Author + information
- Received May 14, 2009
- Revision received September 8, 2009
- Accepted October 6, 2009
- Published online December 1, 2009.
- Scot Garg, MBChB⁎,
- Patrick Serruys, MD, PhD⁎,⁎ (, )
- Yoshinobu Onuma, MD⁎,
- Cécile Dorange, MSc†,
- Susan Veldhof, RN†,
- Karine Miquel-Hébert, PhD†,
- Krishnankutty Sudhir, MD, PhD‡,
- Jean Boland, MD§,
- Kurt Huber, MD∥,
- Eulogio Garcia, MD¶,
- Jan A.M. te Riele, MD#,
- SPIRIT II Investigators
- ↵⁎Reprint requests and correspondence:
Prof. Patrick Serruys, Ba583a, Thoraxcenter, Erasmus MC,'s-Gravendijkwal 230, 3015 CE Rotterdam, the Netherlands
Objectives This paper reports the 3-year clinical outcomes of the XIENCE V (Abbott Vascular, Santa Clara, California) everolimus-eluting stent (EES) compared with the TAXUS (Boston Scientific, Natick, Massachusetts) paclitaxel-eluting stent (PES) in the randomized SPIRIT II (Clinical Evaluation of the Xience V Everolimus Eluting Coronary Stent System in the Treatment of Patients with de novo Native Coronary Artery Lesions) study.
Background The Xience V EES is a new-generation drug-eluting stent (DES) that might offer advantages over the first-generation DES in terms of improved clinical outcomes and a better safety profile.
Methods The SPIRIT II trial was a multicenter, prospective, randomized, single-blind, clinical trial, randomizing 300 patients with de novo coronary artery lesions in a ratio of 3:1 to either EES or PES. The primary end point was in-stent late loss at 180 days.
Results At 3-year clinical follow-up cardiac death was numerically lower with EES than PES (0.5% vs. 4.3%, p = 0.056). The observed rate of myocardial infarction was 3.6% for EES and 7.2% for PES (p = 0.31). The rate of ischemia-driven target lesion revascularization was 4.6% and 10.1% for EES and PES, respectively (p = 0.14). Overall, there was a trend for lower major adverse cardiovascular events in the EES group compared with PES (7.2% vs. 15.9%, p = 0.053). The rate of stent thrombosis was low and comparable in both groups (EES 1.0% vs. PES 2.9%).
Conclusions The present study reports the favorable 3-year clinical outcomes of the EES, which are consistent with the results from other studies of the EES with shorter follow-up.
Drug-eluting stents (DES) revolutionized the field of percutaneous coronary intervention (PCI) after their introduction in 2002, by significantly reducing rates of restenosis (1). After their introduction there was a rapid and unprecedented uptake of their use, such that within 3 years they were used in 80% to 90% of revascularization procedures in the U.S. (2). Recently, concerns have emerged that the first generation of DES, coated with sirolimus and paclitaxel, are associated with an increased risk of very late stent thrombosis (>1 year) when compared with bare-metal stents (BMS) (3). An everolimus-eluting stent (EES) has been developed with the goal of improving the safety of DES.
The FUTURE (The First Use To Underscore restenosis Reduction with Everolimus) I (4,5) and FUTURE II (6) studies were the first to demonstrate the feasibility of using everolimus on a DES. The SPIRIT (Clinical Evaluation of the Xience V Everolimus Eluting Coronary Stent System in the Treatment of Patients with de novo Native Coronary Artery Lesions) FIRST study has subsequently demonstrated clinical safety and efficacy of the EES out to 4 years' follow-up (7). In particular, significantly lower in-stent late loss was demonstrated at 12-month angiographic follow-up, compared with an identical BMS (8).
The assessment of the EES continued with SPIRIT II and the larger SPIRIT III studies. Both involved the randomized comparison of EES to the TAXUS (Boston Scientific, Natick, Massachusetts) paclitaxel-eluting stent (PES) in patients with a maximum of 2 de novo coronary artery lesions. In both studies, there was a significant reduction in major adverse cardiac events (MACE) with EES compared with PES at 12-month follow-up (9,10). A “late loss catch-up” with EES was suggested by the 2-year outcome data from SPIRIT II that showed no significant difference in angiographic and clinical outcomes between the 2 stents (11). The 2-year follow-up data from SPIRIT III, however, has shown promising results with improvements in event-free survival and lower rates of stent thrombosis with the use of an EES (12).
