Evaluation of a New Polymer-Coated Paclitaxel-Eluting Stent
for Treatment of De Novo Lesions: Six-Month Clinical and Angiograph

In-stent restenosis as a result of excessive neointimal proliferation is the main limiting factor to the long-term success of coronary stenting, but the advent of drug-eluting stents has reduced this problem significantly. Paclitaxel is an antiproliferative drug that affects cellular proliferation and migration by interfering with the function of cellular microtubules,^1,2 and various clinical trials have shown that paclitaxel-eluting stents can effectively suppress neointimal proliferation after coronary stenting of de novo lesions.^3–10 The APPLAUSE (amg Pico^Elite Paclitaxel-Eluting Stent) study is a first-in-man safety and efficacy randomized trial of the Pico^Elite stent (amg International GmbH, Raesfeld-Erle, Germany), a new paclitaxel-eluting stent with a polymer coating. Materials and Methods Device description. The drug-eluting Pico^Elite stent (Figure 1) is coated with paclitaxel (dose density of 1 mcg/mm2) in a 3- to 4-mcg thick biostable polysulphone polymer on a cobalt-chromium stent platform. The polymer enables a controlled and uniform release of the drug over a period of Pico bare metal stent, which is identical to the cobalt-chromium platform of the Pico^Elite. Both stents are available in 2 size ranges: a smaller range (2.0, 2.25, 2.5 and 2.75 mm), with lengths of 8, 12, 16 and 19 mm, and a larger range (3.0, 3.25, 3.5 and 4.0 mm), with lengths of 10, 14, 18, 24, 28, 34 and 38 mm. Patient selection. This was a single-center, randomized, controlled trial. Local ethics committee approval was obtained prior to study commencement, and informed written consent was obtained from all participating patients. Inclusion criteria were as follows: patients between 25 and 80 years of age with angina and documented ischemia, documented silent ischemia or unstable angina (excluding acute myocardial infarction), with a de novo native coronary artery lesions of percent diameter stenosis greater than or equal to 50%, reference vessel size of 2.0–4.0 mm, and a lesion length that could be fully covered by a single stent. Patients with diabetes mellitus were not excluded. Exclusion criteria included: left main disease, chronic total occlusion > 3 months old, major side branch of greater than or equal to 2.0 mm, multiple contiguous stenting, in-stent restenosis, saphenous vein or arterial graft lesion, left ventricular ejection fraction Study procedure. In addition to aspirin, patients were pretreated with 300 mg clopidogrel in the 24 hours prior to the procedure unless they were already previously taking it. Intravenous heparin was administered during the procedure according to standard practice. Direct stenting was not allowed, and predilatation with a balloon equal to or smaller than the vessel diameter was recommended. A single stent of a length that would cover the whole lesion was deployed. After stenting, aspirin was continued indefinitely and clopidogrel 75 mg/day was prescribed for 6 months postintervention. An example of a successful case is shown in Figure 2. The levels of creatine kinase (MB fraction) and troponin were checked every 8 hours for 24 hours after the intervention. A clinical follow-up visit was conducted at 30 days and at 6 months; angiographic follow up was performed at 6 months postprocedure. Study endpoints. The primary endpoint of the study was the rate of major adverse cardiac events (MACE), which is inclusive of death, myocardial infarction, target lesion revascularization with percutaneous coronary intervention (PCI), or coronary artery bypass surgery (CABG) at 30-day follow up. The secondary endpoints were MACE and quantitative angiographic late loss at 6-month follow up. Quantitative angiographic measurements. After intracoronary nitrate administration, two or more orthogonal views were taken to show nonforeshortened views of the target lesion. Quantitative angiographic endpoints included minimal lumen diameter (MLD), percent diameter stenosis, late lumen loss and binary restenosis, defined as greater than or equal to 50% diameter stenosis. In-lesion measurements included the stented segment as well as the margins 5 mm proximal and distal to the stent. Quantitative coronary angiographic analysis (QCA) was performed for baseline and follow-up angiograms using commercially available software (Medis QCA-CMS System Version 5.3, Leiden). Statistical analysis. Discrete variables were presented as counts and percentages, and compared by the Chi-square or Fisher’s exact test, as appropriate. Continuous variables were reported as mean ± SD, and compared by independent samples T-test. All tests were two-tailed. A probability value of p (SPSS, Inc., Chicago, Illinois). Results Enrollment and baseline characteristics. Thirty patients, with 35 