate polymer and then applied to bare-metal stents. Drug elution was tested in PBS perfusion circuit for up to 4 weeks. Efficacy of eluting eptifibatide was determined by measuring deposition of 111indium-labeled platelets on stents after 1 hour perfusion and inhibition of platelet aggregation in response to adenosine diphosphate (ADP). Finally, drug-loaded stents were placed in SMC culture, and area of growth inhibition around the stents determined. Results: 111 ␮g of eptifibatide was loaded on 3.0 ⫻ 18 mm stents. Elution profile consisted of an early rapid phase (24% loss over 1 hour) followed by a sustained release with 44% still present on the stent after 30 days. Platelet deposition on drug-coated stent was reduced by 48% vs controls (p ⬍0.01). Eluted eptifibatide inhibited platelet aggregation by 95% in response to ADP (p ⬍0.01). Eptifibatide-loaded stents placed in SMC culture showed a distinct zone of cell growth inhibition within 1 mm2 of stent (88 vs 208 SMCs in control) and within 2 mm2 of stent (131 vs 191 SMCs in control; both p ⬍0.01). Conclusions: Eptifibatide can be loaded successfully on stents, and elution shows a biphasic elution pattern. Eptifibatide-coated stents inhibited SMC proliferation and reduced platelet adhesion onto stents in vitro. Eluted drug retained inhibitory activity on platelet aggregation. These studies pave the way to developing stent-based delivery of a potent antiplatelet agent, which additionally may inhibit SMC activity.

TCT-495 Monocyte L-Selectin Downregulation Triggered by PlateletMonocyte Adhesion (PMA): A Novel Target to Improve

The American Journal of Cardiology姞

Outcome Following Coronary Intervention? H. El Gendi, T.F. Ismail, A.G. Violaris, A.A. Gomma, D.J. Sheridan. Imperial College, St Mary’s Hospital, London, UK. Background: Monocyte activation induces pro-coagulant and proadhesive inflammatory responses and may play an important role in thrombotic complications after coronary intervention. Platelet-monocyte adhesion (PMA) may trigger this. The aim of our study was to determine the level of PMA during coronary intervention and to characterize its effect on monocyte activation. Methods: PMA and monocyte activation was prospectively examined in 30 patients undergoing left coronary system intervention (19 men, mean age 62). Coronary sinus (CS) and peripheral samples were obtained at baseline, after first inflation, inflation immediately after intervention, and 24 hours later. For PMA, a novel technique was used. Blood samples were labeled with CD14 (monocyte-specific marker) and GP1b (platelet-specific marker). The percent of CD14-GP1b positive particles (platelet-monocyte aggregates) was measured with flow cytometry. Monocyte activation was assessed by down-regulation of L-selectin. Results: PMA increased significantly in CS samples immediately after the first balloon inflation (56.4 ⫾ 7.6 vs 36.5 ⫾ 3.3 at baseline p ⫽ 0.014), this was transient and returned to baseline levels immediately after angioplasty (33.2 ⫾ 3.0 vs 36.5 ⫾ 3.3 at baseline, p ⫽ NS). No increase was seen in peripheral samples 36.5 ⫾ 3.3 (baseline) vs 36.2 ⫾ 2.8 (after first inflation) vs 31.7 ⫾ 3.0 (postprocedure). Monocyte activation (assessed by measuring L-selectin mean channel fluorescence) increased from a baseline level of 30.2 ⫾ 2.5 to 29.3 ⫾ 3 (p ⫽ NS) immediately after angioplasty and 20.9 ⫾ 2.5 (p ⫽ 0.016 vs baseline) 24 hours later. Conclusions: Our data suggest that PMA is transiently increased at the balloon injury site during angioplasty. This adhesion results in prolonged monocyte activation and may play an important role in the development of complications following coronary intervention.

