Although stenting has improved clinical outcomes of patients undergoing percutaneous coronary intervention (PCI), bare-metal stents are associated with a considerable risk of restenosis.1,2 The main cause of in-stent restenosis is excessive neointimal hyperplasia formation resulting from proliferation and migration of smooth muscle cells and extracellular matrix production.3–5
Lately, drug eluting-stents (DES) have markedly reduced neointimal hyperplasia (NIH) via local delivery of antiproliferative agents.6–8 Several clinical studies have shown that sirolimus- and paclitaxel-eluting stents significantly reduce neointimal hyperplasia and the need for repeat coronary revascularization compared to bare-metal stents.9–11 However, concerns about long-term safety of these two DES12 have stimulated the search for new DES with comparable efficacy and an improved safety profile.
Recently developed, the ZoMaxx™ stent (Abbott Vascular, Redwood City, California) combines a sirolimus-analogous agent, zotarolimus, a phosphorylcoline polymer, and a newgeneration stainless steel and tantalum platform. Zotarolimus blocks the activation of the mammalian target of rapamycin, arresting the cell cycle. The potential for a zotarolimus-eluting stent to reduce target lesion revascularization (TLR) has been previously demonstrated.13,14
We sought to assess the efficacy of the ZoMaxx stent in reducing the amount of neointimal hyperplasia when compared to its non-drug-coated equivalent, the TriMaxx™ stent (Abbott Vascular).
Study design and population. This is a single-center, prospective, nonrandomized study comparing 40 consecutive patients treated with ZoMaxx stent to a control group of 50 patients treated with the TriMaxx stent.
Patient enrollment. Since the ZoMaxx stent comprises a new platform, polymer and drug as part of the initial experience with this system, our institution conducted a pilot safety study with 50 patients receiving the non-drug-eluting platform (TriMaxx stent), which combines a stainless steel and tantalum platform and a phosphorylcoline polymer. Following that, 40 more patients were enrolled and received the ZoMaxx stent, consisting of the same platform and polymer with the addition of zotarolimus.
Patients included in this study were aged 18 years or older, with stable or unstable angina pectoris or documented silent ischemia, with a single, significant de novo lesion (> 50% stenosis by quantitative assessment) in a native coronary artery. Patients were excluded from the analysis if they had recent myocardial infarction (< 72 hours), poor left ventricular ejection fraction (< 30%), more than 50% unprotected left main coronary stenosis, a serum creatine level > 2.0 mg/dl (179 μmol/L), or contraindication to aspirin, clopidogrel, ticlopidine or heparin.
The ethics committee of our institution approved this protocol. Written informed consent was obtained from all patients.
Study devices. The stent used in the control group was the TriMaxx stent, which comprises a tri-layer composite of stainless steel and tantalum, with a strut thickness of 74 μm that allows an ultra-low crossing profile and a phosphorylcholine polymer. TriMaxx stents were available in a length of 18 mm and sizes of 3.0 or 3.5 mm.
The ZoMaxx stent system consists of three components: (1) the metallic platform is the same as the bare-metal Tri- Maxx stent; (2) the pharmacoactive agent is zotarolimus, a new, highly lipophyllic synthetic agent that inhibits inflammation and proliferation of smooth muscle cells by a sirolimus analogue mechanism; and (3) the polymer coating of this stent is a specific formulation of phosphorylcholine (Pharmacoat™) with an extra cap coating that allows elution of nearly 100% of the drug within the first month.13 This polymer contains 10 μg of zotarolimus per millimeter of stent. The ZoMaxx system is available in a single size (3.0 x 18 mm).
Procedures and antiplatelet therapy. All interventions were performed according to standard guidelines and the final interventional strategy, including the use of glycoprotein IIb/IIIa inhibitors, was left to the discretion of the operator. Balloon predilatation was recommended and multiple stent placement was not allowed. In the event of edge dissection or incomplete lesion coverage, additional stents could be implanted.
