Author + information
- Received June 19, 2009
- Revision received August 27, 2009
- Accepted September 20, 2009
- Published online December 1, 2009.
- Azeem Latib, MB BCh⁎,‡,
- Luca Ferri, MD⁎,
- Alfonso Ielasi, MD⁎,
- Cosmo Godino, MD⁎,†,
- Alaide Chieffo, MD⁎,
- Valeria Magni, MD⁎,
- Giorgio Bassanelli, MD⁎,
- Andrew S.P. Sharp, MD†,
- Robert Gerber, MD†,
- Iassen Michev, MD⁎,†,
- Mauro Carlino, MD⁎,
- Flavio Airoldi, MD⁎,
- Giuseppe M. Sangiorgi, MD†,
- Matteo Montorfano, MD⁎ and
- Antonio Colombo, MD⁎,†,⁎ ()
- ↵⁎Reprint requests and correspondence:
Dr. Antonio Colombo, EMO-GVM Centro Cuore Columbus, 48 Via M. Buonarroti, 20145 Milan, Italy
Objectives The aim of this study was to evaluate the efficacy and safety of unrestricted everolimus-eluting stent (EES) implantation in a contemporary cohort of real-world patients.
Background The randomized SPIRIT (A Clinical Evaluation of the XIENCE V Everolimus Eluting Coronary Stent System in the Treatment of Patients With de Novo Native Coronary Artery Lesions) trials have evaluated the performance of EES, resulting in their approval by the Food and Drug Administration, but data regarding unselected usage, including off-label indications are lacking.
Methods Consecutive patients treated with EES (either PROMUS, Boston Scientific Corp., Natick, Massachusetts, or XIENCE-V, Abbott Vascular Devices, Santa Clara, California) between October 2006 and February 2008 were analyzed. End points were cardiac death, myocardial infarction (MI), ischemic-driven target lesion revascularization (TLR), stent thrombosis (ST), and major adverse cardiac events (MACE) (a composite of cardiac death, MI, TLR) during follow-up.
Results We identified 345 patients (573 lesions) treated with EES. The majority of patients (71.9%) were treated for ≥1 off-label or untested indication. Clinical follow-up was completed in 99%. At a median follow-up of 378 days (interquartile range 334 to 473), MACE occurred in 36 (10.6%) patients, TLR in 27 (7.9%), MI in 7 (2.1%), and cardiac death in 7 (2.1%). Definite and probable ST was observed in 3 (0.9%) cases. Off-label EES implantation was not associated with a statistically significant increased risk of MACE (12.2% vs. 6.3%, p = 0.17), TLR (9.3% vs. 4.2%, p = 0.18), or ST (0.8% vs. 1.1%, p = 1.0). On multivariable analysis, previous bypass surgery (p = 0.002) and diabetes (p = 0.03) were associated with MACE.
Conclusions In unrestricted daily practice, EES were implanted predominantly for off-label indications and associated with a relative low rate of MACE and TLR.
The polymer-based everolimus-eluting stent (EES) (either XIENCE V, Abbott Vascular, Santa Clara, California; or PROMUS, Boston Scientific Corp., Natick, Massachusetts) is a combination product composed of 3 major design components: 1) a thin-strut (81 μm), cobalt-chromium alloy coronary stent; 2) a thin drug-carrying matrix, an ultrapure copolymer composed of vinylidene fluoride and hexafluoropropylene monomers; and 3) everolimus, an analog of rapamycin, at a dose of 100 μg/cm2 with 80% of the drug eluted in <30 days (1,2). The polymer-based EES is the most recent drug-eluting stent (DES) to undergo U.S. Food and Drug Administration (FDA) approval. On the basis of the positive outcomes of the SPIRIT (A Clinical Evaluation of the XIENCE V Everolimus Eluting Coronary Stent System in the Treatment of Patients With de Novo Native Coronary Artery Lesions) family of randomized trials (2–6), the FDA approved the EES for U.S. commercial sale in July 2008 with the indication of “improving coronary luminal diameter in patients with symptomatic heart disease due to de novo native coronary artery lesions (length <28 mm) with reference vessel diameters of 2.5 mm to 4.25 mm” (1).