lesions were recruited over a period of 4 months (August through November 2004), and randomized in a 2:1 ratio to either the paclitaxel-eluting Pico^Elite stent (PES) group or the bare metal Arthos^Pico stent (BMS) group), respectively. Baseline clinical and lesion characteristics (Tables 1 and 2) were similar, other than a younger population in the PES group (63.5 years vs. 71.7 years in the BMS group; p = 0.032). QCA results are shown in Table 3. Baseline preintervention lesion characteristics were similar, except for a shorter lesion length in the PES group (9.56 mm vs. 14.25 mm in the BMS group; p = 0.002). The mean reference vessel diameter was similar (2.81 mm in the PES group vs. 2.98 mm in the BMS group; p = 0.46). One patient in the BMS group required a second bare metal stent (Driver, Medtronic, Inc, Minneapolis, Minnesota) implanted proximal and overlapping with the study stent due to the presence of a residual lesion not fully covered by the first stent. Angiographic follow-up results. Twenty-six of 30 patients (86.7%) were available for 6-month angiographic follow up: this was comprised of 17 patients in the PES group (total of 20 lesions) and 9 patients in the BMS group (total of 10 lesions). The 6-month in-stent MLD was significantly larger in the PES group (2.26 mm vs. 1.65 mm in the BMS group; p = 0.015). The in-stent diameter stenosis was significantly less in the PES group (21.7% vs. 41.2% in the BMS group; p = 0.001), and in-stent binary restenosis was also reduced in the PES group (5.0% vs. 40.0% in the BMS group; p = 0.031). The in-stent and in-segment late loss was significantly less in the PES group (0.47 mm and 0.72 mm, respectively vs. 1.10 mm and 1.16 mm in the BMS group; p = 0.004 and 0.016, respectively). In the PES group, 2 of the target lesions developed in-stent restenosis, 1 of which was a focal Type I pattern and the other a diffuse intrastent Type II pattern (Table 3). Clinical follow-up results. There was no incidence of MACE at 30-day follow up in both groups of patients. In 29 of 30 patients (96.7%), 6-month clinical follow up was available. In the PES group, there was a nonsignificant trend towards less MACE (10.5% vs. 40.0% in the BMS group; p = 0.143). MACE was comprised mainly of target lesion revascularization. In the PES group, 1 patient with in-stent restenosis underwent PCI with a Taxus^® drug-eluting stent (Boston Scientific, Natick, Massachusetts), while the other patient with a Type II intrastent restenosis underwent successful balloon angioplasty. Another patient in the PES group underwent PCI to a circumflex artery (nontarget vessel) lesion due to disease progression. In the BMS group, all 4 patients with in-stent restenosis were treated with Taxus stents. One patient in the BMS group developed angina on day-24 post-stenting, but no in-stent restenosis was found at reangiography, although there was a distal left anterior descending artery lesion that was previously present, but that was too distal and too small-caliber to be treated. However, at 6-month follow up, this patient was found to have a Type III proximal stent edge restenosis that was then treated with a single Taxus stent. Unfortunately, this patient died suddenly 2 days after reintervention, which was attributed to subacute stent thrombosis of the newly-implanted Taxus stent. No stent thrombosis in the PES group occurred within the 6-month follow up period. Discussion Paclitaxel-eluting stents can be generally divided into two categories: those with and those without a polymer coating. Nonpolymeric paclitaxel-eluting stents were an attractive idea, as there were concerns that the presence of polymers may provoke excessive inflammatory response and more neointimal proliferation, as has been shown in some animal studies.^11,12 The small ASPECT and ELUTES trials showed promising results, with 6-month in-stent late loss in the high-dose groups of 0.29 mm and 0.11 mm, respectively.^8,9 However, the results of the larger DELIVER trial did not confirm this initial promise; although the in-stent late loss of 0.81 mm in the paclitaxel-stent group was significantly better than 0.98 mm in the BMS group, it was relatively high compared to other trials of paclitaxel-eluting stents (Table 5). In addition, there was no significant difference in the primary endpoint of 9-month target vessel failure rate (11.9% for the PES group vs. 14.5% for the BMS group; p = 0.12).10 A meta-analysis by Babapulle et al. also found that nonpolymeric paclitaxel-eluting stents did not appear as effective as sirolimus-eluting and polymeric paclitaxel-eluting stents in reducing the rates of TLR and MACE. The pooled rates of MACE for the polymeric paclitaxel stent compared to BMS were 8.7% versus 16.7% (odds ratio 0.47 [95% confidence interval 0.25–0.71]), and for nonpolymeric paclitaxel, the MACE rate was 7.7% versus 9.5% (0.64 [0.42–1.00]).