Long-Term Safety and Efficacy of the Everolimus-Eluting Stent Compared to First-Generation Drug-Eluting Stents in Contemporary Clinical Practice

Abstract: Objective. This study aimed to assess the long-term safety and clinical effectiveness of the Xience V everolimus-eluting stent (EES) compared to both Taxus paclitaxel-eluting stent (PES) and Cypher sirolimus-eluting stent (SES) in an unselected patient population. Background. There are limited long-term data comparing Xience V EES vs the first-generation Cypher SES. Methods. This retrospective analysis included 6069 patients treated with Cypher SES, Taxus PES, or Xience V EES from 2003-2009 at our institution. Patients were followed by telephone contact or office visit up to 2 years after the index procedure. Results. Baseline characteristics were generally comparable, with the exception of a significantly higher prevalence of diabetes mellitus, systemic hypertension, history of angioplasty, and coronary bypass surgery among Xience V EES patients. At 2 years, the incidence of major adverse cardiovascular events was 13.3% (Xience V EES) vs 17.8% (Cypher SES) vs 22% (Taxus PES) (P<.001). The main drivers for the differences in event rates were lower mortality, the need for target vessel revascularization, and Q-wave myocardial infarction. Stent thrombosis was lowest in Xience V EES patients (0.2% vs 1.2% SES vs 0.7% PES, respectively; P=.01). A landmark analysis after 1 year showed that the benefits of Xience V EES continued in long-term follow-up. Conclusions. In a contemporary clinical United States practice with an unselected patient population, Xience V EES use was associated with improved safety profile and reduction of all-cause mortality and stent thrombosis when compared to both first-generation drug-eluting stents. This superiority continues to widen from 1 to 2 years. 

J INVASIVE CARDIOL 2014;26(4):154-160

Key words: percutaneous coronary intervention, drug-eluting stents, stent thrombosis

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While the introduction of drug-eluting stent (DES) implantation for percutaneous coronary intervention (PCI) has mitigated some of the limitations of bare-metal stents,^1,2 serious concerns about late complications, such as in-stent restenosis and late stent thrombosis, still remain.^3,4 Data regarding long-term (>1 year) clinical follow-up on the outcomes of patients receiving the Xience V everolimus-eluting stent (EES) (Abbott Vascular) are rather limited⁵ and are mostly derived from long-term follow-up of clinical trials,^6-9 which typically include a highly selected patient population that might not represent the contemporary practice with broad inclusion criteria. Furthermore, all major clinical trials and registries performed to date have evaluated the safety and efficacy of EES versus paclitaxel-eluting stent (PES), and there is a small amount of data comparing the long-term outcomes of Xience V EES with sirolimus-eluting stent (SES), which is considered the most efficacious of the first-generation DESs.^10,11

The Registry Experience at Washington Hospital Center, DES – Xience V (REWARDS XV) is a physician-initiated study assessing contemporary utilization of first-generation stents as compared to Xience V EES for all-comer PCI procedures. This report focuses on the 2-year clinical outcomes of all patients enrolled in the REWARDS XV registry comparing the safety and efficacy of Xience V EES to Taxus PES (Boston Scientific) as well as Cypher SES (Cordis Corporation) in a real-world practice.

Methods

The treatment group included patients who received ≥1 Xience V EES at MedStar Washington Hospital Center from 2003-2009. The two control groups comprised patients who received a Cypher SES or a Taxus PES during the study period. Patients who received an EES other than Xience V or a bare-metal stent at the time of initial Xience V EES implantation were excluded. All patients provided written informed consent. The study complied with the Declaration of Helsinki for investigation in humans and was approved by the institutional ethics committee of MedStar Washington Hospital Center.

Interventional strategy and use of adjunctive devices and pharmacotherapy were at the discretion of the operating interventional cardiologist. All patients received aspirin 325 mg before the procedure and were recommended to continue this regimen indefinitely. In addition, clopidogrel 75 mg/day, after a 300 or 600 mg loading dose, was begun before the procedure and continued for 12 months. Cardiac history, baseline demographics, and angiographic data were prospectively collected. Patients were followed via telephone or survey for all major adverse cardiovascular event (MACE) occurrences during index hospitalization and up to 2 years after the initial Xience V implantation.

