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Polymer-Based Paclitaxel-Eluting Stents Are Superior to Nonpolymer-Based Paclitaxel-Eluting Stents in the Treatment of De Novo Coronary Lesions
Polymer-Based Paclitaxel-Eluting Stents Are Superior to Nonpolymer-Based Paclitaxel-Eluting Stents in the Treatment of De Novo Coronary Lesions Ekaterina Iofina, MD, Roswitha Langenberg, Rüdiger Blindt, MD, Harald Kühl, MD, Malte Kelm, MD, and Rainer Hoffmann, MD* Although polymer coating of coronary stents enables sufficient loading and release of incorporated drugs, it has also been associated with potentially negative effects. This study compared the clinical, angiographic, and intravascular ultrasound (IVUS) outcomes of patients treated with polymer- versus nonpolymer-based paclitaxel-eluting stents (PESs). Sixty-five consecutive patients (70 de novo lesions) treated with polymer-based PESs (TAXUS, 1 g/mm2 of paclitaxel; Boston Scientific Corp.) and 65 consecutive patients (65 de novo lesions) treated with nonpolymer-based PESs (V-Flex Plus, 2.7 g/mm2 of paclitaxel; Cook, Inc.) were enrolled in the study. Six-month angiographic follow-up was performed on 54 lesions of the polymer-based PES group and 51 lesions of the nonpolymerbased PES group. IVUS at angiographic follow-up was performed in 61 of the first 70 included lesions. At 6-month IVUS follow-up, mean intimal hyperplasia cross-sectional area was 2.36 ⴞ 1.60 mm2 in the nonpolymer-based PES group versus 0.62 ⴞ 0.41 mm2 in the polymer-based PES group (p ⴝ 0.003). Implantation of polymer-based PESs resulted in significantly lower in-stent late lumen loss (0.22 ⴞ 0.27 vs 0.74 ⴞ 0.61 mm, respectively, p <0.001). In-stent binary restenosis rate was 5% versus 20%, respectively (p <0.001). Target lesion revascularization rate was 9% after implantation of polymer-based PES versus 18% (p ⴝ 0.128) after implantation of nonpolymer-based PES, and the major adverse cardiac event rate was 9% versus 23%, respectively (p ⴝ 0.032). In conclusion, polymer-based PESs result in superior angiographic and IVUS follow-up findings compared with nonpolymerbased PESs. © 2006 Elsevier Inc. All rights reserved. (Am J Cardiol 2006;98:1022–1027)
This study compared the clinical, angiographic, and intravascular ultrasound (IVUS) outcomes of patients treated with polymer- or nonpolymer-based paclitaxel-eluting stents (PESs) for de novo coronary lesions. Methods Patients and lesions: Sixty-five consecutive patients with 70 de novo lesions treated with nonbioerodable polymer-based PESs (1 g/mm2 of paclitaxel; Taxus, Boston Scientific Corp., Natick, Massachusetts) between November 2003 and April 2004 and 65 consecutive patients with 65 de novo lesions treated with nonpolymer-based PESs (coated directly with 2.7 g/mm2 of paclitaxel using a proprietary system of surface modification; V-Flex-Plus, Cook, Inc., Bloomington, Indiana) between May 2004 and December 2004 were enrolled in the study. Lesions included in this prospective study had to be in a native vessel of 2.5 to 4.0 mm in diameter with a lesion length ⬍30 mm. In the first 35 patients of the 2 stent groups, IVUS follow-up at 6-month control angiography was intended.
The Medical Clinic I, University Aachen, Aachen, Germany. Manuscript received March 18, 2006; revised manuscript received and accepted May 9, 2006. *Corresponding author: Tel: 49-241-808-8468; fax: 49-241-808-2303. E-mail address: [email protected] (R. Hoffmann). 0002-9149/06/$ – see front matter © 2006 Elsevier Inc. All rights reserved. doi:10.1016/j.amjcard.2006.05.019
Coronary intervention: Heparin was administered during the procedure according to standard practice. Aspirin (100 mg/day) and clopidogrel (300-mg loading dose) were started before the procedure. After the procedure, clopidogrel (75 mg/day) was administered for 6 months in the 2 groups in addition to aspirin. In case of predilatation, a stent longer than the initial balloon length was encouraged. The 2 stents were available in lengths of 12, 16, and 20 mm and in diameters of 2.5, 3.0, and 3.5 mm. In-hospital and 6-month clinical follow-up: Procedural success was defined as ⬍30% final diameter stenosis in the treated lesion and the absence of major clinical complications (in-hospital death, Q-wave myocardial infarction, or emergency coronary bypass surgery). All patients were monitored for 6 months after the procedure for any major adverse cardiac event, defined as death, myocardial infarction, or need for target lesion revascularization. Baseline clinical demographics, in-hospital complications, and occurrence of death, myocardial infarction, and late recurrent coronary intervention during follow-up were verified by independent hospital chart review and source documentation. Quantitative coronary angiography: Quantitative angiographic analysis was performed at the angiographic core laboratory of the University Aachen (Aachen, Germany) using a validated quantitative angiographic system (CAAS II System, PieMedical, Maastricht, The Netherlands) with www.AJConline.org
Coronary Artery Disease/Impact of Polymer Stent Coating Table 1 Baseline clinical characteristics Variable
The lesion was described as ostial when it was within 3 mm of the coronary ostia.
Polymer-based PES (n ⫽ 65)
Nonpolymer-based PES (n ⫽ 65)
p Value
49 (75%) 61 ⫾ 11 26 (40%)
43 (66%) 60 ⫾ 18 30 (46%)
0.25 0.62 0.48
19 (29%) 56 (86%) 59 (94%) 39 (60%) 5 (8%)
18 (28%) 50 (77%) 53 (82%) 42 (65%) 2 (3%)
0.85 0.18 0.13 0.59 0.24
Men Age (yrs) Previous myocardial infarction Diabetes mellitus Hypertension* Hyperlipidemia† Smoker‡ Coronary bypass
Values are numbers of patients (percentages) or means ⫾ SD. * Arterial pressure ⬎ 160/90 mm Hg or medically treated. † Serum cholesterol level ⬎240 mg/L or medically treated. ‡ Current and/or former smoker.