¹³ The ability of the polymer to control the drug elution pharmacokinetics more precisely may be advantageous. The large-scale TAXUS II, IV and V trials involving lesions of increasing complexity all show that the polymer-based Taxus stent significantly reduces angiographic late loss at follow up, together with significantly lower TLR rates (Table 5).^4–6 The Pico^Elite stent used in this study has similarities to the Taxus stent in that it has a similar drug density of paclitaxel (1 mcg/mm2), is also polymer-based, and after 30 days of controlled elution of the paclitaxel, 80% of the drug remains in the polymer. The drug release curve of the Pico^Elite stent lies between that of the Taxus slow-release stents (where 90% of the paclitaxel remains in the polymer after 30 days) and the Taxus moderate-release stents (70% remains in polymer). This feasibility study established that this stent could effectively reduce neointimal proliferation when compared to a control BMS group, as demonstrated in the significantly lower amount of in-stent and in-segment angiographic late loss. From a safety standpoint, the primary endpoint of 30-day MACE was 0% in both groups, and it was reassuring to see that no stent thrombosis occurred in the PES group at 6-month follow up. The results from the APPLAUSE trial are summarized together with results from other paclitaxel-eluting stent trials in Table 5, although they are only shown as a reference, since we cannot directly compare the results of APPLAUSE to these other trials. Study limitations. This was a single-center early feasibility study involving only a small number of patients, which can lead to dissimilar baseline characteristics, as seen in this study where the PES group had younger patients and shorter lesions. The rate of follow up was satisfactory; 26 of 30 patients (86.7%) were available for 6-month angiographic follow up, and 29 of 30 patients (96.7%) were available for 6-month clinical follow up. However, it would still have been preferable to have a higher rate of follow up, as each patient represents a significant percentage point in a small study. Conclusions This first-in-man study provided early evidence for the safety and efficacy of the new polymer-based paclitaxel-eluting Pico^Elite coronary stent when compared to bare metal stents at 6-month follow up. Larger studies with longer follow up periods are essential to demonstrate whether these encouraging results are maintained over a longer time frame. Acknowledgement. The authors would like to thank Mr. Jucelmo Schmitt for his assistance with data collection and management.

1. Axel DI, Kunert W, Goggelmann C, et al. Paclitaxel inhibits arterial smooth muscle cell proliferation and migration in vitro and in vivo using local drug delivery. Circulation 1997:96:636–645. 2. Giannakakou P, Robey R, Fojo T, et al. Low concentrations of paclitaxel induce cell type-dependent p53, p21 and G1/G2 arrest instead of mitotic arrest: Molecular determinants of paclitaxel-induced cytotoxicity. Oncogene 2001;20:3806–3813. 3. Grube E, Silber S, Hauptmann KE, et al. 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. 4. Colombo A, Drzewiecki J, Banning A, et al. TAXUS II Study Group. Randomized study to assess the effectiveness of slow- and moderate-release polymer-based paclitaxel-eluting stents for coronary artery lesions. Circulation 2003;108:788–794. 5. Stone GW, Ellis SG, Cox DA, et al. for the TAXUS-IV Investigators. A polymer-based, paclitaxel-eluting stent in patients with coronary artery disease. N Engl J Med 2004;350:221–231. 6. Stone GW, Ellis SG, Cox DA, et al. for the TAXUS-IV Investigators. One-year clinical results with the slow-release, polymer-based, paclitaxel-eluting TAXUS stent. The TAXUS-IV trial. Circulation 2004;109:1942–1947. 7. Stone GW. Results of the TAXUS V trial. Presented at the American College of Cardiology, 54th Annual Scientific Session, March 2005, Orlando, Florida. 8. Park SJ, Shim WH, Ho DS, et al. A paclitaxel-eluting stent for the prevention of coronary restenosis. N Engl J Med 2003;348:1537–1545. 9. Gershlick A, De Scheerder I, Chevalier B, 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. 10. Lansky AJ, Costa RA, Mintz GS, 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. 11. De Scheerder IK, Wilczek KL, Verbeken EV, et al. Biocompatability of polymer-coated oversized metallic stents implanted in normal porcine coronary arteries. Atherosclerosis 1995;114:105–114. 12. Van der Giessen WJ, Lincoff M, Schwartz R, et al. Marked inflammatory sequelae to implantation of biodegradable and non-biodegradable polymers in porcine coronary arteries. Circulation 1996;94:1690–1697. 13. Babapulle MN, Joseph L, Bélisle P, et al. A hierarchical Bayesian meta-analysis of randomised clinical trials of drug-eluting stents. Lancet 2004;364:583–591.