Author + information
- Received December 7, 2010
- Revision received February 4, 2011
- Accepted February 22, 2011
- Published online June 28, 2011.
- Pieter C. Smits, MD, PhD⁎,⁎ (, )
- Elvin Kedhi, MD⁎,
- Kees-Jan Royaards, MD⁎,
- Kaiyum Sheik Joesoef, MD⁎,
- Jochem Wassing, MD⁎,
- Tessa A.M. Rademaker-Havinga, MSc† and
- Eugene McFadden, MD⁎
- ↵⁎Reprint requests and correspondence:
Dr. Pieter C. Smits, Interventional Cardiology, Department of Cardiology, Maasstad Ziekenhuis, Groene Hilledijk 315, Rotterdam 3075 EA, the Netherlands
Objectives The purpose of this study was to compare the safety and efficacy of the Xience V (Abbott Vascular, Santa Clara, California) everolimus-eluting stent (EES) with the Taxus Liberté (Boston Scientific, Natick, Massachusetts) paclitaxel-eluting stent (PES) at 2-year follow-up.
Background COMPARE (Comparison of the everolimus eluting XIENCE-V stent with the paclitaxel eluting TAXUS LIBERTÉ stent in all-comers: a randomized open label trial) demonstrated a superior clinical outcome of EES over PES at 1 year in all comers. Whether this superiority is maintained after discontinuation, at 12 months, of dual antiplatelet therapy is unclear.
Methods Patients undergoing percutaneous coronary intervention with limited exclusion criteria were randomly allocated to EES or PES. The 2-year pre-specified endpoints are composites of safety and efficacy and stent thrombosis.
Results Follow-up was completed in 1,795 of 1,800 patients (99.7%). The groups had similar baseline characteristics. At 2 years, significantly fewer EES patients took dual antiplatelet therapy (11.4% vs. 15.4%, p = 0.02). The primary composite of all death, nonfatal myocardial infarction, and target vessel revascularization occurred in 9.0% of EES patients and 13.7% of PES patients (relative risk [RR]: 0.66; 95% confidence interval [CI]: 0.50 to 0.86) driven by a lower rate of myocardial infarction (3.9% vs. 7.5%; RR: 0.52; 95% CI: 0.35 to 0.77) and target vessel revascularization (3.2% vs. 8.0%; RR: 0.41; 95% CI: 0.27 to 0.62), in parallel with a lower rate of definite or probable stent thrombosis (0.9% vs. 3.9%; RR: 0.23; 95% CI: 0.11 to 0.49). Differences significantly increased between 1- and 2-year follow-up for the primary composite endpoint (p = 0.04), target vessel revascularization (p = 0.02), and definite or probable stent thrombosis (p = 0.02).
Conclusions The substantial clinical benefit of the EES over the PES with regard to measures of both safety and efficacy is maintained at 2 years in real-life practice with an increasing benefit in terms of safety and efficacy between 1 year and 2 years. Comparison of the everolimus eluting XIENCE-V stent with the paclitaxel eluting TAXUS LIBERTÉ stent in all-comers: a randomized open label trial: The COMPARE Trial [COMPARE 1]; NCT01016041)
Previous randomized trials involving highly selected patients with either 1 or 2 de novo coronary artery lesions have shown that the everolimus-eluting stent (EES) has a superior angiographic outcome in comparison with the paclitaxel-eluting stent (PES) (1,2). COMPARE (Comparison of the everolimus eluting XIENCE-V stent with the paclitaxel eluting TAXUS LIBERTÉ stent in all-comers: a randomized open label trial) and SPIRIT IV trials, in less selected patient populations, showed that the use of EES was associated with a significantly lower rate of the pre-specified primary endpoints compared to PES (3,4). In the COMPARE trial, the composite of all death, myocardial infarction (MI), and target vessel revascularization (TVR) was reduced by 31%. In the SPIRIT IV (Clinical Evaluation of the XIENCE V Everolimus Eluting Coronary Stent System in the Treatment of Subjects With de Novo Native Coronary Artery Lesions) trial, the rate of target lesion failure (TLF) at 12 months was reduced by 39%. In addition, both trials showed significant decreases in rates of MI, ischemia-driven target lesion revascularization (TLR), and definite or probable stent thrombosis (ST) with EES.
Whether the demonstrated superiority of EES over PES at 1 year is maintained at 2 years remains unclear.
The methodology of the trial has been published previously (3). In summary, consecutive patients, between 18 and 85 years of age, referred to Maasstad Ziekenhuis for elective or emergent percutaneous coronary intervention were eligible to participate. There were no limitations on the number of lesions or vessels, the location of lesions, or their length. Major exclusion criteria were contraindications to or expected nonadherence to dual antiplatelet therapy (DAPT) in the 12 months after the procedure, planned major surgery within 30 days, and inability to give informed consent. Patients were assigned on a 1:1 basis to EES or PES. All patients provided written informed consent. The study was investigator-initiated. Funding was provided by unrestricted research grants from Abbott Vascular and Boston Scientific, which had no involvement in the study. The study was approved by the institutional ethics committee of the Maasstad Ziekenhuis, Rotterdam, the Netherlands, and the Dutch Central Committee on Research Involving Human Subjects (CCMO trial no. NL15206.101.06).
