Three-Year Clinical Outcomes of Everolimus-Eluting Stents From the Post-Marketing Surveillance Study of Cobalt-Chromium Everolimus-Eluting Stent (XIENCE V/PROMUS) in Japan

Abstract

Background: The Cobalt-Chromium Everolimus-Eluting Stent (CoCr-EES) Post-marketing Surveillance (PMS) is a prospective multicenter registry designed to evaluate the safety and efficacy of XIENCE V/PROMUS everolimus-eluting stents in routine clinical practice at 47 centers representative of the clinical environment in Japan.

Methods and Results: We enrolled 2,010 consecutive patients (2,649 lesions) who underwent PCI using CoCr-EES. Clinical outcomes were evaluated for up to 3 years. Clinical follow-up was available in 1,930 patients (96%) at 3 years. Major adverse cardiovascular events (MACE) occurred in 6.8% of patients, including cardiac death (1.7%), myocardial infarction (1.5%), and clinically driven target lesion revascularization (CD-TLR, 4.2%). Late CD-TLR rate was 0.8% from 1 to 2 years, and 0.5% from 2 to 3 years. Definite or probable stent thrombosis occurred in 7 patients (0.3%) up to 1 year. There was no very late definite or probable stent thrombosis from 1 to 3 years. Significant independent predictors for MACE were hemodialysis, prior coronary intervention, triple-vessel coronary artery disease, and age >70 years.

Conclusions: Three-year clinical outcomes from the CoCr-EES PMS demonstrated a low incidence of clinical events. There was no major concern about very late stent thrombosis or late catch-up phenomenon in patients treated with EES in routine clinical practice in Japan. (Circ J 2016; 80: 906–912)

Late stent thrombosis and late in-stent restenosis are the 2 major limitations of first-generation drug-eluting stents (DES).^1,2 Second-generation DES are associated with significantly lower in-stent restenosis rate and lower rate of late stent thrombosis as compared with first-generation DES.^3–6 Therefore, second-generation DES are used currently as the first-line coronary stents in routine clinical practice. Clinical outcomes of first-generation DES, such as sirolimus- and paclitaxel-eluting stents, in earlier Japanese post-marketing surveillance studies (PMS) have been published previously,^7–9 but long-term clinical outcomes for second-generation DES, such as cobalt-chromium everolimus-eluting stents (CoCr-EES), have not been fully evaluated in routine clinical practice in Japan. Therefore, we evaluated 3-year clinical outcomes after EES implantations in a real-world setting at 47 Japanese sites using the EES Japan PMS database.

Methods

Subjects and Follow-up

CoCr-EES PMS Japan is a prospective multicenter registry enrolling 2,000 patients who received CoCr-EES. The study was designed to evaluate the safety and efficacy of the CoCr-EES in routine clinical practice shortly after the launch of CoCr-EES in Japan. A total of 47 centers across Japan participated in the PMS. Patients were eligible for the study if ≥1 native coronary artery lesions were treated exclusively with CoCr-EES (XIENCE V or PROMUS) during the index percutaneous coronary intervention (PCI) procedure and written informed consent was obtained. We excluded those patients who were treated with stents other than CoCr-EES, or underwent concomitant treatment of a graft vessel. Patients were invited to enroll in the study after apparently successful PCI. The relevant review boards in all participating centers approved the study protocol.

Pre-procedural patient preparations were performed according to the health-care facility’s standard of care for interventional cardiology, and the treatment strategy was left to the discretion of the attending physicians and PCI operators. The sizes of CoCr-EES available for use were: 2.5, 2.75, 3.0 and 3.5 mm in diameter, and 8, 12, 15, 18, 23 and 28 mm in length. Use of multiple overlapping of stents was allowed, if necessary. Clinical data were collected and documented in an electronic case report form (Medidata, NY, USA) at the following time points: baseline, after the procedure, 8 months, 1 year, 2 years, and 3 years. Pre-specified clinical events such as death, myocardial infarction (MI), and target lesion/vessel revascularization were adjudicated by an independent clinical event committee consisting of 3 cardiologists (Junya Ako, Koji Todaka, and Takao Shimohama). Follow-up angiography was to be performed in all patients at 8 months after the study stent implantation. Qualitative and quantitative coronary angiography (QCA) was performed by an independent core laboratory (Cardiocore Japan, Tokyo, Japan) with QCA-CMS version 6.3 (Medis, Leiden, Netherlands). Although antiplatelet therapy was ultimately managed according to physician normal standard of care, enrolled patients were encouraged to receive adjunctive antiplatelet therapy consisting of an indefinite duration of aspirin, along with a required minimum of 6 months of thienopyridine.