Table 2 Lesion characteristics Variable
Lesion location Left anterior descending coronary artery Right coronary artery Left circumflex coronary Lesion type A B1 B2 C
Polymer-based PES (n ⫽ 70)
Nonpolymer-based PES (n ⫽ 65)
p Value
38 (54%)
34 (52%)
0.82
14 (20%) 18 (26%)
10 (15%) 21 (32%)
0.48 0.40
32 (46%) 26 (37%) 9 (13%) 3 (4%)
28 (43%) 19 (29%) 15 (23%) 3 (5%)
0.76 0.33 0.12 0.93
Table 3 Procedural characteristics Variable
Stent length (mm) Stent diameter (mm) Maximal implantation pressure (atm)
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Polymer-based PES (n ⫽ 70)
Nonpolymer-based PES (n ⫽ 65)
p Value
14.8 ⫾ 3.2 3.06 ⫾ 0.18 13.9 ⫾ 1.4
15.8 ⫾ 3.4 3.10 ⫾ 0.34 13.4 ⫾ 1.5
0.09 0.80 0.16
the contrast-filled catheter as the calibration standard. Quantitative measurements included reference diameter, lesion length, minimal lumen diameter in lesion (defined as instent segment plus proximal and distal 5-mm edge segments) and in stent (without adjacent edge segment) before and after the procedure and at follow-up. Late loss (defined as decrease in minimum lumen diameter from immediately after the procedure to 6-month follow-up), acute gain (defined as an increase in minimal luminal diameter immediately after percutaneous transluminal coronary angioplasty), net gain (difference between acute gain and late loss), and loss index (ratio of late loss to acute gain) were calculated.
IVUS analysis: Among the first 35 patients in the 2 stent groups, IVUS follow-up was intended. IVUS studies were performed at the time of 6-month control angiography after intracoronary administration of nitroglycerin using a 40MHz, 2.6Fr, IVUS catheter (Atlantis Boston Scientific) with an automated pullback at 0.5 mm/s to perform the imaging sequence. Area measurements were performed with a commercially available program for computerized planimetry (TapeMeasure, Indec Systems, Mountain View, California). If the neointimal tissue encompassed the imaging catheter, the luminal cross-sectional area (CSA) was assumed to be the physical size of the imaging catheter (0.9 mm2). The following calculations were then performed for every 1 mm within the stent length: (1) intimal hyperplasia CSA (square millimeters) ⫽ stent CSA ⫺ lumen CSA at follow-up; (2) mean stent diameter (millimeters) ⫽ 2 ⫻ (stent CSA/ )⫺1/2; (3) mean lumen diameter (millimeters) ⫽ 2 ⫻ (lumen CSA/)⫺1/2; (4) mean intimal hyperplasia thickness (millimeters) ⫽ mean stent radius at follow-up ⫺ mean lumen radius at follow-up; and (5) mean intimal hyperplasia CSA/stent CSA. To analyze the intimal hyperplasia distribution within the longitudinal stent direction, measurements at 7 equally distributed points from the proximal to the distal stent edges were performed. Statistical analysis: Statistical analysis was performed with SPSS software (SPSS, Inc., Chicago, Illinois). Categorical data were presented as frequencies and compared with the Pearson chi-square test. Continuous data were presented as mean ⫾ SD and compared with the Student t test or analysis of variance, if appropriate. A p value ⬍0.05 was considered statistically significant. Multivariate analysis to identify predictors for recurrent angiographic restenosis and linear regression analysis to identify predictors of intimal hyperplasia thickness were performed, with diabetes mellitus, reference vessel diameter, lesion length, minimal lumen diameter in the lesion before intervention, lesion location in the left anterior descending artery, and type of stent as parameters. Results Baseline characteristics: Clinical and angiographic characteristics at baseline were similar for the 2 groups (Tables 1 and 2). Eight patients (12%) in the polymer-based PES group and 7 (11%) in the nonpolymer-based PES group presented with acute coronary syndromes (p ⫽ 0.784). Procedural data: Procedural success using the intended stent was achieved in all cases (Table 3). Mean stent length, stent diameter, and stent implantation pressure were similar for the 2 groups. Additional stenting with overlapping of stents was used in case of dissection or remaining stenosis in 2 lesions (3%) in the polymer-based PES group and 4 lesions (6%) in the nonpolymer-based PES group (p ⫽ 0.35). Predilatation was performed in 28 lesions (40%) before implantation of polymer-based PESs and in 35 lesions (54%) before implantation of nonpolymer-based PESs (p ⫽ 0.11).
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Table 4 Quantitative angiographic results Variable Before intervention Mean lesion length (mm) Mean reference lumen diameter (mm) Minimum lumen diameter (mm) Diameter stenosis (%) After intervention Minimum lumen diameter in stent (mm) Minimum lumen diameter in lesion (mm) Diameter stenosis in stent (%) Diameter stenosis in lesion (%) Follow-up Mean reference lumen diameter (mm) Minimum lumen diameter in stent (mm) Minimum lumen diameter in lesion (mm) Diameter stenosis in stent (%) Diameter stenosis in lesion (%) Binary restenosis in lesion Binary restenosis in stent Late loss in stent (mm) Late loss in lesion (mm) Loss index in stent (mm) Loss index in lesion (mm)
Polymer-based PES (n ⫽ 54)
Nonpolymer-based PES (n ⫽ 51)
p Value
9.81 ⫾ 3.75 2.96 ⫾ 0.48 1.09 ⫾ 0.36 62.87 ⫾ 11.24
10.48 ⫾ 3.65 2.85 ⫾ 0.56 0.97 ⫾ 0.42 65.35 ⫾ 13.40
0.30 0.12 0.07 0.26
2.73 ⫾ 0.37 2.55 ⫾ 0.45 5.05 ⫾ 9.92 11.99 ⫾ 10.77
2.65 ⫾ 0.38 2.49 ⫾ 0.45 5.33 ⫾ 12.38 11.77 ⫾ 13.21
0.18 0.37 0.89 0.91
2.83 ⫾ 0.38 2.47 ⫾ 0.43 2.17 ⫾ 0.53 11.92 ⫾ 14.28 22.92 ⫾ 16.82 5 (9%) 2 (4%) 0.22 ⫾ 0.27 0.28 ⫾ 0.34 0.13 ⫾ 0.20 0.36 ⫾ 0.57
2.80 ⫾ 0.50 1.92 ⫾ 0.80 1.81 ⫾ 0.76 32.71 ⫾ 24.37 36.54 ⫾ 23.07 14 (27%) 10 (20%) 0.74 ⫾ 0.61 0.68 ⫾ 0.62 0.41 ⫾ 0.39 0.66 ⫾ 0.65
0.75 ⬍0.001 0.002 ⬍0.001 ⬍0.001 0.016 0.010 ⬍0.001 ⬍0.001 ⬍0.001 0.009
Table 5 Intravascular ultrasound results at follow-up Variable
Polymer-based Nonpolymer-based PES PES (n ⫽ 32) (n ⫽ 29)
Mean reference lumen CSA (mm2) Mean lumen CSA (mm2) Mean lumen diameter (mm) Mean stent CSA (mm2) Mean intimal hyperplasia CSA (mm2) Mean intimal hyperplasia thickness (mm) Mean IH CSA/stent CSA Figure 1. Cumulative frequency distribution curves for in-stent minimum lumen diameter for the nonpolymer-based (solid lines) and polymer-based (dotted lines) PESs.