The current study presents the 3-year clinical outcome of patients enrolled in the SPIRIT II study treated with either EES or a PES. This represents the longest available clinical follow-up for EES in a moderately sized population.
The patient population has been described previously (13). In brief, SPIRIT II was a multicenter trial enrolling 300 patients who were randomized in a ratio of 3:1 to receive either an EES, XIENCE V (Abbott Vascular, Santa Clara, California) (n = 223), or a PES (n = 77). Both TAXUS Express2 (73% of lesions) and TAXUS Liberté (27% of lesions) were used in the control arm. A detailed description of everolimus and the EES is provided elsewhere (13,14). The ethics committee of each participating institution approved the study protocol, and all patients gave written informed consent.
All patients were over the age of 18, with evidence of myocardial ischemia and a maximum of 2 de novo native coronary artery lesions in different major epicardial vessels. For inclusion, on visual estimation, target lesion(s) were required to be: in a vessel with a reference vessel diameter of between 2.5 and 4.25 mm; <28 mm in length; and have a percentage diameter stenosis (DS) of between 50% and 99%, with a Thrombolysis In Myocardial Infarction flow grade >1. Patients with documented evidence of recent (<3 days) myocardial infarction (MI); a left ventricular ejection fraction <30%; waiting heart transplantation; or having a known sensitivity or contraindications to aspirin, heparin, bivalirudin, clopidogrel or ticlopidine, cobalt, chromium, nickel, tungsten, everolimus, paclitaxel, acrylic, and fluoropolymers were excluded. Angiographic lesions involving the left main stem lesion or the aorto-ostial junction; located within 2 mm of the origin of the left anterior descending or left circumflex; that were heavily calcified; or that had associated visible thrombus were also excluded.
Patients were randomized between EES and PES after the identification of suitable lesions on preliminary angiography. Physicians were not blinded, in view of the different packaging for each stent. Standard interventional techniques were used to treat the lesion; in particular pre-dilation was mandatory, and stent implantation was performed at a pressure not exceeding the rated burst pressure. Post-dilation was left to the operator's discretion; however, if post-dilation was performed, balloons were required to be shorter than the length of the deployed stent. In the event of a bailout procedure and the need for an additional stent, the stent was required to be of the same type as the first implanted stent.
In a subset of 152 consecutive patients enrolled in pre-selected centers, intravascular ultrasound (IVUS) was performed after optimal stent placement had been achieved. Periprocedural pharmaceutical treatment was administrated according to standard hospital practice. Procedural anticoagulation was achieved with unfractionated heparin or bivalirudin. The use of glycoprotein IIb/IIIa inhibitors was left to the operator's discretion. All patients enrolled into the study were to receive ≥75 mg of aspirin daily for a minimum of 1 year and clopidogrel 75 mg for a minimum of 6 months after the index procedure.
Patient review was initially planned at 1, 6, 9, 12, and 24 months after the index procedure; however, a subsequent protocol amendment enabled further clinical evaluation to be performed on an annual basis out to 5 years. At outpatient visits, patients were specifically questioned about the development of angina or the occurrence of any adverse events. Angiographic follow-up for all patients was planned at 180 days, with IVUS planned in a subset of 152 consecutive patients (from selected centers). Angiography and IVUS were repeated after 2 years in these 152 consecutive patients.
Study end points
The clinical end point of this 3-year follow-up study was MACE, defined as a composite of cardiac death, MI, and ischemia-driven target lesion revascularization (ID-TLR) by coronary artery bypass graft surgery (CABG) or PCI. Secondary clinical end points included target vessel failure (TVF), a composite of cardiac death, MI, ID-TLR, and non–target lesion ischemia-driven target vessel revascularization (ID-TVR). An independent blinded clinical events committee (CEC) evaluated all clinical end points, and a data and safety monitoring board, not affiliated with the study, ensured the safe conduct of the trial.