Definitions

In this registry, definitions of coronary risk factors were decided in each participating hospital. All deaths were considered as cardiac death unless an unequivocal non-cardiac cause was established. Specifically, any unexpected death, even in patients with coexisting potentially fatal non-cardiac disease (eg, cancer, infection), was classified as a cardiac death. MI was defined as development of new, pathological Q waves on electrocardiogram, or elevation of creatinine kinase (CK) ≥2-fold the upper limit of normal with elevated CK-MB in the absence of new pathological Q waves. Target lesion revascularization (TLR) was defined as any repeat PCI of the target lesion or bypass surgery of the target vessel performed for restenosis or other complication of the target lesion. All TLR was classified prospectively as clinically indicated or non-clinically indicated by the physician prior to repeat angiography. The target lesion was defined as the treated segment from 5 mm proximal to the stent to 5 mm distal to the stent. Target vessel revascularization (TVR) was defined as any repeat percutaneous intervention or surgical bypass for any segment in the target vessel. Major adverse cardiac events (MACE) were defined as the composite of cardiac death, MI, and clinically driven TLR. Target lesion failure (TLF) and target vessel failure (TVF) were defined as the composite of cardiac death, target vessel MI, clinically driven TLR, and the composite of cardiac death, MI, and TVR, respectively. Stent thrombosis was defined as definite, probable, and possible according to the ARC definition.¹⁰ Revascularization was considered clinically indicated if: (1) in addition to an angiographic minimum lumen % diameter stenosis (DS) ≥50% on core laboratory QCA, the patient also presented with one of the following: positive history of recurrent angina pectoris, presumably related to the target vessel; objective signs of ischemia at rest or during exercise test, presumably related to the target vessel; abnormal results of any invasive functional diagnostic test; or (2) TLR or TVR was performed for a lesion with %DS ≥70% on core laboratory QCA even in the absence of the aforementioned ischemic signs or symptoms.

Statistical Analysis

Statistical analysis was performed using SAS (version 9.3; SAS Institute; Cary, NC, USA). For binary variables, counts, percentages, and 95% CI were calculated. Pearson chi-squared test or Fisher’s exact test was performed when appropriate. For continuous variables, mean±SD, and 95% CI for the mean were calculated. Cumulative event curves were estimated according to the Kaplan-Meier method. Finally, predictors for MACE were identified using multivariate stepwise cox regression, in which variables were entered into the model at the 0.2 significance level and removed at the 0.05 level (from the Wald chi-square statistic). Variables were eligible for inclusion in the multivariate model construction process if the variable was available in ≥90% of the subjects, and had a univariate P<0.2 (Table S1). If a given variable was highly correlated with other variables (r>0.5 and P<0.05), we selected the variable with the highest level of significance. Candidate predictors are listed in Tables 1–3. Two-tailed P<0.05 was considered significant.

Table 1. Patient Characteristics

	n=2,010	95% CI†
Age (years)	68.8±10.1	68.4–69.2
Male	76.1	74.1–77.9
BMI (kg/m2)	24.2±3.4	24.0–24.3
Current tobacco use	23.2	21.3–25.1
Hypertension	78.7	76.8–80.4
Dyslipidemia	67.5	65.4–69.5
Diabetes mellitus	41.9	39.7–44.1
Treated with insulin	9.1	7.9–10.4
Clinical presentation
Stable angina	45.4	43.1–47.7
Unstable angina	19.5	17.7–21.3
Acute MI	8.5	7.3–9.9
STEMI	5.8	4.8–7.0
Silent ischemia	20.3	18.5–22.2
Angiographic stenosis only	6.3	5.2–7.5
Prior CVA	9.9	8.6–11.4
Prior MI	28.6	26.5–30.6
Prior coronary intervention	50.2	48.0–52.5
Chronic renal dysfunction
eGFR 30–60 ml/min/1.73 m2	26.4	24.5–28.4
eGFR <30 ml/min/1.73 m2	16.0	14.4–17.7
Hemodialysis	4.9	4.0–5.9

Data given as mean±SD or %. ^†Normal approximation for continuous variables and Clopper-Pearson exact confidence interval for binary variables. BMI, body mass index; CVA, cerebrovascular accident; eGFR, estimated glomerular filtration rate; MI, myocardial infarction; STEMI, ST-segment elevation MI.

