Vascular Response to Drug-Eluting Stent With Biodegradable vs. Durable Polymer

– Optical Coherence Tomography Substudy of the NEXT –

Abstract

Background: The aim of the present study was to compare vascular healing response between everolimus-eluting stent (EES) and biolimus-eluting stent (BES) using optical coherence tomography (OCT).

Methods and Results: In the NOBORI Biolimus-Eluting Versus XIENCE V/PROMUS Everolimus-Eluting Stent Trial (NEXT), a formal OCT substudy investigated 91 patients (55 EES-treated lesions in 48 patients and 51 BES-treated lesions in 43 patients) with 8–12 months follow-up imaging at 18 centers. A total of 980 frames with 8,996 struts in EES and 907 frames with 8,745 struts in BES were analyzed. Mean neointima thickness in EES and BES was 105±82μm and 91±80μm, respectively (P<0.001). With regard to stent-treated lesions, the percentage of struts not covered by neointima (3±7% vs. 9±10%, P<0.001) and the frequency of stent-treated lesions with any uncovered struts (n=28, 51% vs. n=42, 82%; P<0.001) were significantly lower in EES compared with BES. In addition, the percentage of malapposed struts (0.2±0.8% vs. 1.3±2.8%, P=0.006) and the frequency of stent-treated lesions with any malapposed struts (n=6, 11% vs. n=14, 27%; P=0.028) were significantly lower in EES compared with BES.

Conclusions: Incomplete vascular healing characterized by the presence of struts not covered by neointima and malapposed struts was less common in EES compared with BES. (Circ J 2014; 78: 2408–2414)

Compared with bare-metal stents (BMS), first-generation drug-eluting stents (DES) dramatically reduced the incidence of restenosis after percutaneous coronary intervention (PCI). Reintervention rates, however, were still high in patients with complex coronary artery disease, and late stent thrombosis emerged as a major safety concern with these stents. Recently, second-generation DES have been developed to improve safety, efficacy, and device performance. The XIENCE V (Abbot Vascular, Santa Clara, CA, USA)/PROMUS (Boston Scientific, Natick, MA, USA) everolimus-eluting stent (EES) is a cobalt chromium alloy stent with thin struts (81 μm), which is coated with a thin, non-adhesive, durable, biocompatible fluorinated copolymer releasing everolimus. Several clinical trials have demonstrated that EES is associated with a markedly lower risk for in-stent restenosis and thrombosis as compared to both BMS and first-generation DES, indicating that EES should be regarded as the current standard for DES-vs.-DES trials.^1–3 The NOBORI biolimus-eluting stent (BES; Terumo, Tokyo, Japan) is a stainless steel alloy stent with relatively thick struts (125 μm) using an abluminally coated biodegradable polymer (polylactic acid) eluting biolimus A9, a highly lipophilic analogue of sirolimus. Whether the efficacy and safety of biodegradable polymer BES are similar to those of durable polymer EES has not been fully investigated. Although DES reduce in-stent restenosis, excessive inhibition of neointimal hyperplasia may induce incomplete endothelialization of the stent and be associated with the potential development of very late stent thrombosis.⁴ Intravascular optical coherence tomography (OCT) is a high-resolution imaging modality that has the unique capability of assessing clinically important coronary microstructures, including thin-layer neointimal tissue and malapposition of stent struts.⁵ A recent clinical study showed that the OCT evidence of uncovered struts and late stent malapposition was associated with very late DES thrombosis.⁶ The aim of the present study was to compare vascular response after stent implantation between EES and BES using OCT.