The primary endpoint was MACE at 2 years, defined as a composite of death, myocardial infarction (MI), and target lesion revascularization. Q-wave MI was defined as evidence of new Q-waves on the electrocardiogram. Myocardial infarction was defined as a total creatinine kinase increase ≥2x the upper limit of normal and/or creatinine kinase (MB fraction) ≥20 ng/mL, together with symptoms and/or ischemic electrocardiographic changes. Hypercholesterolemia was defined as fasting cholesterol >250 mg/dL or the use of lipid-lowering therapy. Systemic hypertension was defined as blood pressure >140/90 mm Hg or the use of antihypertensive therapy. Renal impairment was defined as serum creatinine >1.2 mg/dL. Congestive heart failure was defined as evidence of fluid retention from cardiac causes before admission. Angiographic success was defined as postprocedural stenosis of <30% and Thrombolysis in Myocardial Infarction (TIMI) flow grade 3. Target lesion revascularization was defined as ischemia-driven percutaneous or surgical repeat intervention in the stent or within 5 mm proximal or distal to the stent. Stent thrombosis was defined in accordance with the Academic Research Consortium definitions as definite or probable stent thrombosis.

Statistical analysis was performed using SAS version 9.2 (SAS Institute). Continuous variables and categorical variables are expressed as mean ± standard deviation and percentages, respectively. Analyses of difference among the three DES types were performed using analysis of variance for continuous variables and the chi-square test or Fisher’s exact test for categorical variables. For variables with a 3-group P-value <.05, two subsequent pair-wise comparisons for Xience V EES vs Taxus PES and Cypher SES were performed with Bonferroni’s correction for P-value significance (P<.025). 

After univariable analysis for baseline clinical and procedural characteristics, the following characteristics with P<.10 were incorporated into the multivariate analysis to assess independent association with MACE and stent thrombosis at two years: stent type used, history of coronary artery disease, systemic hypertension, left ventricular ejection fraction, diabetes mellitus, number of diseased vessels, left anterior descending artery disease, American College of Cardiology/American Heart Association lesion type classification, number of treated lesions per patient, maximum stent length and diameter, number of implanted stents, acute MI, and clopidogrel compliance. 

Clopidogrel compliance was expressed as a time-dependent covariate, defined as the days to cessation for those patients who ceased their prescription. The stent type was entered as a categorical variable with Xience V EES as the reference. The results are presented as adjusted hazard ratios with 95% confidence intervals. Survival, MACE, and stent thrombosis rates up to 2 years were measured using the Kaplan-Meier method, and differences in parameters were assessed using the log-rank test. P-values <.05 were considered statistically significant.

Results

A total of 4949 patients were analyzed. Of them, 2758 (56%) received Cypher SES, 1203 (24%) received Taxus PES, and 998 (20%) received Xience V EES. As seen in Table 1, the average age was 65 ± 12 years; the majority were male (65%) and 67% of the patients presented with an acute MI or unstable angina pectoris. Baseline patient characteristics were generally comparable among the 3 groups (Table 1). However, patients who received a Xience V EES had a significantly higher prevalence of cardiovascular risk factors, including diabetes mellitus, arterial hypertension, history of PCI, and coronary artery bypass surgery. Indication for the PCI was acute MI or unstable angina in 71% of the Xience V EES patients as compared with 64% of Cypher SES and 71% of Taxus PES patients. 

Anatomic characteristics of the treated vessels varied among the groups, with lower rates of left anterior descending and vein graft PCI among Taxus PES and Xience V EES patients, and higher rates of right coronary and circumflex arteries PCI among Taxus PES and Xience V EES patients (Table 2). Patients treated with Xience V EES had the most complicated lesions as indicated by a nearly 2-fold higher rate of American College of Cardiology/American Heart Association type-C lesions when compared to the other two stent groups. The number of stents used per lesion (average, 1.5 ± 0.8) was generally comparable among patients, as was the total stent length (average, 20 ± 6.4 mm) (Table 2).