Table 2. Lesion and Procedural Characteristics

	n=2,010 patients n=2,649 lesions	95% CI†
Target vessel
LAD	48.0	46.1–49.9
LCX	18.3	16.9–19.8
RCA	30.2	28.4–32.0
LMCA	2.8	2.2–3.5
Graft	0.6	0.4–1.0
Lesion type
De novo	89.0	87.8–90.2
Restenosis	11.0	9.8–12.2
Access site
Femoral	37.2	35.1–39.4
Radial	53.4	51.2–55.6
Brachial	8.7	7.5–10.1
Other	0.7	0.4–1.2
No. target lesions	1.3±0.6	1.3–1.3
No. implanted stents
Per patient	1.5±0.8	1.5–1.6
Per lesion	1.2±0.5	1.2–1.2
Direct stenting	26.0	24.3–27.7
Post-dilatation	66.2	64.4–68.0

Data given as mean±SD or %. ^†Normal approximation for continuous variables and Clopper-Pearson exact confidence interval for binary variables. LAD, left anterior descending coronary artery; LCX, left circumflex coronary artery; LMCA, left main coronary artery; RCA, right coronary artery.

Table 3. Coronary Analysis by Core Laboratory

	n=1,848 lesions	95% CI†
Pre-treatment analysis
ACC/AHA lesion classification
A	5.4	4.4–6.6
B1	12.7	11.2–14.3
B2	43.3	41.1–45.6
C	38.6	36.3–40.8
Thrombus	2.9	2.2–3.8
Eccentric	69.6	67.4–71.7
Bend >90°	1.7	1.2–2.4
Severe or moderate tortuosity	14.9	13.3–16.6
Severe or moderate calcification	22.0	20.2–24.0
Bifurcation	44.9	42.6–47.2
Chronic total lesion	5.8	4.8–7.0
Ostial lesion	11.8	10.4–13.4
Lesion length (mm)	17.8±12.0	17.3–18.4
Reference vessel diameter (mm)	2.57±1.63	2.50–2.65
MLD (mm)	0.77±0.44	0.75–0.79
% DS (%)	69.6±15.4	68.9–70.3
Post-treatment analysis
In-stent MLD (mm)	2.54±0.50	2.52–2.56
In-stent % DS (%)	13.9±7.6	13.5–14.2
In-stent acute gain (mm)	1.77±0.54	1.74–1.79
In-segment acute gain (mm)	1.41±0.58	1.38–1.43
Follow-up analysis (8-month)
In-stent MLD (mm)	2.32±0.58	2.29–2.36
In-stent % DS (%)	17.6±13.1	16.9–18.3
In-stent late loss (mm)	0.22±0.44	0.20–0.24
In-segment late loss (mm)	0.13±0.54	0.10–0.16
In-stent binary restenosis rate	3.5	2.5–4.6
In-segment binary restenosis rate	6.7	5.4–8.2

Data given as mean±SD or %. ^†Normal approximation for continuous variables and Clopper-Pearson exact confidence interval for binary variables. DS, diameter stenosis; MLD, minimum lumen diameter.

Results

From March 2010 to June 2011, a total of 2,033 patients were consecutively enrolled at 47 sites in Japan (Table S2). We excluded 23 patients due to non-study stent implantation (n=10), study stent implantation only within a bypass graft (n=4), withdrawal of consent (n=4), or repeated enrollment (n=5). Thus, a total 2,010 patients (2,649 lesions) constituted the subject group (Figure 1).

Figure 1.

Patient selection.

Patient, lesion and procedural characteristics were typical of the PMS of DES in Japan (Tables 1,2). The average age was 68.8±10.1 years. The prevalence of diabetes was 41.9% and dialysis was 4.9%. Average reference vessel diameter was 2.57±1.36 mm, and lesion length was 17.8±12.0 mm. Prevalence of type B2/C lesion was 81.9%. An average of 1.3±0.6 lesions were treated with an average of 1.2±0.5 stents per lesion.