Editorial p 2376

Methods

Subjects

This is a pre-specified substudy of the NOBORI Biolimus-Eluting Versus XIENCE V/PROMUS Everolimus-Eluting Stent Trial (NEXT). The NEXT is a prospective, multicenter, randomized, assessor-blind, non-inferiority trial comparing EES with BES in Japan. Details of the study protocol have been reported.⁷ Between May and October 2011, 3,241 patients were enrolled in the NEXT without any exclusion criteria and randomly assigned to undergo PCI with either EES or BES. Randomization was done using a Web-based allocation system and was stratified by center, diabetic status, and participation in the imaging substudies (angiography, intravascular ultrasound, OCT, and coronary endothelial function). The OCT sites (n=18 centers) were preselected based on their willingness to participate in the present substudy. The primary endpoint in the present OCT substudy was percentage of uncovered struts at 8–12 months after stent implantation. At study initiation, we did not know the estimated percentage of uncovered struts necessary to determine the sample size. Therefore, all patients enrolled in the OCT sites were candidates for the present substudy. The exclusion criteria for follow-up OCT were as follows: (1) apparent congestive heart failure; (2) renal insufficiency (serum creatinine >2.0 mg/dl); and (3) lesions unsuitable for OCT imaging (left main coronary artery lesions, ostial right coronary artery lesions, excessively tortuous vessel, and vessel size >4.0 mm). As a result, 121 patients were assigned to the OCT substudy for follow-up OCT at 8–12 months after the index PCI procedure. The study was approved by the institutional review board or medical ethics committee at each participating center, and all patients gave written informed consent. The trial was registered with http://www.clinicaltrials.gov, unique identifier NCT01303640.

Coronary Angiography

Angiograms before the procedure, immediately after the procedure, and at 8–12 months follow-up were evaluated at a single angiographic core laboratory (Cardiocore, Tokyo, Japan) with use of CAAS 5.9 (Pie Medical Imaging, Maastricht, The Netherlands). The reference lumen diameter, minimum lumen diameter, percent diameter stenosis [(1−minimum lumen diameter/reference lumen diameter)×100], acute gain (minimum lumen diameter immediately after the index procedure-minimum lumen diameter before the index procedure), and in-stent late lumen loss (minimum lumen diameter immediately after the index procedure-minimum lumen diameter at follow-up) were calculated. In-stent binary restenosis was defined as diameter stenosis >50% at follow-up angiography.

OCT Acquisition

A time-domain (TD)-OCT system (Model M2 Cardiology Imaging System, St. Jude Medical, St. Paul, MN, USA) or frequency-domain (FD)-OCT imaging system (C7-XRTM, St. Jude Medical) was used in the present study. TD-OCT image acquisition was as follows. After a Z-offset adjustment, a 0.016-in. ImageWire^TM (St. Jude Medical) was advanced to the distal end of the stent-treated lesion through a 3-F occlusion balloon catheter (Helious; Goodman, Nagoya, Japan). To remove the blood from the field of view, the occlusion balloon was inflated at 0.4–0.6 atm at the proximal site of the stent-treated lesion, and lactated Ringer’s solution was infused into the coronary artery from the distal tip of the occlusion balloon catheter at 0.5 ml/s. The entire stent-treated lesion was imaged with an automatic pullback device traveling at 1 mm/s. FD-OCT image acquisition was as follows. After a Z-offset adjustment, a Dragonfly^TM imaging catheter (St. Jude Medical) was advanced distally to the stent-treated lesion over a 0.014-in. conventional angioplasty guidewire. After the catheter placement, preheated contrast media at 37°C was flushed through the guiding catheter at a rate of 2–4 ml/s for approximately 3–6 s using an injector pump. When a blood-free image was observed, the FD-OCT imaging core was withdrawn up to 50 mm at a rate of 20 mm/s using an automatic pullback device. The OCT images were digitally stored and submitted to the core laboratory (Wakayama Medical University, Wakayama, Japan) for offline analysis.