However, when DES are implanted in everyday clinical practice, they are often implanted for off-label indications in complex patients and lesions where the benefit in reducing restenosis and repeat revascularization might be greater (7,8). As has been seen with the first-generation DES, the clinical event rates are often higher in real world registries compared with those seen in the randomized trials, and as a result, concerns have been raised about the efficacy and safety in off-label indications (9–12). Data regarding EES in these complex patients and lesions are lacking. Thus we sought to evaluate the clinical outcomes of unrestricted EES implantation in daily practice.
All consecutive patients successfully treated with only EES implantation at our center between October 2006 (when EES became available in our institution) and February 2008 (in order to have a minimum of 1-year follow-up in most patients) were included in this retrospective analysis. Stent selection, although at the operator's discretion, was carried out in an aleatory fashion during the study period. Selecting an EES over another DES was performed without any specific preference and not based on patient risk or lesion morphology. It is the usual practice in our institutions to alternate the implantation of different types of DES. We provide a flow chart in Figure 1 describing the selection of bare-metal stents (BMS) and different DES at our institutions during the period of this study. The only exclusion criteria were a mixture of different types of DES or a mixture of BMS and DES. Also patients undergoing primary angioplasty for ST-segment elevation myocardial infarction (MI) were excluded, because it is the practice of our institution not to implant a DES in these patients. All patients provided informed consent for both the procedure and subsequent data collection.
All patients were pre-treated with aspirin and clopidogrel or ticlopidine. A loading dose of 300 to 600 mg clopidogrel was given to patients not treated in the prior 5 days. Aspirin was continued indefinitely, and thienopyridine was prescribed for at least 12 months. Glycoprotein IIb/IIIa inhibitors, interventional approaches, and intravascular ultrasound (IVUS) usage were at the operator's discretion. Angiographic follow-up was clinically driven or scheduled at the operator's discretion.
Data collection, end points, and definitions
Clinical follow-up was performed by telephone contact or office visit at 1, 6, and 12 months after the index procedure. The clinical end points analyzed were periprocedural MI, death, after-discharge MI, stent thrombosis (ST), target vessel revascularization (TVR), target lesion revascularization (TLR), and major adverse cardiac events (MACE). The MACE was defined, as it was in the SPIRIT trials (2–5,13), as a composite of cardiac death, MI, and TLR during the follow-up period, which were evaluated on a per-patient basis. We also analyzed TLR separately on a per-lesion basis. All deaths were considered cardiac unless otherwise documented. We defined post-procedural non–Q-wave MI as a creatinine kinase-myocardial band elevation of >3 times the upper limit of normal (14). Creatinine kinase was routinely measured after percutaneous coronary intervention in all patients at both centers. Non-procedural or after-discharge MI was defined as an elevation of troponin above the upper range limit in combination with at least 1 of the following: symptoms of ischemia, electrocardiography changes indicative of new ischemia, or the development of pathological Q waves on electrocardiography (14,15). We defined TLR as repeat revascularization within the stent or within the 5-mm borders proximal or distal to the stent edge at the follow-up angiogram. The TLR was considered to be ischemic-driven if associated with a positive functional study result and/or ischemic symptoms and a target lesion diameter stenosis of ≥50% by visual estimation or a target lesion diameter stenosis of ≥70% with or without documented ischemia (2). These are exactly the same criteria used in the SPIRIT trials (2–5,13). We defined TVR as any repeat revascularization of the target vessel. The ST was defined as “acute” if within 24 h of the procedure, “subacute” at 1 to 30 days, and “late” after 30 days. The definition of ST was in accordance with the Academic Research Committee definitions of definite, probable, possible ST (15). In this study we also analyzed the outcomes of EES when implanted for “on-label” and “off-label” (or untested) indications. For the purpose of this study, an off-label indication was defined as implantation of an EES in: 1) left main coronary artery lesions; 2) chronic total occlusions; 3) bifurcation lesions (i.e., main vessel treated by stent implantation and side branch treated by angioplasty or stent implantation); 4) BMS or DES restenosis; 5) bypass graft lesions; 6) left ventricular ejection fraction ≤35%; 7) ostial lesions (either aorto-ostial or ostium of left anterior descending or circumflex arteries); and 8) diffuse disease defined as 2 or more overlapping stents with stented length >28 mm.