At 8 months, serial QCA was available in 1,848 lesions (69.8%). In-stent late loss was 0.22±0.44 mm, and in-stent binary restenosis rate was 3.5% (Table 3).

Three-year clinical follow up was available for 1,930 patients (96%). Dual antiplatelet therapy (DAPT) was continued in 84.6% of patients at 1 year, in 71.5% at 2 years and in 64.0% at 3 years. At 3 years, MACE occurred in 137 patients (6.8%; Table 4). Cumulative incidences of MACE and of clinically driven TLR were 7.1% and 4.4% at 3 years, respectively (Figure 2). Late clinically driven TLR was 0.8% from 1 to 2 years, and 0.5% from 2 to 3 years. Three-year clinically driven TLR rate in the complex lesion subsets was 4.3% in the bifurcation lesions, 7.6% in the chronic total occlusive lesions, 7.1% in in-stent restenosis lesions, 9.9% in the ostial lesions, 5.6% in the overlap stenting lesions, and 6.5% in the moderate or severe calcified lesions, respectively. Incidence of definite or probable stent thrombosis was 0.3% at 1 year without any further increase beyond 1 year and up to 3 years (Table 4). Within 3 years, 6 definite and 1 probable stent thrombosis occurred (Table 5). Significant independent multivariate predictors of MACE were hemodialysis, prior coronary intervention, 3-vessel disease, and age >70 years (Table 6).

Table 4. Clinical Outcomes (n=2,010)

	1 year (0–365 days)	2 years (0–730 days)	3 years (0–1,095 days)
Clinical outcomes
Death	2.3 (47)	3.9 (79)	5.4 (108)
Cardiac death	0.8 (17)	1.3 (27)	1.7 (34)
All MI	1.0 (20)	1.4 (29)	1.5 (30)
Target vessel MI	0.7 (15)	0.9 (19)	1.0 (20)
All TLR	3.6 (72)	4.6 (92)	5.2 (105)
Clinically driven TLR	2.9 (59)	3.7 (74)	4.2 (84)
All TVR	5.6 (113)	7.2 (145)	8.3 (166)
MACE	4.5 (90)	6.0 (121)	6.8 (137)
TLF	4.3 (86)	5.6 (112)	6.4 (128)
TVF	7.0 (141)	9.3 (186)	10.6 (213)
Stent thrombosis
Definite	0.3 (6)	0.3 (6)	0.3 (6)
Probable	0.0 (1)	0.0 (1)	0.0 (1)
Definite or probable	0.3 (7)	0.3 (7)	0.3 (7)
Possible	0.3 (6)	0.6 (12)	0.8 (16)
Definite/probable/possible	0.6 (13)	0.9 (19)	1.1 (23)

Data given as % (n). MACE, major adverse cardiac event; TLF, target lesion failure; TLR, target lesion revascularization; TVF, target vessel failure; TVR, target vessel revascularization. Other abbreviations as in Table 1.

Figure 2.

Kaplan-Meier curve for 3-year (A) major adverse cardiac events (MACE) and (B) clinically driven target lesion revascularization (CD-TLR).

Table 5. Definite or Probable Stent Thrombosis Patient Characteristics

	Patient ID no.
	1	2	3	4	5	6	7
Stent thrombosis	Definite	Definite	Probable	Definite	Definite	Definite	Definite
Days	35	1	6	68	1	188	9
DAPT	On	On	On	On	On	On	On
Age (years)	64	74	79	66	68	60	65
Gender	Male	Female	Female	Male	Male	Male	Male
Diabetes mellitus	No	No	No	No	Yes	No	No
Hemodialysis	No	No	No	No	No	No	No
Clinical presentation†	UAP	STEMI	STEMI	Silent ischemia	UAP	Silent ischemia	UAP
Treated vessel†	RCA	NA	NA	RCA	RCA	RCA	LAD
Calcification†	Moderate	NA	NA	Severe	None/Mild, None/Mild	Severe, Severe	None/Mild
Bifurcation†	No	NA	NA	No	No, No	No, No	Yes
In-stent restenosis†	No	NA	NA	Yes	No, No	Yes, Yes	No
Chronic total occlusion†	Yes	NA	NA	No	No, No	No, No	No
In-stent post %DS (%)†	20	NA	NA	2	9,11	9,9	28
Overlap stenting†	Yes	NA	NA	No, No	No, No	No, No	No

^†Analyzed by the independent core laboratory. DAPT, dual antiplatelet therapy; NA, not available; UAP, unstable angina pectoris. Other abbreviations as in Tables 1–3.