OCT Analysis

OCT image analysis was performed using a dedicated off-line review system with semi-automated contour-detection software (St. Jude Medical). All cross-sectional images (frames) were initially screened for quality assessment. Frames with inadequate images including residual blood, sew-up artifacts, reverberation, and out-of-screen of any portion of the stent caused by imaging wire bias were excluded from analysis. Frames with bifurcations of side branches and stent overlapping segments were also excluded because of difficulty with assessing lumen border and stent strut conditions.⁸ Qualitative OCT analysis was performed at every frame to detect intra-stent thrombus. Intra-stent thrombus was identified as a mass protruding into the lumen with significant attenuation behind the mass.⁹ After calibration adjustment, quantitative OCT analysis was performed at intervals of 1 mm in the stent-treated lesion. Neointimal coverage was assessed on each individual strut. If neointimal coverage was observed, its thickness was measured from the lumen border to the center of the strut blooming. The proportion of frames with >30% uncovered struts was calculated in each stent-treated lesion.^4,8 The maximum length of segment with uncovered struts was estimated as the number of consecutive frames with uncovered struts. A malapposed strut was defined as a strut with a distance between the center of the strut blooming and the adjacent lumen border ≥110 μm in EES and ≥160 μm in BES. This criterion was determined by adding the actual strut thickness and polymer thickness to the OCT resolution limit (EES: 81 μm+7.8 μm+20 μm=108.8 μm; BES: 125 μm+5 μm [non-absorbable polymer: Parylene C]+3 μm [absorbable polymer thickness at 8–12 months]+20 μm=153 μm). Intraobserver and interobserver variability for strut apposition was assessed in 30 randomly selected struts and showed excellent concordance (κ=0.93 and κ=0.86, respectively). The maximum length of segment with stent malapposition was estimated as the number of consecutive frames with malapposed struts. Each stent strut condition was classified into 1 of 4 categories: 1, well-apposed to the vessel wall with neointimal coverage over the strut; 2, well-apposed to the vessel wall without neointimal coverage; 3, malapposed to the vessel wall with neointimal coverage; and 4, malapposed to the vessel wall without neointimal coverage.¹⁰ Cross-sectional areas of stent, lumen (defined as intra-stent lumen plus extra-stent lumen), neointima (defined as stent minus intra-stent lumen), and malapposition (defined as extra-stent lumen) were also measured at intervals of 1 mm; volumes were calculated using Simpson’s rule. Reproducibility of neointima volume measurement was assessed in 30 randomly selected stent-treated lesions. There was good correlation for repeated measurements by the same observer (r=0.996) and by 2 different observers (r=0.995).

Statistical Analysis

Statistical analysis was performed using Statview 5.0.1 (SAS Institute, Cary, NC, USA). Categorical variables are presented as frequencies, with comparison using chi-squared statistics or Fisher exact test (if there was an expected cell value <5). Continuous variables are presented as mean±SD and were compared using unpaired Student’s t-test. P<0.05 was considered statistically significant.

Results

Patient Characteristics

Of 121 patients enrolled in the OCT substudy of NEXT, 28 patients who withdrew consent for follow-up OCT and 2 patients without OCT image storage were excluded from the analysis. Thus, 91 patients who were treated with EES (55 EES-treated lesions in 48 patients) or BES (51 BES-treated lesions in 43 patients) constituted the final study group. Between the studied and excluded patients, there were no significant differences in baseline clinical characteristics except for age (67±9 years vs. 71±9 years, P=0.027), angiographic findings, procedure characteristics and clinical outcomes. Baseline clinical characteristics in the final study group are listed in Table 1. Although age and gender were different between EES and BES, risk factors and clinical presentation at stenting were similar between the 2 stent types. The mean follow-up time was 10±2 months in either stent type. Aspirin and thienopyridines were continued throughout follow-up for all patients.

Table 1. Patient Characteristics

	EES	BES	P-value
No. patients	48	43
Age (years)	65±9	69±8	0.015
Gender, male	41 (85)	29 (67)	0.042
Coronary risk factors
Hypertension	43 (90)	36 (84)	0.409
Dyslipidemia	40 (83)	35 (81)	0.808
Diabetes mellitus	21 (44)	16 (37)	0.526
Current smoker	31 (65)	22 (51)	0.195
Hemodialysis	1 (2)	2 (5)	0.600
Prior myocardial infarction	12 (25)	15 (35)	0.303
Prior PCI	21 (44)	21 (49)	0.627
Clinical presentation at stenting			0.742
Stable CAD	40 (83)	38 (88)
Unstable angina	7 (15)	4 (9)
Acute myocardial infarction	1 (2)	1 (2)
Medications at follow-up
Aspirin	48 (100)	43 (100)	1.000
Thienopyridine	48 (100)	43 (100)	1.000
ACEI/ARB	31 (65)	28 (65)	0.958
β-blocker	16 (33)	19 (44)	0.288
Statin	37 (77)	36 (79)	0.427
Insulin	6 (13)	3 (7)	0.378