Continuous variables are presented as mean ± SD or median with interquartile ranges, and categorical variables are presented as frequencies. The normality of the distribution of the continuous variables was tested by the Kolmogorov-Smirnov goodness-of-fit test. Continuous variables were compared with independent sample Student t or Mann-Whitney U test. Categorical variables were compared with chi-square statistic or Fisher exact test when appropriate. Patients lost to follow-up in whom no event had occurred before the follow-up windows were not included in the denominator for calculations of binary end points. We calculated 95% confidence intervals (CIs) for proportions by the Wilson method and the relative risk by the exact method. Exploratory multivariable analysis was performed to assess the impact of off-label EES usage on the risk of MACE and TLR by logistic regression. The final model included variables associated at univariate analysis with MACE and TLR (all with a p value < 0.1). The results are reported as adjusted odds ratios (ORs) with associated 95% CI. Goodness of fit of the logistic regression model was assessed with the Hosmer-Lemeshow statistic. Survival curves with all available follow-up data were also constructed for time-to-event variables with Kaplan-Meier estimates. A p value < 0.05 was considered statistically significant, and all reported p values are 2-sided. Statistical analysis was performed with SPSS software (version 11.5, SPSS Inc., Chicago, Illinois) and Confidence Interval Analysis.
A total of 345 patients and 573 lesions were treated with EES during the study period. The baseline clinical and lesion characteristics of the study population are summarized in Table 1. According to the study definitions, EES were implanted for an off-label indication in 337 (66.1%) lesions, with 248 (71.9%) patients having 1 or more off-label lesion treated. The indications for off-label EES use are listed in Table 1. Clinical follow-up was available in 341 (98.8%) patients with a median follow-up time of 378 days (interquartile range 334 to 473). The duration of clinical follow-up was not statistically different between the 2 groups (p = 0.41).
The baseline procedural characteristics of the lesions treated are summarized in Table 2, and the off-label indications for EES implantation are shown in Table 3. The off-label group presented with a more severe clinical profile with a higher frequency of diabetes mellitus (in particular insulin-requiring diabetes), unstable angina, and longer lesions. A larger number of stents and longer total stent lengths were implanted in the off-label group. The rate of periprocedural and in-hospital MI was nonsignificantly higher with off-label EES use (7% vs. 0%; p = 0.2). There were no cases of intra-procedural or acute ST.
Clinical follow-up outcome data are shown in Table 4. At 6 months, the overall rate of MACE was 4.7% (95% CI: 2.9% to 7.5%), and TLR was 3.8% (95% CI: 2.2% to 6.4%). There were no statistically significant differences in any of the adverse events between the on-label and off-label groups. At a median follow-up time of 378 days, there remained no significant difference in MACE between the on-label (6.3%, 95% CI: 2.9% to 13.1%) and off-label groups (12.2%, 95% CI: 8.4% to 17.0%; p = 0.17). The relative risk of MACE for the off-label compared with the on-label group was 1.93 (95% CI: 0.83 to 4.49). A Kaplan-Meier plot of the cumulative incidence of MACE at 1 year is shown in Figure 2. A multivariable model that included age, previous bypass surgery, hypertension, diabetes mellitus, and treatment of a restenotic lesion showed that off-label EES implantation was not associated with MACE (OR: 1.38, 95% CI: 0.50 to 3.83; p = 0.54). Previous bypass surgery (OR: 3.23, 95% CI: 1.52 to 6.86, p = 0.002) and diabetes mellitus (OR: 2.33; 95% CI: 1.09 to 4.96, p = 0.03) were associated with MACE. The Hosmer-Lemeshow statistic was not significant (p = 0.89), confirming the goodness of fit of the logistic regression model. The numerically albeit not significantly higher MACE in the off-label group was predominantly accounted for by a numerically higher TLR rate in the off-label group (9.3% vs. 4.2%; p = 0.18). All-cause mortality, cardiac death, ST, and nonfatal MI were similar between the groups.