Table 6. Multivariate Predictors of 1,095-Day MACE

Variable	HR	95% CI	P-value
Dialysis dependent	5.42	3.46–8.49	<0.0001
Prior PCI	2.14	1.49–3.09	<0.0001
Three-vessel disease	2.09	1.38–3.16	0.0005
Age ≥70 years	1.45	1.02–2.04	0.0406

PCI, percutaneous coronary intervention. Other abbreviations as in Table 4.

Discussion

The major findings of the present study were: (1) CoCr-EES is safe and effective at 3 years in routine daily practice in this multicenter PMS in Japan; (2) binary restenosis rate was low with small late loss at 8 months, and this neointimal suppression was maintained up to 3 years; (3) very late definite or probable stent thrombosis was not observed beyond 1 year; (4) there was no concern about late catch-up phenomenon and late stent thrombosis following CoCr-EES implantation, even in this real world setting; and (5) hemodialysis was the strongest independent predictor of MACE.

Long-Term Safety and Efficacy of EES

The superiority of CoCr-EES compared with first-generation DES, other second-generation DES, and bare metal stents (BMS) has been reported in several meta-analyses.^3–6,11,12 In particular, low stent thrombosis rates were reported in several clinical and lesion subsets. In the EXAMINATION trial, significantly lower stent thrombosis rate as compared with BMS was reported even in patients with ST-segment elevation MI, who are known to have the highest thrombotic risk.^13,14 CoCr-EES was composed of a cobalt-chromium thin (81-μm) strut platform, thromboresistant 7.8-μm-thick fluroride and hexafluoropropylene polymer, and contained a low dose (1.0 μg/mm²) of everolimus. These characteristics all contribute to the high safety profile of CoCr-EES.¹⁵ The present results were obtained in a PMS enrolling consecutive patients with successful CoCr-EES implantation and, therefore, are representative of actual routine clinical practice. Under these circumstances, the definite and probable stent thrombosis rate in this study was 0.3% at 3 years, which is similar to the rates reported in other registries and from randomized trials evaluating CoCr-EES.^11,16–19 These results further confirmed the long-term safety of CoCr-EES. Furthermore, the long-term efficacy of EES was also confirmed in the present study. The late TLR rate following implantation of first-generation DES was reported to be approximately 2% per year in the previous Japanese studies.^2,20 The precise mechanism of this phenomenon is unknown, but delayed healing, persistent inflammation, and in-stent neoatherosclerosis might play important roles in delayed neointimal growth.^21,22 In this study, late TLR rate beyond 1 year was 0.5–0.8%/year, which is less than half that observed with the first-generation DES. The more biocompatible polymer and the lower drug dose may have contributed to this favorable outcome.

Predictors of MACE

Diabetes mellitus is a well-known risk factor for early, late TLR, and MACE following sirolimus-eluting stent (SES) implantation.^2,7,20 One possible mechanism contributing to this higher risk is the attenuation of the anti-proliferative effect of sirolimus under high glucose conditions.²³ In the present univariate analysis, diabetes with treatment (oral drug or insulin) was one of the significant predictors for 3-year MACE (Table S1), but diabetes did not remain in the multivariate analysis, even though everolimus belongs to the limus family of drugs.²⁴ For the subgroup analysis in the Randomized Evaluation of Sirolimus-eluting Versus Everolimus-eluting stent Trial (RESET), the cumulative incidence of TLR in patients with insulin-treated diabetes mellitus was significantly lower in the EES group than in the SES group (9.2% vs. 16.1%; P=0.045).¹⁸ Further studies need to be carried out to determine whether this favorable effect in diabetic patients after EES implantation is a chance finding or not. Interestingly, this observation did not extend to dialysis. Dialysis is a well-known predictor for MACE after coronary stenting.^2,8,25 Although only 4.9% of the patients were on dialysis, dialysis was the strongest predictor for MACE in the present study (Figure S1). Whereas clinically driven TLR rate was 2.5% at 1 year and 3.7% at 3 years in non-dialysis patients, it was 13.1% at 1 year and 18.4% at 3 years in dialysis patients. Similar results were also observed in the OUTCH-PRO study, which noted a relatively high TVR rate following EES implantation (17% at 1 year) in dialysis patients.²⁶ Thus, improved outcomes associated with EES use in non-dialysis patients cannot be generally extrapolated to dialysis patients. Although 1 randomized trial demonstrated superiority of EES compared with SES in dialysis patients,²⁷ careful follow-up is warranted in hemodialysis patients with coronary artery disease treated with EES.