All deaths were considered cardiac unless an undisputed noncardiac cause was present. The onset of the trial was before the publication of the Academic Research Consortium's (ARC) consensus definitions for DES study end points, and therefore the only cardiac enzymes available in all patients to adjudicate events were creatinine kinase (CK), and creatinine kinase-myocardial band (CK-MB) (15). Q-wave MI was defined as the development of new pathological Q waves. A non–Q-wave MI was defined as a typical rise and fall of CK-MB, with at least 1 of the following: ischemic symptoms; electrocardiographic changes indicative of ischemia (ST-segment elevation or depression); or an associated coronary artery intervention. For a nonprocedural/spontaneous MI the CK-MB was required to be ≥2 times the upper limit of normal (ULN). A CK-MB ≥3 times the ULN or ≥5 times the ULN was required for an MI to be defined post-PCI or post-CABG, respectively.
The ID-TLR was defined as revascularization of the target lesion in association with any of the following: a positive test of ischemia, with either exercise testing or fractional/coronary flow reserve; ischemic symptoms and an angiographic DS ≥50% by online quantitative coronary angiography; or DS ≥70% by online quantitative coronary angiography without ischemic symptoms or a positive functional study.
The protocol for stent thrombosis changed after the publication of the ARC definitions for stent thrombosis (15). Those stent thrombotic events occurring before the adoption of the ARC definitions were re-adjudicated by the CEC to the new guidelines.
The rationale for sample size calculations for this study has previously been reported (13). In this article, binary variables are presented as percentages and compared with the Fisher exact test. All analyses are by intention-to-treat with all patients randomized in the study, regardless of the treatment actually received. However, patients who were 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. Survival curves were constructed for time-to-event variables with Kaplan-Meier estimates and compared by the log-rank test. Statistical analyses were performed with the SAS statistical package (version 9.1.3, SAS Institute, Cary, North Carolina).
Patient population and lesion characteristics
The baseline demographic, clinical, and angiographic characteristics of both treatment groups have been published previously (16) and are summarized in Table 1. No significant differences were present in any of the parameters listed.
Figure 1 shows the clinical follow-up of patients from enrolment to 3 years, on an intention-to-treat basis. Overall clinical assessment (on the basis of TVF) was available in 264 patients (88%), made up of 195 of the original 223 EES patients (87.4%) and 69 of the original 77 PES patients (89.6%). The reasons for incomplete follow-up are shown in Figure 1. A similar proportion in each stent group were lost because of failure to complete a new consent form, which was required after a change in the initial protocol to allow extended follow-up out to 5 years. Four patients withdrew from the EES group, of which 1 experienced a noncardiovascular event occurring 1-year after PCI; the other 3 patients were all event-free at last contact.
The angiographic outcomes at 6 months and 2 years and the clinical outcomes at 6 months, 1 year, and 2 years have all been presented elsewhere (10,11,16). In brief, at 6 months EES demonstrated significantly reduced in-stent late loss and percentage volume obstruction when compared with PES (p < 0.001). Clinical outcomes in terms of MACE, TVF, MI, cardiac death, and ID-TLR were all better with EES at 6 months, 1 year, and 2 years when compared with PES. Angiographic follow-up at 2 years demonstrated a late increase in neointimal hyperplasia with the EES stent, such that a significant difference was no longer observed between EES and PES for in-stent late loss or percentage volume obstruction.
Clinical outcomes at 3-year follow-up
The hierarchical and non-hierarchical events at 3-year clinical follow-up are shown in Tables 2 and 3,⇓⇓ respectively; and Figure 2 shows the Kaplan-Meier survival curves for cardiac death, MI, ID-TLR, and MACE.
At 3-year follow-up, the use of EES was associated with nonsignificant reductions in cardiac death, (relative risk [RR]: 0.12, 95% confidence interval [CI]: 0.01 to 1.12, p = 0.056) all-cause death (RR: 0.46, 95% CI: 0.18 to 1.20, p = 0.14), and MI (RR: 0.50, 95% CI: 0.16 to 1.51, p = 0.31). The rates of MI were consistently higher with PES; however, this difference did not reach significance at any time during follow-up.
During the 3-year follow-up period, 7 PES patients (10.1%) and 9 EES patients (4.6%) underwent ID-TLR (RR: 0.45, 95% CI: 0.18 to 1.17, p = 0.14). All of these were with PCI, apart from 1 patient in the EES group who underwent CABG. The Kaplan-Meier curve for ID-TLR (Fig. 2B) shows significantly lower ID-TLR with EES at 1-year follow-up; however, this significance was not maintained during long-term follow-up.