In-hospital outcomes were the worst for patients treated with Taxus PES (Table 3). Despite the higher in-hospital mortality, there were no significant differences among groups in terms of other in-hospital complications, such as MI, need for reintervention, and stent thrombosis (Table 3).

The primary endpoint of MACE at 2 years occurred in 879 patients (17.9%). MACE rates at 2 years were lowest for Xience V EES patients (13.2%) compared with Cypher SES patients (17.8%; P<.001 for Xience V EES vs Cypher SES) and Taxus PES patients (22%; P<.001 for Xience V EES vs Taxus PES) (Figures 1 and 2). MACE rate was driven mainly by the 2-year all-cause mortality, which was lowest among Xience V EES patients (5.5%) as compared with Taxus PES (13.8%; P<.001 for Xience V EES vs Taxus PES) and Cypher SES (9.9%; P<.001 for Xience V EES vs Cypher SES) (Figures 1 and 3) and by target lesion revascularization events, which were comparable among the 3 groups (Cypher SES 9.2%, Taxus PES 9.7%, Xience V EES 8.1%; P=.45) (Figure 1). 

Interestingly, a 12-month landmark analysis indicated a continuous advantage of Xience V EES compared to Cypher SES and Taxus PES up to 2 years, with a MACE rate of 3.6% vs 5.6% and 6.1%, respectively (P=.02) during the second year (Figure 4). The difference in MACE rate was driven mainly by lower all-cause mortality (1.7% vs 3.6% and 3.7%, respectively; P=.01) and low incidence of Q-wave MI (0.2% vs 0.1% and 0.7%, respectively; P=.02).

A multivariable model designed to assess association among stent type, baseline and procedural characteristics, and MACE at 2 years showed that Xience V EES use is independently associated with a lower MACE rate as compared with Taxus PES (hazard ratio [HR], 1.6; 95% confidence interval [CI], 1.19-2.19), but not Cypher SES (Table 4). Additional parameters associated with poor 2-year outcomes included history of coronary artery disease, low ejection fraction at baseline, diabetes mellitus, acute MI, multivessel disease, lesion characteristics, longer stent length, and increasing number of stents used (Table 4).

Compliance with dual-antiplatelet therapy up to 1 year was, on average, 82%. Xience V patients demonstrated the highest compliance rates (86%) (Figure 5); however, in a longer follow-up of 1-2 years, significantly fewer Xience V EES patients continued to take dual-antiplatelet medications (83% in Cypher SES, 87% Taxus PES and 75% Xience V EES; P<.001) (Figure 5). Despite the low rates of dual-antiplatelet therapy compliance in the extended follow-up period, the rates of definite and probable stent thrombosis up to 2 years were lowest in the Xience V patients (0.4%) as compared with Cypher SES (1.7%, P=.01 for Xience V EES vs Cypher SES) or Taxus PES (1.7%, P=.01 for Xience V EES vs Taxus PES) (Figures 1 and 6). Figure 6 demonstrates the cumulative incidence of stent thrombosis throughout the follow-up period, indicating that the majority of events occurred early or late (<1 year) rather than very late (>1 year). Multivariable analysis (Table 5) indicated that when compared with either Cypher SES or Taxus PES, Xience V EES use had a borderline non-significant association with lower rates of stent thrombosis at 2 years. Left ventricular ejection function, number of treated lesions and stents implanted, and clopidogrel cessation were independently associated with higher risk for stent thrombosis (Table 5). 

Discussion

Late hazard phenomena for DES, such as very late stent thrombosis and neoatherosclerosis, have received growing appreciation in the past few years.^12-15 Considering these pathological processes and the recent commercialization of the new Xpedition EES, which is practically an identical stent design to the Xience V EES, there is a greater need for data regarding the long-term performance of this stent platform and drug. In the context of these concerns, the major findings of the present study provide reassuring data on the long-term safety of second-generation DESs in an unselected cohort of patients with reduction in all-cause mortality and stent thrombosis when compared to first-generation DESs. This safety profile is evident despite lower rates of treatment with dual-antiplatelet medication in extended follow-up from 1 to 2 years. However, despite clear superiority of the Xience V EES over Taxus PES in terms of 2-year MACE, no significant differences were found in multivariable analysis when compared to Cypher SES. The present study did show lower cumulative stent thrombosis rates for Xience V EES at 2 years compared to Cypher SES and Taxus PES. A major strength of the present study is that it is an investigator-sponsored, real-world registry that represents contemporary clinical practice in the United States. 

