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Two-year vascular responses to drug-eluting stents with biodegradable polymer versus durable polymer: An optical coherence tomography sub-study of the NEXT
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JJCC-1499; No. of Pages 7 Journal of Cardiology xxx (2017) xxx–xxx
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Journal of Cardiology journal homepage: www.elsevier.com/locate/jjcc
Original article
Two-year vascular responses to drug-eluting stents with biodegradable polymer versus durable polymer: An optical coherence tomography sub-study of the NEXT Yosuke Katayama (MD)a, Takashi Kubo (MD, PhD, FJCC)a,*, Takashi Akasaka (MD, PhD, FJCC)a, Yasushi Ino (MD, PhD)a, Kazuo Kimura (MD, PhD, FJCC)b, Hiroyuki Okura (MD, PhD, FJCC)c, Toshiro Shinke (MD, PhD, FJCC)d, Keiichi Igarashi (MD, PhD)e, Kazushige Kadota (MD, PhD, FJCC)f, Ken Kozuma (MD, PhD)g, Kengo Tanabe (MD, PhD)h, Yoshihisa Nakagawa (MD, PhD)i, Toshiya Muramatsu (MD, FJCC)j, Yoshihiro Morino (MD, PhD, FJCC)k, Takeshi Kimura (MD, PhD, FJCC)l, on behalf of the NEXT investigators a
Department of Cardiovascular Medicine, Wakayama Medical University, Wakayama, Japan Division of Cardiology, Yokohama City University Medical Center, Yokohama, Japan c Division of Cardiology, Kawasaki Medical School Hospital, Kurashiki, Japan d Division of Cardiology, Kobe University Hospital, Kobe, Japan e Division of Cardiology, Hokkaido Social Insurance Hospital, Sapporo, Japan f Division of Cardiology, Kurashiki Central Hospital, Kurashiki, Japan g Division of Cardiology, Teikyo University Hospital, Tokyo, Japan h Division of Cardiology, Mitsui Memorial Hospital, Tokyo, Japan i Division of Cardiology, Tenri Hospital, Tenri, Japan j Division of Cardiology, Saiseikai Yokohamashi Tobu Hospital, Yokohama, Japan k Division of Cardiology, Iwate Medical University, Morioka, Japan l Department of Cardiovascular Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan a Department of Cardiovascular Medicine, Wakayama Medical University, Wakayama, Japan b
A R T I C L E I N F O
A B S T R A C T
Article history: Received 9 January 2017 Received in revised form 29 March 2017 Accepted 25 April 2017 Available online xxx
Background: This study aimed to compare very late vascular response after stent implantation between everolimus-eluting stent (EES) with a thin, non-adhesive, durable, biocompatible fluorinated polymer and biolimus-eluting stent (BES) with a biodegradable polymer by optical coherence tomography (OCT). Methods and results: In the NOBORI-BES Versus XIENCE V/PROMUS-EES Trial (NEXT), a formal OCT substudy investigated 48 patients (27 EES-treated lesions in 23 patients and 28 BES-treated lesions in 25 patients) with 2-year (18–30 months) follow-up imaging at 18 centers. The percentage of uncovered strut by neointima was significantly lower in EES compared with BES (2.1 4.7% vs. 7.9 10.8%, p = 0.013). The percentage of malapposed strut was not different between EES and BES (0.1 0.3% vs. 0.5 1.3%, p = 0.138). The frequency of stent with evagination, which is identified as outward bulges in the luminal contour between struts, was significantly lower in EES compared with BES (22% vs. 86%, p < 0.001). The frequency of neoatherosclerosis was not different between EES and BES (11% vs. 11%, p = 1.000). Conclusions: At 2 years after stent implantation, uncovered stent strut by neointima and evagination were less frequently observed in EES compared with BES. This OCT study suggests that the very late vascular response is different between EES and BES. ß 2017 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved.
Keywords: Optical coherence tomography Drug-eluting stents Percutaneous coronary intervention
* Corresponding author at: Department of Cardiovascular Medicine, Wakayama Medical University, 811-1, Kimiidera, Wakayama, 641-8510, Japan. E-mail address: [email protected] (T. Kubo). http://dx.doi.org/10.1016/j.jjcc.2017.04.005 0914-5087/ß 2017 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved.
Please cite this article in press as: Katayama Y, et al. Two-year vascular responses to drug-eluting stents with biodegradable polymer versus durable polymer: An optical coherence tomography sub-study of the NEXT. J Cardiol (2017), http://dx.doi.org/10.1016/ j.jjcc.2017.04.005
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Introduction Drug eluting stents (DES) have reduced late (<1 year) in-stent restenosis as compared to drug-free bare metal stents. However, concerns have been raised about the very late (>1 year) prognosis of DES. Several studies in first-generation DESs have suggested that permanent polymers lead to persistent inflammation, which might be associated with vessel positive remodeling, late-acquired stent malapposition, neoatherosclerosis, and very late stent thrombosis [1]. To overcome this problem, second-generation DESs with improved polymers have been designed. The XIENCE V (Abbot Vascular, Santa Clara, CA, USA)/PROMUS (Boston Scientific, Natick, MA, USA) everolimus-eluting stent (EES) is coated with a thin, nonadhesive, durable, biocompatible fluorinated polymer releasing everolimus. The NOBORI biolimus-eluting stent (BES; Terumo, Tokyo, Japan) is coated with a biodegradable polymer (polylactic acid) eluting biolimus A9, a highly lipophilic analogue of sirolimus. The aim of the present study was to compare very late vascular response at 2 years (18–30 months) after stent implantation between EES with durable polymer and BES with biodegradable coating by using optical coherence tomography (OCT). Methods Study population This is a pre-specified sub-study of the NOBORI BiolimusEluting 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 [2]. Between May and October 2011, 3241 patients were enrolled in the NEXT without any exclusion criteria and randomly assigned to undergo percutaneous coronary intervention (PCI) with either EES or BES. Randomization was performed by a webbased allocation system and was stratified by center, diabetic status, and participation in the imaging sub-studies (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 sub-study. The primary endpoint in the present OCT substudy was percentage of uncovered struts at 2 years (18–30 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 sub-study. The exclusion criteria for the follow-up OCT examination 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). Eventually, 121 patients were assigned to the OCT sub-study scheduling follow-up OCT examination at 2 years (18–30 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 2 years (18–30 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 a diameter stenosis >50% at follow-up angiography. OCT image acquisition Frequency-domain OCT imaging system (ILUMINE OPTISTM, St. Jude Medical, St. Paul, MN, USA) was used in the present study. The procedure of the