DAPT

Prolonged use of DAPT was associated with significantly lower incidence of stent thrombosis and MACE in the DAPT study, but it was also associated with a trend for increasing mortality.^28,29 The prevalence of prolonged use of DAPT was high in this CoCr-EES PMS (71.5% at 2 years and 64.0% at 3 years) and no very late stent thrombosis was observed. Data on bleeding events, however, were not collected in the present study³⁰ and, thus, untoward effects of this prolonged use of DAPT cannot be determined. The advantages and disadvantages of prolonged DAPT following EES could not be evaluated in this study. Further study is warranted to determine the optimal DAPT duration after EES implantation in routine daily practice.

Study Limitations

This study is a single-arm registry. Therefore, direct comparison with other therapies is not possible. The study sample size was not sufficient to evaluate the incidence of stent thrombosis, although the rate of stent thrombosis (very late stent thrombosis in particular), was remarkably low in the present study. Additionally, important data such as implanted stent diameter, stent length, use of coronary imaging (intravascular ultrasound and optical coherence tomography), and bleeding events were not obtained. This is the first large-scale multicenter study, however, to report long-term outcomes of second-generation EES based on routine clinical practice in Japan.

Conclusions

Three-year clinical outcomes of the XIENCE V/PROMUS PMS demonstrated a low incidence of clinical events in routine clinical practice in Japan. There were no major concerns about very late stent thrombosis or late catch-up phenomenon at up to 3 years.

Acknowledgments

The authors thank the members of the cardiac catheterization laboratory and clinical research coordinators at the participating centers. XIENCE V/PROMUS PMS was sponsored and funded by Abbott Vascular (ClinicalTrials.gov ID: NCT01086228).

Disclosures

K.K. and K.T. receive remuneration from Abbott Vascular; H.K. is an employee of Abbott Vascular and has stocks of Abbott Vascular; H.N. is an employee of Abbott Vascular; and T.K. receives research and scholar funds from Abbott Vascular. The other authors declare no conflicts of interest.

Supplementary Files

Supplementary File 1

Table S1. Univariate predictors of 1,095-day MACE

Table S2. Participating hospitals

Figure S1. Kaplan-Meier curves for 3-year major adverse cardiac events (MACE) vs. presence of hemodialysis.

Please find supplementary file(s);