Data given as n (%) or mean±SD. ACEI, angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker; BES, biolimus-eluting stent; CAD, coronary artery disease; EES, everolimus-eluting stent; PCI, percutaneous coronary intervention.

Angiography

Angiographic findings and procedural characteristics are shown in Table 2. Quantitative angiographic measurements before index procedures, stent profiles, and procedural characteristics were similar between EES and BES. Although minimum lumen diameter at follow-up (2.36±0.48 mm vs. 2.57±0.52 mm, P=0.034) was smaller in EES compared with BES, percent diameter stenosis at follow-up (12±11% vs. 11±9%, P=0.712) and late lumen loss (0.16±0.35 mm vs. 0.09±0.26 mm, P=0.298) were not different between the 2 stent types. In-stent binary restenosis appeared in 3 EES-treated lesions (5%) and 3 BES-treated lesions (6%; P=0.999), which received target lesion revascularization.

Table 2. Angiographic Findings and Procedural Characteristics

	EES	BES	P-value
No. stent-treated lesions	55	51
Before index procedure
Target imaging vessels			0.538
LAD	23 (42)	26 (51)
LCX	14 (25)	9 (18)
RCA	18 (33)	16 (31)
Reference lumen diameter (mm)	2.55±0.56	2.76±0.57	0.053
Minimum lumen diameter (mm)	0.76±0.42	0.89±0.43	0.142
Percent diameter stenosis (%)	71±15	68±14	0.373
Chronic total occlusion	0 (0)	1 (2)	0.481
In-stent restenosis	4 (7)	5 (10)	0.735
Bifurcation	21 (38)	18 (35)	0.758
Moderate or heavy calcification	5 (9)	8 (16)	0.301
Procedural characteristics
No. stent/lesion			0.323
1	48 (87)	48 (94)
>2	7 (13)	3 (6)
Stent diameter (mm)	3.1±0.4	3.2±0.3	0.192
Total stent length/lesion (mm)	21±10	20±8	0.565
Post-dilatation	36 (65)	33 (65)	0.936
Kissing balloon dilatation	3 (5)	1 (2)	0.619
Maximum inflation pressure, atm	12±4	12±4	0.541
After index procedure
Minimum lumen diameter (mm)	2.52±0.40	2.66±0.46	0.088
Percent diameter stenosis (%)	7±7	9±6	0.162
Acute gain (mm)	1.76±0.45	1.78±0.48	0.809
Follow-up
Minimum lumen diameter (mm)	2.36±0.48	2.57±0.52	0.034
Percent diameter stenosis (%)	12±11	11±9	0.712
Late lumen loss (mm)	0.16±0.35	0.09±0.26	0.298

Data given as % or mean±SD. LAD, left anterior descending coronary artery; LCX, left circumflex coronary artery; RCA, right coronary artery. Other abbreviations as in Table 1.