OCT image acquisition was as follows. After a Zoffset adjustment, a Dragonfly JPTM imaging catheter (St. Jude Medical) was advanced distally to the stent-treated lesion over a 0.014-inch conventional angioplasty guidewire. After the catheter placement, preheated contrast media at 37 8C 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 OCT imaging core was withdrawn across the entire stenttreated lesion at a rate of 20 mm/s using automatic pullback device. The OCT images were digitally stored and submitted to the core laboratory (Wakayama Medical University, Wakayama, Japan) for offline analysis. OCT image 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-the-screen of any portion of the stent caused by imaging catheter 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 [3]. After calibration adjustment, qualitative OCT analysis was performed at every frame to identify neoatherosclerosis, intra-stent thrombus, and evagination. Neoatherosclerosis is characterized by atherosclerotic findings in neointima including lipid (defined as a signal-poor, poorly delineated region), thin-cap fibroatheroma (TCFA: defined as a fibrous-cap of <65 mm thick over the lipid), calcification (defined as a signal-poor, well-delineated region), and microvessel (defined as a signal-poor, well-delineated void within neointima) [4]. Intrastent thrombus was identified as a mass protruding into the lumen with significant attenuation behind the mass [5]. Evagination is identified as outward bulges in the luminal contour between struts, with the depth of the bulge exceeding the actual strut thickness [6,7] (Fig. 1). 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. A malapposed strut was defined as a strut with a distance between the center of the strut blooming and the adjacent lumen border 110 mm in EES and 160 mm in BES. This criterion was determined by adding the actual strut thickness and polymer thickness to the OCT resolution limit (EES: 81 mm + 7.8 mm + 20 mm = 108.8 mm; and BES: 125 mm + 5 mm [non-absorbable polymer: Parylene C] + 20 mm = 150 mm). Intraobserver and interobserver reproducibility for strut apposition were excellent (k = 0.93 and k = 0.86, respectively) in the core laboratory [3]. Each stent strut condition was classified into one of four categories: (1) well-apposed to the vessel wall with neointimal coverage over the strut, (2) well-apposed to the vessel
Please cite this article in press as: Katayama Y, et al. Two-year vascular responses to drug-eluting stents with biodegradable polymer versus durable polymer: An optical coherence tomography sub-study of the NEXT. J Cardiol (2017), http://dx.doi.org/10.1016/ j.jjcc.2017.04.005
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Fig. 1. Representative OCT image of evagination. OCT-detected evagination is identified as outward bulges in the luminal contour between struts, with the depth of the bulge exceeding the actual strut thickness. Evagination is sometimes referred to as inter-strut ulcer like appearance or peri-strut halo. OCT, optical coherence tomography.
wall without neointimal coverage, (3) malapposed to the vessel wall with neointimal coverage, (4) malapposed to the vessel wall without neointimal coverage. 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 the trapezoid rule. Intraobserver and interobserver reproducibility for neointima volume measurement were excellent (r = 0.996 and r = 0.995, respectively) in the core laboratory [3]. At the maximum neointima area site, neointima appearance was assessed and classified into one of three categories: (1) homogenous (defined as uniform optical properties without focal variations in backscattering pattern), (2) heterogeneous (defined as focally changing optical properties with various backscattering pattern), and (3) layered (defined as concentric layers with different optical properties: an adluminal high scattering layer and an abluminal low scattering layer) [8,9]. Statistical analysis Statistical analysis was performed using Statview 5.0.1 (SAS Institute, Cary, NC, USA). Categorical variables were presented as frequencies, with comparison using chi-square statistics or Fisher exact test (if there was an expected cell value <5). Continuous variables were presented as mean 1 standard deviation and were compared using unpaired Student’s t test. We conducted a multivariate logistic regression analysis to identify independent predictors of evagination. The model included clinical, angiographic, and procedural characteristics with p < 0.20 in the univariate analyses. A p-value < 0.05 was considered statistically significant.
Results Patient characteristics Of 121 patients enrolled in the OCT substudy of NEXT, 73 patients withdrew consent for 2-year (18–30 months) follow-up OCT. Thus, 48 patients who were treated with EES (27 EES-treated lesions in 23 patients) or BES (28 BES-treated lesions in 25 patients) constituted the final study group. Patient
Table 1 Patient characteristics. EES
BES
Number of patients Age, years Gender, male
23 65 11 20 (87)
25 67 10 20 (80)
0.513 0.703
Coronary risk factor Hypertension Dyslipidemia Diabetes mellitus Current smoker
20 (87) 18 (78) 10 (43) 7 (30)
19 (76) 19 (76) 8 (32) 7 (28)
0.466 0.999 0.552 0.999
Hemodialysis Prior myocardial infarction Prior PCI
2 (9) 4 (17) 8 (35)
0 (0) 8 (32) 10 (40)
0.224 0.324 0.771
Clinical presentation at stenting Stable CAD Unstable angina Acute myocardial infarction
22 (96) 1 (4) 0 (0)
21 (84) 3 (12) 1 (4)
0.349 0.61 0.999
24 (96) 14 (56) 15 (60) 10 (40) 21 (84) 2 (8)
0.609 0.563 0.771 0.555 0.310 0.407
Medications at 2-year (18–30 months) follow-up Aspirin 21 (91) Thienopyridine 10 (43) ACEI/ARB 15 (65) Beta blocker 7 (30) Statin 16 (70) Insulin 4 (17)
p-Value
Values are given as n (%) or mean and standard deviation. EES, everolimus-eluting stent; BES, biolimus-eluting stent; PCI, percutaneous coronary intervention; CAD, coronary artery disease; ACEI, angiotensinconverting enzyme inhibitor; ARB, angiotensin receptor blocker.
characteristics in the final study group are listed in Table 1. Baseline clinical characteristics were not different between EES and BES. At follow-up, 10 (43%) patients in EES and 14 (56%) patients in BES were treated with thienopyridine. There were no patients who received target lesion revascularization during the follow-up period. Angiographic findings Angiographic findings and procedural characteristics are shown in Table 2. Quantitative angiographic measurements before index
Please cite this article in press as: Katayama Y, et al. Two-year vascular responses to drug-eluting stents with biodegradable polymer versus durable polymer: An optical coherence tomography sub-study of the NEXT. J Cardiol (2017), http://dx.doi.org/10.1016/ j.jjcc.2017.04.005
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4 Table 2 Angiographic findings and procedural characteristics.
