CLINICAL RESEARCH: INTERVENTIONAL CARDIOLOGY
Polymer-Based, Paclitaxel-Eluting TAXUS Liberté Stent in De Novo Lesions
The Pivotal TAXUS ATLAS Trial
Mark A. Turco, MD*,*,
John A. Ormiston, MBChB
,
Jeffrey J. Popma, MD
,
Lazar Mandinov, MD
,
Charles D. O’Shaughnessy, MD||,
Tift Mann, MD¶,
Thomas F. McGarry, MD#,
Chiung-Jen Wu, MD**,
Charles Chan, MD,
Mark W.I. Webster, MBChB,
Jack J. Hall, MD,
Gregory J. Mishkel, MD||||,
Louis A. Cannon, MD¶¶,
Donald S. Baim, MD and
Joerg Koglin, MD
* Center for Cardiac & Vascular Research, Washington Adventist Hospital, Takoma Park, Maryland
Mercy Angiography Unit, Mercy Hospital, Auckland, New Zealand
Department of Internal Medicine (Cardiovascular Division), Brigham and Women’s Hospital, Boston, Massachusetts
Boston Scientific Corporation, Marlborough, Massachusetts
|| Elyria Memorial Hospital, Elyria, Ohio
¶ Wake Heart Associates, Wake Medical Center, Raleigh, North Carolina
# Oklahoma Foundation for Cardiovascular Research, Oklahoma Heart Hospital, Oklahoma City, Oklahoma
** Cardiology Section, Chang-Gung Memorial Hospital, Kaohsiung, Taiwan
National Heart Centre, Singapore, Singapore
Cardiac Investigations Unit, Auckland City Hospital, Auckland, New Zealand
The Heart Center, St. Vincent’s Hospital, Indianapolis, Indiana
|||| Prairie Heart Institute, St. John’s Hospital, Springfield, Illinois
¶¶ Cardiac & Vascular Research Center, Northern Michigan Hospital, Petoskey, Michigan.
Manuscript received October 16, 2006;
revised manuscript received January 4, 2007,
accepted January 9, 2007.
* Reprint requests and correspondence: Dr. Mark A. Turco, Center for Cardiac & Vascular Research, Washington Adventist Hospital, 7600 Carroll Avenue, Takoma Park, Maryland 20912. (Email: MTurco{at}ahm.com).
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Abstract
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Objectives: The goal of this research was to assess non-inferiority of the next-generation TAXUS Liberté stent (Boston Scientific Corp., Natick, Massachusetts) versus the TAXUS Express stent (Boston Scientific Corp.).
Background: The introduction of drug-eluting stents (DES) has shifted clinical practice towards more complex lesion subsets, prompting the need for more deliverable DES. TAXUS Liberté was designed to combine the established polymer-based, paclitaxel-elution TAXUS technology with the more advanced Liberté stent platform.
Methods: The TAXUS ATLAS study is a global, prospective, single-arm trial evaluating outcomes in de novo coronary lesions visually estimated to be 10 to 28 mm in length in vessels 2.5 to 4.0 mm in diameter. The control group is an entry-criteria-matched population of TAXUS Express patients from the TAXUS IV and V trials. The primary end point is non-inferiority of TAXUS Liberté versus TAXUS Express for 9-month target vessel revascularization.
Results: Despite similar inclusion criteria, quantitative coronary angiography-determined baseline lesion characteristics were significantly more complex for TAXUS Liberté than TAXUS Express. The primary non-inferiority end point was met with the 1-sided 95% confidence bound of 2.98% less than the pre-specified non-inferiority margin of 3% (p = 0.0487).
Conclusions: Despite the treatment of more complex lesions with TAXUS Liberté, the primary end point was met, demonstrating that TAXUS Liberté is non-inferior to TAXUS Express. The successful transfer of the proven TAXUS technology to the more advanced TAXUS Liberté platform was demonstrated. (TAXUS ATLAS: TAXUS Liberté-SR Stent for the Treatment of De Novo Coronary Artery Lesions; http://www.clinicaltrials.gov/ct/show/NCT00371709?order=1; NCT00371709
[ClinicalTrials.gov]
)
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Abbreviations and Acronyms
| | DES = drug-eluting stent(s) | | ITT = intention-to-treat | | MACE = major adverse cardiac events | | MI = myocardial infarction | | MLD = minimum lumen diameter | | PP = per protocol | | QCA = quantitative coronary angiography | | TVR = target vessel revascularization |
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The effectiveness of first-generation drug-eluting stents (DES) in reducing restenosis after percutaneous coronary intervention has been established (1–3). While reducing restenosis in all lesion and patient populations studied, the use of first-generation DES in more complex lesions has been limited by stent design.