OCT

The rates of TD-OCT and FD-OCT use were similar between EES (64% and 36%) and BES (63% and 37%). Of all recorded frames in the stent-treated lesion, 4% in EES and 5% in BES were excluded from analysis due to inadequate image, bifurcation, or stent overlapping segments. A total of 980 frames with 8,996 struts in EES and 907 frames with 8,745 struts in BES were analyzed. OCT analysis results are summarized in Table 3. With regard to stent struts, >90% of struts in both EES and BES were covered by neointima. Mean neointima thickness in EES and BES was 105±82 μm and 91±80 μm, respectively (P<0.001; Figure 1). With regard to stent-treated lesions, the percentage of uncovered struts (3±7% vs. 9±10%, P<0.001) and the frequency of stent-treated lesions with any uncovered struts (n=28, 51% vs. n=42, 82%; P<0.001) were significantly lower in EES compared with BES. Although the percentage of frames with >30% uncovered struts was not different between the 2 stent types (4±10% vs. 6±11%, P=0.375), the maximum length of segment with uncovered struts was significantly shorter in EES compared with BES (1.0±1.4 mm vs. 3.1±3.2 mm, P<0.001). The percentage of malapposed struts (0.2±0.8% vs. 1.3±2.8%, P=0.006) and the frequency of stent-treated lesion with any malapposed struts (n=6, 11% vs. n=14, 27%; P=0.028) were significantly lower in EES compared with BES. The maximum length of segment with malapposed struts was significantly shorter in EES compared with BES (0.1±0.3 mm vs. 0.3±0.5 mm, P=0.030). The frequency of intra-stent thrombus was not different between EES and BES (n=2, 4% vs. n=5, 10%; P=0.258). There were no significant differences in morphometric analysis including area and volume of lumen, stent, neointima, and stent malapposition between EES and BES. Representative OCT images of EES and BES are shown in Figure 2.

Table 3. OCT Findings at 8–12-Month Follow-up

	EES	BES	P-value
Stent struts
No. struts	8,996	8,745
Well-apposed and covered struts	8,762 (97.4)	7,920 (90.6)	<0.001
Well-apposed and uncovered struts	217 (2.4)	712 (8.1)	<0.001
Malapposed and covered struts	2 (0.02)	25 (0.3)	<0.001
Malapposed and uncovered struts	15 (0.2)	88 (1.0)	<0.001
Stent-treated lesions
No. stent-treated lesions	55	51
Neointimal coverage over stent struts
Uncovered struts (%)	3±7	9±10	<0.001
Lesions with any uncovered struts	28 (51)	42 (82)	<0.001
Frames with >30% uncovered struts (%)	4±10	6±11	0.375
Maximum length of segments with uncovered struts (mm)	1.0±1.4	3.1±3.2	<0.001
Stent malapposition
Malapposed struts (%)	0.2±0.8	1.3±2.8	0.006
Lesions with any malapposed struts	6 (11)	14 (27)	0.028
Maximum length of segments with stent malapposition (mm)	0.1±0.3	0.3±0.5	0.030
Intra-stent thrombus	2 (4)	5 (10)	0.258
Morphometry
Minimum lumen area (mm2)	5.20±2.19	5.69±2.05	0.242
Minimum stent area (mm2)	6.13±2.24	6.41±2.20	0.515
Maximum neointima area (mm2)	1.56±0.66	1.31±0.75	0.069
Maximum stent malapposition area (mm2)	0.16±0.60	0.30±0.69	0.275
Lumen volume (mm3)	108.07±53.74	115.96±40.50	0.398
Stent volume (mm3)	123.54±61.05	128.47±46.44	0.643
Neointima volume (mm3)	15.79±11.54	13.09±12.58	0.253
Stent malapposition volume (mm3)	0.31±1.28	0.58±1.57	0.336

Data given as n (%) or mean±SD. OCT, optical coherence tomography. Other abbreviations as in Table 1.

Figure 1.

Neointima thickness at intervals of 50 μm. In biolimus-eluting stent, the percentage of stent struts with a neointima thickness of 0, 10–50, 60–100, 110–150, 160–200, 210–250, 260–300, and ≥310 μm was 8%, 32%, 31%, 13%, 7%, 4%, 3%, and 2%, respectively. That for everolimus-eluting stent was 2%, 26%, 34%, 18%, 9%, 5%, 2%, and 3%, respectively.

Figure 2.

Representative optical coherence tomography of stent struts at 8–12 months follow-up with (A,D) neointimal coverage, (B,E) stent malapposition, and (C,F) intra-stent thrombus in everolimus-eluting stent and biolimus-eluting stent.