Patients were premedicated with aspirin (200 mg/day) and a 300 mg loading dose of clopidogrel at least 12 hours before the procedure. After intervention, patients were recommended to stay on thienopyridines for a minimum of 3 months after ZoMaxx and 1 month after TriMaxx stent deployment.
Procedural success was defined as residual stenosis < 20% by visual analysis in the presence of Thrombolysis In Myocardial Infarction (TIMI) 3 flow grade, without major in-hospital complications.
Follow up. Baseline and follow-up demographic and clinical data were obtained from personal interviews and hospital record chart review. Clinical follow up was conducted at 1, 4 and 12 months after the index procedure. Quantitative coronary angiographic (QCA) and three-dimensional (3-D) intravascular ultrasound (IVUS) analysis were performed immediately after the procedure and repeated 4 to 6 months later as part of a predetermined follow-up protocol.
Quantitative coronary angiographic evaluation. Baseline, postprocedure and follow-up QCA analysis were performed using the semiautomatic edge contour detectioncomputer analysis system. Quantitative measurements of the in-stent and in-segment (in-stent segment plus 5 mm edge proximally and distally) were performed in two orthogonal projections. Late loss was defined as the difference in minimal lumen diameter (MLD) measured immediately after the procedure and at follow up. Binary restenosis was defined in each segment (in-stent or in-segment) as diameter stenosis > 50% by QCA analysis at follow up.
Quantitative 3-D IVUS. Serial IVUS studies were performed after intracoronary administration of 0.1–0.2 mg of nitroglycerin using a motorized transducer pullback system (0.5 mm/second) and commercial scanners (CVIS and Galaxy 2, Boston Scientific Corp., Natick, Massachusetts) consisting of a rotating 40 MHz transducer with a 2.6 Fr imaging sheath. The imaging catheter was advanced approximately 10 mm beyond the stent into the distal vessel. All IVUS images were recorded on 0.5 inch high-quality VHS videotapes or on CD/DVD for offline analysis.
All IVUS images were digitized to perform quantitative and qualitative analysis according to the criteria of the American College of Cardiology’s Clinical Expert Consensus Document on IVUS.15 A coronary segment starting at the distal stent edge and extending to its proximal edge was analyzed. A computer-based contour detection program was used for automated 3-D reconstruction of the stented segment (Echoplaque, Indec Systems, Inc., Mountain View, California). Cross-sectional area (CSA) measurements every 0.5 mm included lumen, stent and external elastic membrane CSA. Vessel (external elastic membrane), stent (SV) and lumen (LV) volumes were calculated according to the Simpson’s rule. The in-stent intimal volume was calculated as SV minus LV. The percentage of stent obstruction was calculated as neointimal volume (NV) divided by SV x 100. The plaque volume behind the stent was also expressed (vessel volume minus SV). All volumetric IVUS and QCA analyses were performed by an experienced independent operator blinded to the stent deployed.
Endpoints. The aim of the present study was to compare, using 3-D IVUS, the percentage of in-stent neointimal volume obstruction between the TriMaxx stent and its drug-eluting version, the Zomaxx stent at follow up.
Additionally, we evaluated in-stent and in-segment late loss and binary restenosis rate as well as the occurrence of major adverse cardiac events (MACE), defined as cardiac death, Q-wave or non-Q-wave myocardial infarction (MI) and/or target lesion revascularization (TLR) at one year clinical follow up.
All deaths were considered cardiac unless they were unequivocally documented as noncardiac. MI was defined as an elevation in the creatine kinase (CPK) level to more than twice the upper normal limit with an increased CK-MB accompanied by new abnormal Q-waves (Q-wave MI) or not (non-Q-wave MI). TLR was defined as a new revascularization (coronary artery bypass grafting or percutaneous intervention) of the lesion (in-stent or in-segment).