http://dx.doi.org/10.1253/circj.CJ-15-1181

References

• 1.    Daemen  J,  Wenaweser  P,  Tsuchida  K,  Abrecht  L,  Vaina  S,  Morger  C, et al. Early and late coronary stent thrombosis of sirolimus-eluting and paclitaxel-eluting stents in routine clinical practice: Data from a large two-institutional cohort study. Lancet 2007; 369: 667–678.
• 2.    Kimura  T,  Morimoto  T,  Nakagawa  Y,  Kawai  K,  Miyazaki  S,  Muramatsu  T, et al. Very late stent thrombosis and late target lesion revascularization after sirolimus-eluting stent implantation: Five-year outcome of the j-Cypher Registry. Circulation 2012; 125: 584–591.
• 3.    Palmerini  T,  Biondi-Zoccai  G,  Della Riva  D,  Stettler  C,  Sangiorgi  D,  D’Ascenzo  F, et al. Stent thrombosis with drug-eluting and bare-metal stents: Evidence from a comprehensive network meta-analysis. Lancet 2012; 379: 1393–1402.
• 4.    Baber  U,  Mehran  R,  Sharma  SK,  Brar  S,  Yu  J,  Suh  JW, et al. Impact of the everolimus-eluting stent on stent thrombosis: A meta-analysis of 13 randomized trials. J Am Coll Cardiol 2011; 58: 1569–1577.
• 5.    Navarese  EP,  Tandjung  K,  Claessen  B,  Andreotti  F,  Kowalewski  M,  Kandzari  DE, et al. Safety and efficacy outcomes of first and second generation durable polymer drug eluting stents and biodegradable polymer biolimus eluting stents in clinical practice: Comprehensive network meta-analysis. BMJ 2013; 347: f6530, doi:10.1136/bmj.f6530.
• 6.    Navarese  EP,  Kowalewski  M,  Kandzari  D,  Lansky  A,  Gorny  B,  Koltowski  L, et al. First-generation versus second-generation drug-eluting stents in current clinical practice: Updated evidence from a comprehensive meta-analysis of randomised clinical trials comprising 31 379 patients. Open Heart 2014; 1: e000064, doi:10.1136/openhrt-2014-000064.
• 7.    Ikari  Y,  Kotani  J,  Kozuma  K,  Kyo  E,  Nakamura  M,  Yokoi  H; J-PMS study group. Assessment of sirolimus-eluting coronary stent implantation with aspirin plus low dose ticlopidine administration: One year results from CYPHER Stent Japan Post-Marketing Surveillance Registry (J-PMS). Circ J 2009; 73: 1038–1044.
• 8.    Kotani  J,  Ikari  Y,  Kyo  E,  Nakamura  M,  Yokoi  H,  Furuno  K, et al. Five-year outcomes of Cypher coronary stent: Report from J-PMS study. Cardiovasc Interv Ther 2012; 27: 63–71.
• 9.    Nakamura  M,  Kotani  J,  Kozuma  K,  Uchida  T,  Iwabuchi  M,  Muramatsu  T, et al. Effectiveness of paclitaxel-eluting stents in complex clinical patients: Insights from the TAXUS Japan Postmarket surveillance study. Circ J 2011; 75: 2573–2580.
• 10.    Cutlip  DE,  Windecker  S,  Mehran  R,  Boam  A,  Cohen  DJ,  van Es  GA, et al. Clinical end points in coronary stent trials: A case for standardized definitions. Circulation 2007; 115: 2344–2351.
• 11.    Dangas  GD,  Serruys  PW,  Kereiakes  DJ,  Hermiller  J,  Rizvi  A,  Newman  W, et al. Meta-analysis of everolimus-eluting versus paclitaxel-eluting stents in coronary artery disease: Final 3-year results of the SPIRIT clinical trials program (Clinical Evaluation of the Xience V Everolimus Eluting Coronary Stent System in the Treatment of Patients with De Novo Native Coronary Artery Lesions). JACC Cardiovasc Interv 2013; 6: 914–922.
• 12.    Raber  L,  Magro  M,  Stefanini  GG,  Kalesan  B,  van Domburg  RT,  Onuma  Y, et al. Very late coronary stent thrombosis of a newer-generation everolimus-eluting stent compared with early-generation drug-eluting stents: A prospective cohort study. Circulation 2012; 125: 1110–1121.
• 13.    Sabate  M,  Cequier  A,  Iniguez  A,  Serra  A,  Hernandez-Antolin  R,  Mainar  V, et al. Everolimus-eluting stent versus bare-metal stent in ST-segment elevation myocardial infarction (examination): 1 year results of a randomised controlled trial. Lancet 2012; 380: 1482–1490.
• 14.    Kozuma  K,  Kimura  T,  Kadota  K,  Suwa  S,  Kimura  K,  Iwabuchi  M, et al. Angiographic findings of everolimus-eluting as compared to sirolimus-eluting stents: Angiographic sub-study from the randomized evaluation of sirolimus-eluting versus everolimus-eluting stent trial (RESET). Cardiovasc Interv Ther 2013; 28: 344–351.