The next-generation TAXUS Liberté (Boston Scientific Corp., Natick, Massachusetts) paclitaxel-eluting stent platform was developed to improve deliverability, conformability, and drug distribution homogeneity while maintaining the established antirestenotic properties of the TAXUS polymer-based, paclitaxel-elution technology. Since both stents use the same drug-eluting technology, we hypothesized that TAXUS Liberté would be as safe and effective as TAXUS Express (Boston Scientific Corporation) while being more deliverable. Therefore, we initiated the prospective, single-arm, non-inferiority TAXUS ATLAS trial to evaluate the safety and efficacy of TAXUS Liberté versus historical TAXUS Express controls in single, de novo coronary lesions.
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Methods
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Device description.
Both TAXUS Express2-SR and TAXUS Liberté-SR consist of a balloon-expandable stent with a polymer coating containing 1 µg/mm2 of paclitaxel in a slow-release formulation on the Express or Liberté platforms, respectively (Fig. 1).
Patient selection and study flow.
A total of 871 patients were enrolled at 61 centers in 7 countries in North America and Asia Pacific from August 2004 to February 2005 to receive the TAXUS Liberté stent. Eligible patients were 
18 years old with a single de novo lesion 10 and 
28 mm in length (by visual estimate) in a native coronary artery with a reference vessel diameter of 2.5 and 4.0 mm (by visual estimate). Patients with acute (<72 h) myocardial infarction (MI), left main disease, ostial or bifurcation lesions, total occlusion or thrombus, calcification, or tortuosity were excluded. Additional study stents were allowed in the target lesion when clinically indicated for bailout reasons. The study protocol was approved by local ethics review committees. All patients provided written informed consent.
Loading doses of clopidogrel (300 mg) or ticlopidine (500 mg) and aspirin (300 mg) were administered before stent implantation. After implantation, all patients were prescribed clopidogrel (75 mg daily) or ticlopidine (250 mg twice daily) for a minimum of 6 months, and aspirin (100 mg daily) for at least 9 months but recommended indefinitely.
Clinical follow-up was scheduled at 1, 4, and 9 months and yearly thereafter for 5 years. Follow-up quantitative coronary angiography (QCA) and intravascular ultrasound were scheduled at 9 months for a randomized subset of patients (Fig. 2A).
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Figure 2 Study Flow and Control Group Selection
(A) The TAXUS ATLAS study flow. (B) Selection of the TAXUS Express control group. Patients from the TAXUS IV and V trials were selected based on entry criteria for the TAXUS ATLAS trial. All 662 TAXUS Express patients from the TAXUS IV trial were included. Of the 577 TAXUS Express patients in the TAXUS V trial, 248 were excluded for reference vessel diameter (RVD) <2.5 mm, lesion length >28 mm, or >1 study stent planned for implantation. *Based on visual estimate. Angio = angiography; F/U = follow-up; ITT = intention-to-treat population; IVUS = intravascular ultrasound; PP = per-protocol population.
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Control group.
The control group consisted of a historical population of TAXUS Express-SR patients from the TAXUS IV and V trials (2,3); inclusion and exclusion criteria were similar to those for the TAXUS ATLAS trial (Fig. 2B).
Data management and definitions.
Independent monitors verified all data from case report forms. Stent thrombosis, death, and major adverse cardiac events (MACE), including cardiac death, MI, and target vessel revascularization (TVR), were adjudicated by an independent Clinical Events Committee. A data monitoring committee periodically reviewed safety data. The clinical and angiographic end point definitions were identical to those in the TAXUS IV and V trials (2,3).
Blinded angiographic analysis was performed using validated quantitative methods (4). The same core lab (Brigham and Women’s Hospital, Boston, Massachusetts) and procedures were used as for the TAXUS IV and V trials.
Pre-specified non-inferiority end points.