Details of periprocedural oral antiplatelet and anticoagulant therapy have been published (3). At discharge, all patients were receiving 100 mg of aspirin daily indefinitely and 75 mg of clopidogrel daily for 12 months.
Study endpoints and definitions
Adverse events were assessed in the hospital, and at 1, 12, and 24 months. Study monitors collected data by visits, phone calls, and postal questionnaires. Data were stored in our institution. Data processing and adjudication of adverse events, including ST, were done in a blinded fashion by an independent contract research organization and core laboratory (Cardialysis, Rotterdam, the Netherlands).
The pre-specified primary endpoint was a composite of all death, nonfatal MI, and TVR at 12 months. The secondary endpoints were the primary composite endpoint at 2-year follow-up and the composite of major adverse cardiac events (cardiac death, nonfatal MI, and clinically driven TLR at 2-year follow-up). Definitions of endpoints are presented elsewhere (3).
Categorical variables, including events between 1 year and 2 years and up to 2 years, were evaluated using the chi-square test or Fisher's exact test, whereas continuous variables were evaluated with use of Wilcoxon rank-sum test. Events between 1 year and 2 years were evaluated with Fisher's exact test after patients with the specified event up to 1 year were removed from the analysis.
The time to the pre-specified endpoints was evaluated according to the Kaplan-Meier method, and the log-rank test was used to compare endpoint frequencies between groups. Relative risk (RR) with 95% confidence interval (CI) were calculated using the normal approximation to the binomial distribution. The statistical analysis was performed according to the intention-to-treat principle. All p values were 2-sided, and a p value <0.05 was considered to indicate statistical significance. Analyses were performed using SAS version 8.02 (SAS Institute, Cary, North Carolina).
Between February 2007 and September 2008, 1,800 patients were enrolled. Randomization and patient flow is summarized in Figure 1.
Baseline demographic data
Baseline demographic data and lesion characteristics (Table 1) were comparable between groups (3). A high number of patients presented with an acute coronary syndrome (59% PES vs. 60% EES). Most lesions treated were complex (74% type B2 or C), resulting in a mean stented length of 28 mm in both groups.
Table 2 shows clinical events at 1- and 2-year follow-up. At 2-year follow-up, the primary endpoint (Fig. 2A) occurred in 9.0% of the EES group versus 13.7% in the PES group (RR: 0.66, 95% CI: 0.50 to 0.86, p = 0.002). This reflected a lower rate of both MI and TVR in the EES group. All-cause mortality did not differ between groups (Figs. 2B to 2D). Between 1-year and 2-year follow-up, the event curves for the primary composite endpoint (p = 0.04) and TVR (p = 0.02) (Table 3) widened significantly.
The secondary endpoint, a composite of cardiac death, nonfatal MI, and TLR, occurred in 7.4% of EES patients and 11.3% of PES patients at 2 years (RR: 0.65, 95% CI: 0.48 to 0.88, p = 0.004). As for the primary endpoint, this difference was driven by a reduction in MI and TLR. The rate of cardiac death did not differ between groups.
In accordance with European percutaneous coronary intervention guidelines, the protocol specified that DAPT should be prescribed for 1 year after stent implantation. At 1 year of follow-up, 70% of patients in both groups were receiving DAPT. At 2 years, 11.4% of patients in the EES group and 15.2% in the PES group (p = 0.02) were receiving DAPT (Fig. 3).
Definite and probable ST rate differed significantly between groups at 1 year (0.6% for EES vs. 2.5% for PES, RR: 0.22, 95% CI: 0.08 to 0.57, p < 0.001). At 2 years of follow-up, this absolute difference increased to 3.0% (0.9% for EES vs. 3.9% for PES, RR: 0.23, 95% CI: 0.11 to 0.49, p < 0.001) (Fig. 4). Between 1-year and 2-year follow-up, this event curve widened significantly (p = 0.02) (Table 3).
Early definite and probable ST occurred significantly more often in the PES group (0.2% EES vs. 1.7% PES, RR: 0.13, 95% CI: 0.03 to 0.59, p = 0.002). The rate of late definite and probable ST was numerically higher in the PES group, but did not differ significantly between groups. The rate of very late definite and probable ST was significantly higher in the PES group (0.3% EES vs. 1.4% PES, RR: 0.23, 95% CI: 0.07 to 0.81, p = 0.01) (Fig. 5).
In a stratified analysis of the primary endpoint, the difference between EES and PES was consistent across all subgroups apart from patients with diabetes mellitus, for whom no difference in the primary composite outcome was noted at 1- or 2-year follow-up; however, the test of interaction was not significant (Fig. 6).
In a more detailed analysis of the diabetic population, no differences were found in mortality, MI, and ST at 2 years; however, significantly more patients had clinically indicated TVR (9.3% vs. 2.0%, RR: 0.20, 95% CI: 0.04 to 0.70, p = 0.008), and there was a trend toward more TLR in the PES group compared with the EES group (5.8% vs. 2.0%, respectively; p = 0.09).