Discussion

At 8–12 months after DES implantation, (1) both EES and BES provided excellent suppression of neointimal growth; and (2) stent struts not covered by neointima and malapposed struts were significantly less frequently observed in EES compared with BES. The present results suggest that the vascular healing response is different between EES and BES.

EES with a thin strut and biocompatible durable polymer is a second-generation DES designed to overcome the limitations of first-generation DES. Several clinical studies have compared the efficacy and safety between EES and first-generation DES. Previously, 2 randomized trials reported lower binary restenosis rates for EES in comparison with first-generation sirolimus-eluting stent (SES).^11,12 In a recent observational study comparing EES with SES, EES was associated with marked reduction of stent thrombosis.¹³ OCT studies have also reported favorable vascular healing response after EES implantation. In a 9 months follow-up OCT study, EES had a significantly lower incidence of uncovered stent struts per stent-treated lesion (4±5% vs. 11±13%, P=0.016) and intra-stent thrombus than SES (5% vs. 34%, P=0.001).¹⁴ At present, EES is the most extensively studied and most widely used second-generation DES.

Nobori-BES is a novel DES, incorporating a biolimus A9-eluting biodegradable polymer coated only on the abluminal surface of the stent. These unique features of BES have been developed to address the risk of thrombosis associated with first-generation DES. The LEADERS trial showed that BES was non-inferior to SES for the composite endpoint of cardiac death, myocardial infarction, or clinically indicated target vessel revascularization at 9 months after stent implantation (9% vs. 11%, rate ratio 0.88; 95% confidence interval [95% CI]: 0.64–1.19; P for non-inferiority=0.003, P for superiority=0.39).¹⁵ In the OCT substudy of the LEADERS trial, neointimal coverage of stent was better in BES than SES (weighted difference, –1.4%; 95% CI: –3.7 to 0.0, P=0.04).¹⁶ BES with biodegradable polymer appears to be more safe and effective as compared to first-generation DES with durable polymer.

The relative safety and efficacy of EES and BES have been incompletely characterized. We designed a large-scale randomized trial termed NEXT for comparing BES with EES, powered to evaluate non-inferiority in terms of efficacy outcomes.⁷ NEXT demonstrated that the rate of target lesion revascularization at 1 year was not different between the 2 stent types, but this trial was not sized sufficiently to identify potential differences in low frequency endpoints such as stent thrombosis. Recently, OCT assessment of neointimal coverage has emerged as a useful surrogate for risk stratification of very late DES thrombosis.⁶ An investigative OCT study at 6–8 months after stent implantation showed similar neointimal coverage between EES and BES,¹⁷ but the present 8–12-month follow-up OCT substudy of NEXT found better neointimal coverage in EES compared with BES. This favorable vascular healing in EES might be due to several factors. The polymer composed of vinylidene fluoride and hexafluoropylene is biocompatible and induces less inflammatory reactions.¹⁸ Thin stent struts are advantageous in achieving more rapid vascular healing after DES implantation.^18,19 In addition, the flexible stent design contributes to a more adequate apposition to the vessel wall, which may help promote early neointimal coverage.⁸ Recently, a network meta-analysis from 89 trials including 85,490 patients found that EES was associated with lower rates of 1-year and long-term definite stent thrombosis in comparison with BES.²⁰ The consistency between these large-scale clinical data and the present OCT results may support the speculation that careful investigation of vascular healing with neointimal coverage may provide valuable information for understanding the risk of stent thrombosis.

In addition to incomplete neointimal coverage of stent, neointimal atherosclerotic change (neoatherosclerosis) is considered to be an important contributing factor to very late (>1-year) stent thrombosis. Pathological studies have reported that the polymer of DES induced vessel wall inflammation and accelerated neoatherosclerosis. Although biodegradable polymer used in Nobori-BES is persistent (approximately 10%) at 8–12 months after stent implantation, it is resorbed completely after 1 year. Therefore, the development of neoatherosclerosis may be different between EES and BES. Long-term OCT follow-up over 1 year is needed to confirm the very late benefits of biodegradable polymer in BES.