The rate of MACE (cardiac death, MI, ID-TLR), which was 7.2% in those patients treated with EES and 15.9% in those treated with PES (RR: 0.45, 95% CI: 0.21 to 0.94, p = 0.053), was consistently lower for EES compared with PES; however, the difference between the 2 varied with follow-up. As shown on the Kaplan-Meier curve (Fig. 2), a significant difference in MACE between the 2 stents was observed as early as 12 months (EES vs. PES, 2.7% vs. 9.1%, hazard ratio [HR]: 0.29, 95% CI: 0.10 to 0.87, plogrank = 0.018); however, between years 1 and 2 EES seemed to “catch-up.” Nevertheless, a significant difference re-emerged by the third year of follow-up (EES vs. PES, 6.4% vs. 14.9%, HR: 0.43, 95% CI: 0.19 to 0.94, plogrank = 0.029), which was the result of 3 additional patients with MACE observed in the PES group, whereas no new patients experienced MACE in the EES group.
The rates of stent thrombosis as per ARC definitions are listed in Table 4. After the 2-year follow-up, no definite/probable stent thrombosis occurred in the EES group, compared with 1 in the PES group. Overall, at 3-year follow-up the rate of stent thrombosis was numerically lower in the EES group (1.0% vs. 2.9%, p = 0.28). The proportion of patients returning for 3-year follow-up, who remained on dual antiplatelet therapy at 3 years, was 14.1% and 21.2% for patients treated with EES and PES, respectively (Fig. 3).
This randomized prospective study of the EES has confirmed its favorable clinical outcomes at 3-year follow-up and enhances the work of the previous EES studies (5–8,17).
In the present study, patients randomized to EES experienced fewer MIs, fewer ID-TLR, and had a trend for less cardiac death compared with those patients treated with PES. The overall rates of both MACE and TVF were numerically lower in favor of EES. These 3-year results demonstrate the maintenance of the superior outcomes with EES, which were observed as early as 6 months (13).
Two-year outcome data from SPIRIT II showed the maintenance of the advantage of EES over PES; however, HRs were less prominent than previously observed at 12 months (11). Furthermore, the results of 2-year angiographic follow-up in 97 EES patients demonstrated a 94% increase in the mean in-stent late loss among EES between 6 months and 2 years (0.17 ± 0.32 mm vs. 0.33 ± 0.37 mm), whereas a 3% increase was observed with PES over the same time period (0.33 ± 0.32 mm vs. 0.34 ± 0.34 mm). It is worth noting, however, that angiographic follow-up at 2 years was in a subset and not the entire SPIRIT II population, and as such, an unintended selection bias in this subset cannot be ruled out.
Nevertheless, concerns were raised as to the clinical relevance of this “late-catch up phenomenon” that was observed with EES. The present study, however, confirms that this increase in neointimal hyperplasia did not translate into any clinical events. In fact, between years 2 and 3, 2 ID-TLR were performed for EES (1 of which in a patient who already had ID-TLR before 6 months), and similarly, 2 ID-TLR were performed for PES. The absolute difference in rates of ID-TLR between EES and PES actually increased from 4.7% at 1 year to 5.2% at 3 years (Fig. 2). In addition, no cardiac deaths occurred with EES between years 2 and 3. Of note, the Kaplan-Meier curves for MACE and all its components at 3 years seem to diverge, further supporting the superior performance of the EES with long-term follow-up.
The much larger SPIRIT III trial randomized EES to PES in a 2:1 ratio and enrolled 1,002 patients with similar inclusion and exclusion criteria. The demographic data of both patient populations were similar. The SPIRIT III trial again confirmed the superior performance of EES compared with PES with long-term follow-up with a 45% reduction in MACE at 2 years (7.3% vs. 12.8%; HR: 0.55; 95% CI: 0.36 to 0.83, p = 0.004). Importantly, and unlike in SPIRIT II, there was no reduction in HRs between 1 and 2 years; in fact, the clinical benefits of EES seem to increase (12).