Clinical follow-up results: There was 1 death due to acute Q-wave myocardial infarction caused by subacute stent thrombosis 4 days after implantation of a polymerbased PES in a patient with multivessel disease and a history of repeated stent thrombosis in another coronary vessel. The 30-day major adverse cardiac event rates were 1.4% and 0% (p ⫽ 0.32) in the polymer-based and nonpolymer-based PES groups, respectively. At 6-month follow-up, target lesion revascularization was required in 6 lesions (9%, 5 cases of binary restenosis and 1 case of subacute stent thrombosis) in the polymerbased PES group. Major adverse cardiac events were also observed in 6 of 65 patients (9%). The major adverse car-
p Value
8.66 ⫾ 2.31
9.34 ⫾ 2.75
0.32
7.34 ⫾ 1.66 3.04 ⫾ 0.32
7.48 ⫾ 2.71 3.02 ⫾ 0.60
0.80 0.93
7.95 ⫾ 1.66 0.62 ⫾ 0.41
9.83 ⫾ 2.07 2.36 ⫾ 1.60
⬍0.001 ⬍0.001
0.06 ⫾ 0.42
0.25 ⫾ 0.18
⬍0.001
0.08 ⫾ 0.05
0.25 ⫾ 0.18
⬍0.001
IH ⫽ intimal hyperplasia.
diac event rate in the nonpolymer-based PES group was significantly higher at 23% (15 of 65 patients, p ⫽ 0.032). This was due to repeat target lesion revascularization in 18% (11 cases of binary restenosis and 1 case of stent thrombosis at 5 months, p ⫽ 0.13 vs polymer-based PES), 2 noncardiac deaths, and 1 cardiac death related to myocardial infarction. Six-month angiographic results: Six-month follow-up angiography was performed on 54 lesions (77%) in the polymer-based PES group and 51 lesions (78%) in the nonpolymer-based PES group. Quantitative angiographic results are presented in Table 4. At follow-up, patients in the polymer-based PES group showed larger in-stent and in-lesion minimal lumen diameters. Figure 1 shows cumulative frequency distribution
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Intimal hyperplasia CSA and intimal hyperplasia thickness were significantly larger for nonpolymer-based PESs than for polymer-based PESs. Segmental analysis demonstrated intimal hyperplasia CSA to be uniformly greater over the entire stent length of the nonpolymer-based PES compared with the polymer-based PES (Figure 2). A similar result was found for intimal hyperplasia thickness (Figure 3).
Figure 2. Plot of mean IVUS intimal hyperplasia CSAs at follow-up at 7 different points within the stent length for the polymer-based (diamonds) and nonpolymer-based (squares) PESs.
Predictors of binary restenosis and intimal hyperplasia thickness: In a multivariate model, independent predictors of binary restenosis were type of stent coating (odds ratio 3.72, 95% confidence interval 1.11 to 11.92, p ⫽ 0.028) and mean vessel reference diameter (odds ratio 0.20, 95% confidence interval 0.05 to 0.93, p ⫽ 0.034). In a linear regression analysis on predictors of intimal hyperplasia thickness, type of stent coating (p ⬍0.001) and lesion length (p ⫽ 0.010) were found to have a significant effect. Discussion
Figure 3. Plot of mean IVUS intimal hyperplasia thickness at follow-up at 7 different points within the stent length for the polymer-based (diamonds) and nonpolymer-based (squares) PESs.
curves for in-stent minimal lumen diameter before and after stent implantation and at follow-up. Significantly lower in-stent and in-segment late lumen losses were observed with polymer-based PESs compared with nonpolymerbased PESs (0.22 ⫾ 0.27 vs 0.74 ⫾ 0.61 mm, p ⬍0.001; 0.28 ⫾ 0.34 vs 0.68 ⫾ 0.62 mm, p ⬍0.001, respectively). This translated into significantly lower in-stent and in-lesion binary restenosis rates in the polymer-based PES group (5% vs 20%, p ⬍0.001; 9% vs 27%, p ⬍0.001, respectively). Six-month IVUS results: Placement of the IVUS catheter was not possible in 1 lesion after polymer-based PES implantation due to severe vessel calcification and in 1 lesion after nonpolymer-based PES implantation due to pronounced intimal hyperplasia and binary restenosis. Thus, IVUS follow-up at 6-month coronary angiography was performed in 32 lesions in the polymer-based PES group and in 29 lesions in the nonpolymer-based PES group. Results of the IVUS studies are presented in Table 5.
The present study is the first direct comparison of polymerand nonpolymer-based PESs in the treatment of de novo coronary lesions. This study demonstrated (1) significant differences in the extent of intimal hyperplasia between polymer- and nonpolymer-based PESs, with favorable results within the polymer-based PES platform, (2) translation of the difference in intimal hyperplasia into superior angiographic results after implantation of polymer-based PESs, and (3) similar intimal hyperplasia distribution within stent length of the 2 groups. Paclitaxel has been reported to suppress vascular cell proliferation and subsequent excessive formation of intimal hyperplasia.1,2 Randomized clinical trials have demonstrated remarkable and consistent effectiveness of polymerbased PESs in the decrease of in-stent restenosis and repeat target lesion revascularization at 6 and 9 months.3–5 Use of polymer-based PESs has been shown in clinical trials to result in lesion lumen loss in the range of 0.30 ⫾ 0.39 to 0.36 ⫾ 0.48 mm, angiographic restenosis rates of 0% to 9%, and intimal hyperplasia CSAs of 0.6 ⫾ 0.8 mm2 for de novo coronary lesions at 6- to 9-month follow-up.3,4 In this study, in-lesion lumen loss was 0.28 ⫾ 0.34 mm, restenosis rate was 9%, and intimal hyperplasia CSA was 0.62 ⫾ 0.41 mm2 for the polymer-based PES group. Thus, the findings were consistent with angiographic and IVUS results of previous randomized trials on polymer-based PESs in de novo coronary lesions. In addition, the target lesion revascularization rate of 11% at 6-month follow-up for the polymer-based PES group was similar to that in previous reports that indicated target lesion revascularization rates of 0% to 9%.3–5 Although the polymer coating ensures a controlled drug release, local hypersensitivity reactions to the polymer stent coating have been observed in an animal model and in clinical studies6 –10 and have raised concerns about sustained long-term effectiveness of polymer-based drug-eluting stents. Nonpolymer-based drug delivery has been suggested as a different approach to deliver paclitaxel. Multicenter studies such as the Asian Paclitaxel-Eluting Stent Clinical Trial (ASPECT), the European Evaluation of Paclitaxel-
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Eluting Stent (ELUTES), and the RX Achieve Drug-eluting Coronary Stent System in the Treatment of Patients With De Novo Native Coronary Lesions (DELIVER I) evaluated PESs without polymer coating for treatment of de novo coronary lesions.11–13 A significant decrease in neointimal proliferation was observed only in high-dose groups of the ASPECT and ELUTES trials. The DELIVER I trial demonstrated only a minor decrease in late loss for the nonpolymer-based PES compared with the bare metal stent, which did not translate into a significant decrease in restenosis and need for recurrent revascularization. In the present study, implantation of the nonpolymerbased PES resulted in an in-stent late loss of 0.74 ⫾ 0.61 mm and a binary angiographic restenosis rate of 20%. These findings are similar to the results reported in the DELIVER I trial (0.81 ⫾ 0.60 mm late loss and 14.9% restenosis rate), but considerably worse than the results reported for the high-dose drug-eluting stent groups in ASPECT and ELUTES. Possible reasons for the higher late loss in this study compared with the ASPECT and ELUTES trials relate to differences in patient characteristics, with a higher rate of diabetics (28% in the present study vs 16% in ELUTES) and a more complex lesion morphology (25% of type B2/C lesions in the present study vs 9% and 7% in ELUTES and ASPECT, respectively). Significant