BES
EES
p-Value
No. of stent-treated lesions
27
28
Before index procedure Target imaging vessels LAD LCX RCA
11 (41) 7 (26) 9 (33)
14 (50) 5 (18) 9 (32)
2.82 0.85 0.45 0.43 84.9 12.9 2 (7) 1 (4) 8 (30) 2 (7)
3.08 0.47 0.58 0.35 82.8 13.4 1 (4) 3 (11) 9 (32) 3 (11)
27 (100) 0 (0)
26 (93) 2 (7)
2.96 0.43 18 6 17 (63) 2 (7) 16 4
3.13 0.39 20 5 19 (68) 2 (7) 15 4
0.130 0.184 0.781 0.999 0.358
After index procedure Minimum lumen diameter, mm Percent diameter stenosis, % Acute gain, mm
3.00 0.51 4.3 8.1 2.39 0.91
3.10 0.61 2.7 6.4 2.15 1.10
0.513 0.419 0.383
2-year (18–30 months) follow-up Minimum lumen diameter, mm Percent diameter stenosis, % Late lumen loss, mm
2.24 0.67 4.4 6.5 0.21 0.31
2.40 0.79 3.8 6.2 0.22 0.23
0.434 0.727 0.896
Reference lumen diameter, mm Minimum lumen diameter, mm Percent diameter stenosis, % Chronic total occlusion In-stent restenosis Bifurcation Moderate or heavy calcification Procedural characteristics No. of stent/lesion 1 >2 Stent diameter, mm Total stent length/lesion, mm Post-dilatation Kissing balloon dilatation Maximum inflation pressure, atm
0.913
0.164 0.223 0.556 0.611 0.611 0.999 0.999
0.491
Values are given as n (%) or mean and standard deviation. LAD, left anterior descending coronary artery; LCX, left circumflex coronary artery; RCA, right coronary artery.
procedures, stent profiles, and procedural characteristics were similar between EES and BES. Percent diameter stenosis at followup (4.4 6.5% vs. 3.8 6.2%, p = 0.727) and late loss (0.21 0.31 mm vs. 0.22 0.23 mm, p = 0.896) were not different between EES and BES.
observed in EES but detected in BES (0% vs. 4%, p = 0.999). Areas and volumes in lumen, stent neointima, and stent malapposition were not different between EES and BES.
OCT findings
Multivariable analysis demonstrated that BES (odds ratio: 51.99, 95% confidence interval: 8.39–684.72, p < 0.001) and absence of post-dilatation (odds ratio: 0.11, 95% confidence interval: 0.01–0.81, p = 0.028) were independent predictors of evagination (Table 4).
Of all recorded OCT frames in the stent-treated lesions, 11% in EES and 5% in BES were excluded from analysis due to inadequate image, bifurcation, or stent overlapping segments. A total of 557 frames with 5129 struts in EES and 543 frames with 5099 struts in BES were analyzed. OCT findings at follow-up are shown in Table 3. Mean neointima thickness in EES and BES was 137 53 mm and 117 100 mm, respectively (p = 0.361). The percentage of uncovered struts (2.1 4.7% vs. 7.9 10.8%, p = 0.013) and the frequency of stent-treated lesions with any uncovered struts (26% vs. 57%, p = 0.029) were significantly lower in EES compared with BES. The percentage of malapposed struts (0.1 0.3% vs. 0.5 1.3%, p = 0.138) and the frequency of stenttreated lesion with any malapposed struts (19% vs. 32%, p = 0.999) were not different between EES and BES. The percentage of frames with evagination (8 17% vs. 36 29%, p < 0.001) and the frequency of stent-treated lesion with any evagination (22% vs. 86%, p < 0.001) were significantly lower in EES compared with BES. The neointima appearance was not different between the two groups (p = 0.977), and homogenous pattern was most frequently observed in both EES (81%) and BES (96%). The frequency of neoatherosclerosis including lipid, TCFA, calcification, and microvessels were not different between EES and BES (11% vs. 11%, p = 1.000). Intra-stent thrombus was not
Potential predictors of evagination
Discussion At 2 years (18–30 months) after stent implantation, uncovered stent struts by neointima and evagination were less frequently observed in EES compared with BES. The present study suggests that the very late vascular response is different between EES and BES. Neointimal coverage Incomplete neointimal coverage of stent has been used as a surrogate in place of very late stent thrombosis after DES implantation. An autopsy study showed that the presence of > 30% uncovered struts was identified to be highly predictive of stent thrombosis [10]. Also, several clinical studies using OCT reported that the uncovered struts were frequently observed in the stented lesion with very late thrombosis [11]. Previously, in the NEXT-OCT substudy, we disclosed that the frequency of
Please cite this article in press as: Katayama Y, et al. Two-year vascular responses to drug-eluting stents with biodegradable polymer versus durable polymer: An optical coherence tomography sub-study of the NEXT. J Cardiol (2017), http://dx.doi.org/10.1016/ j.jjcc.2017.04.005
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Table 3 OCT findings at 2-year (18–30 months) follow-up. BES
EES
p-Value
No. stent-treated lesions Mean neointima thickness, mm
27 137 53
28 117 100
0.361
Neointimal coverage over stent struts Uncovered struts, % Lesions with any uncovered struts
2.1 4.7 7 (26)
7.9 10.8 16 (57)
0.013 0.029
Stent malapposition Malapposed struts, % Lesions with any malapposed struts
0.1 0.3 5 (19)
0.5 1.3 9 (32)
0.138 0.999
Evagination Frames with evagination, % Lesions with any evagination
8 17 6 (22)
36 29 24 (86)
<0.001 <0.001
Neointima appearance Homogenous Heterogeneous Layered
22 (81) 2 (7) 3 (11)
27 (96) 1 (4) 0 (0)
Neoatherosclerosis Lipid TCFA Calcification Microvessels
2 0 0 1
2 0 0 1
Intra-stent thrombus
0 (0)
1 (4)
Area measurements Minimum lumen area, mm2 Minimum stent area, mm2 Maximum neointima area, mm2 Maximum stent malapposition area, mm2
4.62 2.38 5.92 2.60 1.98 0.95 0.10 0.32
5.22 2.83 6.16 2.72 1.65 1.27 0.22 0.44
0.399 0.739 0.281 0.254
Volume measurements Lumen volume, mm3 Stent volume, mm3 Neointima volume, mm3 Stent malapposition volume, mm3
127.23 105.79 149.64 124.73 24.48 22.16 0.16 0.61
122.53 47.99 140.76 52.05 18.82 19.12 0.61 1.54
0.831 0.730 0.314 0.163
0.977
1.000 (7) (0) (0) (4)
(7) (0) (0) (4)
Values are given as n (%) or mean and standard deviation. OCT, optical coherence tomography; EES, everolimus-eluting stent; BES, biolimus-eluting stent; TCFA, thin-cap fibroatheroma.