Initial data on the performance and safety of EES as compared to PES demonstrated promising results in favor of the second-generation EES. The SPIRIT randomized control trial series showed superior angiographic outcomes and clinical outcomes at 6 and 8 months when compared to PES.^16-18 These initial reports in selected patients were followed by multiple patient registries and retrospective analyses supporting the clinical trial data.^19-21 However, data were limited to 12-month follow-up and the representative first-generation DES in most of the studies was the Taxus PES, which is known to be inferior to the Cypher SES. 

Concerns were raised regarding the long-term performance of the Xience V EES when 2-year intravascular ultrasound (IVUS) and angiographic data from the SPIRIT II trial suggested a “late

loss catch-up” with EES from 0.17 ± 0.32 mm at 6 months to 0.33 ± 0.37 mm at 2-year follow up. These qualitative coronary angiography findings are in accordance with the IVUS data that showed loss of EES advantage compared to PES in terms of neointimal hyperplasia volumes and percentage volume obstruction.²²

Thus, there was a need to obtain long-term clinical follow-up on the EES. A pooled analysis of SPIRIT II and III clinical trials, with follow-up to 3 years, showed the superiority of Xience V EES as compared to Taxus PES with lower MACE rates (9.1% vs 13.7%), which were mainly driven by the lower rates of myocardial infarction and target lesion revascularization.⁶ As indicated by the authors, the clinical benefits provided by Xience V EES were the result of persistent benefit of Xience V EES beyond 1 and 2 years of follow-up with continuous divergence of the time-to-event curves for target vessel failure and MACE beyond 1 year. Recently, 5-year data from SPIRIT II were published.²³ It included 244 patients and demonstrated lower MACE and cardiac mortality rates for EES patients. Registry data comparing EES to PES up to 2 years showed comparable results with superior clinical outcomes associated with EES use.^5,8 

One of the limitations of the previously published studies is the lack of data comparing EES to SES, which is the most effective first-generation DES. The most comprehensive assessment of EES performance compared to SES performance comes from a meta-analysis by Park et al.²⁴ The analysis showed that all major clinical outcomes were comparable between the 2 stents except for the need for repeat revascularization, which achieved borderline significance (HR, 0.85; 95% CI, 0.72-1.0) in favor of EES. However, again, these data are mostly limited to 1-year follow-up. Thus, there is a great need for assessment of long-term performance of Xience V EES in comparison to first-generation DES. 

The findings from the present analysis add meaningful data regarding the performance and safety of the Xience V EES in an unselected, all-comer patient population that underwent elective or urgent revascularization. Data presented suggest that the high performance of Xience V EES is maintained to 2 years as compared to Taxus PES and Cypher SES. Similar to the COMPARE (comparison of the everolimus-eluting Xience V stent with the paclitaxel-eluting Taxus Liberté stent in all-comers: a randomized open label trial) registry,⁸ second-year landmark analysis performed in the present study indicated that MACE rates continued to diverge between Xience V EES and Taxus PES during the second year of follow-up. In COMPARE, these lower rates were driven mainly by lower MI and target vessel revascularization rates.⁸ In the present study, the lower MACE rates from1 to 2 years were mostly driven by lower all-cause mortality and a low incidence of Q-wave MI. 