• 15.    Otsuka  F,  Vorpahl  M,  Nakano  M,  Foerst  J,  Newell  JB,  Sakakura  K, et al. Pathology of second-generation everolimus-eluting stents versus first-generation sirolimus- and paclitaxel-eluting stents in humans. Circulation 2014; 129: 211–223.
• 16.    Lee  JM,  Park  KW,  Han  JK,  Yang  HM,  Kang  HJ,  Koo  BK, et al. Three-year patient-related and stent-related outcomes of second-generation everolimus-eluting Xience V stents versus zotarolimus-eluting resolute stents in real-world practice (from the Multicenter Prospective EXCELLENT and RESOLUTE-Korea Registries). Am J Cardiol 2014; 114: 1329–1338.
• 17.    Seth  A,  Patel  TM,  Stuteville  M,  Kumar  R,  Mullasari  AS,  Kaul  U, et al. Three-year data from the XIENCE V INDIA study: Safety and efficacy of XIENCE V in 1000 real world Indian patients. Indian Heart J 2014; 66: 302–308.
• 18.    Shiomi  H,  Kozuma  K,  Morimoto  T,  Igarashi  K,  Kadota  K,  Tanabe  K, et al. Long-term clinical outcomes after everolimus- and sirolimus-eluting coronary stent implantation: Final 3-year follow-up of the randomized evaluation of sirolimus-eluting versus everolimus-eluting stent trial. Circulation Cardiovasc Interv 2014; 7: 343–354.
• 19.    Jensen  LO,  Thayssen  P,  Maeng  M,  Christiansen  EH,  Ravkilde  J,  Hansen  KN, et al. Three-year outcomes after revascularization with everolimus- and sirolimus-eluting stents from the SORT OUT IV trial. JACC Cardiovasc Interv 2014; 7: 840–848.
• 20.    Hara  H,  Aoki  J,  Tanabe  K,  Tanimoto  S,  Nakajima  Y,  Yahagi  K, et al. Incidence and predictors for late target lesion revascularization after sirolimus-eluting stent implantation. Circ J 2013; 77: 988–994.
• 21.    Joner  M,  Nakazawa  G,  Finn  AV,  Quee  SC,  Coleman  L,  Acampado  E, et al. Endothelial cell recovery between comparator polymer-based drug-eluting stents. J Am Coll Cardiol 2008; 52: 333–342.
• 22.    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: 2051–2057.
• 23.    Patterson  C,  Mapera  S,  Li  HH,  Madamanchi  N,  Hilliard  E,  Lineberger  R, et al. Comparative effects of paclitaxel and rapamycin on smooth muscle migration and survival: Role of AKT-dependent signaling. Arterioscler Thromb Vasc Biol 2006; 26: 1473–1480.
• 24.    Iwasaki  M,  Otake  H,  Shinke  T,  Nakagawa  M,  Hariki  H,  Osue  T, et al. Vascular responses in patients with and without diabetes mellitus after everolimus-eluting stent implantation: Optical coherence tomography study. Circ J 2014; 78: 2188–2196.
• 25.    Buronova  N,  Kamishima  K,  Yamaguchi  J,  Jujo  K,  Watanabe  E,  Inagaki  Y, et al. Effect of hemodialysis on 7-year clinical outcomes after sirolimus-eluting stent implantation. Circ J 2015; 79: 2169–2176.
• 26.    Ikari  Y,  Kyono  H,  Isshiki  T,  Ishizuka  S,  Nasu  K,  Sano  K, et al. Usefulness of everolimus-eluting coronary stent implantation in patients on maintenance hemodialysis. Am J Cardiol 2015; 116: 872–876.
• 27.    Sakakibara  T,  Ishii  H,  Toriyama  T,  Aoyama  T,  Takahashi  H,  Kamoi  D, et al. Sirolimus-eluting stent vs. everolimus-eluting stent for coronary intervention in patients on chronic hemodialysis. Circ J 2012; 76: 351–355.
• 28.    Mauri  L,  Yeh  RW,  Kereiakes  DJ. Duration of dual antiplatelet therapy after drug-eluting stents. N Engl J Med 2015; 372: 1373–1374.
• 29.    Palmerini  T,  Benedetto  U,  Bacchi-Reggiani  L,  Riva  DD,  Biondi-Zoccai  G,  Feres  F, et al. Mortality in patients treated with extended duration dual antiplatelet therapy after drug-eluting stent implantation: A pairwise and Bayesian network meta-analysis of randomised trials. Lancet 2015; 385: 2371–2382.
• 30.    Mehran  R,  Rao  SV,  Bhatt  DL,  Gibson  CM,  Caixeta  A,  Eikelboom  J, et al. Standardized bleeding definitions for cardiovascular clinical trials: A consensus report from the Bleeding Academic Research Consortium. Circulation 2011; 123: 2736–2747.