incomplete neointimal coverage of stent was significantly lower in EES compared with BES at 1 year after stent implantation. To date, several OCT studies have investigated neointimal coverage of stent at 1 year; however, there was no follow-up study for longer than 1 year. Therefore, we designed the present NEXT-OCT substudy at 2 years. In the results, incomplete neointimal coverage of stent remains less common in EES compared with BES at 2 years after stent implantation. Because the OCT-measured neointima thickness and volume were not different between the two stents, the difference of stent strut thickness (EES < BES) might influence neointimal coverage of the stent [12]. Neoatherosclerosis In addition to incomplete neointimal coverage of stent, development of atherosclerosis in neointima, so-called neoatherosclerosis is a significant risk for very late stent thrombosis and stent restenosis [12]. Pathological studies of first-generation DESs have reported that the polymer of stent might induce inflammation in vessel wall and accelerate neoatherosclerosis [13]. In second-generation DESs, XIENCE/PROMUS-EES has a durable fluorinated polymer with high biocompatibility while NOBORIBES equips a biodegradable polymer taking place during a period of 6–12 months. Therefore, the difference in neoatherosclerosis occurring more than 12 months after stent implantation between EES and BES is of great interest. In the present OCT study, degree of neoatherosclerosis at 2 years (18–30 months) after stent implantation was similar and minor in both stents. The influence of the durable polymer in EES on the development of
neoatherosclerosis appears to be comparable with that of the metal platform in BES. Evagination Evagination is identified as outward bulges in the luminal contour between struts, with the depth of the bulge exceeding the actual strut thickness [6,7]. Evagination is sometimes referred to as inter-strut ulcer like appearance or peri-strut halo. This unique phenomenon after stent implantation appeared to be associated with late-acquired positive vessel remodeling [6,7]. An autopsy study disclosed that the artery implanted a durable-polymercoated first-generation DES had a focal giant cell reaction surrounding polymer of the stent and a larger external elastic membrane area as compared with polymer-free DES [14,15]. Therefore, the late-acquired positive vessel remodeling is considered to be triggered by the polymer. On the other hand, a biodegradable polymer in BES is absorbed until 1 year after stent implantation. However, as is obvious, metal of stent also has a risk for leading focal inflammation. In the present study, evagination was less frequently observed in the permanent fluoropolymercoated EES than in the biodegradable polymer-coated BES. Our result suggests that the polymer of EES might have a high biocompatibility. Clinical implication The present OCT sub-study of the NEXT trial disclosed different vascular responses at two years after stent implantation between
Please cite this article in press as: Katayama Y, et al. Two-year vascular responses to drug-eluting stents with biodegradable polymer versus durable polymer: An optical coherence tomography sub-study of the NEXT. J Cardiol (2017), http://dx.doi.org/10.1016/ j.jjcc.2017.04.005
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Table 4 Univariate and multivariate analysis of potential predictors of evagination. Univariate analysis
UAP/AMI Statin RCA Stent diameter, mm Post-dilatation Percent diameter stenosis after index procedure, % BES
Multivariate analysis
OR (95% CI)
p-Value
OR (95% CI)
p-Value
4.80 (0.71–95.51) 3.06 (0.83–12.98) 2.67 (0.82–9.77) 2.61 (0.72–10.12) 0.41 (0.12–1.29) 0.94 (0.86–1.02) 21.00 (5.71–96.43)
0.116 0.094 0.106 0.145 0.130 0.127 <0.001
2.50 (0.24–61.24) 2.51 (0.27–27.12) 6.05 (0.85–59.87) 0.34 (0.01–4.23) 0.11 (0.01–0.81) 0.99 (0.86–1.15) 51.99 (8.39–684.72)
0.461 0.415 0.073 0.422 0.028 0.925 <0.001
UAP, unstable angina; AMI, acute myocardial infarction; ACEI, angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker; BES, biolimus-eluting stent; CI, confidence interval; OR, odds ratio; RCA, right coronary artery.
EES and BES. Although, in the NEXT trial, the clinical outcomes up to three years were comparable between EES and BES [16], our results suggest that further study should be needed to compare longer clinical outcomes between the two stents. Limitations There are several limitations in the present study. First, selection bias might affect the results because the patients in the present OCT sub-study were not randomly selected from the NEXT. Second, because the patients were free of major adverse events after DES implantation until the OCT follow-up, the DEStreated lesions of the present study may not represent those seen in real world practice [17]. Third, OCT was not necessary to be performed at baseline and 1-year follow-up. Therefore, the longitudinal OCT analysis was not available, and it was unclear whether the OCT findings acquired at 2-year follow-up were persistent or newly acquired. Fourth, the present study is not designed to investigate the mechanism of evagination. Further research is required to more precisely define the predictors of evagination. Fifth, the qualitative OCT tissue classification for neoatherosclerosis has some ambiguity [18–20], which may lead to biased results. Finally, the present study was not powered to assess the relationship between the suboptimal stent results as determined by OCT and future coronary events. Additional studies are needed to investigate the clinical impact of these OCT findings acquired at 2-year (18–30 months) follow-up after DES implantation. Conclusions The present OCT study demonstrated that uncovered stent struts by neointima and evagination were less frequently observed in EES compared with BES at 2 years (18–36 months) after stent implantation. Funding Terumo is a study sponsor of the NEXT trial. Conflict of interest Dr Kubo has served on the advisory boards of Terumo; and has received lecture fees from Terumo, Abbott Vascular, and St. Jude Medical. Dr Akasaka has served on the advisory boards of Terumo, Abbott Vascular, and St Jude Medical; and has received lecture fees and research grants from Terumo, Abbott Vascular, and St. Jude Medical. 