loss of drug from the platform during stent delivery and rapid release of the remaining drug may be possible reasons for the attenuated effectiveness of nonpolymer-based PESs in the suppression of neointimal formation despite almost 3 times the surface-related initial loading dose of paclitaxel compared with the polymer-based PESs. Preclinical studies of the nonpolymer-based PES have indicated that a significant loss of paclitaxel occurs before the stent reaches the lesion, and subsequent paclitaxel release to the surrounding tissue is rapid and completed within days to a few weeks. At this time, potential intimal proliferation due to trauma of stent expansion is not finished.13 Gershlick et al12 demonstrated in an experimental study on nonpolymer-based PESs that amounts of the drug remaining on the stent are 70% 4 hours after stent deployment and 30% at 14 days. Paclitaxel levels after deployment in an in vitro study with Palmaz-Schatz stents dip-coated with paclitaxel demonstrated that only 68% of the drug originally deposited on the stent could be recovered.14 Thus, the drugelution curve is considerably different from that of polymerbased PESs, which are characterized by a drug release extending over several weeks. Another issue with regard to the effectiveness of paclitaxel relates to tissue uptake and subsequent persistence of drug within the tissue. Uptake of paclitaxel is determined by the rate at which it crosses the cell membrane. In the absence of a polymer platform, the amount of drug delivered to the tissue is determined by the tissue characteristics being targeted. It has been suggested that paclitaxel easily passes through the hydrophobic barrier of cell membranes and remains present and active within the vessel wall long after delivery from the stent due to its lipophilic nature.1 This may lessen the importance of a long drug release period. At the same time, variations in the lipid content of the atherosclerotic human artery may not provide even distribution and sufficient levels of paclitaxel in the vessel
wall, and paclitaxel may also be lost again from the vessel wall, thus jeopardizing the ability of a prolonged neointimal suppression after arterial injury in case the drug is already released soon after stent implantation. In a recent randomized comparison of rapamycin-coated, polymer-free Yukon stents (Translumina, Munich, Germany) and polymer-based PESs, no difference in late loss was found.15 Comparison with the present study with respect to the effect of the polymer on late loss is difficult. In a study by Mehilli et al,15 2 different drugs were used. With respect to several recent randomized studies, polymer-based sirolimus-eluting stents appear to be more effective in decreasing late lumen loss than polymer-based PESs.16,17 Thus, the more effective drug might have compensated for the disadvantage of the polymer-free coating compared with the polymer-based PESs. This was not a randomized study. Patients were enrolled in the 2 study groups in a sequential manner. Nevertheless, there were no significant differences with respect to clinical, angiographic, and IVUS baseline characteristics. IVUS analyses were performed on only 32 lesions in the polymerbased PES group and 29 lesions in the nonpolymer-PES group when considering the first 35 included lesions of the 2 groups. The stent platform was different between the 2 stent groups in addition to the 2 different coatings. However, the difference in late loss and intimal hyperplasia between the 2 stent groups was significantly higher than has been described between different bare metal stent designs, indicating that stent configuration has contributed little to the overall difference between the 2 evaluated stent types.18,19 IVUS analysis demonstrated larger mean stent CSA in the nonpolymer-based PES group compared with the polymer-based PES group. Thus, larger absolute intimal hyperplasia CSA in the nonpolymer-based PES group may be a consequence of a different stent size. However, even intimal hyperplasia thickness and the ratio of intimal hyperplasia CSA to stent CSA as stent-size independent parameters of tissue proliferation were significantly different between the 2 stent types. The difference in stent size in favor of the nonpolymer-based PES did not result in superior lumen CSA at follow-up. This was due to excessive intimal hyperplasia within the nonpolymer-based PES. Although angiographic and IVUS results demonstrated a significant advantage of the polymer-based PES, clinical event rates failed to show a significant difference. A significant difference in clinical end points would have been likely with larger patient numbers. 1. Drachman DE, Edelman ER, Seifert P, Groothuis AR, Bornstein DA, Kamath KR, Palasis M, Yang D, Nott SH, Rogers C. Neointimal thickening after stent delivery of paclitaxel: change in composition and arrest of growth over six months. J Am Coll Cardiol 2000;36:2325– 2332. 2. Herdeg C, Oberhoff M, Baumbach A, Blattner A, Axel DI, Schroder S, Heinle H, Karsch KR. Local paclitaxel delivery for the prevention of restenosis: biological effects and efficacy in vivo. J Am Coll Cardiol 2000;35:1969 –1976. 3. Grube E, Silber S, Hauptmann KE, Mueller R, Buellesfeld L, Gerckens U, Russell ME. TAXUS I: six- and twelve-month results from a randomized, double-blind trial on a slow-release paclitaxel-eluting stent for de novo coronary lesions. Circulation 2003;107:38 – 42.
Coronary Artery Disease/Impact of Polymer Stent Coating 4. Colombo A, Drzewiecki J, Banning A, Grube E, Hauptmann K, Silber S, Dudek D, Fort S, Schiele F, Zmudka K, et al, for the TAXUS II Study Group. Randomized study to assess the effectiveness of slowand moderate-release polymer-based paclitaxel-eluting stents for coronary artery lesions. TAXUS-II trial. Circulation 2003;108:788 –794. 5. Stone GW, Ellis SG, Cannon L, Mann JT, Greenberg JD, Spriggs D, O’Shaughnessy CD, DeMaio S, Hall P, Popma JJ, et al, for the TAXUS V Investigators. Comparison of a polymer-based paclitaxeleluting stent with a bare metal stent in patients with complex coronary artery disease: a randomized controlled trial. JAMA 2005;294:1215– 1223. 6. van der Giessen WJ, Lincoff AM, Schwartz RS, van Beusekom HM, Serruys PW, Holmes DR Jr, Ellis SG, Topol EJ. Marked inflammatory sequelae to implantation of biodegradable and nonbiodegradable polymers in porcine coronary arteries. Circulation 1996;94:1690 –1697. 7. Virmani R, Guagliumi G, Farb A, Musumeci G, Grieco N, Motta T, Mihalcsik L, Tespili M, Valsecchi O, Kolodgie FD. Localized hypersensitivity and late coronary thrombosis secondary to a sirolimuseluting stent: should we be cautious? Circulation 2004;109:701–705. 8. Nebeker JR, Virmani R, Bennett CL, Hoffman JM, Samore MH, Alvarez J, Davidson CJ, McKoy JM, Raisch DW, Whisenant BK, et al. Hypersensitivity cases associated with drug-eluting coronary stents. J Am Coll Cardiol 2006;47:175–181. 9. Virmani R, Liistro F, Stankovic G, Di Mario C, Montorfano M, Farb A, Kolodgie FD, Colombo A. Mechanism of late in-stent restenosis after implantation of a paclitaxel derivate-eluting stent system in humans. Circulation 2002;106:2649 –2651. 10. Grube E, Lansky A, Hauptmann KE, Di Mario C, Di Sciascio G, Colombo A, Silber S, Stumpf J, Reifart N, Fajadet J, et al, for the SCORE Randomized Trial. High-dose 7-hexanoyltaxol-eluting stent with polymer sleeves for coronary revascularization: one-year results from the SCORE randomized trial. J Am Coll Cardiol 2004;44:1368 – 1372. 11. Hong MK, Mintz GS, Lee CW, Song JM, Han KH, Kang DH, Song JK, Kim JJ, Weissman NJ, Fearnot NE, 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 2003; 107:517–520.