The primary end point was 9-month TVR. In-stent percent diameter stenosis, binary restenosis, minimum lumen diameter (MLD), and late loss were also tested for non-inferiority.
Statistical methodology.
P values are 2-sided unless specified otherwise. Student t test was used to compare independent continuous variables, while chi-square or Fisher exact test was used to compare proportions. A p value of <0.05 was considered statistically significant. Kaplan-Meier analysis was used to assess time-to-event outcomes. Baseline characteristics and 9-month end points are reported for the intention-to-treat (ITT) population, while 12-month end points are reported for the per-protocol (PP) population (excludes patients without study stent). Non-inferiority testing for the primary end point was performed on both populations, but the main population of interest was PP.
For the primary end point, the pre-specified, non-inferiority margin of 3.0% was based on one-third of the treatment effect with TAXUS Express versus the bare metal control observed in the TAXUS IV trial (2). Margins for non-inferiority testing of secondary QCA end points were also pre-specified based on results from the TAXUS IV trial. Assuming a non-inferiority margin of 3.0%, a 9-month TVR rate of 5.7% (from the TAXUS IV trial), and 10% attrition, the required enrollment for the TAXUS ATLAS trial was 822 subjects for 80% power.
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Results
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Baseline demographics and lesion characteristics.
Both groups were well-matched for baseline patient and visually estimated lesion characteristics (Table 1). However, QCA demonstrated that lesions treated with TAXUS Liberté were significantly more complex versus those treated with TAXUS Express (Table 2).
Procedural information and antiplatelet usage.
Technical success was similar between groups. The average procedure time was significantly lower for TAXUS Liberté (Table 3); this benefit was maintained even when groups were adjusted for geographical differences or intravascular ultrasound usage. Furthermore, the "bailout" rate was reduced by nearly 50% for TAXUS Liberté (p = 0.0038).
Aspirin was prescribed at discharge to more than 99.5% of patients in both groups (Fig. 3). By 12 months, 96.1% of TAXUS Express patients and 95.5% of TAXUS Liberté patients were taking aspirin. At discharge, thienopyridines were administered to 99.9% of patients in each group; however, compliance decreased over time such that only 93% of TAXUS Liberté patients were taking a thienopyridine at 6 months. At 9 and 12 months, more TAXUS Liberté than TAXUS Express patients were taking thienopyridines (9 months: 62.6% vs. 54.2%, p = 0.0004; 12 months: 51.9% vs. 47.4%, p = 0.0521).
Primary end point.
The difference in TVR between the 2 PP populations was 0.94% (Table 4). The upper 1-sided 95% confidence bound of 2.98% was less than the pre-specified non-inferiority margin of 3.0% (p = 0.0487). A similar outcome was demonstrated for the ITT populations. Therefore, the primary end point was met.
Additional clinical outcomes.
There were no differences between the groups in any clinical outcomes analyzed at either 9 or 12 months (Table 5). Freedom from MACE or TVR through 12 months was similar between the groups (Fig. 4).
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Figure 4 Cumulative Freedom-From-Event Rates
(A) Major adverse cardiac events (MACE) or (B) target vessel revascularization (TVR). Data shown are for the per-protocol population (n = 1,845).
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By 12 months, there were 7 stent thromboses for TAXUS Express and 8 for TAXUS Liberté (p = 0.63) (Table 5). Two stent thromboses occurred in TAXUS Liberté beyond 6 months. An 83-year-old man suffered a stent thrombosis with Q-wave MI on day 258. He was taking both aspirin and clopidogrel at the time of thrombosis. A 45-year-old man who had stent thrombosis and non–Q-wave MI on day 365 had discontinued clopidogrel, but was taking aspirin. There were no sudden cardiac deaths after 30 days and out to 12 months that could possibly be attributed to additional stent thromboses in the TAXUS Liberté group.
QCA outcomes.
Baseline, post-procedure, and 9-month angiographies were performed on 75% of angiographic substudy patients (Fig. 2B). Noninferiority was demonstrated for all pre-specified QCA parameters (Table 4). TAXUS Liberté had a significantly lower MLD pre-procedure; however, paired assessment of angiographic outcomes showed comparable in-stent acute gain (p = 0.68) and late loss in both groups (p = 0.69) (Fig. 5). Despite the higher lesion complexity in the TAXUS Liberté group, no significant differences between the groups were found in any of the QCA parameters analyzed at 9 months (Table 6).