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 have reported that they have no relationships relevant to the contents of this paper to disclose. References [1] Nakazawa G, Finn AV, Joner M, Ladich E, Kutys R, Mont EK, Gold HK, Burke AP, Kolodgie FD, Virmani R. Delayed arterial healing and increased late stent thrombosis at culprit sites after drug-eluting stent placement for acute myocardial infarction patients: an autopsy study. Circulation 2008;118:1138–45. [2] Natsuaki M, Kozuma K, Morimoto T, Kadota K, Muramatsu T, Nakagawa Y, Akasaka T, Igarashi K, Tanabe K, Morino Y, Ishikawa T, Nishikawa H, Awata M, Abe M, Okada H, et al. Biodegradable polymer biolimus-eluting stent versus durable polymer everolimus-eluting stent: a randomized, controlled, noninferiority trial. J Am Coll Cardiol 2013;62:181–90. [3] Kubo T, Akasaka T, Kozuma K, Kimura K, Fusazaki T, Okura H, Shinke T, Ino Y, Hasegawa T, Takashima H, Takamisawa I, Yamaguchi H, Igarashi K, Kadota K, Tanabe K, et al. Vascular response to drug-eluting stent with biodegradable vs. durable polymer. Optical coherence tomography substudy of the NEXT. Circ J 2014;78:2408–14. [4] Kubo T, Tanaka A, Ino Y, Kitabata H, Shiono Y, Akasaka T. Assessment of coronary atherosclerosis using optical coherence tomography. J Atheroscler Thromb 2014;21:895–903. [5] Kubo T, Akasaka T, Tanimoto T, Takano M, Seino Y, Nasu K, Itoh T, Mizuno K, Okura H, Shinke T, Kotani J, Ito S, Yokoi H, Muramatsu T, Nakamura M, et al. Assessment of vascular response after drug-eluting stents implantation in patients with diabetes mellitus: an optical coherence tomography sub-study of the J-DESsERT. Heart Vessels 2016;31:465–73. [6] Radu MD, Pfenniger A, Ra¨ber L, de Marchi SF, Obrist D, Kelbæk H, Windecker S, Serruys PW, Vogel R. Flow disturbances in stent-related coronary evaginations: a computational fluid-dynamic simulation study. EuroIntervention 2014;10:113–23. [7] Radu MD, Ra¨ber L, Kalesan B, Muramatsu T, Kelbæk H, Heo J, Jørgensen E, Helqvist S, Farooq V, Brugaletta S, Garcia-Garcia HM, Ju¨ni P, Saunama¨ki K, Windecker S, Serruys PW. Coronary evaginations are associated with positive vessel remodelling and are nearly absent following implantation of newergeneration drug-eluting stents: an optical coherence tomography and intravascular ultrasound study. Eur Heart J 2014;35:795–807. [8] Gonzalo N, Serruys PW, Okamura T, van Beusekom HM, Garcia-Garcia HM, van Soest G, van der Giessen W, Regar E. Optical coherence tomography patterns of stent restenosis. Am Heart J 2009;158:284–93. [9] Kubo T, Akasaka T, Kozuma K, Kimura K, Kawamura M, Sumiyoshi T, Ino Y, Morino Y, Tanabe K, Kadota K, Kimura T. Comparison of neointimal coverage between everolimus-eluting stents and sirolimus-eluting stents: an optical coherence tomography substudy of the RESET (Randomized Evaluation of Sirolimus-eluting versus Everolimus-eluting stent Trial). EuroIntervention 2015;11:564–71. [10] Finn AV, Joner M, Nakazawa G, Kolodgie F, Newell J, John MC, Gold HK, Virmani R. Pathological correlates of late drug-eluting stent thrombosis: stent coverage as a marker of endothelialization. Circulation 2007;115:2435–41. [11] Guagliumi G, Sirbu V, Musumeci G, Gerber R, Biondi-Zoccai G, Ikejima H, Ladich E, Lortkipanidze N, Matiashvili A, Valsecchi O, Virmani R, Stone GW. 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. [12] Kitabata H, Kubo T, Komukai K, Ishibashi K, Tanimoto T, Ino Y, Takarada S, Ozaki Y, Kashiwagi M, Orii M, Shiono Y, Shimamura K, Hirata K, Tanaka A, Kimura K, et al. Effect of strut thickness on neointimal atherosclerotic change over an extended follow-up period (4 years) after bare-metal stent
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Contents lists available at ScienceDirect
Journal of Cardiology journal homepage: www.elsevier.com/locate/jjcc
Original article
Two-year vascular responses to drug-eluting stents with biodegradable polymer versus durable polymer: An optical coherence tomography sub-study of the NEXT Yosuke Katayama (MD)a, Takashi Kubo (MD, PhD, FJCC)a,*, Takashi Akasaka (MD, PhD, FJCC)a, Yasushi Ino (MD, PhD)a, Kazuo Kimura (MD, PhD, FJCC)b, Hiroyuki Okura (MD, PhD, FJCC)c, Toshiro Shinke (MD, PhD, FJCC)d, Keiichi Igarashi (MD, PhD)e, Kazushige Kadota (MD, PhD, FJCC)f, Ken Kozuma (MD, PhD)g, Kengo Tanabe (MD, PhD)h, Yoshihisa Nakagawa (MD, PhD)i, Toshiya Muramatsu (MD, FJCC)j, Yoshihiro Morino (MD, PhD, FJCC)k, Takeshi Kimura (MD, PhD, FJCC)l, on behalf of the NEXT investigators a
Department of Cardiovascular Medicine, Wakayama Medical University, Wakayama, Japan Division of Cardiology, Yokohama City University Medical Center, Yokohama, Japan c Division of Cardiology, Kawasaki Medical School Hospital, Kurashiki, Japan d Division of Cardiology, Kobe University Hospital, Kobe, Japan e Division of Cardiology, Hokkaido Social Insurance Hospital, Sapporo, Japan f Division of Cardiology, Kurashiki Central Hospital, Kurashiki, Japan g Division of Cardiology, Teikyo University Hospital, Tokyo, Japan h Division of Cardiology, Mitsui Memorial Hospital, Tokyo, Japan i Division of Cardiology, Tenri Hospital, Tenri, Japan j Division of Cardiology, Saiseikai Yokohamashi Tobu Hospital, Yokohama, Japan k Division of Cardiology, Iwate Medical University, Morioka, Japan l Department of Cardiovascular Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan a Department of Cardiovascular Medicine, Wakayama Medical University, Wakayama, Japan b
A R T I C L E I N F O
A B S T R A C T
Article history: Received 9 January 2017 Received in revised form 29 March 2017 Accepted 25 April 2017 Available online xxx
Background: This study aimed to compare very late vascular response after stent implantation between everolimus-eluting stent (EES) with a thin, non-adhesive, durable, biocompatible fluorinated polymer and biolimus-eluting stent (BES) with a biodegradable polymer by optical coherence tomography (OCT). Methods and results: In the NOBORI-BES Versus XIENCE V/PROMUS-EES Trial (NEXT), a formal OCT substudy investigated 48 patients (27 EES-treated lesions in 23 patients and 28 BES-treated lesions in 25 patients) with 2-year (18–30 months) follow-up imaging at 18 centers. The percentage of uncovered strut by neointima was significantly lower in EES compared with BES (2.1 4.7% vs. 7.9 10.8%, p = 0.013). The percentage of malapposed strut was not different between EES and BES (0.1 0.3% vs. 0.5 1.3%, p = 0.138). The frequency of stent with evagination, which is identified as outward bulges in the luminal contour between struts, was significantly lower in EES compared with BES (22% vs. 86%, p < 0.001). The frequency of neoatherosclerosis was not different between EES and BES (11% vs. 11%, p = 1.000). Conclusions: At 2 years after stent implantation, uncovered stent strut by neointima and evagination were less frequently observed in EES compared with BES. This OCT study suggests that the very late vascular response is different between EES and BES. ß 2017 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved.
Keywords: Optical coherence tomography Drug-eluting stents Percutaneous coronary intervention
* Corresponding author at: Department of Cardiovascular Medicine, Wakayama Medical University, 811-1, Kimiidera, Wakayama, 641-8510, Japan. E-mail address: [email protected] (T. Kubo). http://dx.doi.org/10.1016/j.jjcc.2017.04.005 0914-5087/ß 2017 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved.