Study Limitations

There are several limitations in the present study. First, the patient groups were highly selected, and there was age and gender bias. Nonetheless, important variables that could exert a strong influence on vascular healing after stenting, such as coronary risk factors, and stent, lesion and procedural characteristics, were not different between the 2 groups. Second, OCT data before and immediately after stent implantation were not available. Therefore, it was unclear whether the stent malapposition and intra-stent thrombus were persistent or newly acquired. Third, the present study was not powered or designed to assess the relationship between OCT suboptimal stent results and future development of stent thrombosis. Further studies are required to investigate the clinical implications of these OCT findings at 8–12 months after DES implantation. Fourth, current OCT systems cannot detect <10-μm tissue coverage over the stent struts. Endothelial cell dimensions are below the resolution of even OCT, and it is possible that some struts appearing bare were covered by endothelium, and thus misclassified. Fifth, OCT cannot differentiate very small amounts of fibrin deposition or inflammatory cellular response from underlying neointimal hyperplasia. Future developments in OCT technology are necessary to allow tissue characterization. Finally, the present study used either conventional TD-OCT or recently developed FD-OCT, but it is unlikely that assessment of neointimal coverage and its thickness would be affected.

Conclusions

At 8–12 months after stent implantation OCT showed that incomplete vascular healing, characterized by the presence of stent struts not covered by neointima, and malapposed struts, was less common in EES compared with BES.

Disclosures

Funding Sources: Terumo is a study sponsor of the NEXT trial. Conflict of Interest: Dr Kozuma has served on the advisory boards of Terumo and Abbott Vascular, and has received lecture fees from Terumo and Abbott Vascular. Dr Kadota has received honoraria from Terumo and Abbott Vascular, and has served on the advisory boards of Abbott Vascular. Dr Tanabe served on the advisory board of Terumo and Abbott Vascular. Dr Morino has served on the advisory board of Terumo and Abbott Vascular. Dr T. Kimura has served on the advisory board of Terumo and Abbott Vascular. All other authors report that they have no relationships relevant to the contents of this paper to disclose.