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12. Gershlick A, De Scheerder I, Chevalier B, Stephens-Lloyd A, Camenzind E, Vrints C, Reifart N, Missault L, Goy JJ, Brinker JA, et al. Inhibition of restenosis with a paclitaxel-eluting, polymer-free coronary stent: the European evaLUation of pacliTaxel Eluting Stent (ELUTES) Trial. Circulation 2004;109:487– 493. 13. Lansky AJ, Costa RA, Mintz GS, Tsuchiya Y, Midei M, Cox DA, O’Shaughnessy C, Applegate RA, Cannon LA, Mooney M, et al. Non-polymer-based paclitaxel-coated coronary stents for the treatment of patients with de novo coronary lesions: angiographic follow-up of the DELIVER clinical trial. Circulation 2004;109:1948 –1954. 14. Heldman AW, Cheng L, Jenkins GM, Heller PF, Kim DW, Ware M Jr, Nater C, Hruban RH, Rezai B, Abella BS, et al. Paclitaxel stent coating inhibits neointimal hyperplasia at 4 weeks in a porcine model of coronary restenosis. Circulation 2001;103:2289 –2295. 15. Mehilli J, Kastrati A, Wessely R, Dibra A, Hausleiter J, Jaschke B, Dirschinger J, Schömig A, for the Intracoronary Stenting and Angiographic Restenosis-Test Equivalence Between 2 Drug-Eluting Stents (ISAR-TEST) Trial Investigators. Randomized trial of a nonpolymerbased rapamycin-eluting stent versus a polymer-based paclitaxel-eluting stent for the reduction of late lumen loss. Circulation 2006;113: 273–279. 16. Morice MC, Colombo A, Meier B, Serruys P, Tamburino C, Guagliumi G, Sousa E, Stoll HP, for the REALITY Trial Investigators. Sirolimus- vs paclitaxel-eluting stents in de novo coronary artery lesions: the REALITY trial: a randomized controlled trial. JAMA 2006;295:895–904. 17. Windecker S, Remondino A, Eberli FR, Jüni P, Räber L, Wenaweser P, Togni M, Billinger M, Tüller D, Seiler C, et al. Sirolimus-eluting and paclitaxel-eluting stents for coronary revascularization. N Eng J Med 2005;353:653– 662. 18. Kastrati A, Mehilli J, Dirschinger J, Dotzer F, Schühlen J, Neumann FJ, Fleckstein M, Pfafferott C, Seyfarth M, Schömig A. Intracoronary stenting and angiographic results. Strut thickness effect on restenosis outcome (ISAR-STEREO). Circulation 2001;103:2816 –2821. 19. Hoffmann R, Jansen C, König A, Haager PK, Kerckhoff G, vom Dahl J, Klauss V, Hanrath P, Mudra H. Stent design related neointimal tissue proliferation in human coronary arteries. Eur Heart J 2001;22:2007– 2014.
This study compared the clinical, angiographic, and intravascular ultrasound (IVUS) outcomes of patients treated with polymer- or nonpolymer-based paclitaxel-eluting stents (PESs) for de novo coronary lesions. Methods Patients and lesions: Sixty-five consecutive patients with 70 de novo lesions treated with nonbioerodable polymer-based PESs (1 g/mm2 of paclitaxel; Taxus, Boston Scientific Corp., Natick, Massachusetts) between November 2003 and April 2004 and 65 consecutive patients with 65 de novo lesions treated with nonpolymer-based PESs (coated directly with 2.7 g/mm2 of paclitaxel using a proprietary system of surface modification; V-Flex-Plus, Cook, Inc., Bloomington, Indiana) between May 2004 and December 2004 were enrolled in the study. Lesions included in this prospective study had to be in a native vessel of 2.5 to 4.0 mm in diameter with a lesion length ⬍30 mm. In the first 35 patients of the 2 stent groups, IVUS follow-up at 6-month control angiography was intended.
The Medical Clinic I, University Aachen, Aachen, Germany. Manuscript received March 18, 2006; revised manuscript received and accepted May 9, 2006. *Corresponding author: Tel: 49-241-808-8468; fax: 49-241-808-2303. E-mail address: [email protected] (R. Hoffmann). 0002-9149/06/$ – see front matter © 2006 Elsevier Inc. All rights reserved. doi:10.1016/j.amjcard.2006.05.019
Coronary intervention: Heparin was administered during the procedure according to standard practice. Aspirin (100 mg/day) and clopidogrel (300-mg loading dose) were started before the procedure. After the procedure, clopidogrel (75 mg/day) was administered for 6 months in the 2 groups in addition to aspirin. In case of predilatation, a stent longer than the initial balloon length was encouraged. The 2 stents were available in lengths of 12, 16, and 20 mm and in diameters of 2.5, 3.0, and 3.5 mm. In-hospital and 6-month clinical follow-up: Procedural success was defined as ⬍30% final diameter stenosis in the treated lesion and the absence of major clinical complications (in-hospital death, Q-wave myocardial infarction, or emergency coronary bypass surgery). All patients were monitored for 6 months after the procedure for any major adverse cardiac event, defined as death, myocardial infarction, or need for target lesion revascularization. Baseline clinical demographics, in-hospital complications, and occurrence of death, myocardial infarction, and late recurrent coronary intervention during follow-up were verified by independent hospital chart review and source documentation. Quantitative coronary angiography: Quantitative angiographic analysis was performed at the angiographic core laboratory of the University Aachen (Aachen, Germany) using a validated quantitative angiographic system (CAAS II System, PieMedical, Maastricht, The Netherlands) with www.AJConline.org
Coronary Artery Disease/Impact of Polymer Stent Coating Table 1 Baseline clinical characteristics Variable
The lesion was described as ostial when it was within 3 mm of the coronary ostia.