TCT-496 Is Drug-Eluting Stent Type a Determinant of the Amount of Neointimal Hyperplasia? A Volumetric Intravascular Ultrasound Analysis. J.S. Mun˜ oz, A. Abizaid, F. Feres, L.F. Tanajura, M. Albertal, V.D. Vaz, R. Staico, L.A. Mattos, G. Maldonado, A.S. Abizaid, M. Centemero, E.J. Ferreira, A. Chaves, A. Seixas, I. Pinto, A. Sousa, J.E. Sousa. Institute Dante Pazzanese of Cardiology, Sa˜ o Paulo, Brazil. Background: Various antiproliferative drug-eluting stent (DES) studies have demonstrated a significant reduction in restenosis compared with bare-metal stents. At present, there are no comparative data among the various DES and the amount of in-stent neointimal growth. The aim of this study was to use follow-up volumetric intravascular ultrasound (IVUS) analysis to compare in-stent neoinitmal hyperplasia using 6 different stents (one bare-metal stent, one coated stent, and four DES). Methods: Patients (n ⫽ 225) with de novo native coronary lesions were successfully treated with the following stents: bare metal stent (BX-Velocity stent, n ⫽ 45 patients), amorphous silicon-carbide (aSIC)-coated stents (n ⫽ 46), sirolimus-eluting stents (n ⫽ 50 patients), 17␤-estradiol-eluting stents (n ⫽ 30 patients), actinomicyn-eluting stents (n ⫽ 22 patients), and mycophenolic acid (MPA)-eluting stents (n ⫽ 32 patients). All lesions were ⱖ3.0 mm and ⱕ3.5 mm in diameter. Target lesion was to be covered by a single 18-mm-long stent in all stent groups. Routine volumetric intravascular ultrasound (IVUS) images were obtained after procedure and at 6-month follow-up. Results: Baseline demographics and angiographic characteristics were similar in all groups. Average stent length was 18 ⫾ 3.2 mm. IVUS analysis is shown below.

SEPTEMBER 30, 2004

TCT ABSTRACTS/Poster

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THURSDAY 9/30/04 10:30 Conclusions: Based on this IVUS volumetric analysis, the sirolimus-eluting stent was the most effective system to reduce in-stent neointimal proliferation. Also, the estradiol-eluting stent showed superior results compared with bare metal, a-SIC, actinomicyn, and MPA stents. Bare Metal

a-SIC

Sirolimus 17␤-Estradiol Actinomicyn

IH mm3/mm 2.6 ⫾ 1.0 3.1 ⫾ 1.8 0.09 ⫾ 0.3* stent % obstruction 38.7 ⫾ 13 36.4 ⫾ 10 1.5 ⫾ 5.8* IH thickness, 1.3 ⫾ 0.5 1.6 ⫾ 0.9 0.7 ⫾ 2.6* mm

2.2 ⫾ 1.3† 24.0 ⫾ 13† 1.1 ⫾ 0.7

3.3 ⫾ 1.1

MPA

p ANOVA

2.9 ⫾ 1.2 ⬍0.0001

39.4 ⫾ 11.4 32.2 ⫾ 14 ⬍0.0001 1.7 ⫾ 0.6 1.5 ⫾ 0.6 0.01

ANOVA ⫽ analysis of variance; IH ⫽ intimal hyperplasia; % obstruction ⫽ [IH (mm3)/stent (mm3) ⫻ 100]. IH thickness ⫽ (mean follow-up stent diameter ⫺ mean follow-up lumen diameter)/2. *p ⬍0.05 vs 5 stents. † p ⬍0.05 vs. bare metal, a-SIC, actinomicyn, and MPA stents.

12-week follow-up (43.3 ⫾ 4.5%, 39.3 ⫾ 4.8%, and 49.8 ⫾ 9.3% at 1, 4 and 12 weeks, respectively) and reduced Ki67 (14.8 ⫾ 1.5%) at 4 weeks. Conclusions: Neointimal hyperplasia is prevented by RAP-eluting stents at least through 12-week follow-up. RAP-eluting stents also induced a reduction in Ki67 and increased P27KIP expression.

TCT-498 Is There Any Increased Risk of Thrombosis after Complex Coronary Lesions Treatment with Sirolimus-Eluting Stents? D. Trabattoni, S. Galli, P. Montorsi, F. Fabbiocchi, A. Lualdi, L. Grancini, P. Ravagnani, G. Teruzzi, A.L. Bartorelli. Centro Cardiologico Monzino, IRCC S, University of Milan, Milan, Italy.

