Long‐term (beyond 5 years) clinical impact of Xience everolimus‐eluting stent implantation

Abstract Objects We aim at examining the long‐term clinical outcome after Xience everolimus‐eluting stent (X‐EES) implantation. Background Long‐term clinical outcomes beyond 5 years after X‐EES implantation remain unclear. Methods This retrospective study has collected data from 1184 consecutive patients, corresponding to 1463 lesions, who were treated with X‐EES alone in the Nagoya Heart Center between January 2010 and December 2013. The primary endpoint was the 10‐year cumulative incidence of target lesion failure (TLF), defined as cardiac death, target vessel myocardial infarction (MI), and clinically indicated target lesion revascularization (TLR). Definite/probable stent thrombosis (ST) was evaluated as a secondary outcome. Results At 10 years, the cumulative incidence of TLF was recorded to be 12.4%, whereas that of cardiac death, target vessel MI, and clinically indicated TLR was at 4.4%, 4.1%, and 7.8%, respectively. The cumulative rate of definite/probable ST was observed to remain low (0.3% at 30 days; 0.3% at 1 year; 0.6% at 5 years; and 1.1% at 10 years). In the multivariate analysis, the risk factors of TLF were insulin‐treated diabetes (hazard ratio (HR), 1.93; 95% confidence interval (CI), 1.13‐3.29; P = .02), left ventricular dysfunction (HR, 2.28; 95% CI, 1.43‐3.62; P < .01), hemodialysis (HR, 2.22; 95% CI, 1.39‐3.56; P < .01), prior percutaneous coronary intervention (HR, 1.68; 95% CI, 1.18‐2.41; P < .01), peripheral vascular disease (HR, 1.70; 95% CI, 1.07‐2.69; P < .01), severe calcification (HR, 2.08; 95% CI, 1.36‐3.09; P < .01), and in‐stent restenosis (HR, 2.93; 95% CI, 1.64‐4.89; P < .01). Conclusions The incidence rates of the long‐term adverse effects after X‐EES implantation, such as late TLR and ST, were determined to be low in this study; however, they increased over time until 10 years after stent implantation.

Also, compared with the other second-generation DES, the X-ESS has never been reported to be superiority to safety and efficacy in mid-to long term. 9,10 However, the occurrence rate of its long-term (beyond 5 years) clinical effects, including its risk factors, remains unclear.
Therefore, this retrospective cohort study investigated the long-term safety and efficacy of X-EES. and P2Y12 inhibitor (300 mg clopidogrel). During the procedure, unfractionated heparin (100 U/kg) was administered to all the patients who reached an activated clotting time of 250 seconds. After the procedure, all patients were prescribed with optimal pharmacologic therapy based on the current guidelines, including statins, beta-blockers, or reninangiotensin system blockers. Moreover, the duration of dual antiplatelet therapy (DAPT) was also dependent on the surgeon's discretion.

| Data collection and clinical follow-up
All the patients were followed up at 1, 3, 6, and 12 months after their index procedure and annually thereafter. Additional information was obtained by telephone communication or medical records, as needed,

| Endpoints and definitions
The primary endpoint of this study was the target lesion failure (TLF) up to 10 years after the index procedure, which is defined as a com-

| Baseline characteristics
Baseline patient, lesion, and procedural characteristics are summarized in Tables 1 and 2. High-risk factors such as diabetes mellitus, hemodialysis, prior MI, prior PCI, and peripheral vascular diseases were also found prevalent in the study population (Table 1), as were complex lesion characteristics (AHA/ACC type B2/C lesions) such as bifurcation, diffuse lesion, severe calcification, chronic total occlusion, and in-stent restenosis (

| Clinical outcomes
The cumulative incidence of each clinical event for the 10-year period is summarized in Table 3.
TLF after X-EES implantation was observed to occur in 36 patients For secondary endpoints, the cumulative 10-year incidence of definite/probable ST was determined to be at 0.3% at 1 year, 0.6% at 5 years, and 1.1% at 10 years (Table 3, Figure 2). There was no significant difference in the definite/probable ST rates among AMI and non-AMI cases (Figure 3).

| Risk factors of TLF
We used multivariate analysis to identify the risk factors for TLF. were considered significant throughout the follow-up (Table 4).  Widespread use of second-generation DES has resolved several clinical issues related to major adverse cardiac events. [12][13][14] In our cohort, the TLF was dominated by clinical indicated TLR and the annual incidence of late clinical indicated TLR beyond 5 years after X-EES implantation remained at 0.67% per year; this rate is much lower than that reported by previous studies. 6,7,12,13 Serruys et al, based on intravascular ultrasound (IVUS) findings, have suggested that X-EES is more effective in reducing neointimal hyperplasia than the firstgeneration DES. 15 It is known that IVUS-guided PCI is superior to angiography-guided PCI with respect to reducing the risk of clinically indicated TLR or ST 16 ; in this study, the IVUS-guided PCI was performed for all the cases. Furthermore, as the risk factors of TLF in this cohort, insulin-treated diabetes, hemodialysis, peripheral vascular disease, and in-stent restenosis were those of clinically indicated TLR (Tables 4 and 5). However, achieving complete resolution in such patients is considered to be difficult, even with the IVUS-guided PCI using second-generation DES. Therefore, more careful follow-up during routine clinical practice is required in such patients.

| Risk factors of clinically indicated TLR
To date, several large-scale registries of first-generation DES have recorded annual VLST incidence rates of 0.21% to 0.53%. 4,5,16 In contrast, some studies on X-EES have reported annual VLST incidence rates of 0.13% to 0.18%, although this is based on data up to 5 years only. 6,7,13 Thus, it is possible that the use of the X-EES is associated with a lower incidence of long-term events such as late ST and VLST compared with the first-generation DES. 17

| LIMITATIONS
There are several important limitations to our study. First, this was a retrospective, single-center study, which might have significantly affected some results, especially because confounding factors were not controlled for. Therefore, these results, which represent the posthoc analysis of a trial, should be used only for hypothesis generation.
Next, no information on bleeding complications during the follow-up period was available, and this outcome was, therefore, not analyzed.

| CONCLUSIONS
In conclusion, the incidence rates of long-term outcomes such as late TLR and definite/probable ST after X-EES implantation were very low in this study; however, they gradually increased during the follow-up period of 10 years. Larger trials based on clinical follow-up are needed to confirm the use of X-EES as an optimal long-term strategy.

ACKNOWLEDGMENTS
We thank Himika Hattori, Yuji Tsunekawa, and Kazuya Konakano for their assistance with the manuscript.

CONFLICT OF INTEREST
The authors have no conflicts of interest to declare. The corresponding author or manuscript guarantor will have to confirm that he/she had full access to all of the data in the study and takes complete responsibility for the integrity of the data and the accuracy of the data analysis.

TRANSPARENCY STATEMENT
The lead author, Hiroaki Matsuda, affirms that this manuscript is an honest, accurate, and transparent account of the study being reported; that no important aspects of the study have been omitted; and that any discrepancies from the study as planned (and if relevant, registered) have been explained.

DATA AVAILABILITY STATEMENT
The data that support the findings of this study are available from the corresponding author upon reasonable request.