Please cite this article in press as: Katayama Y, et al. Two-year vascular responses to drug-eluting stents with biodegradable polymer versus durable polymer: An optical coherence tomography sub-study of the NEXT. J Cardiol (2017), http://dx.doi.org/10.1016/ j.jjcc.2017.04.005
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Introduction Drug eluting stents (DES) have reduced late (<1 year) in-stent restenosis as compared to drug-free bare metal stents. However, concerns have been raised about the very late (>1 year) prognosis of DES. Several studies in first-generation DESs have suggested that permanent polymers lead to persistent inflammation, which might be associated with vessel positive remodeling, late-acquired stent malapposition, neoatherosclerosis, and very late stent thrombosis [1]. To overcome this problem, second-generation DESs with improved polymers have been designed. The XIENCE V (Abbot Vascular, Santa Clara, CA, USA)/PROMUS (Boston Scientific, Natick, MA, USA) everolimus-eluting stent (EES) is coated with a thin, nonadhesive, durable, biocompatible fluorinated polymer releasing everolimus. The NOBORI biolimus-eluting stent (BES; Terumo, Tokyo, Japan) is coated with a biodegradable polymer (polylactic acid) eluting biolimus A9, a highly lipophilic analogue of sirolimus. The aim of the present study was to compare very late vascular response at 2 years (18–30 months) after stent implantation between EES with durable polymer and BES with biodegradable coating by using optical coherence tomography (OCT). Methods Study population This is a pre-specified sub-study of the NOBORI BiolimusEluting 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 [2]. Between May and October 2011, 3241 patients were enrolled in the NEXT without any exclusion criteria and randomly assigned to undergo percutaneous coronary intervention (PCI) with either EES or BES. Randomization was performed by a webbased allocation system and was stratified by center, diabetic status, and participation in the imaging sub-studies (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 sub-study. The primary endpoint in the present OCT substudy was percentage of uncovered struts at 2 years (18–30 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 sub-study. The exclusion criteria for the follow-up OCT examination 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). Eventually, 121 patients were assigned to the OCT sub-study scheduling follow-up OCT examination at 2 years (18–30 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 2 years (18–30 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 a diameter stenosis >50% at follow-up angiography. OCT image acquisition Frequency-domain OCT imaging system (ILUMINE OPTISTM, St. Jude Medical, St. Paul, MN, USA) was used in the present study. The procedure of the OCT image acquisition was as follows. After a Zoffset adjustment, a Dragonfly JPTM imaging catheter (St. Jude Medical) was advanced distally to the stent-treated lesion over a 0.014-inch conventional angioplasty guidewire. After the catheter placement, preheated contrast media at 37 8C 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 OCT imaging core was withdrawn across the entire stenttreated lesion at a rate of 20 mm/s using automatic pullback device. The OCT images were digitally stored and submitted to the core laboratory (Wakayama Medical University, Wakayama, Japan) for offline analysis. OCT image 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-the-screen of any portion of the stent caused by imaging catheter 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 [3]. After calibration adjustment, qualitative OCT analysis was performed at every frame to identify neoatherosclerosis, intra-stent thrombus, and evagination. Neoatherosclerosis is characterized by atherosclerotic findings in neointima including lipid (defined as a signal-poor, poorly delineated region), thin-cap fibroatheroma (TCFA: defined as a fibrous-cap of <65 mm thick over the lipid), calcification (defined as a signal-poor, well-delineated region), and microvessel (defined as a signal-poor, well-delineated void within neointima) [4]. Intrastent thrombus was identified as a mass protruding into the lumen with significant attenuation behind the mass [5]. Evagination is identified as outward bulges in the luminal contour between struts, with the depth of the bulge exceeding the actual strut thickness [6,7] (Fig. 1). 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. A malapposed strut was defined as a strut with a distance between the center of the strut blooming and the adjacent lumen border 110 mm in EES and 160 mm in BES. This criterion was determined by adding the actual strut thickness and polymer thickness to the OCT resolution limit (EES: 81 mm + 7.8 mm + 20 mm = 108.8 mm; and BES: 125 mm + 5 mm [non-absorbable polymer: Parylene C] + 20 mm = 150 mm). Intraobserver and interobserver reproducibility for strut apposition were excellent (k = 0.93 and k = 0.86, respectively) in the core laboratory [3]. Each stent strut condition was classified into one of four categories: (1) well-apposed to the vessel wall with neointimal coverage over the strut, (2) well-apposed to the vessel
Please cite this article in press as: Katayama Y, et al. Two-year vascular responses to drug-eluting stents with biodegradable polymer versus durable polymer: An optical coherence tomography sub-study of the NEXT. J Cardiol (2017), http://dx.doi.org/10.1016/ j.jjcc.2017.04.005
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Fig. 1. Representative OCT image of evagination. OCT-detected evagination is identified as outward bulges in the luminal contour between struts, with the depth of the bulge exceeding the actual strut thickness. Evagination is sometimes referred to as inter-strut ulcer like appearance or peri-strut halo. OCT, optical coherence tomography.
wall without neointimal coverage, (3) malapposed to the vessel wall with neointimal coverage, (4) malapposed to the vessel wall without neointimal coverage. 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 the trapezoid rule. Intraobserver and interobserver reproducibility for neointima volume measurement were excellent (r = 0.996 and r = 0.995, respectively) in the core laboratory [3]. At the maximum neointima area site, neointima appearance was assessed and classified into one of three categories: (1) homogenous (defined as uniform optical properties without focal variations in backscattering pattern), (2) heterogeneous (defined as focally changing optical properties with various backscattering pattern), and (3) layered (defined as concentric layers with different optical properties: an adluminal high scattering layer and an abluminal low scattering layer) [8,9]. Statistical analysis Statistical analysis was performed using Statview 5.0.1 (SAS Institute, Cary, NC, USA). Categorical variables were presented as frequencies, with comparison using chi-square statistics or Fisher exact test (if there was an expected cell value <5). Continuous variables were presented as mean 1 standard deviation and were compared using unpaired Student’s t test. We conducted a multivariate logistic regression analysis to identify independent predictors of evagination. The model included clinical, angiographic, and procedural characteristics with p < 0.20 in the univariate analyses. A p-value < 0.05 was considered statistically significant.
Results Patient characteristics Of 121 patients enrolled in the OCT substudy of NEXT, 73 patients withdrew consent for 2-year (18–30 months) follow-up OCT. Thus, 48 patients who were treated with EES (27 EES-treated lesions in 23 patients) or BES (28 BES-treated lesions in 25 patients) constituted the final study group. Patient
Table 1 Patient characteristics. EES
BES
Number of patients Age, years Gender, male
23 65 11 20 (87)
25 67 10 20 (80)
0.513 0.703
Coronary risk factor Hypertension Dyslipidemia Diabetes mellitus Current smoker
20 (87) 18 (78) 10 (43) 7 (30)
19 (76) 19 (76) 8 (32) 7 (28)
0.466 0.999 0.552 0.999
Hemodialysis Prior myocardial infarction Prior PCI
2 (9) 4 (17) 8 (35)
0 (0) 8 (32) 10 (40)
0.224 0.324 0.771
Clinical presentation at stenting Stable CAD Unstable angina Acute myocardial infarction
22 (96) 1 (4) 0 (0)
21 (84) 3 (12) 1 (4)
0.349 0.61 0.999
24 (96) 14 (56) 15 (60) 10 (40) 21 (84) 2 (8)
0.609 0.563 0.771 0.555 0.310 0.407
Medications at 2-year (18–30 months) follow-up Aspirin 21 (91) Thienopyridine 10 (43) ACEI/ARB 15 (65) Beta blocker 7 (30) Statin 16 (70) Insulin 4 (17)
p-Value
Values are given as n (%) or mean and standard deviation. EES, everolimus-eluting stent; BES, biolimus-eluting stent; PCI, percutaneous coronary intervention; CAD, coronary artery disease; ACEI, angiotensinconverting enzyme inhibitor; ARB, angiotensin receptor blocker.