A lesion-based analysis revealed that there was a 3.6% (95% CI: 1.8% to 7.3%) TLR rate in on-label EES use compared with 6.1% (95% CI: 4.1% to 9.0%) in the off-label group (p = 0.18). All repeat revascularization was ischemic-driven. The variables entered into the multivariable model for TLR were treatment of a restenotic lesion, IVUS usage, stent length, and diabetes mellitus. This showed that off-label EES implantation was not associated with TLR (OR: 1.18, 95% CI: 0.44 to 3.19, p = 0.74). Only diabetes mellitus (OR: 3.39, 95% CI: 1.56 to 7.37, p = 0.002) was associated with TLR. The Hosmer and Lemeshow goodness-of-fit test p value was 0.90, indicating the model adequately fit the data.
At the last clinical follow-up contact, 3.8% (13) of patients had prematurely discontinued dual antiplatelet therapy before the prescribed 12 months. There were no differences in the rates of ST between the groups. In the total study population, there were 3 (0.9%) cases of definite ST (2 late, and 1 subacute), no probable ST, and 8 cases of possible ST due to unexplained death after 30 days. All 3 cases of definite ST occurred in patients still taking dual antiplatelet therapy, and all of them survived the thrombotic event. There were 2 cases of definite ST in the off-label group. The first was a late ST at 262 days in an 82-year-old man with a normal ejection fraction. He had undergone percutaneous coronary intervention of an ostial left anterior descending artery lesion with a cross-over technique and implantation of a 3.5 × 23 mm EES from the distal left main to the left anterior descending artery, a provisional approach to the circumflex, and final kissing inflation to the bifurcation. He presented with a non–ST-segment elevation MI; angiography demonstrated thrombus intrastent in the distal left main involving the ostia of the circumflex and left anterior descending arteries. He was treated with intravenous glycoprotein IIb/IIIa inhibitors, balloon angioplasty, and BMS implantation. The second definite ST in the off-label group was in a 77-year-old woman with a normal ejection fraction and diabetes treated with insulin. In the index procedure, she underwent stenting of an ostial circumflex lesion with a 3.5 × 12 mm EES. She presented 27 days later with a subacute ST and acute MI that was treated with repeat BMS implantation. The only case of definite ST in the on-label group occurred in a 62-year-old man who presented at 73 days with a late ST after having a mid-circumflex lesion treated with a 3 × 23 mm EES. He underwent primary angioplasty with repeat DES implantation at another institution.
The main findings of this real-world registry are: 1) in unrestricted daily practice, EES were implanted predominantly for off-label indications and were associated with a relatively low rate of ischemic-driven TLR and MACE during short- and medium-term follow-up; 2) although MACE and TLR in this complex cohort were slightly higher than those seen in the SPIRIT randomized trials (2–6), the results of on-label use were comparable; 3) the rates of cardiac death, MI, and ST were not statistically different for on-label and off-label EES implantation; 4) on multivariable analysis, previous bypass surgery and diabetes were associated with MACE and diabetes also with TLR, but off-label EES implantation was not a risk factor for either MACE or TLR; and 5) even though TLR was twice as frequent in off-label patients, it did not reach statistical significance.