Background: The purpose of this study was to evaluate the efficacy of implanting a novel biodegradable polymer-coated rapamycin-eluting stent on a time course of p27kip expression and Ki67 index in a porcine coronary model. Methods: PLLA-coated stents containing 100 ␮g rapamycin (RAP, n ⫽ 18), bare-metal stents (n ⫽ 16), and stents coated with PLLA alone (n ⫽ 16) were overexpanded (balloon/artery ratio 1.3:1) in a porcine coronary artery. The expression of p27kip and Ki67 were determined in coronary arteries harvested at 1, 2, 4, and 12 weeks after stenting, using immunohistochemical methods. Neointimal thickness was analyzed by histomorphometry at 12 weeks. Results: Neointimal thickness (0.14 ⫾ 0.12 mm) was reduced in the RAP group at 12 weeks, compared with the bare-metal group (0.68 ⫾ 0.20 mm) and PLLA-only group (0.96 ⫾ 0.58 mm, p ⬍0.01 vs RAP). After implanting bare-metal stents, a gradual increase in p27kip and Ki67 expression were observed from 1 week to 2 weeks, reaching maximum levels at 4 weeks (p27kip 2.1 ⫾ 0.3% vs 10.8 ⫾ 0.7%, p ⬍0.01; Ki67 3.8 ⫾ 0.4% vs 24.4 ⫾ 4.4%,p ⬍0.01 at 1 and 4 weeks), then returned to a 1-week baseline level at 12 weeks. RAP eluting from stent increased p27kip expression from the first week, persisted at

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TCT-497

A B S T R A C T S

(Hall D and E on Level 2)

Background: Stent thrombosis has been associated with patient, lesion, and procedural factors with bare-metal stents. It is unknown whether these factors may increase the risk of thrombosis when drugeluting stents are used. The aim of our study was to assess the incidence of acute, subacute, and late stent thrombosis after sirolimus-eluting stent (SES) implantation in patients with complex coronary lesions. Methods: Between April 2002 and January 2004, SES were implanted in 300 patients (81% men; mean age 64 ⫾ 9.8 yrs; 13% diabetic). Clinical indication was stable angina (80%); acute myocardial infarction patients were not included. Small vessels, long lesions, ostial lesions, chronic total occlusions, and in-stent restenosis were treated with a stent:patient ratio of 1.7 ⫾ 0.97. A total of 510 SES were implanted in 395 coronary vessels for single (45%) or multivessel disease (55%). Long (ⱖ18 mm) or multiple stents were used in 64% and 46% patients, respectively, with a mean stented segment length of 38.4 ⫾ 14.4 mm (range 8 – 89 mm). All lesions were predilated, and stents were postdilated at high pressure (14.2 ⫾ 2.2 atm). Antithrombotic regimen included aspirin (325 mg/day, indefinitely) and clopidogrel (300 mg loading dose and 75 mg/day for 3 months). ReoPro use was 20%. Results: Acute clinical and angiographic success was 100%. No acute stent thrombosis was observed. Three cases (1%) of subacute stent thrombosis occurred, causing unstable angina 7 to 10 days after PCI in 2 patients. In a third case, acute myocardial infarction followed by cardiogenic shock and death occurred 21 days after stenting because of antiplatelet therapy withdrawal. No late stent thrombosis were diagnosed at 6-month clinical follow-up, available in 50% of patients at this time. Conclusions: Despite long and multiple SES use for treatment of complex coronary lesions, acute, subacute, and late stent thrombosis incidence was low and comparable to that previously observed in historical bare metal stent control patients.

The Modulation of Ki67 Proliferative Index and P27kip Expression after Implanting Novel Rapamycin-Eluting Stents in the Porcine Coronary Model. X. Liu, J. Ge, K. Wang, J. Qian, J. Jia, N. Cai. Zhongshan Hospital, Fudan University, Shanghai Institute of Cardiovascular Disease, Shanghai, China.

P O S T E R

AM-12:30 PM

The American Journal of Cardiology姞

TCT ABSTRACTS/Poster