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Figure 5 Angiographic Measures
(A) In-stent or in-lesion minimum lumen diameter (MLD) measures over time. Data from the intention-to-treat population (n = 1,862) at pre- and post-procedure, and from the angiographic subset (n = 1,247) at 9 months. (B) Cumulative frequency distribution curves for in-stent late loss as determined by quantitative coronary angiography in the angiographic subset (n = 1,247).
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Discussion
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The TAXUS ATLAS trial evaluates the TAXUS Liberté stent versus a historical control of TAXUS IV and V patients. Despite using similar inclusion and exclusion criteria, the contemporary TAXUS Liberté cohort had more complex lesions when compared with the historic TAXUS Express controls, suggesting a change in the use of DES. Despite this increase in lesion complexity, the clinical outcomes at 9 and 12 months demonstrate that TAXUS Liberté is as safe and effective as TAXUS Express. Additionally, the shorter procedure time and lower bailout rate may represent a clinical surrogate for the improved deliverability and conformability of TAXUS Liberté. These results demonstrate the successful transfer of the TAXUS technology to a new stent platform with optimized design.
The current study compares 2 cohorts enrolled 5 to 35 months apart. Cross comparison of baseline and procedural characteristics and outcomes provides insight into the continuing change in clinical practice since the introduction of DES. Even with similar inclusion and exclusion criteria, more challenging lesions are treated now, suggesting an increased confidence in the benefits provided by DES. The duration of thienopyridine administration has increased, which may reflect the increased sensitivity to potential late thrombotic events after DES implantation. Finally, a more pronounced "oculostenotic reflex" (5), as suggested by the steeper decline in freedom-from-TVR during the mandated angiographic follow-up window, was observed. Decreased visual tolerance of the operator to intermediate re-narrowing within the stent segment since the introduction of DES may contribute to this development.
The TAXUS ATLAS trial was designed as a prospective, non-inferiority trial with a historic control group to leverage the large amount of data available for TAXUS Express. The purpose of this trial design is to provide proof-of-concept in a patient population controlled by strict inclusion and exclusion criteria. As with the actively controlled TAXUS trials, the historically controlled TAXUS ATLAS trial has complete data monitoring: a Clinical Events Committee to adjudicate clinical events, and an independent core lab to perform QCA analysis. Nevertheless, a limitation of a historically controlled trial is the potential for bias due to changes in practice patterns or lack of blinding.
The TAXUS ATLAS trial shows the successful transfer of a proven drug/polymer combination from the TAXUS Express stent to the next-generation TAXUS Liberté stent with an optimized platform design. Despite increased lesion complexity in patients treated with TAXUS Liberté, procedural characteristics suggest improved deliverability and conformability of the new TAXUS stent while the clinical and angiographic outcomes demonstrate non-inferiority of TAXUS Liberté versus TAXUS Express.
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Acknowledgments
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The authors thank Leslie E. Stolz, PhD, and Katherine H. Lewis, MA (both of Boston Scientific Corp.), for their assistance in drafting this manuscript.
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Footnotes
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This study was supported by Boston Scientific Corporation, Natick, Massachusetts. Dr. Turco has received consulting fees/honoraria, is on the Speakers’ Bureau, and has received research grants from Boston Scientific Corporation. Dr. Ormiston has received consulting fees/honoraria and is on the Advisory Board of Boston Scientific Corporation. Dr. O’Shaughnessy has received consulting fees/honoraria and is on the Speakers’ Bureau and the Advisory Board of Boston Scientific Corporation. Dr. Chan has received consulting fees/honoraria, is on the Speakers’ Bureau, and has received research grants from Boston Scientific Corporation. Dr. Mishkel has received consulting fees/honoraria, is on the Speakers’ Bureau, and has received research grants from Boston Scientific Corporation. Dr. Cannon is on the Speakers’ Bureau of Boston Scientific Corporation. Drs. Popma and Webster have received research grants from Boston Scientific Corporation. Dr. Ormiston is on the Advisory Board of Boston Scientific Corporation. Dr. Baim is a stockholder and full-time employee of Boston Scientific Corporation. Dr. McGarry is a stockholder of Boston Scientific Corporation. Drs. Mandinov and Koglin are full-time employees of Boston Scientific Corporation.
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References
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