characteristics in the final study group are listed in Table 1. Baseline clinical characteristics were not different between EES and BES. At follow-up, 10 (43%) patients in EES and 14 (56%) patients in BES were treated with thienopyridine. There were no patients who received target lesion revascularization during the follow-up period. Angiographic findings Angiographic findings and procedural characteristics are shown in Table 2. Quantitative angiographic measurements before index
Please cite this article in press as: Katayama Y, et al. Two-year vascular responses to drug-eluting stents with biodegradable polymer versus durable polymer: An optical coherence tomography sub-study of the NEXT. J Cardiol (2017), http://dx.doi.org/10.1016/ j.jjcc.2017.04.005
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4 Table 2 Angiographic findings and procedural characteristics.
BES
EES
p-Value
No. of stent-treated lesions
27
28
Before index procedure Target imaging vessels LAD LCX RCA
11 (41) 7 (26) 9 (33)
14 (50) 5 (18) 9 (32)
2.82 0.85 0.45 0.43 84.9 12.9 2 (7) 1 (4) 8 (30) 2 (7)
3.08 0.47 0.58 0.35 82.8 13.4 1 (4) 3 (11) 9 (32) 3 (11)
27 (100) 0 (0)
26 (93) 2 (7)
2.96 0.43 18 6 17 (63) 2 (7) 16 4
3.13 0.39 20 5 19 (68) 2 (7) 15 4
0.130 0.184 0.781 0.999 0.358
After index procedure Minimum lumen diameter, mm Percent diameter stenosis, % Acute gain, mm
3.00 0.51 4.3 8.1 2.39 0.91
3.10 0.61 2.7 6.4 2.15 1.10
0.513 0.419 0.383
2-year (18–30 months) follow-up Minimum lumen diameter, mm Percent diameter stenosis, % Late lumen loss, mm
2.24 0.67 4.4 6.5 0.21 0.31
2.40 0.79 3.8 6.2 0.22 0.23
0.434 0.727 0.896
Reference lumen diameter, mm Minimum lumen diameter, mm Percent diameter stenosis, % Chronic total occlusion In-stent restenosis Bifurcation Moderate or heavy calcification Procedural characteristics No. of stent/lesion 1 >2 Stent diameter, mm Total stent length/lesion, mm Post-dilatation Kissing balloon dilatation Maximum inflation pressure, atm
0.913
0.164 0.223 0.556 0.611 0.611 0.999 0.999
0.491
Values are given as n (%) or mean and standard deviation. LAD, left anterior descending coronary artery; LCX, left circumflex coronary artery; RCA, right coronary artery.
procedures, stent profiles, and procedural characteristics were similar between EES and BES. Percent diameter stenosis at followup (4.4 6.5% vs. 3.8 6.2%, p = 0.727) and late loss (0.21 0.31 mm vs. 0.22 0.23 mm, p = 0.896) were not different between EES and BES.
observed in EES but detected in BES (0% vs. 4%, p = 0.999). Areas and volumes in lumen, stent neointima, and stent malapposition were not different between EES and BES.
OCT findings
Multivariable analysis demonstrated that BES (odds ratio: 51.99, 95% confidence interval: 8.39–684.72, p < 0.001) and absence of post-dilatation (odds ratio: 0.11, 95% confidence interval: 0.01–0.81, p = 0.028) were independent predictors of evagination (Table 4).
Of all recorded OCT frames in the stent-treated lesions, 11% in EES and 5% in BES were excluded from analysis due to inadequate image, bifurcation, or stent overlapping segments. A total of 557 frames with 5129 struts in EES and 543 frames with 5099 struts in BES were analyzed. OCT findings at follow-up are shown in Table 3. Mean neointima thickness in EES and BES was 137 53 mm and 117 100 mm, respectively (p = 0.361). The percentage of uncovered struts (2.1 4.7% vs. 7.9 10.8%, p = 0.013) and the frequency of stent-treated lesions with any uncovered struts (26% vs. 57%, p = 0.029) were significantly lower in EES compared with BES. The percentage of malapposed struts (0.1 0.3% vs. 0.5 1.3%, p = 0.138) and the frequency of stenttreated lesion with any malapposed struts (19% vs. 32%, p = 0.999) were not different between EES and BES. The percentage of frames with evagination (8 17% vs. 36 29%, p < 0.001) and the frequency of stent-treated lesion with any evagination (22% vs. 86%, p < 0.001) were significantly lower in EES compared with BES. The neointima appearance was not different between the two groups (p = 0.977), and homogenous pattern was most frequently observed in both EES (81%) and BES (96%). The frequency of neoatherosclerosis including lipid, TCFA, calcification, and microvessels were not different between EES and BES (11% vs. 11%, p = 1.000). Intra-stent thrombus was not
Potential predictors of evagination
Discussion At 2 years (18–30 months) after stent implantation, uncovered stent struts by neointima and evagination were less frequently observed in EES compared with BES. The present study suggests that the very late vascular response is different between EES and BES. Neointimal coverage Incomplete neointimal coverage of stent has been used as a surrogate in place of very late stent thrombosis after DES implantation. An autopsy study showed that the presence of > 30% uncovered struts was identified to be highly predictive of stent thrombosis [10]. Also, several clinical studies using OCT reported that the uncovered struts were frequently observed in the stented lesion with very late thrombosis [11]. Previously, in the NEXT-OCT substudy, we disclosed that the frequency of
Please cite this article in press as: Katayama Y, et al. Two-year vascular responses to drug-eluting stents with biodegradable polymer versus durable polymer: An optical coherence tomography sub-study of the NEXT. J Cardiol (2017), http://dx.doi.org/10.1016/ j.jjcc.2017.04.005
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Table 3 OCT findings at 2-year (18–30 months) follow-up. BES
EES
p-Value
No. stent-treated lesions Mean neointima thickness, mm
27 137 53
28 117 100
0.361
Neointimal coverage over stent struts Uncovered struts, % Lesions with any uncovered struts
2.1 4.7 7 (26)
7.9 10.8 16 (57)
0.013 0.029
Stent malapposition Malapposed struts, % Lesions with any malapposed struts
0.1 0.3 5 (19)
0.5 1.3 9 (32)
0.138 0.999
Evagination Frames with evagination, % Lesions with any evagination
8 17 6 (22)
36 29 24 (86)
<0.001 <0.001
Neointima appearance Homogenous Heterogeneous Layered
22 (81) 2 (7) 3 (11)
27 (96) 1 (4) 0 (0)
Neoatherosclerosis Lipid TCFA Calcification Microvessels
2 0 0 1
2 0 0 1
Intra-stent thrombus
0 (0)
1 (4)
Area measurements Minimum lumen area, mm2 Minimum stent area, mm2 Maximum neointima area, mm2 Maximum stent malapposition area, mm2
4.62 2.38 5.92 2.60 1.98 0.95 0.10 0.32
5.22 2.83 6.16 2.72 1.65 1.27 0.22 0.44
0.399 0.739 0.281 0.254
Volume measurements Lumen volume, mm3 Stent volume, mm3 Neointima volume, mm3 Stent malapposition volume, mm3
127.23 105.79 149.64 124.73 24.48 22.16 0.16 0.61
122.53 47.99 140.76 52.05 18.82 19.12 0.61 1.54
0.831 0.730 0.314 0.163
0.977
1.000 (7) (0) (0) (4)
(7) (0) (0) (4)
Values are given as n (%) or mean and standard deviation. OCT, optical coherence tomography; EES, everolimus-eluting stent; BES, biolimus-eluting stent; TCFA, thin-cap fibroatheroma.