Statistical analysis. Continuous variables were expressed as mean ± 1 standard deviation (SD) and were compared using the Student’s t-test or the Wilcoxon unpaired test, when appropriate. Categorical variables are presented as counts and percentages, and were compared using the chisquare or Fischer’s test. A two-tailed p-value < 0.05 was considered significant. Statistical analyses were performed using SPSS software, version 13 (SPSS Inc., Chicago, Illinois). Results Baseline clinical and angiographic characteristics were similar in both groups and are presented in Table 1. The majority of our patients were men (58%), with a mean age of 58.9 ± 9.9 years. Diabetes mellitus was present in 31% of the cohort, and the left anterior descending artery was the most frequent target vessel (43%). Procedural success was achieved in all patients, and no in-hospital adverse events were detected in both groups.
QCA and IVUS results. The mean angiographic and IVUS follow-up interval time was 5.5 ± 0.9 months. QCA follow up was available in 100% of control patients and in 95% of the ZoMaxx population, whereas IVUS follow up was available in 90% of the control group and in 92.5% of the ZoMaxx group. The results are presented in Tables 2 and 3.
Reference vessel diameter was slightly higher in the control group (2.87 ± 0.26 mm vs. 2.77 ± 0.23 mm; p = 0.06) compared to the DES group, as was the case for the mean stent diameter (3.21 ± 0.25 mm in the TriMaxx group vs. 3.0 ± 0 mm in the ZoMaxx group; p < 0.001), but resulted in a similar stent diameter-to-vessel diameter ratio between the two groups (1.12 ± 0.09 vs 1.09 ± 0.10; p = 0.14). In all cases, predilatation with a balloon catheter was performed according to a predefined protocol.
Postprocedure minimal lumen diameter (MLD) was significantly higher in the control group (3.01 ± 0.29 vs 2.69 ± 0.25 mm; p < 0.001), however, residual stenosis after stent implantation was similar in both groups (Table 2).
At follow up, patients who received a ZoMaxx stent had significantly less late loss, both in-stent (0.92 ± 0.34 mm vs. 0.22 ± 0.25 mm; p < 0.001) and in-segment (0.66 ± 0.36 mm vs. 0.18 ± 0.27 mm; p < 0.001), when compared to the control group. Therefore, binary in-stent and in-segment restenosis were significantly higher in the TriMaxx group than in the ZoMaxx group (24% vs. 2.7%; p = 0.01 and 24% vs 5.4%; p = 0.03, respectively) (Table 2).
IVUS analyses revealed that the amount of NIH represented by the volume of neointimal tissue was significantly higher in the control group than in the DES group (52.35 ± 27.6 mm3 vs 7.47 ± 7.8 mm3, respectively; p < 0.0001), with a stent volume of 178.5 ± 49.8 mm3 in the non-drug-coated group, and 145.2 ± 53.2 mm3 in DES group (p = 0.004), resulting in a mean neointimal volume obstruction of 31.2 ± 15% in the TriMaxx group, and 4.6 ± 3.6% in the ZoMaxx group (p < 0.0001) (Table 3).
The cumulative frequency of neointimal volume obstruction in our analysis demonstrated that nearly 90% of the stented segments in the ZoMaxx group did not exhibit more than 10% of volume obstruction (Figure 1A). Conversely, only 10% of the TriMaxx stent group had < 10% volume obstruction (Figure 1B).
No incidences of late-acquired stent malapposition, a potential contributory mechanism to stent thrombosis, were detected in either group. Only 1 patient in the DES group required a second stent with overlapping in the baseline procedure.
Of note, we divided the ZoMaxx stents into 4 segments (each 4.5 mm) from distal to proximal edge, and observed that NIH distribution was significantly suppressed and equally distributed in all segments of the stent (Figure 2).
Clinical follow up. At 12-month clinical follow up, there were neither cardiac deaths nor MI in the ZoMaxx group.One Q-wave and 1 non-Q-wave MI were reported in the control group. TLR was performed in 4 patients (8%) in the Tri- Maxx group, and in 2 patients (5.4%) in the ZoMaxx group. The difference in TLR was not statistically significant (p = 0.5). The cumulative major adverse cardiac events (MACE) rate (cardiac death, MI or TLR) was 10% in the non-drugcoated cohort versus 5% in the DES group (p = 0.62).