References

• 1.    Stone  GW,  Rizvi  A,  Sudhir  K,  Newman  W,  Applegate  RJ,  Cannon  LA, 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: 19–25.
• 2.    Kimura  T,  Morimoto  T,  Natsuaki  M,  Shiomi  H,  Igarashi  K,  Kadota  K, et al. Comparison of everolimus-eluting and sirolimus-eluting coronary stents: 1-year outcomes from the Randomized Evaluation of Sirolimus-eluting Versus Everolimus-eluting stent Trial (RESET). Circulation 2012; 126: 1225–1236.
• 3.    Wiemer  M,  Serruys  PW,  Miquel-Hebert  K,  Neumann  FJ,  Piek  JJ,  Grube  E, et al. 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 lesions: The SPIRIT FIRST trial. Catheter Cardiovasc Interv 2010; 75: 997–1003.
• 4.    Finn  AV,  Joner  M,  Nakazawa  G,  Kolodgie  F,  Newell  J,  John  MC, et al. Pathological correlates of late drug-eluting stent thrombosis: Strut coverage as a marker of endothelialization. Circulation 2007; 115: 2435–2441.
• 5.    Kubo  T,  Tanaka  A,  Kitabata  H,  Ino  Y,  Tanimoto  T,  Akasaka  T. Application of optical coherence tomography in percutaneous coronary intervention. Circ J 2012; 76: 2076–2083.
• 6.    Guagliumi  G,  Sirbu  V,  Musumeci  G,  Gerber  R,  Biondi-Zoccai  G,  Ikejima  H, et al. Examination of the in vivo mechanisms of late drug-eluting stent thrombosis: Findings from optical coherence tomography and intravascular ultrasound imaging. JACC Cardiovasc Interv 2012; 5: 12–20.
• 7.    Natsuaki  M,  Kozuma  K,  Morimoto  T,  Kadota  K,  Muramatsu  T,  Nakagawa  Y, et al. Biodegradable polymer biolimus-eluting stent versus durable polymer everolimus-eluting stent: A randomized, controlled, non-inferiority trial. J Am Coll Cardiol 2013; 62: 181–190.
• 8.    Takano  M,  Murakami  D,  Yamamoto  M,  Kurihara  O,  Murai  K,  Inami  T, et al. Six-month follow-up evaluation for everolimus-eluting stents by intracoronary optical coherence tomography: Comparison with paclitaxel-eluting stents. Int J Cardiol 2013; 166: 181–186.
• 9.    Kubo  T,  Akasaka  T,  Shite  J,  Suzuki  T,  Uemura  S,  Yu  B, et al. OCT compared with IVUS in a coronary lesion assessment: The OPUS-CLASS study. JACC Cardiovasc Imaging 2013; 6: 1095–1104.
• 10.    Miyoshi  N,  Shite  J,  Shinke  T,  Otake  H,  Tanino  Y,  Ogasawara  D, et al. Comparison by optical coherence tomography of paclitaxel-eluting stents with sirolimus-eluting stents implanted in one coronary artery in one procedure: Six-month follow-up. Circ J 2010; 74: 903–908.
• 11.    Byrne  RA,  Kastrati  A,  Massberg  S,  Wieczorek  A,  Laugwitz  KL,  Hadamitzky  M, et al. Biodegradable polymer versus permanent polymer drug eluting stents and everolimus- versus sirolimus-eluting stents in patients with coronary artery disease: 3-year outcomes from a randomized clinical trial. J Am Coll Cardiol 2011; 58: 1325–1331.
• 12.    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.
• 13.    Räber  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.
• 14.    Choi  HH,  Kim  JS,  Yoon  DH,  Hong  KS,  Kim  TH,  Kim  BK, et al. Favorable neointimal coverage in everolimus-eluting stent at 9 months after stent implantation: Comparison with sirolimus-eluting stent using optical coherence tomography. Int J Cardiovasc Imaging 2012; 28: 491–497.
• 15.    Windecker  S,  Serruys  PW,  Wandel  S,  Buszman  P,  Trznadel  S,  Linke  A, et al. Biolimus-eluting stent with biodegradable polymer versus sirolimus-eluting stent with durable polymer for coronary revascularisation (LEADERS): A randomised non-inferiority trial. Lancet 2008; 372: 1163–1173.
• 16.    Barlis  P,  Regar  E,  Serruys  PW,  Dimopoulos  K,  van der Giessen  WJ,  van Geuns  RJ, et al. An optical coherence tomography study of a biodegradable vs. durable polymer-coated limus-eluting stent: A LEADERS trial sub-study. Eur Heart J 2010; 31: 165–176.
• 17.    Tada  T,  Kastrati  A,  Byrne  RA,  Schuster  T,  Cuni  R,  King  LA, et al. Randomized comparison of biolimus-eluting stents with biodegradable polymer versus everolimus-eluting stents with permanent polymer coatings assessed by optical coherence tomography. Int J Cardiovasc Imaging 2014; 30: 495–504.
• 18.    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.
• 19.    Kitabata  H,  Kubo  T,  Komukai  K,  Ishibashi  K,  Tanimoto  T,  Ino  Y, et al. Effect of strut thickness on neointimal atherosclerotic change over an extended follow-up period (≥4 years) after bare-metal stent implantation: Intracoronary optical coherence tomography examination. Am Heart J 2012; 163: 608–616.
• 20.    Palmerini  T,  Biondi-Zoccai  G,  Della Riva  D,  Mariani  A,  Sabaté  M,  Smits  PC, et al. Clinical outcomes with bioabsorbable polymer-based versus durable polymer-based drug-eluting stents and bare metal stents: Evidence from a comprehensive network meta-analysis. J Am Coll Cardiol 2014; 63: 299–307.