incomplete neointimal coverage of stent was significantly lower in EES compared with BES at 1 year after stent implantation. To date, several OCT studies have investigated neointimal coverage of stent at 1 year; however, there was no follow-up study for longer than 1 year. Therefore, we designed the present NEXT-OCT substudy at 2 years. In the results, incomplete neointimal coverage of stent remains less common in EES compared with BES at 2 years after stent implantation. Because the OCT-measured neointima thickness and volume were not different between the two stents, the difference of stent strut thickness (EES < BES) might influence neointimal coverage of the stent [12]. Neoatherosclerosis In addition to incomplete neointimal coverage of stent, development of atherosclerosis in neointima, so-called neoatherosclerosis is a significant risk for very late stent thrombosis and stent restenosis [12]. Pathological studies of first-generation DESs have reported that the polymer of stent might induce inflammation in vessel wall and accelerate neoatherosclerosis [13]. In second-generation DESs, XIENCE/PROMUS-EES has a durable fluorinated polymer with high biocompatibility while NOBORIBES equips a biodegradable polymer taking place during a period of 6–12 months. Therefore, the difference in neoatherosclerosis occurring more than 12 months after stent implantation between EES and BES is of great interest. In the present OCT study, degree of neoatherosclerosis at 2 years (18–30 months) after stent implantation was similar and minor in both stents. The influence of the durable polymer in EES on the development of
neoatherosclerosis appears to be comparable with that of the metal platform in BES. Evagination Evagination is identified as outward bulges in the luminal contour between struts, with the depth of the bulge exceeding the actual strut thickness [6,7]. Evagination is sometimes referred to as inter-strut ulcer like appearance or peri-strut halo. This unique phenomenon after stent implantation appeared to be associated with late-acquired positive vessel remodeling [6,7]. An autopsy study disclosed that the artery implanted a durable-polymercoated first-generation DES had a focal giant cell reaction surrounding polymer of the stent and a larger external elastic membrane area as compared with polymer-free DES [14,15]. Therefore, the late-acquired positive vessel remodeling is considered to be triggered by the polymer. On the other hand, a biodegradable polymer in BES is absorbed until 1 year after stent implantation. However, as is obvious, metal of stent also has a risk for leading focal inflammation. In the present study, evagination was less frequently observed in the permanent fluoropolymercoated EES than in the biodegradable polymer-coated BES. Our result suggests that the polymer of EES might have a high biocompatibility. Clinical implication The present OCT sub-study of the NEXT trial disclosed different vascular responses at two years after stent implantation between
Please cite this article in press as: Katayama Y, et al. Two-year vascular responses to drug-eluting stents with biodegradable polymer versus durable polymer: An optical coherence tomography sub-study of the NEXT. J Cardiol (2017), http://dx.doi.org/10.1016/ j.jjcc.2017.04.005
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Table 4 Univariate and multivariate analysis of potential predictors of evagination. Univariate analysis
UAP/AMI Statin RCA Stent diameter, mm Post-dilatation Percent diameter stenosis after index procedure, % BES
Multivariate analysis
OR (95% CI)
p-Value
OR (95% CI)
p-Value
4.80 (0.71–95.51) 3.06 (0.83–12.98) 2.67 (0.82–9.77) 2.61 (0.72–10.12) 0.41 (0.12–1.29) 0.94 (0.86–1.02) 21.00 (5.71–96.43)
0.116 0.094 0.106 0.145 0.130 0.127 <0.001
2.50 (0.24–61.24) 2.51 (0.27–27.12) 6.05 (0.85–59.87) 0.34 (0.01–4.23) 0.11 (0.01–0.81) 0.99 (0.86–1.15) 51.99 (8.39–684.72)
0.461 0.415 0.073 0.422 0.028 0.925 <0.001
UAP, unstable angina; AMI, acute myocardial infarction; ACEI, angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker; BES, biolimus-eluting stent; CI, confidence interval; OR, odds ratio; RCA, right coronary artery.
EES and BES. Although, in the NEXT trial, the clinical outcomes up to three years were comparable between EES and BES [16], our results suggest that further study should be needed to compare longer clinical outcomes between the two stents. Limitations There are several limitations in the present study. First, selection bias might affect the results because the patients in the present OCT sub-study were not randomly selected from the NEXT. Second, because the patients were free of major adverse events after DES implantation until the OCT follow-up, the DEStreated lesions of the present study may not represent those seen in real world practice [17]. Third, OCT was not necessary to be performed at baseline and 1-year follow-up. Therefore, the longitudinal OCT analysis was not available, and it was unclear whether the OCT findings acquired at 2-year follow-up were persistent or newly acquired. Fourth, the present study is not designed to investigate the mechanism of evagination. Further research is required to more precisely define the predictors of evagination. Fifth, the qualitative OCT tissue classification for neoatherosclerosis has some ambiguity [18–20], which may lead to biased results. Finally, the present study was not powered to assess the relationship between the suboptimal stent results as determined by OCT and future coronary events. Additional studies are needed to investigate the clinical impact of these OCT findings acquired at 2-year (18–30 months) follow-up after DES implantation. Conclusions The present OCT study demonstrated that uncovered stent struts by neointima and evagination were less frequently observed in EES compared with BES at 2 years (18–36 months) after stent implantation. Funding Terumo is a study sponsor of the NEXT trial. Conflict of interest Dr Kubo has served on the advisory boards of Terumo; and has received lecture fees from Terumo, Abbott Vascular, and St. Jude Medical. Dr Akasaka has served on the advisory boards of Terumo, Abbott Vascular, and St Jude Medical; and has received lecture fees and research grants from Terumo, Abbott Vascular, and St. Jude Medical. 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
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Please cite this article in press as: Katayama Y, et al. Two-year vascular responses to drug-eluting stents with biodegradable polymer versus durable polymer: An optical coherence tomography sub-study of the NEXT. J Cardiol (2017), http://dx.doi.org/10.1016/ j.jjcc.2017.04.005