Polymer-based PES (n ⫽ 65)
Nonpolymer-based PES (n ⫽ 65)
p Value
49 (75%) 61 ⫾ 11 26 (40%)
43 (66%) 60 ⫾ 18 30 (46%)
0.25 0.62 0.48
19 (29%) 56 (86%) 59 (94%) 39 (60%) 5 (8%)
18 (28%) 50 (77%) 53 (82%) 42 (65%) 2 (3%)
0.85 0.18 0.13 0.59 0.24
Men Age (yrs) Previous myocardial infarction Diabetes mellitus Hypertension* Hyperlipidemia† Smoker‡ Coronary bypass
Values are numbers of patients (percentages) or means ⫾ SD. * Arterial pressure ⬎ 160/90 mm Hg or medically treated. † Serum cholesterol level ⬎240 mg/L or medically treated. ‡ Current and/or former smoker.
Table 2 Lesion characteristics Variable
Lesion location Left anterior descending coronary artery Right coronary artery Left circumflex coronary Lesion type A B1 B2 C
Polymer-based PES (n ⫽ 70)
Nonpolymer-based PES (n ⫽ 65)
p Value
38 (54%)
34 (52%)
0.82
14 (20%) 18 (26%)
10 (15%) 21 (32%)
0.48 0.40
32 (46%) 26 (37%) 9 (13%) 3 (4%)
28 (43%) 19 (29%) 15 (23%) 3 (5%)
0.76 0.33 0.12 0.93
Table 3 Procedural characteristics Variable
Stent length (mm) Stent diameter (mm) Maximal implantation pressure (atm)
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Polymer-based PES (n ⫽ 70)
Nonpolymer-based PES (n ⫽ 65)
p Value
14.8 ⫾ 3.2 3.06 ⫾ 0.18 13.9 ⫾ 1.4
15.8 ⫾ 3.4 3.10 ⫾ 0.34 13.4 ⫾ 1.5
0.09 0.80 0.16
the contrast-filled catheter as the calibration standard. Quantitative measurements included reference diameter, lesion length, minimal lumen diameter in lesion (defined as instent segment plus proximal and distal 5-mm edge segments) and in stent (without adjacent edge segment) before and after the procedure and at follow-up. Late loss (defined as decrease in minimum lumen diameter from immediately after the procedure to 6-month follow-up), acute gain (defined as an increase in minimal luminal diameter immediately after percutaneous transluminal coronary angioplasty), net gain (difference between acute gain and late loss), and loss index (ratio of late loss to acute gain) were calculated.
IVUS analysis: Among the first 35 patients in the 2 stent groups, IVUS follow-up was intended. IVUS studies were performed at the time of 6-month control angiography after intracoronary administration of nitroglycerin using a 40MHz, 2.6Fr, IVUS catheter (Atlantis Boston Scientific) with an automated pullback at 0.5 mm/s to perform the imaging sequence. Area measurements were performed with a commercially available program for computerized planimetry (TapeMeasure, Indec Systems, Mountain View, California). If the neointimal tissue encompassed the imaging catheter, the luminal cross-sectional area (CSA) was assumed to be the physical size of the imaging catheter (0.9 mm2). The following calculations were then performed for every 1 mm within the stent length: (1) intimal hyperplasia CSA (square millimeters) ⫽ stent CSA ⫺ lumen CSA at follow-up; (2) mean stent diameter (millimeters) ⫽ 2 ⫻ (stent CSA/ )⫺1/2; (3) mean lumen diameter (millimeters) ⫽ 2 ⫻ (lumen CSA/)⫺1/2; (4) mean intimal hyperplasia thickness (millimeters) ⫽ mean stent radius at follow-up ⫺ mean lumen radius at follow-up; and (5) mean intimal hyperplasia CSA/stent CSA. To analyze the intimal hyperplasia distribution within the longitudinal stent direction, measurements at 7 equally distributed points from the proximal to the distal stent edges were performed. Statistical analysis: Statistical analysis was performed with SPSS software (SPSS, Inc., Chicago, Illinois). Categorical data were presented as frequencies and compared with the Pearson chi-square test. Continuous data were presented as mean ⫾ SD and compared with the Student t test or analysis of variance, if appropriate. A p value ⬍0.05 was considered statistically significant. Multivariate analysis to identify predictors for recurrent angiographic restenosis and linear regression analysis to identify predictors of intimal hyperplasia thickness were performed, with diabetes mellitus, reference vessel diameter, lesion length, minimal lumen diameter in the lesion before intervention, lesion location in the left anterior descending artery, and type of stent as parameters. Results Baseline characteristics: Clinical and angiographic characteristics at baseline were similar for the 2 groups (Tables 1 and 2). Eight patients (12%) in the polymer-based PES group and 7 (11%) in the nonpolymer-based PES group presented with acute coronary syndromes (p ⫽ 0.784). Procedural data: Procedural success using the intended stent was achieved in all cases (Table 3). Mean stent length, stent diameter, and stent implantation pressure were similar for the 2 groups. Additional stenting with overlapping of stents was used in case of dissection or remaining stenosis in 2 lesions (3%) in the polymer-based PES group and 4 lesions (6%) in the nonpolymer-based PES group (p ⫽ 0.35). Predilatation was performed in 28 lesions (40%) before implantation of polymer-based PESs and in 35 lesions (54%) before implantation of nonpolymer-based PESs (p ⫽ 0.11).
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Table 4 Quantitative angiographic results Variable Before intervention Mean lesion length (mm) Mean reference lumen diameter (mm) Minimum lumen diameter (mm) Diameter stenosis (%) After intervention Minimum lumen diameter in stent (mm) Minimum lumen diameter in lesion (mm) Diameter stenosis in stent (%) Diameter stenosis in lesion (%) Follow-up Mean reference lumen diameter (mm) Minimum lumen diameter in stent (mm) Minimum lumen diameter in lesion (mm) Diameter stenosis in stent (%) Diameter stenosis in lesion (%) Binary restenosis in lesion Binary restenosis in stent Late loss in stent (mm) Late loss in lesion (mm) Loss index in stent (mm) Loss index in lesion (mm)
Polymer-based PES (n ⫽ 54)
Nonpolymer-based PES (n ⫽ 51)
p Value
9.81 ⫾ 3.75 2.96 ⫾ 0.48 1.09 ⫾ 0.36 62.87 ⫾ 11.24
10.48 ⫾ 3.65 2.85 ⫾ 0.56 0.97 ⫾ 0.42 65.35 ⫾ 13.40
0.30 0.12 0.07 0.26
2.73 ⫾ 0.37 2.55 ⫾ 0.45 5.05 ⫾ 9.92 11.99 ⫾ 10.77
2.65 ⫾ 0.38 2.49 ⫾ 0.45 5.33 ⫾ 12.38 11.77 ⫾ 13.21
0.18 0.37 0.89 0.91
2.83 ⫾ 0.38 2.47 ⫾ 0.43 2.17 ⫾ 0.53 11.92 ⫾ 14.28 22.92 ⫾ 16.82 5 (9%) 2 (4%) 0.22 ⫾ 0.27 0.28 ⫾ 0.34 0.13 ⫾ 0.20 0.36 ⫾ 0.57
2.80 ⫾ 0.50 1.92 ⫾ 0.80 1.81 ⫾ 0.76 32.71 ⫾ 24.37 36.54 ⫾ 23.07 14 (27%) 10 (20%) 0.74 ⫾ 0.61 0.68 ⫾ 0.62 0.41 ⫾ 0.39 0.66 ⫾ 0.65
0.75 ⬍0.001 0.002 ⬍0.001 ⬍0.001 0.016 0.010 ⬍0.001 ⬍0.001 ⬍0.001 0.009
Table 5 Intravascular ultrasound results at follow-up Variable
Polymer-based Nonpolymer-based PES PES (n ⫽ 32) (n ⫽ 29)
Mean reference lumen CSA (mm2) Mean lumen CSA (mm2) Mean lumen diameter (mm) Mean stent CSA (mm2) Mean intimal hyperplasia CSA (mm2) Mean intimal hyperplasia thickness (mm) Mean IH CSA/stent CSA Figure 1. Cumulative frequency distribution curves for in-stent minimum lumen diameter for the nonpolymer-based (solid lines) and polymer-based (dotted lines) PESs.