Our major finding was that the demonstrated superiority at 1 year of EES over PES in terms of safety and efficacy was maintained at 2 years. Indeed, the event curves continued to diverge in favor of the EES. This difference, at 2 years, was driven by reductions in both MI and TVR.
At 1 year, the EES group showed a significant absolute risk reduction of 2.6% compared with the PES group in the rate of a first MI. The magnitude of the difference for this safety endpoint widened in the subsequent year, resulting in an absolute risk reduction of 3.6% at 2 years for the EES group. The COMPARE, SPIRIT III, and SPIRIT IV trials all showed either a significant reduction or a trend toward fewer MIs with the EES in the first 30 days (2–4). That might reflect differences in stent design, leading to less side branch compromise with the EES (4). Our results suggest that other mechanisms may also contribute. When periprocedural and early (<30 days) events were excluded, we observed that event curves significantly diverged from the 30-day timepoint up to 2 years (data not shown). A similar trend (p = 0.22) was noted in the pooled SPIRIT II and III trial reports; between 1- year and 2-year follow-up, MI occurred in 0.8% of EES patients versus 1.7% of PES patients (5).
As previously reported, the rate of ST in the COMPARE study at 1 year was significantly lower with EES. Between 1 and 2 years, there was a further significant divergence of the event curves due to a significantly lower definite and probable ST in the EES group, despite low rates of DAPT, which were not protocol mandated after 1 year. The small, but significantly higher rate of DAPT in the PES group at 2 years parallels differences in MI and ST rates, events that likely led to prolongation or reinstitution of DAPT.
With first-generation DES, the promising low ST rates in initial clinical trials (6) have shown a consistent increase as the patient populations enrolled expanded from those with favorable “research” lesions to “real-world” lesions. Registry studies have clearly demonstrated a continuing risk of very late ST, with annual increments in ST of 0.4% and 0.6% for SES and PES, respectively (7,8). In our all-comer trial, the annual increase of definite ST with PES was comparable (0.7%). Against this background, the ST rates reported with EES to date are much lower and of the same order of magnitude as for bare-metal stents (6,7,9). Two-year pooled (892 patients) ST rates for the SPIRIT II and III studies, with restrictive inclusion criteria, showed a 1.2% rate of probable or definite ST, remarkably similar to that of COMPARE (0.9%) (5).
Differences in stent design, strut thickness, delivery platform, polymer coating, drug, and drug release profile could all play a role in the difference in ST rates between PES and EES. Other potential explanations may be more rapid re-endothelialization with EES, documented in the rabbit iliac model, or the more biocompatible fluorinated copolymer (10–12).
Both TLR and TVR were significantly lower for EES at 2 years, with relative risk reductions of 55% and 60%, respectively. Between 1 and 2 years, the absolute difference for TVR between the PES and EES groups increased significantly from 3.5 to 4.8%.
The recently published SPIRIT IV trial showed results for safety and efficacy endpoints similar to those for the COMPARE trial at 1 year of follow-up (4). At 2-year follow-up, there was a continuing benefit of EES in TLF and ST rates. However, no divergence of the curves between 1 and 2 years was observed. Whether the inclusion of patients and lesions at lower risk in the SPIRIT IV study or the very high rate (72%) of DAPT at 2-year follow-up might account for this discordance is unclear (13).
In summary, we have shown that the substantial clinical benefit of the EES Xience V stent over the PES Taxus Liberté with regard to measures of both safety and efficacy is maintained at 2 years in real-life practice with an increasing benefit in terms of safety and efficacy between 1 and 2 years. Further research is required to understand the lack of benefit of EES over PES in the diabetic population.
The authors gratefully acknowledge the help of the research nurses Jeanine Schaaf, Claudia van Vliet, and Bernie Jones, and technicians and medical staff in Maasstad Ziekenhuis and referring hospitals whose cooperation made this study possible.
The Research Foundation received unrestricted research grants from Abbott Vascular and Boston Scientific. Dr. Smits has received speakers' fees from Abbott Vascular. Dr. Kedhi has received speakers' fees or expenses from Abbott Vascular, Terumo Europe, Boston Scientific, and Medtronic. Dr. McFadden has received honoraria or expenses from Abbot Vascular, Medtronic, Cordis, and Boston Scientific; and has been on Speakers' Bureau for Medtronic. All other authors have reported that they have no relationships to disclose. Drs. Smits and Kedhi contributed equally to this work.
- Abbreviations and Acronyms
- confidence interval
- dual antiplatelet therapy
- everolimus-eluting stent(s)
- myocardial infarction
- paclitaxel-eluting stent(s)
- relative risk
- sirolimus-eluting stent(s)
- stent thrombosis
- target lesion failure
- target lesion revascularization
- target vessel revascularization
- Received December 7, 2010.
- Revision received February 4, 2011.
- Accepted February 22, 2011.
- American College of Cardiology Foundation
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