Although the current study is underpowered to make any definitive conclusions regarding stent thrombosis rates between EES and PES, it does confirm low rates of late stent thrombosis with EES (1.0%), which is comparable to published data for sirolimus-eluting stents (SES) and PES, at similar follow-up (18). Historically, first-generation DES have been associated with a persistent risk of very late stent thrombosis, extending out to 4-year follow-up (18); however, this might not be the same for the newer generation of DES such as the XIENCE V. In the current study EES has demonstrated no episodes of acute or late stent thrombosis, 2 episodes (1 definite and 1 probable) of very late stent thrombosis between year 1 and year 2, and no stent thrombosis events after 2 years. Similarly, the SPIRIT III trial demonstrated a low rate of very late (0.3%) and overall stent thrombosis (1.3%) with EES. The relationship of the late loss catch-up, if any, with lower late stent thrombosis is unclear; it is possible that neointimal healing, reflected as a modest increase in late loss over time, might in fact be protective.
The SES has been demonstrated to be the most efficacious first-generation DES (19–21), and therefore, the use of PES in this study might account for the favorable outcomes observed with EES. In principle, because both everolimus and sirolimus inhibit the mammalian target of rapamycin in a similar manner, a comparison between the 2 might demonstrate similar clinical outcomes. Indirect comparisons do support this; for example, similar rates of late loss occurred in the EES arm of the SPIRIT III trial and the SES arm of the SIRIUS (Sirolimus-Eluting Stent in de novo Native Coronary Lesions) trial (EES 0.16 mm vs. SES 0.17 mm) (9,22); however, as yet no randomized head-to-head comparison has been made between the 2 stents. There are, in addition to the antiproliferative coating, other notable differences between the stents, which might result in different clinical outcomes. In brief, EES is made of cobalt chromium, as opposed to stainless steel (PES and SES), which allows comparative radial strength to be achieved with considerably thinner stent struts. This can reduce vascular injury, intimal hyperplasia, and the risk of restenosis (23). Vascular injury and inflammation are also potentially reduced with the use of more biocompatible polymers as found on the EES, compared with the durable and less biocompatible polymers found on the PES and SES.
A clearer picture will be obtained when the results of the prospective, randomized, multicenter EXCELLENT (Efficacy of Xience/promus versus Cypher in rEducing Late Loss after stENTing) trial are available. This study is enrolling approximately 1,400 patients with the aim of comparing the safety and efficacy of the EES and SES and the optimal duration of dual antiplatelet therapy (6 or 12 months). The co-primary end points are the noninferiority of EES compared with SES in inhibiting neointima hyperplasia and preventing late loss at 9 months and TVF at 12 months for comparison of dual antiplatelet therapy duration (24). Furthermore, additional studies of the EES include the SPIRIT IV, SPIRIT V, XIENCE V SPIRIT WOMEN, XIENCE V USA, and XIENCE V INDIA, which are all designed to evaluate the safety and efficacy of the EES in over 14,000 real-world patients.
This study was not powered to detect significant differences in the safety profiles of either stent. In view of the small number of patients recruited and the loss of 8% of patients from follow-up (which was similar in both groups), caution is required when interpreting the differences in events.
The present study reports the favorable 3-year clinical outcomes of the EES, which are consistent with the results from earlier studies with shorter follow-up. In this study, compared with the PES, the EES demonstrated a reduction in cardiac events, clinical restenosis, and overall MACE rate at long-term follow-up. In addition, the overall lower rate of stent thrombosis and absence of stent thrombosis after 2 years with EES is potentially significant and requires additional investigation.
Cécile Dorange, Susan Veldhof, Dr. Miquel-Hébert, and Dr. Sudhir are employees of Abbott Vascular.
- Abbreviations and Acronyms
- Academic Research Consortium
- bare-metal stent(s)
- coronary artery bypass graft
- confidence interval
- creatinine kinase-myocardial band
- drug-eluting stent(s)
- diameter stenosis
- everolimus-eluting stent(s)
- hazard ratio
- ischemia-driven target lesion revascularization
- intravascular ultrasound
- major adverse cardiovascular events
- myocardial infarction
- percutaneous coronary intervention
- paclitaxel-eluting stent(s)
- relative risk
- sirolimus-eluting stent(s)
- upper limit of normal
- target vessel failure
- target vessel revascularization
- Received May 14, 2009.
- Revision received September 8, 2009.
- Accepted October 6, 2009.
- American College of Cardiology Foundation
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