One of the most striking findings of the present analysis is the fact that the incidence of stent thrombosis for Xience V EES remained low during the first (0.2%) and second years (0.2%) of follow-up. Compared to these low rates of Xience V EES, the present study landmark analysis showed that for Taxus PES stent thrombosis rates continue to accumulate (0.7% at 12-24 months), but for Cypher SES there was a significant decrease in the incidence of stent thrombosis from 1.5% in the first year²⁰ to 0.2% during the second year. The low stent thrombosis rates beyond 1 year were among Xience V EES patients, even when these patients had the lowest rates of dual-antiplatelet therapy use during this period. Possible explanations for the low risk for stent thrombosis for Xience V EES might be attributed to differences in stent design such as strut thickness, delivery platform, polymer coating, drug, and drug release profile. These modifications in stent design may be associated with more rapid reendothelialization with Xience V EES, as was previously shown in preclinical models.²⁵ Compared to previous publications with similar patient populations, cumulative stent thrombosis rates for Xience V EES at 2 years were lower.^5,8 While there is no single explanation for this observation, one hypothesis might be the high use of IVUS. In a recent meta-analysis of nearly 20,000 patients, IVUS utilization during PCI was shown to be associated with lower stent thrombosis rates as compared to angiographically guided PCI. While IVUS utilization rates were not reported for previous registries,^5,8 at our center, the majority of PCIs are performed with IVUS guidance (62% in this cohort). An alternative hypothesis explaining the different stent thrombosis rates among the studies may be related to differences in compliance and duration of dual-antiplatelet therapy; however, data to support this hypothesis are not available in this or in previous publications. 

Study limitations. There are several limitations to our study. The current study was a post hoc analysis, and as such, is subject to the limitations of retrospective studies; results may have been affected by unknown confounders. Despite the large population of patients included in the present study, it is a single-center registry and unknown confounders, such as high rates of IVUS utilization during PCI, might limit the general applicability of our findings. Finally, as this is a longitudinal, observational study, patients were enrolled at different time points and dual-antiplatelet protocols may have changed.