Clinical follow-up results: There was 1 death due to acute Q-wave myocardial infarction caused by subacute stent thrombosis 4 days after implantation of a polymerbased PES in a patient with multivessel disease and a history of repeated stent thrombosis in another coronary vessel. The 30-day major adverse cardiac event rates were 1.4% and 0% (p ⫽ 0.32) in the polymer-based and nonpolymer-based PES groups, respectively. At 6-month follow-up, target lesion revascularization was required in 6 lesions (9%, 5 cases of binary restenosis and 1 case of subacute stent thrombosis) in the polymerbased PES group. Major adverse cardiac events were also observed in 6 of 65 patients (9%). The major adverse car-
p Value
8.66 ⫾ 2.31
9.34 ⫾ 2.75
0.32
7.34 ⫾ 1.66 3.04 ⫾ 0.32
7.48 ⫾ 2.71 3.02 ⫾ 0.60
0.80 0.93
7.95 ⫾ 1.66 0.62 ⫾ 0.41
9.83 ⫾ 2.07 2.36 ⫾ 1.60
⬍0.001 ⬍0.001
0.06 ⫾ 0.42
0.25 ⫾ 0.18
⬍0.001
0.08 ⫾ 0.05
0.25 ⫾ 0.18
⬍0.001
IH ⫽ intimal hyperplasia.
diac event rate in the nonpolymer-based PES group was significantly higher at 23% (15 of 65 patients, p ⫽ 0.032). This was due to repeat target lesion revascularization in 18% (11 cases of binary restenosis and 1 case of stent thrombosis at 5 months, p ⫽ 0.13 vs polymer-based PES), 2 noncardiac deaths, and 1 cardiac death related to myocardial infarction. Six-month angiographic results: Six-month follow-up angiography was performed on 54 lesions (77%) in the polymer-based PES group and 51 lesions (78%) in the nonpolymer-based PES group. Quantitative angiographic results are presented in Table 4. At follow-up, patients in the polymer-based PES group showed larger in-stent and in-lesion minimal lumen diameters. Figure 1 shows cumulative frequency distribution
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Intimal hyperplasia CSA and intimal hyperplasia thickness were significantly larger for nonpolymer-based PESs than for polymer-based PESs. Segmental analysis demonstrated intimal hyperplasia CSA to be uniformly greater over the entire stent length of the nonpolymer-based PES compared with the polymer-based PES (Figure 2). A similar result was found for intimal hyperplasia thickness (Figure 3).
Figure 2. Plot of mean IVUS intimal hyperplasia CSAs at follow-up at 7 different points within the stent length for the polymer-based (diamonds) and nonpolymer-based (squares) PESs.
Predictors of binary restenosis and intimal hyperplasia thickness: In a multivariate model, independent predictors of binary restenosis were type of stent coating (odds ratio 3.72, 95% confidence interval 1.11 to 11.92, p ⫽ 0.028) and mean vessel reference diameter (odds ratio 0.20, 95% confidence interval 0.05 to 0.93, p ⫽ 0.034). In a linear regression analysis on predictors of intimal hyperplasia thickness, type of stent coating (p ⬍0.001) and lesion length (p ⫽ 0.010) were found to have a significant effect. Discussion
Figure 3. Plot of mean IVUS intimal hyperplasia thickness at follow-up at 7 different points within the stent length for the polymer-based (diamonds) and nonpolymer-based (squares) PESs.
curves for in-stent minimal lumen diameter before and after stent implantation and at follow-up. Significantly lower in-stent and in-segment late lumen losses were observed with polymer-based PESs compared with nonpolymerbased PESs (0.22 ⫾ 0.27 vs 0.74 ⫾ 0.61 mm, p ⬍0.001; 0.28 ⫾ 0.34 vs 0.68 ⫾ 0.62 mm, p ⬍0.001, respectively). This translated into significantly lower in-stent and in-lesion binary restenosis rates in the polymer-based PES group (5% vs 20%, p ⬍0.001; 9% vs 27%, p ⬍0.001, respectively). Six-month IVUS results: Placement of the IVUS catheter was not possible in 1 lesion after polymer-based PES implantation due to severe vessel calcification and in 1 lesion after nonpolymer-based PES implantation due to pronounced intimal hyperplasia and binary restenosis. Thus, IVUS follow-up at 6-month coronary angiography was performed in 32 lesions in the polymer-based PES group and in 29 lesions in the nonpolymer-based PES group. Results of the IVUS studies are presented in Table 5.