This pivotal study with a new DES highlights the clinical safety of the ZoMaxx system, as well as its superiority in suppressing NIH formation when compared to its non-drug-eluting equivalent, the TriMaxx stent. Compared to its non-drug-coated version, which comprises the same stent and phosphorylcholine polymer, but without the elution of the antiproliferative drug, the new zotarolimus-eluting stent showed an 85% reduction in percentage of neointimal volume obstruction assessed by IVUS and also showed 76% reduction in in-stent late lumen loss and a 72% reduction in in-segment late loss.
Stent-based delivery of the antiproliferative and immunosuppressive macrocyclic lactone sirolimus (Cypher™, Cordis Corp., Miami, Florida) was the first to reveal a reduction in neointimal formation and restenosis by cytostatic inhibition of vascular smooth muscle cell proliferation.16 Zotarolimus is a new synthetic sirolimus-analogous agent that demonstrated an important antiproliferative effect in animal models. The elution profile of ZoMaxx and Cypher stents are similar.13
The current study showed at follow up a low amount of in-stent NIH, which is similar and comparable to previous studies with drug-coated stents, and is markedly different from those measured in the control bare-metal groups.10,11 Similar efficacy in reducing neointimal proliferation has also been shown among sirolimus- and biolimus-eluting stents assessed by IVUS.17
Although NIH was significantly reduced with the ZoMaxx stent, neointimal proliferation was not totally abolished, as shown in the cumulative frequency curve of neointimal volume.
Interestingly, in the pilot ENDEAVOR I study,14 which used a different platform and polymer, but the same eluting drug, the 4-month follow-up results showed that in-stent late lumen loss and neointimal volume obstruction (0.33 ± 0.36 mm and 4.5 ± 6.1%, respectively) were similar to the figures reported for ZoMaxx in the current study. Another similarity between the two systems is the potential late catch-up observed in the lumen loss. At 8 months, the ENDEAVOR II trial18 showed an instent late lumen loss of 0.61 ± 0.46 mm, markedly higher than its pilot study. Recently, Chevalier et al (Transcatheter Cardiovascular Therapeutics 2006, Washington, D.C., oral presentation) reported a similar occurrence with the ZoMaxx stent at mid-term follow up (ZoMaxx I study). In the 9-month angiography follow up, they noticed an in-stent late loss of 0.67 ± 0.57 mm and a neointimal volume obstruction of 14.6 ± 7.9. However, the potential influence of the late catch-up phenomenon in clinical outcomes still needs to be clarified in a larger study.
It is also worth noting that despite the considerably higher amount of NIH observed with TriMaxx stents, this fact did not translate into a very expressive clinical benefit, with a nonsignificant difference in ischemia-driven target vessel revascularization (8% for the non-drug-coated system vs. 5.4% for DES; p = 0.5).
Our analysis also highlights the safety and feasibility of this novel stent at long-term clinical follow up, with a low 12-month MACE rate for TriMaxx and ZoMaxx systems. Notably, IVUS did not detect a single case of aneurysmal formation, and the comparison of postprocedure and follow-up volumetric measurements did not reveal positive remodeling in either of the groups (Table 3).
Finally, with the recent purchase of part of Guidant Corporation, Abbott Laboratories “inherited” a new DES program (XScience™ drug-eluting stents), and decided to temporarily interrupt the promising ZoMaxx program.
Study limitations. Although the majority of the clinical and angiographic baseline characteristics are equivalent for the two groups, this study was not randomized. Furthermore, the relatively short time between the baseline and follow-up procedures (4 months) may have limited a more accurate long-term assessment of neointimal stent obstruction following ZoMaxx stent deployment. Finally, the relative small sample size limited some additional analysis, and was probably the reason we did not identify significant clinical differences between the two cohorts.
In this preliminary single-center experience, ZoMaxx proved to be clinically safe and superior to its non-drug-coated equivalent, the TriMaxx stent, in reducing in-stent neointimal formation. Further randomized analyses, in more complex cohorts, are essential to confirm these initial findings.