References

1. 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(23):1773-1780.
2. Moses JW, Leon MB, Popma JJ, et al. Sirolimus-eluting stents versus standard stents in patients with stenosis in a native coronary artery. N Engl J Med. 2003;349(14):1315-1323.
3. Shammas NW, Shammas GA, Hahn A, Jerin M, Dippel EJ, Winter M. In-hospital complications and long-term outcomes of the paclitaxel drug-eluting stent in acute ST-elevation myocardial infarction: a real-world experience from a high-volume medical center. Cardiovasc Revasc Med. 2009;10(3):151-155.
4. Vaknin-Assa H, Assali A, Ukabi S, Lev EI, Kornowski R. Stent thrombosis following drug-eluting stent implantation. A single-center experience. Cardiovasc Revasc Med. 2007;8(4):243-247.
5. Hermiller JB, Rutledge DR, Gruberg L, et al. Sustained low clinical event rates in real-world patients receiving everolimus-eluting coronary stent system from a large, prospective, condition of approval study: 2-year clinical outcomes from the XIENCE V USA Study. J Interv Cardiol. 2012;25(6):565-575.
6. Caixeta A, Lansky AJ, Serruys PW, et al. Clinical follow-up 3 years after everolimus- and paclitaxel-eluting stents: a pooled analysis from the SPIRIT II (A Clinical Evaluation of the XIENCE V Everolimus Eluting Coronary Stent System in the Treatment of Patients With De Novo Native Coronary Artery Lesions) and SPIRIT III (A Clinical Evaluation of the Investigational Device XIENCE V Everolimus Eluting Coronary Stent System [EECSS] in the Treatment of Subjects With De Novo Native Coronary Artery Lesions) randomized trials. JACC Cardiovasc Interv. 2010;3(12):1220-1228.
7. Planer D, Smits PC, Kereiakes DJ, et al. Comparison of everolimus- and paclitaxel-eluting stents in patients with acute and stable coronary syndromes: pooled results from the SPIRIT (A Clinical Evaluation of the XIENCE V Everolimus Eluting Coronary Stent System) and COMPARE (A Trial of Everolimus-Eluting Stents and Paclitaxel-Eluting Stents for Coronary Revascularization in Daily Practice) trials. JACC Cardiovasc Interv. 2011;4(10):1104-1115.
8. Smits PC, Kedhi E, Royaards KJ, et al. 2-year follow-up of a randomized controlled trial of everolimus- and paclitaxel-eluting stents for coronary revascularization in daily practice. COMPARE (Comparison of the everolimus eluting Xience-V stent with the paclitaxel eluting Taxus Liberte stent in all-comers: a randomized open label trial). J Am Coll Cardiol. 2011;58(1):11-18.
9. Stone GW, Rizvi A, Sudhir K, et al. Randomized comparison of everolimus- and paclitaxel-eluting stents. 2-year follow-up from the SPIRIT (Clinical Evaluation of the Xience V Everolimus Eluting Coronary Stent System) IV trial. J Am Coll Cardiol. 2011;58(1):19-25.
10. Morice MC, Colombo A, Meier B, et al. Sirolimus- vs paclitaxel-eluting stents in de novo coronary artery lesions: the REALITY trial: a randomized controlled trial. JAMA. 2006;295(8):895-904.
11. Windecker S, Remondino A, Eberli FR, et al. Sirolimus-eluting and paclitaxel-eluting stents for coronary revascularization. N Engl J Med. 2005;353(7):653-662.
12. Nakazawa G, Otsuka F, Nakano M, et al. The pathology of neoatherosclerosis in human coronary implants bare-metal and drug-eluting stents. J Am Coll Cardiol. 2011;57(11):1314-1322.
13. Otsuka F, Nakano M, Ladich E, Kolodgie FD, Virmani R. Pathologic etiologies of late and very late stent thrombosis following first-generation drug-eluting stent placement. Thrombosis. 2012;2012:608593.
14. Park SJ, Kang SJ, Virmani R, Nakano M, Ueda Y. In-stent neoatherosclerosis: a final common pathway of late stent failure. J Am Coll Cardiol. 2012;59(23):2051-2057.
15. Yoshida K, Sadamatsu K. A severely calcified neointima 9 years after bare metal stent implantation. Cardiovasc Revasc Med. 2012;13(6):350-352.
16. Serruys PW, Ruygrok P, Neuzner J, et al. A randomised comparison of an everolimus-eluting coronary stent with a paclitaxel-eluting coronary stent: the SPIRIT II trial. EuroIntervention. 2006;2(3):286-294.
17. Stone GW, Midei M, Newman W, et al. Randomized comparison of everolimus-eluting and paclitaxel-eluting stents: two-year clinical follow-up from the Clinical Evaluation of the Xience V Everolimus Eluting Coronary Stent System in the Treatment of Patients with de novo Native Coronary Artery Lesions (SPIRIT) III trial. Circulation. 2009;119(5):680-686.
18. Stone GW, Rizvi A, Newman W, et al. Everolimus-eluting versus paclitaxel-eluting stents in coronary artery disease. N Engl J Med. 2010;362(18):1663-1674.
19. Kedhi E, Joesoef KS, McFadden E, et al. Second-generation everolimus-eluting and paclitaxel-eluting stents in real-life practice (COMPARE): a randomised trial. Lancet. 2010;375(9710):201-209.
20. Waksman R, Barbash IM, Dvir D, et al. Safety and efficacy of the Xience V everolimus-eluting stent compared to first-generation drug-eluting stents in contemporary clinical practice. Am J Cardiol. 2012;109(9):1288-1294.
21. Krucoff MW, Rutledge DR, Gruberg L, et al. A new era of prospective real-world safety evaluation primary report of Xience V USA (Xience V Everolimus Eluting Coronary Stent System condition-of-approval post-market study). JACC Cardiovasc Interv. 2011;4(12):1298-1309.
22. Claessen BE, Beijk MA, Legrand V, et al. Two-year clinical, angiographic, and intravascular ultrasound follow-up of the Xience V everolimus-eluting stent in the treatment of patients with de novo native coronary artery lesions: the SPIRIT II trial. Circ Cardiovasc Interv. 2009;2(4):339-347.
23. Onuma Y, Miquel-Hebert K, Serruys PW. Five-year long-term clinical follow-up of the Xience V everolimus-eluting coronary stent system in the treatment of patients with de novo coronary artery disease: the SPIRIT II trial. EuroIntervention. 2013;8(9):1047-1051.
24. Park KW, Kang SH, Velders MA, et al. Safety and efficacy of everolimus- versus sirolimus-eluting stents: a systematic review and meta-analysis of 11 randomized trials. Am Heart J. 2013;165(2):241-50 e4.
25. Joner M, Nakazawa G, Finn AV, et al. Endothelial cell recovery between comparator polymer-based drug-eluting stents. J Am Coll Cardiol. 2008;52(5):333-342.