The present study is the first direct comparison of polymerand nonpolymer-based PESs in the treatment of de novo coronary lesions. This study demonstrated (1) significant differences in the extent of intimal hyperplasia between polymer- and nonpolymer-based PESs, with favorable results within the polymer-based PES platform, (2) translation of the difference in intimal hyperplasia into superior angiographic results after implantation of polymer-based PESs, and (3) similar intimal hyperplasia distribution within stent length of the 2 groups. Paclitaxel has been reported to suppress vascular cell proliferation and subsequent excessive formation of intimal hyperplasia.1,2 Randomized clinical trials have demonstrated remarkable and consistent effectiveness of polymerbased PESs in the decrease of in-stent restenosis and repeat target lesion revascularization at 6 and 9 months.3–5 Use of polymer-based PESs has been shown in clinical trials to result in lesion lumen loss in the range of 0.30 ⫾ 0.39 to 0.36 ⫾ 0.48 mm, angiographic restenosis rates of 0% to 9%, and intimal hyperplasia CSAs of 0.6 ⫾ 0.8 mm2 for de novo coronary lesions at 6- to 9-month follow-up.3,4 In this study, in-lesion lumen loss was 0.28 ⫾ 0.34 mm, restenosis rate was 9%, and intimal hyperplasia CSA was 0.62 ⫾ 0.41 mm2 for the polymer-based PES group. Thus, the findings were consistent with angiographic and IVUS results of previous randomized trials on polymer-based PESs in de novo coronary lesions. In addition, the target lesion revascularization rate of 11% at 6-month follow-up for the polymer-based PES group was similar to that in previous reports that indicated target lesion revascularization rates of 0% to 9%.3–5 Although the polymer coating ensures a controlled drug release, local hypersensitivity reactions to the polymer stent coating have been observed in an animal model and in clinical studies6 –10 and have raised concerns about sustained long-term effectiveness of polymer-based drug-eluting stents. Nonpolymer-based drug delivery has been suggested as a different approach to deliver paclitaxel. Multicenter studies such as the Asian Paclitaxel-Eluting Stent Clinical Trial (ASPECT), the European Evaluation of Paclitaxel-
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Eluting Stent (ELUTES), and the RX Achieve Drug-eluting Coronary Stent System in the Treatment of Patients With De Novo Native Coronary Lesions (DELIVER I) evaluated PESs without polymer coating for treatment of de novo coronary lesions.11–13 A significant decrease in neointimal proliferation was observed only in high-dose groups of the ASPECT and ELUTES trials. The DELIVER I trial demonstrated only a minor decrease in late loss for the nonpolymer-based PES compared with the bare metal stent, which did not translate into a significant decrease in restenosis and need for recurrent revascularization. In the present study, implantation of the nonpolymerbased PES resulted in an in-stent late loss of 0.74 ⫾ 0.61 mm and a binary angiographic restenosis rate of 20%. These findings are similar to the results reported in the DELIVER I trial (0.81 ⫾ 0.60 mm late loss and 14.9% restenosis rate), but considerably worse than the results reported for the high-dose drug-eluting stent groups in ASPECT and ELUTES. Possible reasons for the higher late loss in this study compared with the ASPECT and ELUTES trials relate to differences in patient characteristics, with a higher rate of diabetics (28% in the present study vs 16% in ELUTES) and a more complex lesion morphology (25% of type B2/C lesions in the present study vs 9% and 7% in ELUTES and ASPECT, respectively). Significant loss of drug from the platform during stent delivery and rapid release of the remaining drug may be possible reasons for the attenuated effectiveness of nonpolymer-based PESs in the suppression of neointimal formation despite almost 3 times the surface-related initial loading dose of paclitaxel compared with the polymer-based PESs. Preclinical studies of the nonpolymer-based PES have indicated that a significant loss of paclitaxel occurs before the stent reaches the lesion, and subsequent paclitaxel release to the surrounding tissue is rapid and completed within days to a few weeks. At this time, potential intimal proliferation due to trauma of stent expansion is not finished.13 Gershlick et al12 demonstrated in an experimental study on nonpolymer-based PESs that amounts of the drug remaining on the stent are 70% 4 hours after stent deployment and 30% at 14 days. Paclitaxel levels after deployment in an in vitro study with Palmaz-Schatz stents dip-coated with paclitaxel demonstrated that only 68% of the drug originally deposited on the stent could be recovered.14 Thus, the drugelution curve is considerably different from that of polymerbased PESs, which are characterized by a drug release extending over several weeks. Another issue with regard to the effectiveness of paclitaxel relates to tissue uptake and subsequent persistence of drug within the tissue. Uptake of paclitaxel is determined by the rate at which it crosses the cell membrane. In the absence of a polymer platform, the amount of drug delivered to the tissue is determined by the tissue characteristics being targeted. It has been suggested that paclitaxel easily passes through the hydrophobic barrier of cell membranes and remains present and active within the vessel wall long after delivery from the stent due to its lipophilic nature.1 This may lessen the importance of a long drug release period. At the same time, variations in the lipid content of the atherosclerotic human artery may not provide even distribution and sufficient levels of paclitaxel in the vessel
wall, and paclitaxel may also be lost again from the vessel wall, thus jeopardizing the ability of a prolonged neointimal suppression after arterial injury in case the drug is already released soon after stent implantation. In a recent randomized comparison of rapamycin-coated, polymer-free Yukon stents (Translumina, Munich, Germany) and polymer-based PESs, no difference in late loss was found.15 Comparison with the present study with respect to the effect of the polymer on late loss is difficult. In a study by Mehilli et al,15 2 different drugs were used. With respect to several recent randomized studies, polymer-based sirolimus-eluting stents appear to be more effective in decreasing late lumen loss than polymer-based PESs.16,17 Thus, the more effective drug might have compensated for the disadvantage of the polymer-free coating compared with the polymer-based PESs. This was not a randomized study. Patients were enrolled in the 2 study groups in a sequential manner. Nevertheless, there were no significant differences with respect to clinical, angiographic, and IVUS baseline characteristics. IVUS analyses were performed on only 32 lesions in the polymerbased PES group and 29 lesions in the nonpolymer-PES group when considering the first 35 included lesions of the 2 groups. The stent platform was different between the 2 stent groups in addition to the 2 different coatings. However, the difference in late loss and intimal hyperplasia between the 2 stent groups was significantly higher than has been described between different bare metal stent designs, indicating that stent configuration has contributed little to the overall difference between the 2 evaluated stent types.18,19 IVUS analysis demonstrated larger mean stent CSA in the nonpolymer-based PES group compared with the polymer-based PES group. Thus, larger absolute intimal hyperplasia CSA in the nonpolymer-based PES group may be a consequence of a different stent size. However, even intimal hyperplasia thickness and the ratio of intimal hyperplasia CSA to stent CSA as stent-size independent parameters of tissue proliferation were significantly different between the 2 stent types. The difference in stent size in favor of the nonpolymer-based PES did not result in superior lumen CSA at follow-up. This was due to excessive intimal hyperplasia within the nonpolymer-based PES. Although angiographic and IVUS results demonstrated a significant advantage of the polymer-based PES, clinical event rates failed to show a significant difference. A significant difference in clinical end points would have been likely with larger patient numbers. 1. Drachman DE, Edelman ER, Seifert P, Groothuis AR, Bornstein DA, Kamath KR, Palasis M, Yang D, Nott SH, Rogers C. Neointimal thickening after stent delivery of paclitaxel: change in composition and arrest of growth over six months. J Am Coll Cardiol 2000;36:2325– 2332. 2. Herdeg C, Oberhoff M, Baumbach A, Blattner A, Axel DI, Schroder S, Heinle H, Karsch KR. Local paclitaxel delivery for the prevention of restenosis: biological effects and efficacy in vivo. J Am Coll Cardiol 2000;35:1969 –1976. 3. Grube E, Silber S, Hauptmann KE, Mueller R, Buellesfeld L, Gerckens U, Russell ME. TAXUS I: six- and twelve-month results from a randomized, double-blind trial on a slow-release paclitaxel-eluting stent for de novo coronary lesions. Circulation 2003;107:38 – 42.
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