In this study the majority of patients had an off-label lesion treated with an EES—contrary to most randomized trials—with one-half of the off-label patients having more than 1 off-label lesion treated. However, despite this increased complexity of the patients and lesions treated, the cumulative 10.6% MACE and 7.9% TLR rates in this study were not markedly different from the 12-month rates in the SPIRIT III trial of 6.0% and 3.8% (2). In fact, when on-label lesions such as those enrolled in the SPIRIT III trial were considered, the rates of MACE (6.3% vs. 6.0%) and TLR (4.2% vs. 3.8%) were almost identical. The question of whether off-label DES implantation is associated with worse outcomes in particular with regard to hard end points such as death and MI has been an area of great concern for patients, care-givers, and health authorities (1,7,8,16–19). Thus we performed a comparison of EES implanted for on-label (i.e., Food and Drug Administration-approved) indications with off-label and untested usage. Considering the complexity of the lesions in the off-label group (e.g., left main, diffuse disease, chronic total occlusions, and bifurcations), the procedures performed were more complex with more and longer stents implanted, increased intra-aortic balloon pump support, and greater IVUS use. We should also point out that the finding of a larger reference vessel diameter in the off-label group, although seemingly counterintuitive, is most likely due to percutaneous coronary intervention on vessels with a larger vessel diameter, such as the left main and saphenous vein grafts. Indeed, when we excluded these lesions, the reference vessel diameter was similar between the on-label and off-label groups (2.60 ± 0.52 mm vs. 2.69 ± 0.61 mm, p = 0.13). The factors that probably contribute most to the larger acute gain in the off-label group were the inclusion of chronic total occlusions; the slightly higher use of IVUS; and that many off-label lesions were in the context of more diffuse coronary disease, a situation where the mismatch between angiography and IVUS vessel size is larger compared with more simple lesions. This situation will give more advantage in terms of acute gain when IVUS is used in off-label compared with on-label lesions. Despite the increased complexity of the patients, lesions treated, and interventional procedure, the rate of in-hospital adverse events was not statistically different between the 2 groups, but there were numerically more periprocedural MI. The cumulative TLR rate, which was numerically higher in the off-label group (9.3% vs. 4.2%), can be explained by the fact that these patients had a greater number of lesions treated and most of these were complex, justifying a higher rate of re-intervention (20). That these differences were not statistically significant is likely a consequence of the overall insufficient number of patients evaluated. Furthermore, we believe that the TLR rate in this complex cohort is realistic, considering that we do not currently perform routine angiographic follow-up, which occurred only in 45% of patients.
Because the off-label indications are known to form a group at high risk of restenosis that might have greater benefit from DES, a higher TLR rate might be acceptable, especially because the rates of death and MI were not statistically higher. Furthermore, off-label EES usage was not associated with MACE on multivariable analysis, suggesting that the implantation of EES in off-label lesions might be acceptable and without incremental risk.
It has been proposed that EES might have a theoretical advantage over first-generation DES with regard to safety, in that the thin strut design might result in more rapid stent endothelialization (13,21). Indeed the rate of ST is much less than we previously reported with the first-generation DES (7). Furthermore, the 0.9% rate of definite and probable ST in this study of complex lesions is very similar to that reported in on-labels lesions at 12 months in the SPIRIT III trial (1.1%) (2). The low rate of ST might be explained by the high compliance and extended duration of dual antiplatelet therapy. However, it is reassuring that off-label EES implantation was not associated with a higher risk of ST.
This study suffers the obvious limitations of observational nonrandomized registries. However, it does provide important complementary information about the outcomes in real-world patients and lesions that were excluded from the randomized trials. The study is underpowered to permit any strong conclusions to be drawn from the subgroup analyses, which should be considered hypothesis-generating. Furthermore, the small number of events limits the ability to control for all differences among the subgroups without some over-fitting of the multivariable model. Similarly, the relatively small overall sample size prohibits any judgment to be made with regard to ST as a safety parameter, because this is a very rare event. Longer-term follow-up is required, because the incremental risk of ST with DES might emerge beyond 1 year (22). However, in the SPIRIT III trial, there were fewer ST events after 1 year in patients treated with EES rather than paclitaxel-eluting stents (13). The lack of routine angiographic follow-up precludes any comments about the antirestenotic efficacy of EES in complex lesions. However, in this clinical study all TLR was ischemic-driven, and thus the effect of an overzealous oculostenotic reflex might be limited. Despite these shortcomings, these initial observations do provide an important insight into the clinical spectrum and clinical outcomes of patients and lesions currently being treated with this second-generation DES.
In unrestricted daily practice, EES were implanted predominantly for off-label and untested indications and associated with a relatively low rate of MACE and ischemic-driven TLR. However, longer-term data are needed to assess the safety of this new platform in complex lesions.
Azeem Latib and Dr. Ferri contributed equally to the manuscript and are joint first authors.
- Abbreviations and Acronyms
- bare-metal stent(s)
- confidence interval
- drug-eluting stent(s)
- everolimus-eluting stent(s)
- Food and Drug Administration
- intravascular ultrasound
- major adverse cardiac events
- myocardial infarction
- stent thrombosis
- target lesion revascularization
- target vessel revascularization
- Received June 19, 2009.
- Revision received August 27, 2009.
- Accepted September 20, 2009.
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