The authors wish to thank Drs. Dimytri Siqueira, Marcos Franchetti, Guilherme Attizzani, João Loures, Arturo Quispe, Julio Paiva Maia and Edmilson Ishii for their important contribution in the preparation of this manuscript.
1. Kastrati A, Schömig A, Elezi S, et al. Predictive factors of restenosis after coronary stent placement. J Am Coll Cardiol 1997;30:1428–1436.
2. Elezi S, Kastrati A, Pache J, et al. Diabetes mellitus and the clinical and angiographic outcome after coronary st ent placement. J Am Coll Cardiol 1998;32:1866–1873.
3. Nikol S, Huehns TY, Hofling B. Molecular biology and post-angioplasty restenosis. Atherosclerosis 1996;123:17–31.
4. Kornowski R, Hong M, Tio F, et al. In-stent restenosis: Contributions of inflammatory responses and arterial injury to neointimal hyperplasia. J Am Coll Cardiol 1998;31:224–230.
5. Farb A, Weber D, Kolodgie F, et al. Morphological predictors of restenosis after coronary stenting in humans. Circulation 2002;105:2974–2980.
6. Sousa JE, Serruys PW, Costa MA. New frontiers in cardiology: Drug-eluting stents: Part I. Circulation 2003;107:2274–2279.
7. Sousa JE, Serruys PW, Costa MA. New frontiers in cardiology: Drug-eluting stents: Part II. Circulation 2003;107:2383–2389.
8. Serruys PW, Kutryk M, Ong A. Drug therapy: Coronary-artery stents. N Engl J Med 2006;354:483–495.
9. Morice MC, Serruys PW, Sousa JE, et al. A randomized comparison of a sirolimus-eluting stent with a standard stent for coronary revascularization. N Engl J Med 2002;346:1773–1780.
10. Moses JW, Leon MB, Popma JJ, et al. for the SIRIUS Investigators. Sirolimuseluting stents versus standard stents in patients with stenosis in a native coronary artery. N Engl J Med 2003;349:1315–1323.
11. Stone GW, Ellis SG, Cox DA, et al. for the TAXUS-IV Investigators. A polymerbased, paclitaxel-eluting stent in patients with coronary artery disease. N Engl J Med 2004;350;221–231.
12. McFadden EP, Stabile E, Regar E, et al. Late thrombosis in drug-eluting stents after discontinuation of antiplatelet therapy. Lancet 2004;364:1519–1521.
13. DuVall M, Ji Q, Clifford A, et al. ABT-578 elution profile and arterial penetration using the ZoMaxx drug-eluting stent [abstract]. Am J Cardiol 2004;94:223E.
14. Meredith IT, Ormiston J, Whitbourn R, et al. First-in-human study of the Endeavor ABT-578-eluting phosphorylcholine-encapsulated stent system in the de novo native coronary artery lesions: ENDEAVOR I Trial. Eurointervention 2005;1:157–164.
15. Mintz G, Nissen SE, Anderson W, et al. American College of Cardiology clinical expert consensus document on standards for acquisition, measurement and reporting of intravascular ultrasound studies (IVUS). A report of the American College of Cardiology Task Force on Clinical Expert Consensus Documents. J Am Coll Cardiol 2001;37:1478–1492.
16. Sousa JE, Costa MA, Abizaid A, et al. Lack of neointimal proliferation after implantation of sirolimus-coated stents in human coronary arteries: A quantitative coronary angiography and three-dimensional intravascular ultrasound study. Circulation 2001;103:192–195.
17. Lasave LI, Abizaid AS, Abizaid A, et al. Late volumetric analysis of in-stent neointimal hyperplasia among three rapamycin-derivated eluting stents. An intravascular ultrasound study [Abstract]. Am J Cardiol 2006;98:130M.
18. Fajadet J, Wijns W, Laarman GJ, et al. Randomized, double-blind, multicenter study of the Endeavor zotarolimus-eluting phosphorylcholine-encapsulated stent for treatment of native coronary artery lesions. Endeavor II trial. Circulation 2006;114:798–806.